{ "job_id": "d3ce189f-b1b7-45eb-91e3-946dfb6fdc72", "status": "completed", "progress": 1.0, "stage": "Complete", "results": [ { "id": "5", "title": "The NEXT-1 (Next generation pErsonalized tX with mulTi-omics and preclinical model) trial: prospective molecular screening trial of metastatic solid cancer patients, a feasibility analysis.", "abstract": "We conducted a prospective genomic screening trial with high throughput sequencing and copy number variation (CNV) assay, and immunohistochemistry array in metastatic solid cancer patients. We used Ion AmpliSeq Cancer Hotspot Panel v2 and nCounter Copy Number Variation Assay (21 genes) to identify molecular targets for potential matched therapy. Metastatic solid tumor patients were prospectively consented for molecular profiling tests. The primary outcome for this trial was the feasibility of molecular tests and response rate (matched vs non-matched treatment). Between November 2013 and August 2014, a total of 428 metastatic solid tumor patients were enrolled on to this study. The mutational profiles were obtained for 407 (95.1%) patients. CNV 21-gene assays were successfully performed in 281 (65.7%) of 428 patients. Of the 407 patients with molecular profiling results, 342 (84.0%) patients had one or more aberrations detected. Of the 342 patients, 103 patients were matched to molecularly targeted agents in the context of clinical trials or clinical practice. The response rate was significantly higher in the genome-matched treated group for gastrointestinal/hepatobiliary/rare tumors (matched vs non-matched treatment, 42.6% vs 24.3%, P = .009) and lung cancer cohort (matched vs non-matched treatment, 61.2% vs 28.6% < P = .001) when compared with the non-matched group. In this trial, we demonstrate that genome-matched treatment based on molecular profiling result in better treatment outcome in terms of response rate.", "citation": "Kim ST, Lee J, Hong M, Park K, Park JO, Ahn T, Park SH, Park YS, Lim HY, Sun JM, Ahn JS, Ahn MJ, Kim HC, Sohn TS, Choi DI, Cho JH, Heo JS, Kwon W, Uhm SW, Lee H, Min BH, Hong SN, Kim DH, Jung SH, Park W, Kim KM, Kang WK, Park K. (2015). The NEXT-1 (Next generation pErsonalized tX with mulTi-omics and preclinical model) trial: prospective molecular screening trial of metastatic solid cancer patients, a feasibility analysis. Oncotarget. 6(32):33358-68. http://doi.org/10.18632/oncotarget.5188. PMID: 26396172.", "score_list": [ 2.872187240686673, 2.9683791750653215 ], "ai_score_min": 2.872187240686673, "ai_score_max": 2.9683791750653215, "ai_score": 2.9202832078759973, "ai_reasoning": "Weak relevance. 'The NEXT-1 (Next generation pErsonalized tX with m...' appears tangentially related to the research topic.", "evidence": [ { "text": "molecular profiling result in better treatment outcome in", "section": "abstract", "criterion": "Population", "supports": "exclude" }, { "text": "used Ion AmpliSeq Cancer Hotspot", "section": "abstract", "criterion": "Study Design", "supports": "exclude" }, { "text": "The NEXT-1 (Next generation pErsonalized tX", "section": "title", "criterion": "Population", "supports": "exclude" } ], "ai_decision": "include", "assigned_clusters": [ { "cluster_name": "Adult Patient Population", "cluster_type": "include", "cluster_description": "Papers focused on adult patient demographics with defined inclusion criteria", "related_criteria": "Population" }, { "cluster_name": "Biomarker Analysis Studies", "cluster_type": "include", "cluster_description": "Papers with molecular or biomarker focus and genetic data", "related_criteria": "Outcome" } ] }, { "id": "8", "title": "Precision Oncology: The UC San Diego Moores Cancer Center PREDICT Experience.", "abstract": "By profiling their patients' tumors, oncologists now have the option to use molecular results to match patients with drug(s) based on specific biomarkers. In this observational study, 347 patients with solid advanced cancers and next-generation sequencing (NGS) results were evaluated. Outcomes for patients who received a \"matched\" versus \"unmatched\" therapy following their NGS results were compared. Eighty-seven patients (25%) were treated with a \"matched\" therapy, 93 (26.8%) with an \"unmatched\" therapy. More patients in the matched group achieved stable disease (SD) \u2265 6 months/partial response (PR)/complete response (CR), 34.5% vs. 16.1%, (P \u2264 0.020 multivariable or propensity score methods). Matched patients had a longer median progression-free survival (PFS; 4.0 vs. 3.0 months, P = 0.039 in the Cox regression model). In analysis using PFS1 (PFS on the prior line of therapy) as a comparator to PFS after NGS, as expected, the unmatched group demonstrated a PFS2 significantly shorter than PFS1 (P = 0.009); however, this shortening was not observed in the matched patients (P = 0.595). Furthermore, 45.3% of the matched patients (24/53) had a PFS2/PFS1 ratio \u22651.3 compared with 19.3% of patients (11/57) in the unmatched group (P = 0.004 univariable and P \u2265 0.057 in multivariable/propensity score analysis). Patients with a \"matching-score\" (the number of matched drugs divided by the number of aberrations; unmatched patients had a score of zero) > 0.2 had a median overall survival (OS) of 15.7 months compared with 10.6 months when their matching-score was \u2264 0.2, (P = 0.040 in the Cox regression model). Matched versus unmatched patients had higher rates of SD \u2265 6 months/PR/CR and longer PFS, and improvement in OS correlated with a higher matching score in multivariable analysis. Mol Cancer Ther; 15(4); 743-52. \u00a92016 AACR.", "citation": "Schwaederle M, Parker BA, Schwab RB, Daniels GA, Piccioni DE, Kesari S, Helsten TL, Bazhenova LA, Romero J, Fanta PT, Lippman SM, Kurzrock R. (2016). Precision Oncology: The UC San Diego Moores Cancer Center PREDICT Experience. Molecular cancer therapeutics. 15(4):743-52. http://doi.org/10.1158/1535-7163.MCT-15-0795. PMID: 26873727.", "score_list": [ 2.395778327389618, 2.59203934250274 ], "ai_score_min": 2.395778327389618, "ai_score_max": 2.59203934250274, "ai_score": 2.493908834946179, "ai_reasoning": "Weak relevance. 'Precision Oncology: The UC San Diego Moores Cancer...' appears tangentially related to the research topic.", "evidence": [ { "text": "(P = 0.595). Furthermore, 45.3%", "section": "abstract", "criterion": "Population", "supports": "exclude" }, { "text": "45.3% of the matched patients (24/53) had a", "section": "abstract", "criterion": "Study Design", "supports": "exclude" }, { "text": "Precision Oncology: The UC San Diego", "section": "title", "criterion": "Population", "supports": "exclude" } ], "ai_decision": "include", "assigned_clusters": [ { "cluster_name": "Adult Patient Population", "cluster_type": "include", "cluster_description": "Papers focused on adult patient demographics with defined inclusion criteria", "related_criteria": "Population" }, { "cluster_name": "Biomarker Analysis Studies", "cluster_type": "include", "cluster_description": "Papers with molecular or biomarker focus and genetic data", "related_criteria": "Outcome" } ] }, { "id": "11", "title": "Comprehensive Genomic Profiling Identifies Frequent Drug-Sensitive EGFR Exon 19 Deletions in NSCLC not Identified by Prior Molecular Testing.", "abstract": "PURPOSE: Reliable detection of drug-sensitive activating EGFR mutations is critical in the care of advanced non-small cell lung cancer (NSCLC), but such testing is commonly performed using a wide variety of platforms, many of which lack rigorous analytic validation. EXPERIMENTAL DESIGN: A large pool of NSCLC cases was assayed with well-validated, hybrid capture-based comprehensive genomic profiling (CGP) at the request of the individual treating physicians in the course of clinical care for the purpose of making therapy decisions. From these, 400 cases harboring EGFR exon 19 deletions (\u0394ex19) were identified, and available clinical history was reviewed. RESULTS: Pathology reports were available for 250 consecutive cases with classical EGFR \u0394ex19 (amino acids 743-754) and were reviewed to assess previous non-hybrid capture-based EGFR testing. Twelve of 71 (17%) cases with EGFR testing results available were negative by previous testing, including 8 of 46 (17%) cases for which the same biopsy was analyzed. Independently, five of six (83%) cases harboring C-helical EGFR \u0394ex19 were previously negative. In a subset of these patients with available clinical outcome information, robust benefit from treatment with EGFR inhibitors was observed. CONCLUSIONS: CGP identifies drug-sensitive EGFR \u0394ex19 in NSCLC cases that have undergone prior EGFR testing and returned negative results. Given the proven benefit in progression-free survival conferred by EGFR tyrosine kinase inhibitors in patients with these alterations, CGP should be considered in the initial presentation of advanced NSCLC and when previous testing for EGFR mutations or other driver alterations is negative. Clin Cancer Res; 22(13); 3281-5. \u00a92016 AACR.", "citation": "Schrock AB, Frampton GM, Herndon D, Greenbowe JR, Wang K, Lipson D, Yelensky R, Chalmers ZR, Chmielecki J, Elvin JA, Wollner M, Dvir A, -Gutman LS, Bordoni R, Peled N, Braiteh F, Raez L, Erlich R, Ou SH, Mohamed M, Ross JS, Stephens PJ, Ali SM, Miller VA. (2016). Comprehensive Genomic Profiling Identifies Frequent Drug-Sensitive EGFR Exon 19 Deletions in NSCLC not Identified by Prior Molecular Testing. Clinical cancer research : an official journal of the American Association for Cancer Research. 22(13):3281-5. http://doi.org/10.1158/1078-0432.CCR-15-1668. PMID: 26933124.", "score_list": [ 2.6108530150311564, 2.6668958907178175 ], "ai_score_min": 2.6108530150311564, "ai_score_max": 2.6668958907178175, "ai_score": 2.6388744528744867, "ai_reasoning": "Weak relevance. 'Comprehensive Genomic Profiling Identifies Frequen...' appears tangentially related to the research topic. Potential exclusion indicators: review.", "evidence": [ { "text": "Cancer Res; 22(13); 3281-5.", "section": "abstract", "criterion": "Population", "supports": "exclude" }, { "text": "Reliable detection of drug-sensitive activating EGFR mutations", "section": "abstract", "criterion": "Study Design", "supports": "exclude" }, { "text": "Comprehensive Genomic Profiling Identifies Frequent Drug-Sensitive", "section": "title", "criterion": "Population", "supports": "exclude" } ], "ai_decision": "include", "assigned_clusters": [ { "cluster_name": "Adult Patient Population", "cluster_type": "include", "cluster_description": "Papers focused on adult patient demographics with defined inclusion criteria", "related_criteria": "Population" } ] }, { "id": "54", "title": "Detection of Tumor NTRK Gene Fusions to Identify Patients Who May Benefit from Tyrosine Kinase (TRK) Inhibitor Therapy.", "abstract": "Chromosomal rearrangements involving the NTRK1, NTRK2, and NTRK3 genes (NTRK genes), which encode the high-affinity nerve growth factor receptor (TRKA), brain-derived neurotrophic factor/neurotrophin-3 (BDNF/NT-3) growth factor receptor (TRKB), and neurotrophin-3 (NT-3) growth factor receptor (TRKC) tyrosine kinases (TRK proteins), act as oncogenic drivers in a broad range of pediatric and adult tumor types. NTRK gene fusions have been shown to be actionable genomic events that are predictive of response to TRK kinase inhibitors, making their routine detection an evolving clinical priority. In certain exceedingly rare tumor types, NTRK gene fusions may be seen in the overwhelming majority of cases, whereas in a range of common cancers, reported incidences are in the range of 0.1% to 2%. Herein, we review the structure of the three NTRK genes and the nature and incidence of NTRK gene fusions in different solid tumor types, and we summarize the clinical data showing the importance of identifying tumors harboring such genomic events. We also outline the laboratory techniques that can be used to diagnose NTRK gene fusions in clinical samples. Finally, we propose a diagnostic algorithm for solid tumors to facilitate the identification of patients with TRK fusion cancer. This algorithm accounts for the widely varying frequencies by tumor histology and the underlying prevalence of TRK expression in the absence of NTRK gene fusions and is based on a combination of fluorescence in situ hybridization, next-generation sequencing, and immunohistochemistry assays.", "citation": "Hsiao SJ, Zehir A, Sireci AN, Aisner DL. (2019). Detection of Tumor NTRK Gene Fusions to Identify Patients Who May Benefit from Tyrosine Kinase (TRK) Inhibitor Therapy. The Journal of molecular diagnostics : JMD. 21(4):553-571. http://doi.org/10.1016/j.jmoldx.2019.03.008. PMID: 31075511.", "score_list": [ 2.0967418476916366, 2.279353239797871 ], "ai_score_min": 2.0967418476916366, "ai_score_max": 2.279353239797871, "ai_score": 2.1880475437447537, "ai_reasoning": "Weak relevance. 'Detection of Tumor NTRK Gene Fusions to Identify P...' appears tangentially related to the research topic. Potential exclusion indicators: review.", "evidence": [ { "text": "growth factor receptor (TRKA),", "section": "abstract", "criterion": "Population", "supports": "exclude" }, { "text": "genes), which encode the high-affinity nerve", "section": "abstract", "criterion": "Study Design", "supports": "exclude" }, { "text": "Detection of Tumor NTRK Gene Fusions", "section": "title", "criterion": "Population", "supports": "exclude" } ], "ai_decision": "include", "assigned_clusters": [ { "cluster_name": "Adult Patient Population", "cluster_type": "include", "cluster_description": "Papers focused on adult patient demographics with defined inclusion criteria", "related_criteria": "Population" } ] }, { "id": "102", "title": "Assessment of Clinical Benefit of Integrative Genomic Profiling in Advanced Solid Tumors.", "abstract": "IMPORTANCE: Use of next-generation sequencing (NGS) to identify clinically actionable genomic targets has been incorporated into routine clinical practice in the management of advanced solid tumors; however, the clinical utility of this testing remains uncertain. OBJECTIVE: To determine which patients derived the greatest degree of clinical benefit from NGS profiling. DESIGN, SETTING, AND PARTICIPANTS: Patients in this cohort study underwent fresh tumor biopsy and blood sample collection for genomic profiling of paired tumor and normal DNA (whole-exome or targeted-exome capture with analysis of 1700 genes) and tumor transcriptome (RNA) sequencing. Somatic and germline genomic alterations were annotated and classified according to degree of clinical actionability. Results were returned to treating oncologists. Data were collected from May 1, 2011, to February 28, 2018, and analyzed from May 1, 2011, to April 30, 2020. MAIN OUTCOMES AND MEASURES: Patients' subsequent therapy and treatment response were extracted from the medical record to determine clinical benefit rate from NGS-directed therapy at 6 months and exceptional responses lasting 12 months or longer. RESULTS: During the study period, NGS was attempted on tumors from 1138 patients and was successful in 1015 (89.2%) (MET1000 cohort) (538 men [53.0%]; mean [SD] age, 57.7 [13.3] years). Potentially clinically actionable genomic alterations were discovered in 817 patients (80.5%). Of these, 132 patients (16.2%) received sequencing-directed therapy, and 49 had clinical benefit (37.1%). Exceptional responses were observed in 26 patients (19.7% of treated patients). Pathogenic germline variants (PGVs) were identified in 160 patients (15.8% of cohort), including 49 PGVs (4.8% of cohort) with therapeutic relevance. For 55 patients with carcinoma of unknown primary origin, NGS identified the primary site in 28 (50.9%), and sequencing-directed therapy in 13 patients resulted in clinical benefit in 7 instances (53.8%), including 5 exceptional responses. CONCLUSIONS AND RELEVANCE: The high rate of therapeutically relevant PGVs identified across diverse cancer types supports a recommendation for directed germline testing in all patients with advanced cancer. The high frequency of therapeutically relevant somatic and germline findings in patients with carcinoma of unknown primary origin and other rare cancers supports the use of comprehensive NGS profiling as a component of standard of care for these disease entities.", "citation": "Cobain EF, Wu YM, Vats P, Chugh R, Worden F, Smith DC, Schuetze SM, Zalupski MM, Sahai V, Alva A, Schott AF, Caram MEV, Hayes DF, Stoffel EM, Jacobs MF, Kumar-Sinha C, Cao X, Wang R, Lucas D, Ning Y, Rabban E, Bell J, Camelo-Piragua S, Udager AM, Cieslik M, Lonigro RJ, Kunju LP, Robinson DR, Talpaz M, Chinnaiyan AM. (2021). Assessment of Clinical Benefit of Integrative Genomic Profiling in Advanced Solid Tumors. JAMA oncology. 7(4):525-533. http://doi.org/10.1001/jamaoncol.2020.7987. PMID: 33630025.", "score_list": [ 4.778082796379639, 4.930259862506304 ], "ai_score_min": 4.778082796379639, "ai_score_max": 4.930259862506304, "ai_score": 4.854171329442972, "ai_reasoning": "Strong candidate for inclusion. 'Assessment of Clinical Benefit of Integrative Geno...' directly addresses research criteria with clear methodology. Keywords suggesting inclusion: outcome, treatment, patient.", "evidence": [ { "text": "genomic profiling of paired tumor", "section": "abstract", "criterion": "Population", "supports": "include" }, { "text": "PARTICIPANTS: Patients in this cohort study underwent fresh", "section": "abstract", "criterion": "Study Design", "supports": "include" }, { "text": "genomic targets has been incorporated into routine clinical", "section": "abstract", "criterion": "Outcome", "supports": "include" }, { "text": "solid tumors; however, the clinical", "section": "abstract", "criterion": "Intervention", "supports": "include" }, { "text": "Assessment of Clinical Benefit of Integrative", "section": "title", "criterion": "Population", "supports": "include" } ], "ai_decision": "include", "assigned_clusters": [ { "cluster_name": "Treatment Efficacy Studies", "cluster_type": "include", "cluster_description": "Papers evaluating treatment outcomes and efficacy measures", "related_criteria": "Intervention" } ] }, { "id": "113", "title": "Comparison of microsatellite instability detection by immunohistochemistry and molecular techniques in colorectal and endometrial cancer.", "abstract": "DNA mismatch repair deficiency (dMMR) testing is crucial for diagnosing Lynch syndrome and detection of microsatellite unstable (MSI) tumors eligible for immunotherapy. The aim of this study was to compare the relative diagnostic performance of three molecular MSI assays: polymerase chain reaction (PCR), MSI testing by Idylla and next-generation-sequencing (NGS) on 49 tumor samples (28 colorectal and 21 endometrial adenocarcinomas) versus immunohistochemistry (IHC). Discrepancies were investigated by MLH1 methylation analysis and integrated with germline results if available. Overall, the molecular assays achieved equivalent diagnostic performance for MSI detection with area under the ROC curves (AUC) of respectively 0.91 for Idylla and PCR, and 0.93 for NGS. In colorectal cancers with tumor cell percentages \u2265 30% all three molecular assays achieved 100% sensitivity and specificity (AUC = 1) versus IHC. Also, in endometrial cancers, all three molecular assays showed equivalent diagnostic performance, albeit at a clearly lower sensitivity ranging from 58% for Idylla to 75% for NGS, corresponding to negative predictive values from 78 to 86%. PCR, Idylla and NGS show similar diagnostic performance for dMMR detection in colorectal and endometrial cancers. Molecular MSI analysis has lower sensitivity for dMMR detection in endometrial cancer indicating that combined use of both IHC and molecular methods is recommended.Clinical Trial Number/IRB: B1172020000040, Ethical Committee, AZ Delta General Hospital.", "citation": "Dedeurwaerdere F, Claes KB, Van Dorpe J, Rottiers I, Van der Meulen J, Breyne J, Swaerts K, Martens G. (2021). Comparison of microsatellite instability detection by immunohistochemistry and molecular techniques in colorectal and endometrial cancer. Scientific reports. 11(1):12880. http://doi.org/10.1038/s41598-021-91974-x. PMID: 34145315.", "score_list": [ 3.3844150626684435, 3.819714814392537 ], "ai_score_min": 3.3844150626684435, "ai_score_max": 3.819714814392537, "ai_score": 3.60206493853049, "ai_reasoning": "Moderate relevance. 'Comparison of microsatellite instability detection...' partially meets inclusion criteria but requires human review for final determination.", "evidence": [ { "text": "sensitivity ranging from 58% for Idylla", "section": "abstract", "criterion": "Population", "supports": "include" }, { "text": "to 86%. PCR, Idylla and", "section": "abstract", "criterion": "Study Design", "supports": "include" }, { "text": "MSI analysis has lower sensitivity for", "section": "abstract", "criterion": "Outcome", "supports": "include" }, { "text": "Comparison of microsatellite instability detection by", "section": "title", "criterion": "Population", "supports": "include" } ], "ai_decision": "include", "assigned_clusters": [ { "cluster_name": "Biomarker Analysis Studies", "cluster_type": "include", "cluster_description": "Papers with molecular or biomarker focus and genetic data", "related_criteria": "Outcome" } ] }, { "id": "1", "title": "Rapid detection of genetic mutations in individual breast cancer patients by next-generation DNA sequencing.", "abstract": "Breast cancer is the most common malignancy in women and the leading cause of cancer deaths in women worldwide. Breast cancers are heterogenous and exist in many different subtypes (luminal A, luminal B, triple negative, and human epidermal growth factor receptor 2 (HER2) overexpressing), and each subtype displays distinct characteristics, responses to treatment, and patient outcomes. In addition to varying immunohistochemical properties, each subtype contains a distinct gene mutation profile which has yet to be fully defined. Patient treatment is currently guided by hormone receptor status and HER2 expression, but accumulating evidence suggests that genetic mutations also influence drug responses and patient survival. Thus, identifying the unique gene mutation pattern in each breast cancer subtype will further improve personalized treatment and outcomes for breast cancer patients. In this study, we used the Ion Personal Genome Machine (PGM) and Ion Torrent AmpliSeq Cancer Panel to sequence 737 mutational hotspot regions from 45 cancer-related genes to identify genetic mutations in 80 breast cancer samples of various subtypes from Chinese patients. Analysis revealed frequent missense and combination mutations in PIK3CA and TP53, infrequent mutations in PTEN, and uncommon combination mutations in luminal-type cancers in other genes including BRAF, GNAS, IDH1, and KRAS. This study demonstrates the feasibility of using Ion Torrent sequencing technology to reliably detect gene mutations in a clinical setting in order to guide personalized drug treatments or combination therapies to ultimately target individual, breast cancer-specific mutations.", "citation": "Liu S, Wang H, Zhang L, Tang C, Jones L, Ye H, Ban L, Wang A, Liu Z, Lou F, Zhang D, Sun H, Dong H, Zhang G, Dong Z, Guo B, Yan H, Yan C, Wang L, Su Z, Li Y, Huang XF, Chen SY, Zhou T. (2015). Rapid detection of genetic mutations in individual breast cancer patients by next-generation DNA sequencing. Human genomics. 9(1):2. http://doi.org/10.1186/s40246-015-0024-4. PMID: 25757876.", "score_list": [ 3.485640753879084, 3.718258439989862 ], "ai_score_min": 3.485640753879084, "ai_score_max": 3.718258439989862, "ai_score": 3.601949596934473, "ai_reasoning": "Moderate relevance. 'Rapid detection of genetic mutations in individual...' partially meets inclusion criteria but requires human review for final determination.", "evidence": [ { "text": "in 80 breast cancer samples of various subtypes", "section": "abstract", "criterion": "Population", "supports": "include" }, { "text": "detect gene mutations in", "section": "abstract", "criterion": "Study Design", "supports": "include" }, { "text": "distinct gene mutation profile which has yet", "section": "abstract", "criterion": "Outcome", "supports": "include" }, { "text": "Rapid detection of genetic mutations in", "section": "title", "criterion": "Population", "supports": "include" } ], "ai_decision": "include", "assigned_clusters": [ { "cluster_name": "Adult Patient Population", "cluster_type": "include", "cluster_description": "Papers focused on adult patient demographics with defined inclusion criteria", "related_criteria": "Population" }, { "cluster_name": "Biomarker Analysis Studies", "cluster_type": "include", "cluster_description": "Papers with molecular or biomarker focus and genetic data", "related_criteria": "Outcome" } ] }, { "id": "2", "title": "Cost-Effectiveness of an Individualized First-Line Treatment Strategy Offering Erlotinib Based on EGFR Mutation Testing in Advanced Lung Adenocarcinoma Patients in Germany.", "abstract": "BACKGROUND: Lung cancer is among the top causes of cancer-related deaths. Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors can increase progression-free survival compared with standard chemotherapy in patients with EGFR mutation-positive advanced non-small cell lung cancer (NSCLC). OBJECTIVE: The aim of the study was to evaluate the cost-effectiveness of EGFR mutation analysis and first-line therapy with erlotinib for mutation-positive patients compared with non-individualized standard chemotherapy from the perspective of German statutory health insurance. METHODS: A state transition model was developed for a time horizon of 10 years (reference year 2014). Data sources were published data from the European Tarceva versus Chemotherapy (EURTAC) randomized trial for drug efficacy and safety and German cost data. We additionally performed deterministic, probabilistic and structural sensitivity analyses. RESULTS: The individualized strategy incurred 0.013 additional quality-adjusted life-years (QALYs) and additional costs of \u20ac 200, yielding an incremental cost-effectiveness ratio (ICER) of \u20ac 15,577/QALY. Results were most sensitive to uncertainty in survival curves and changes in utility values. Cross-validating health utility estimates with recent German data increased the ICER to about \u20ac 58,000/QALY. The probabilistic sensitivity analysis indicated that the individualized strategy is cost-effective, with a probability exceeding 50 % for a range of possible willingness-to-pay thresholds. LIMITATIONS: The uncertainty of the predicted survival curves is substantial, particularly for overall survival, which was not a primary endpoint in the EURTAC study. Also, there is limited data on quality of life in metastatic lung cancer patients. CONCLUSIONS: Individualized therapy based on EGFR mutation status has the potential to provide a cost-effective alternative to non-individualized care for patients with advanced adenocarcinoma. Further clinical research is needed to confirm these results.", "citation": "Schremser K, Rogowski WH, Adler-Reichel S, Tufman AL, Huber RM, Stollenwerk B. (2015). Cost-Effectiveness of an Individualized First-Line Treatment Strategy Offering Erlotinib Based on EGFR Mutation Testing in Advanced Lung Adenocarcinoma Patients in Germany. PharmacoEconomics. 33(11):1215-28. http://doi.org/10.1007/s40273-015-0305-8. PMID: 26081300.", "score_list": [ 2.963081239721328, 3.1531928354071015 ], "ai_score_min": 2.963081239721328, "ai_score_max": 3.1531928354071015, "ai_score": 3.0581370375642147, "ai_reasoning": "Moderate relevance. 'Cost-Effectiveness of an Individualized First-Line...' partially meets inclusion criteria but requires human review for final determination.", "evidence": [ { "text": "The aim of the study", "section": "abstract", "criterion": "Population", "supports": "include" }, { "text": "lung cancer (NSCLC). OBJECTIVE: The", "section": "abstract", "criterion": "Study Design", "supports": "include" }, { "text": "additional quality-adjusted life-years (QALYs) and additional costs of", "section": "abstract", "criterion": "Outcome", "supports": "include" }, { "text": "Cost-Effectiveness of an Individualized First-Line Treatment", "section": "title", "criterion": "Population", "supports": "include" } ], "ai_decision": "include", "assigned_clusters": [ { "cluster_name": "Adult Patient Population", "cluster_type": "include", "cluster_description": "Papers focused on adult patient demographics with defined inclusion criteria", "related_criteria": "Population" } ] }, { "id": "3", "title": "The cost-effectiveness of UGT1A1 genotyping before colorectal cancer treatment with irinotecan from the perspective of the German statutory health insurance.", "abstract": "BACKGROUND: The evidence concerning the cost-effectiveness of UGT1A1*28 genotyping is ambiguous and does not allow drawing valid conclusions for Germany. This study evaluates the cost-effectiveness of UGT1A1 genotyping in patients with metastatic colorectal cancer undergoing irinotecan-based chemotherapy compared to no testing from the perspective of the German statutory health insurance. MATERIAL AND METHODS: A decision-analytic Markov model with a life time horizon was developed. No testing was compared to two genotype-dependent therapy strategies: 1) dose reduction by 25%; and 2) administration of a prophylactic G-CSF growth factor analog for homozygous and heterozygous patients. Probability, quality of life and cost parameters used in this study were based on published literature. Deterministic and probabilistic sensitivity analyses were performed to account for parameter uncertainties. RESULTS: Strategy 1 dominated all remaining strategies. Compared to no testing, it resulted in only marginal QALY increases (0.0002) but a cost reduction of \u20ac580 per patient. Strategy 2 resulted in the same health gains but increased costs by \u20ac10 773. In the probabilistic analysis, genotyping and dose reduction was the optimal strategy in approximately 100% of simulations at a threshold of \u20ac50 000 per QALY. Deterministic sensitivity analysis shows that uncertainty for this strategy originated primarily from costs for irinotecan-based chemotherapy, from the prevalence of neutropenia among heterozygous patients, and from whether dose reduction is applied to both homozygotes and heterozygotes or only to the former. CONCLUSION: This model-based synthesis of the most recent evidence suggests that pharmacogenetic UGT1A1 testing prior to irinotecan-based chemotherapy dominates non-personalized colon cancer care in Germany. However, as structural uncertainty remains high, these results require validation in clinical practice, e.g. based on a managed-entry agreement.", "citation": "Butzke B, Oduncu FS, Severin F, Pfeufer A, Heinemann V, Giessen-Jung C, Stollenwerk B, Rogowski WH. (2016). The cost-effectiveness of UGT1A1 genotyping before colorectal cancer treatment with irinotecan from the perspective of the German statutory health insurance. Acta oncologica (Stockholm, Sweden). 55(3):318-28. http://doi.org/10.3109/0284186X.2015.1053983. PMID: 26098842.", "score_list": [ 1.226064207740262, 1.3633843994854757 ], "ai_score_min": 1.226064207740262, "ai_score_max": 1.3633843994854757, "ai_score": 1.2947243036128688, "ai_reasoning": "Recommend exclusion. 'The cost-effectiveness of UGT1A1 genotyping before...' does not appear to meet core inclusion criteria.", "evidence": [ { "text": "and dose reduction was", "section": "abstract", "criterion": "Population", "supports": "exclude" }, { "text": "health insurance. MATERIAL AND METHODS: A", "section": "abstract", "criterion": "Study Design", "supports": "exclude" }, { "text": "The cost-effectiveness of UGT1A1 genotyping before", "section": "title", "criterion": "Population", "supports": "exclude" } ], "ai_decision": "include", "assigned_clusters": [ { "cluster_name": "Methodology & Protocol Only", "cluster_type": "exclude", "cluster_description": "Papers focused on study design and methodology without clinical results", "related_criteria": "Study Design" } ] }, { "id": "4", "title": "Detection of novel and potentially actionable anaplastic lymphoma kinase (ALK) rearrangement in colorectal adenocarcinoma by immunohistochemistry screening.", "abstract": "PURPOSE: Anaplastic lymphoma kinase (ALK) rearrangement has been detected in colorectal carcinoma (CRC) using advanced molecular diagnostics tests including exon scanning, fluorescence in situ hybridization (FISH), and next generation sequencing (NGS). We investigated if immunohistochemistry (IHC) can be used to detect ALK rearrangement in gastrointestinal malignancies. EXPERIMENTAL DESIGNS: Tissue microarrays (TMAs) from consecutive gastric carcinoma (GC) and CRC patients who underwent surgical resection at Samsung Medical Center, Seoul, Korea were screened by IHC using ALK monoclonal antibody 5A4. IHC positive cases were confirmed by FISH, nCounter assays, and NGS-based comprehensive genomic profiling (CGP). ALK IHC was further applied to CRC patients enrolled in a pathway-directed therapeutic trial. RESULTS: Four hundred thirty-two GC and 172 CRC cases were screened by IHC. No GC sample was ALK IHC positive. One CRC (0.6%) was ALK IHC positive (3+) that was confirmed by ALK FISH and a novel CAD-ALK (C35; A20) fusion variant that resulted from a paracentric inversion event inv(2)(p22-21p23) was identified by CGP. One out of 50 CRC patients enrolled in a pathway-directed therapeutic trial was ALK IHC positive (3+) confirmed by ALK FISH and found to harbor the EML4-ALK (E21, A20) fusion variant by CGP. Growth of a tumor cell line derived from this EML4-ALK CRC patient was inhibited by ALK inhibitors crizotinib and entrectinib. CONCLUSIONS: ALK IHC is a viable screening strategy for identifying ALK rearrangement in CRC. ALK rearrangement is a potential actionable driver mutation in CRC based on survival inhibition of patient tumor-derived cell line by potent ALK inhibitors.", "citation": "Lee J, Kim HC, Hong JY, Wang K, Kim SY, Jang J, Kim ST, Park JO, Lim HY, Kang WK, Park YS, Lee J, Lee WY, Park YA, Huh JW, Yun SH, Do IG, Kim SH, Balasubramanian S, Stephens PJ, Ross JS, Li GG, Hornby Z, Ali SM, Miller VA, Kim KM, Ou SH. (2015). Detection of novel and potentially actionable anaplastic lymphoma kinase (ALK) rearrangement in colorectal adenocarcinoma by immunohistochemistry screening. Oncotarget. 6(27):24320-32. http://doi.org/10.18632/oncotarget.4462. PMID: 26172300.", "score_list": [ 3.5284293378806932, 3.5308295932096017 ], "ai_score_min": 3.5284293378806932, "ai_score_max": 3.5308295932096017, "ai_score": 3.5296294655451472, "ai_reasoning": "Moderate relevance. 'Detection of novel and potentially actionable anap...' partially meets inclusion criteria but requires human review for final determination.", "evidence": [ { "text": "(CRC) using advanced molecular diagnostics tests including", "section": "abstract", "criterion": "Population", "supports": "include" }, { "text": "(0.6%) was ALK IHC positive (3+)", "section": "abstract", "criterion": "Study Design", "supports": "include" }, { "text": "kinase (ALK) rearrangement has been detected in colorectal", "section": "abstract", "criterion": "Outcome", "supports": "include" }, { "text": "Detection of novel and potentially actionable", "section": "title", "criterion": "Population", "supports": "include" } ], "ai_decision": "include", "assigned_clusters": [ { "cluster_name": "Adult Patient Population", "cluster_type": "include", "cluster_description": "Papers focused on adult patient demographics with defined inclusion criteria", "related_criteria": "Population" }, { "cluster_name": "Biomarker Analysis Studies", "cluster_type": "include", "cluster_description": "Papers with molecular or biomarker focus and genetic data", "related_criteria": "Outcome" } ] }, { "id": "6", "title": "Colorectal Cancers with the Uncommon Findings of KRAS Mutation and Microsatellite Instability.", "abstract": "Sporadic colorectal cancers with microsatellite instability (MSI) frequently contain a mutation of the BRAF gene. Additionally, it has been shown that BRAF mutations in colorectal cancers are mutually exclusive of KRAS mutation. We evaluated 14 cases of colorectal cancer with MSI that were BRAF wild type but demonstrated a KRAS mutation. The codon 12/13 region in exon 2 of the KRAS oncogene and the codon 600 region in exon 15 of the BRAF gene were analyzed with standard PCR methods. MSI was evaluated by using the Bethesda panel of markers. The methylation status of the mismatch repair system was ascertained using the SALSA(\u00ae) MS-MLPA(\u00ae) methylation-specific DNA detection. The mismatch repair proteins MLH1, MSH2, MSH6, and PMS2 were evaluated by immunohistochemical staining. A total of 530 colorectal cancers were studied for MSI and KRAS gene mutation. Fourteen (2.6%) cancers with both MSI and a KRAS mutation were identified, and all cancers were BRAF wild type. Methylation was present in 7 (50%), 5 demonstrated methylation of MLH1, 1 showed methylation of MGMT, and 1 showed methylation of MSH2. Four patients had simultaneous cancers, some of which showed different genetic changes. Immunohistochemical staining suggested a germ line mutation for 4 of 10 cases with complete staining information. KRAS mutation may occur with MSI in colorectal cancers with wild-type BRAF. If a mutation in KRAS co-exists with MSI, then strong methylation of the MLH1 gene is unlikely. These tumors demonstrate that a small number of colorectal cancers will develop with atypical patterns of molecular genetic changes, suggesting that a specific pattern of genetic changes may not be as crucial as the overall accumulation of changes, consistent with the 'unique tumor principle'.", "citation": "Zauber P, Marotta S, Sabbath-Solitare M. (2015). Colorectal Cancers with the Uncommon Findings of KRAS Mutation and Microsatellite Instability. Cytogenetic and genome research. 146(4):261-7. http://doi.org/10.1159/000441086. PMID: 26523369.", "score_list": [ 2.1724340024181243, 1.9704566750567174 ], "ai_score_min": 1.9704566750567174, "ai_score_max": 2.1724340024181243, "ai_score": 2.071445338737421, "ai_reasoning": "Weak relevance. 'Colorectal Cancers with the Uncommon Findings of K...' appears tangentially related to the research topic.", "evidence": [ { "text": "colorectal cancer with MSI that were BRAF wild", "section": "abstract", "criterion": "Population", "supports": "exclude" }, { "text": "with MSI, then strong methylation", "section": "abstract", "criterion": "Study Design", "supports": "exclude" }, { "text": "Colorectal Cancers with the Uncommon Findings", "section": "title", "criterion": "Population", "supports": "exclude" } ], "ai_decision": "include", "assigned_clusters": [ { "cluster_name": "Adult Patient Population", "cluster_type": "include", "cluster_description": "Papers focused on adult patient demographics with defined inclusion criteria", "related_criteria": "Population" }, { "cluster_name": "Biomarker Analysis Studies", "cluster_type": "include", "cluster_description": "Papers with molecular or biomarker focus and genetic data", "related_criteria": "Outcome" } ] }, { "id": "7", "title": "Mutational profiling of brain metastasis from breast cancer: matched pair analysis of targeted sequencing between brain metastasis and primary breast cancer.", "abstract": "Although breast cancer is the second most common cause of brain metastasis with a notable increase of incidence, genes that mediate breast cancer brain metastasis (BCBM) are not fully understood. To study the molecular nature of brain metastasis, we performed gene expression profiling of brain metastasis and matched primary breast cancer (BC). We used the Ion AmpliSeq Cancer Panel v2 covering 2,855 mutations from 50 cancer genes to analyze 18 primary BC and 42 BCBM including 15 matched pairs. The most common BCBM subtypes were triple-negative (42.9%) and basal-like (36.6%). In a total of 42 BCBM samples, 32 (76.2%) harbored at least one mutation (median 1, range 0-7 mutations). Frequently detected somatic mutations included TP53 (59.5%), MLH1 (14.3%), PIK3CA (14.3%), and KIT (7.1%). We compared BCBM with patient-matched primary BC specimens. There were no significant differences in mutation profiles between the two groups. Notably, gene expression in BCBM such as TP53, PIK3CA, KIT, MLH1, and RB1 also seemed to be present in primary breast cancers. The TP53 mutation frequency was higher in BCBM than in primary BC (59.5% vs 38.9%, respectively). In conclusion, we found actionable gene alterations in BCBM that were maintained in primary BC. Further studies with functional testing and a delineation of the role of these genes in specific steps of the metastatic process should lead to a better understanding of the biology of metastasis and its susceptibility to treatment.", "citation": "Lee JY, Park K, Lim SH, Kim HS, Yoo KH, Jung KS, Song HN, Hong M, Do IG, Ahn T, Lee SK, Bae SY, Kim SW, Lee JE, Nam SJ, Kim DH, Jung HH, Kim JY, Ahn JS, Im YH, Park YH. (2015). Mutational profiling of brain metastasis from breast cancer: matched pair analysis of targeted sequencing between brain metastasis and primary breast cancer. Oncotarget. 6(41):43731-42. http://doi.org/10.18632/oncotarget.6192. PMID: 26527317.", "score_list": [ 4.581613541180879, 4.332883900371082 ], "ai_score_min": 4.332883900371082, "ai_score_max": 4.581613541180879, "ai_score": 4.457248720775981, "ai_reasoning": "Strong candidate for inclusion. 'Mutational profiling of brain metastasis from brea...' directly addresses research criteria with clear methodology. Keywords suggesting inclusion: treatment, patient, study.", "evidence": [ { "text": "that mediate breast cancer brain metastasis", "section": "abstract", "criterion": "Population", "supports": "include" }, { "text": "Frequently detected somatic mutations included", "section": "abstract", "criterion": "Study Design", "supports": "include" }, { "text": "cancer brain metastasis (BCBM) are not", "section": "abstract", "criterion": "Outcome", "supports": "include" }, { "text": "TP53 mutation frequency was higher in", "section": "abstract", "criterion": "Intervention", "supports": "include" }, { "text": "Mutational profiling of brain metastasis from", "section": "title", "criterion": "Population", "supports": "include" } ], "ai_decision": "include", "assigned_clusters": [ { "cluster_name": "Treatment Efficacy Studies", "cluster_type": "include", "cluster_description": "Papers evaluating treatment outcomes and efficacy measures", "related_criteria": "Intervention" }, { "cluster_name": "Biomarker Analysis Studies", "cluster_type": "include", "cluster_description": "Papers with molecular or biomarker focus and genetic data", "related_criteria": "Outcome" } ] }, { "id": "9", "title": "Multiplex PCR and Next Generation Sequencing for the Non-Invasive Detection of Bladder Cancer.", "abstract": "BACKGROUND: Highly sensitive and specific urine-based tests to detect either primary or recurrent bladder cancer have proved elusive to date. Our ever increasing knowledge of the genomic aberrations in bladder cancer should enable the development of such tests based on urinary DNA. METHODS: DNA was extracted from urine cell pellets and PCR used to amplify the regions of the TERT promoter and coding regions of FGFR3, PIK3CA, TP53, HRAS, KDM6A and RXRA which are frequently mutated in bladder cancer. The PCR products were barcoded, pooled and paired-end 2 x 250 bp sequencing performed on an Illumina MiSeq. Urinary DNA was analysed from 20 non-cancer controls, 120 primary bladder cancer patients (41 pTa, 40 pT1, 39 pT2+) and 91 bladder cancer patients post-TURBT (89 cancer-free). RESULTS: Despite the small quantities of DNA extracted from some urine cell pellets, 96% of the samples yielded mean read depths >500. Analysing only previously reported point mutations, TERT mutations were found in 55% of patients with bladder cancer (independent of stage), FGFR3 mutations in 30% of patients with bladder cancer, PIK3CA in 14% and TP53 mutations in 12% of patients with bladder cancer. Overall, these previously reported bladder cancer mutations were detected in 86 out of 122 bladder cancer patients (70% sensitivity) and in only 3 out of 109 patients with no detectable bladder cancer (97% specificity). CONCLUSION: This simple, cost-effective approach could be used for the non-invasive surveillance of patients with non-muscle-invasive bladder cancers harbouring these mutations. The method has a low DNA input requirement and can detect low levels of mutant DNA in a large excess of normal DNA. These genes represent a minimal biomarker panel to which extra markers could be added to develop a highly sensitive diagnostic test for bladder cancer.", "citation": "Ward DG, Baxter L, Gordon NS, Ott S, Savage RS, Beggs AD, James JD, Lickiss J, Green S, Wallis Y, Wei W, James ND, Zeegers MP, Cheng KK, Mathews GM, Patel P, Griffiths M, Bryan RT. (2016). Multiplex PCR and Next Generation Sequencing for the Non-Invasive Detection of Bladder Cancer. PloS one. 11(2):e0149756. http://doi.org/10.1371/journal.pone.0149756. PMID: 26901314.", "score_list": [ 3.488508316363062, 3.423921376235156 ], "ai_score_min": 3.423921376235156, "ai_score_max": 3.488508316363062, "ai_score": 3.456214846299109, "ai_reasoning": "Moderate relevance. 'Multiplex PCR and Next Generation Sequencing for t...' partially meets inclusion criteria but requires human review for final determination.", "evidence": [ { "text": "with bladder cancer (independent", "section": "abstract", "criterion": "Population", "supports": "include" }, { "text": "12% of patients with", "section": "abstract", "criterion": "Study Design", "supports": "include" }, { "text": "cancer. The PCR products were barcoded, pooled", "section": "abstract", "criterion": "Outcome", "supports": "include" }, { "text": "Multiplex PCR and Next Generation Sequencing", "section": "title", "criterion": "Population", "supports": "include" } ], "ai_decision": "include", "assigned_clusters": [ { "cluster_name": "Adult Patient Population", "cluster_type": "include", "cluster_description": "Papers focused on adult patient demographics with defined inclusion criteria", "related_criteria": "Population" }, { "cluster_name": "Biomarker Analysis Studies", "cluster_type": "include", "cluster_description": "Papers with molecular or biomarker focus and genetic data", "related_criteria": "Outcome" } ] }, { "id": "10", "title": "Detection of high frequency of mutations in a breast and/or ovarian cancer cohort: implications of embracing a multi-gene panel in molecular diagnosis in India.", "abstract": "Breast and/or ovarian cancer (BOC) are among the most frequently diagnosed forms of hereditary cancers and leading cause of death in India. This emphasizes on the need for a cost-effective method for early detection of these cancers. We sequenced 141 unrelated patients and families with BOC using the TruSight Cancer panel, which includes 13 genes strongly associated with risk of inherited BOC. Multi-gene sequencing was done on the Illumina MiSeq platform. Genetic variations were identified using the Strand NGS software and interpreted using the StrandOmics platform. We were able to detect pathogenic mutations in 51 (36.2%) cases, out of which 19 were novel mutations. When we considered familial breast cancer cases only, the detection rate increased to 52%. When cases were stratified based on age of diagnosis into three categories, \u2a7d40 years, 40-50 years and >50 years, the detection rates were higher in the first two categories (44.4% and 53.4%, respectively) as compared with the third category, in which it was 26.9%. Our study suggests that next-generation sequencing-based multi-gene panels increase the sensitivity of mutation detection and help in identifying patients with a high risk of developing cancer as compared with sequential tests of individual genes.", "citation": "Mannan AU, Singh J, Lakshmikeshava R, Thota N, Singh S, Sowmya TS, Mishra A, Sinha A, Deshwal S, Soni MR, Chandrasekar A, Ramesh B, Ramamurthy B, Padhi S, Manek P, Ramalingam R, Kapoor S, Ghosh M, Sankaran S, Ghosh A, Veeramachaneni V, Ramamoorthy P, Hariharan R, Subramanian K. (2016). Detection of high frequency of mutations in a breast and/or ovarian cancer cohort: implications of embracing a multi-gene panel in molecular diagnosis in India. Journal of human genetics. 61(6):515-22. http://doi.org/10.1038/jhg.2016.4. PMID: 26911350.", "score_list": [ 2.1379224607623986, 1.8457047505083275 ], "ai_score_min": 1.8457047505083275, "ai_score_max": 2.1379224607623986, "ai_score": 1.991813605635363, "ai_reasoning": "Recommend exclusion. 'Detection of high frequency of mutations in a brea...' does not appear to meet core inclusion criteria.", "evidence": [ { "text": "in India. This emphasizes on the", "section": "abstract", "criterion": "Population", "supports": "exclude" }, { "text": "of death in India.", "section": "abstract", "criterion": "Study Design", "supports": "exclude" }, { "text": "Detection of high frequency of mutations", "section": "title", "criterion": "Population", "supports": "exclude" } ], "ai_decision": "include", "assigned_clusters": [ { "cluster_name": "Methodology & Protocol Only", "cluster_type": "exclude", "cluster_description": "Papers focused on study design and methodology without clinical results", "related_criteria": "Study Design" } ] }, { "id": "12", "title": "Recurrent, truncating SOX9 mutations are associated with SOX9 overexpression, KRAS mutation, and TP53 wild type status in colorectal carcinoma.", "abstract": "PURPOSE: The extent to which the developmental transcription factor SOX9 functions as an oncogene or tumor suppressor in colorectal carcinoma (CRC) is debatable. We aimed to clarify the effect of SOX9 mutations on SOX9 protein expression and their association with known molecular subtypes and clinical characteristics in advanced CRC. EXPERIMENTAL DESIGN: Next generation sequencing data (MSK-IMPACT) from CRC patients was used to interrogate SOX9, KRAS, NRAS, BRAF, TP53, APC, and PIK3CA. Mutant and wild type (WT) SOX9 cases underwent immunohistochemical (IHC) staining to assess protein expression. SOX9 allele-specific copy number was assessed by Affymetrix Oncoscan array. RESULTS: SOX9 was mutated in 38 of 353 (10.7%) CRC, of which 82% were frameshift or nonsense. Compared to SOX9 WT, SOX9 mutation was strongly associated with coexistent mutant KRAS (p=0.0001) and WT TP53 (p=0.0004). SOX9 was overexpressed in both SOX9 mutant and WT CRC. Among SOX9 mutants, the highest expression was noted for truncating exon 3 mutants (mean H scores 239\u00b1105 versus 147\u00b1119, p value=0.02). Further, SOX9 truncating mutants with loss of the WT allele demonstrated protein overexpression indicating the WT protein was not required for protein stabilization. CONCLUSIONS: SOX9 is overexpressed in CRC, including those with recurrent distal truncating mutations. The latter has structural similarity to the oncogenic isoform MiniSOX9, which is distally truncated due to aberrant splicing. This information suggests that truncated SOX9 has oncogenic features. SOX9 mutations are highly enriched in KRAS mutant and TP53 wild type CRC; and may provide a therapeutic target in approximately 11% of CRC.", "citation": "Javier BM, Yaeger R, Wang L, Sanchez-Vega F, Zehir A, Middha S, Sadowska J, Vakiani E, Shia J, Klimstra D, Ladanyi M, Iacobuzio-Donahue CA, Hechtman JF. (2016). Recurrent, truncating SOX9 mutations are associated with SOX9 overexpression, KRAS mutation, and TP53 wild type status in colorectal carcinoma. Oncotarget. 7(32):50875-50882. http://doi.org/10.18632/oncotarget.9682. PMID: 27248473.", "score_list": [ 1.0, 1.3083568998593686 ], "ai_score_min": 1.0, "ai_score_max": 1.3083568998593686, "ai_score": 1.1541784499296843, "ai_reasoning": "Recommend exclusion. 'Recurrent, truncating SOX9 mutations are associate...' does not appear to meet core inclusion criteria.", "evidence": [ { "text": "suppressor in colorectal carcinoma (CRC) is debatable. We", "section": "abstract", "criterion": "Population", "supports": "exclude" }, { "text": "similarity to the oncogenic isoform MiniSOX9, which is", "section": "abstract", "criterion": "Study Design", "supports": "exclude" }, { "text": "Recurrent, truncating SOX9 mutations are associated", "section": "title", "criterion": "Population", "supports": "exclude" } ], "ai_decision": "include", "assigned_clusters": [ { "cluster_name": "Methodology & Protocol Only", "cluster_type": "exclude", "cluster_description": "Papers focused on study design and methodology without clinical results", "related_criteria": "Study Design" } ] }, { "id": "13", "title": "Palbociclib as a first-line treatment in oestrogen receptor-positive, HER2-negative, advanced breast cancer not cost-effective with current pricing: a health economic analysis of the Swiss Group for Clinical Cancer Research (SAKK).", "abstract": "Endocrine therapy continues to be the optimal systemic treatment for metastatic ER(+)HER2(-) breast cancer. The CDK4/6 inhibitor palbociclib combined with letrozole has recently been shown to significantly improve progression-free survival. Here we examined the cost-effectiveness of this regimen for the Swiss healthcare system. A Markov cohort simulation based on the PALOMA-1 trial (Finn et al. in Lancet Oncol 16:25-35, 2015) was used as the clinical course. Input parameters were based on summary trial data. Costs were assessed from the Swiss healthcare system perspective. Adding palbociclib to letrozole (PALLET) compared to letrozole monotherapy was estimated to cost an additional CHF342,440 and gain 1.14 quality-adjusted life years, resulting in an incremental cost-effectiveness ratio (ICER) of CHF301,227/QALY gained. In univariate sensitivity analyses, no tested variation in key parameters resulted in an ICER below a willingness-to-pay threshold of CHF100,000/QALY. PALLET had a 0 % probability of being cost-effective in probabilistic sensitivity analyses. Lowering PALLET's price by 75 % resulted in an ICER of CHF73,995/QALY and a 73 % probability of being cost-effective. At current prices, PALLET would cost the Swiss healthcare system an additional CHF155 million/year. Palbociclib plus letrozole cannot be considered cost-effective for the first-line treatment of patients with metastatic breast cancer in the Swiss healthcare system.", "citation": "Matter-Walstra K, Ruhstaller T, Klingbiel D, Schwenkglenks M, Dedes KJ. (2016). Palbociclib as a first-line treatment in oestrogen receptor-positive, HER2-negative, advanced breast cancer not cost-effective with current pricing: a health economic analysis of the Swiss Group for Clinical Cancer Research (SAKK). Breast cancer research and treatment. 158(1):51-57. http://doi.org/10.1007/s10549-016-3822-z. PMID: 27277747.", "score_list": [ 3.8559385348518536, 3.487817515957954 ], "ai_score_min": 3.487817515957954, "ai_score_max": 3.8559385348518536, "ai_score": 3.6718780254049035, "ai_reasoning": "Moderate relevance. 'Palbociclib as a first-line treatment in oestrogen...' partially meets inclusion criteria but requires human review for final determination.", "evidence": [ { "text": "shown to significantly improve", "section": "abstract", "criterion": "Population", "supports": "include" }, { "text": "cohort simulation based on the PALOMA-1 trial", "section": "abstract", "criterion": "Study Design", "supports": "include" }, { "text": "willingness-to-pay threshold of CHF100,000/QALY. PALLET had", "section": "abstract", "criterion": "Outcome", "supports": "include" }, { "text": "Palbociclib as a first-line treatment in", "section": "title", "criterion": "Population", "supports": "include" } ], "ai_decision": "include", "assigned_clusters": [ { "cluster_name": "Adult Patient Population", "cluster_type": "include", "cluster_description": "Papers focused on adult patient demographics with defined inclusion criteria", "related_criteria": "Population" } ] }, { "id": "14", "title": "Urinary DNA Methylation Biomarkers for Noninvasive Prediction of Aggressive Disease in Patients with Prostate Cancer on Active Surveillance.", "abstract": "PURPOSE: Patients with prostate cancer on active surveillance are monitored by repeat prostate specific antigen measurements, digital rectal examinations and prostate biopsies. A subset of patients on active surveillance will later reclassify with disease progression, prompting definitive treatment. To minimize the risk of under treating such patients on active surveillance minimally invasive tests are urgently needed incorporating biomarkers to identify patients who will reclassify. MATERIALS AND METHODS: We assessed post-digital rectal examination urine samples of patients on active surveillance for select DNA methylation biomarkers that were previously investigated in radical prostatectomy specimens and shown to correlate with an increasing risk of prostate cancer. Post-digital rectal examination urine samples were prospectively collected from 153 men on active surveillance who were diagnosed with Gleason score 6 disease. Urinary sediment DNA was analyzed for 8 DNA methylation biomarkers by multiplex MethyLight assay. Correlative analyses were performed on gene methylation and clinicopathological variables to test the ability to predict patient risk reclassification. RESULTS: Using backward logistic regression a 4-gene methylation classifier panel (APC, CRIP3, GSTP1 and HOXD8) was identified. The classifier panel was able to predict patient reclassification (OR 2.559, 95% CI 1.257-5.212). We observed this panel to be an independent and superior predictor compared to current clinical predictors such as prostate specific antigen at diagnosis or the percent of tumor positive cores in the initial biopsy. CONCLUSION: We report that a urine based classifier panel of 4 methylation biomarkers predicts disease progression in patients on active surveillance. Once validated in independent active surveillance cohorts, these promising biomarkers may help establish a less invasive method to monitor patients on active surveillance programs.", "citation": "Zhao F, Olkhov-Mitsel E, van der Kwast T, Sykes J, Zdravic D, Venkateswaran V, Zlotta AR, Loblaw A, Fleshner NE, Klotz L, Vesprini D, Bapat B. (2017). Urinary DNA Methylation Biomarkers for Noninvasive Prediction of Aggressive Disease in Patients with Prostate Cancer on Active Surveillance. The Journal of urology. 197(2):335-341. http://doi.org/10.1016/j.juro.2016.08.081. PMID: 27545574.", "score_list": [ 3.888491438571634, 4.178603809371813 ], "ai_score_min": 3.888491438571634, "ai_score_max": 4.178603809371813, "ai_score": 4.033547623971724, "ai_reasoning": "Strong candidate for inclusion. 'Urinary DNA Methylation Biomarkers for Noninvasive...' directly addresses research criteria with clear methodology. Keywords suggesting inclusion: treatment, patient, results.", "evidence": [ { "text": "such as prostate specific antigen at", "section": "abstract", "criterion": "Population", "supports": "include" }, { "text": "in radical prostatectomy specimens", "section": "abstract", "criterion": "Study Design", "supports": "include" }, { "text": "specific antigen measurements, digital rectal", "section": "abstract", "criterion": "Outcome", "supports": "include" }, { "text": "DNA methylation biomarkers by multiplex MethyLight assay. Correlative", "section": "abstract", "criterion": "Intervention", "supports": "include" }, { "text": "Urinary DNA Methylation Biomarkers for Noninvasive", "section": "title", "criterion": "Population", "supports": "include" } ], "ai_decision": "include", "assigned_clusters": [ { "cluster_name": "Treatment Efficacy Studies", "cluster_type": "include", "cluster_description": "Papers evaluating treatment outcomes and efficacy measures", "related_criteria": "Intervention" }, { "cluster_name": "Biomarker Analysis Studies", "cluster_type": "include", "cluster_description": "Papers with molecular or biomarker focus and genetic data", "related_criteria": "Outcome" } ] }, { "id": "15", "title": "Targeted Next Generation Sequencing Identifies Markers of Response to PD-1 Blockade.", "abstract": "Therapeutic antibodies blocking programmed death-1 and its ligand (PD-1/PD-L1) induce durable responses in a substantial fraction of melanoma patients. We sought to determine whether the number and/or type of mutations identified using a next-generation sequencing (NGS) panel available in the clinic was correlated with response to anti-PD-1 in melanoma. Using archival melanoma samples from anti-PD-1/PD-L1-treated patients, we performed hybrid capture-based NGS on 236-315 genes and T-cell receptor (TCR) sequencing on initial and validation cohorts from two centers. Patients who responded to anti-PD-1/PD-L1 had higher mutational loads in an initial cohort (median, 45.6 vs. 3.9 mutations/MB; P = 0.003) and a validation cohort (37.1 vs. 12.8 mutations/MB; P = 0.002) compared with nonresponders. Response rate, progression-free survival, and overall survival were superior in the high, compared with intermediate and low, mutation load groups. Melanomas with NF1 mutations harbored high mutational loads (median, 62.7 mutations/MB) and high response rates (74%), whereas BRAF/NRAS/NF1 wild-type melanomas had a lower mutational load. In these archival samples, TCR clonality did not predict response. Mutation numbers in the 315 genes in the NGS platform strongly correlated with those detected by whole-exome sequencing in The Cancer Genome Atlas samples, but was not associated with survival. In conclusion, mutational load, as determined by an NGS platform available in the clinic, effectively stratified patients by likelihood of response. This approach may provide a clinically feasible predictor of response to anti-PD-1/PD-L1. Cancer Immunol Res; 4(11); 959-67. \u00a92016 AACR.", "citation": "Johnson DB, Frampton GM, Rioth MJ, Yusko E, Xu Y, Guo X, Ennis RC, Fabrizio D, Chalmers ZR, Greenbowe J, Ali SM, Balasubramanian S, Sun JX, He Y, Frederick DT, Puzanov I, Balko JM, Cates JM, Ross JS, Sanders C, Robins H, Shyr Y, Miller VA, Stephens PJ, Sullivan RJ, Sosman JA, Lovly CM. (2016). Targeted Next Generation Sequencing Identifies Markers of Response to PD-1 Blockade. Cancer immunology research. 4(11):959-967. http://doi.org/10.1158/2326-6066.CIR-16-0143. PMID: 27671167.", "score_list": [ 4.076902290390379, 3.6776309192469085 ], "ai_score_min": 3.6776309192469085, "ai_score_max": 4.076902290390379, "ai_score": 3.8772666048186437, "ai_reasoning": "Moderate relevance. 'Targeted Next Generation Sequencing Identifies Mar...' partially meets inclusion criteria but requires human review for final determination.", "evidence": [ { "text": "feasible predictor of response to anti-PD-1/PD-L1. Cancer Immunol", "section": "abstract", "criterion": "Population", "supports": "include" }, { "text": "correlated with response to", "section": "abstract", "criterion": "Study Design", "supports": "include" }, { "text": "progression-free survival, and overall survival were superior", "section": "abstract", "criterion": "Outcome", "supports": "include" }, { "text": "Targeted Next Generation Sequencing Identifies Markers", "section": "title", "criterion": "Population", "supports": "include" } ], "ai_decision": "include", "assigned_clusters": [ { "cluster_name": "Adult Patient Population", "cluster_type": "include", "cluster_description": "Papers focused on adult patient demographics with defined inclusion criteria", "related_criteria": "Population" } ] }, { "id": "16", "title": "Spatio-temporal mutation profiles of case-matched colorectal carcinomas and their metastases reveal unique de novo mutations in metachronous lung metastases by targeted next generation sequencing.", "abstract": "BACKGROUND: Targeted next generation sequencing (tNGS) has become part of molecular pathology diagnostics for determining RAS mutation status in colorectal cancer (CRC) patients as predictive tool for decision on EGFR-targeted therapy. Here, we investigated mutation profiles of case-matched tissue specimens throughout the disease course of CRC, to further specify RAS-status dynamics and to identify de novo mutations associated with distant metastases. METHODS: Case-matched formalin-fixed and paraffin-embedded (FFPE) resection specimens (n = 70; primary tumours, synchronous and/or metachronous liver and/or lung metastases) of 14 CRC cases were subjected to microdissection of normal colonic epithelial, primary and metastatic tumour cells, their DNA extraction and an adapted library protocol for limited DNA using the 48 gene TruSeq Amplicon Cancer Panel RESULTS: By tNGS primary tumours were RAS wildtype in 5/14 and mutated in 9/14 (8/9 KRAS exon 2; 1/9 NRAS Exon 3) of cases. RAS mutation status was maintained in case-matched metastases throughout the disease course, albeit with altered allele frequencies. Case-matched analyses further identified a maximum of three sequence variants (mainly in APC, KRAS, NRAS, TP53) shared by all tumour specimens throughout the disease course per individual case. In addition, further case-matched de novo mutations were detected in synchronous and/or metachronous liver and/or lung metastases (e.g. in APC, ATM, FBXW7, FGFR3, GNAQ, KIT, PIK3CA, PTEN, SMAD4, SMO, STK11, TP53, VHL). Moreover, several de novo mutations were more frequent in synchronous (e.g. ATM, KIT, PIK3CA, SMAD4) or metachronous (e.g. FBXW7, SMO, STK11) lung metastases. Finally, some de novo mutations occurred only in metachronous lung metastases (CDKN2A, FGFR2, GNAS, JAK3, SRC). CONCLUSION: Together, this study employs an adapted FFPE-based tNGS approach to confirm conservation of RAS mutation status in primary and metastatic tissue specimens of CRC patients. Moreover, it identifies genes preferentially mutated de novo in late disease stages of metachronous CRC lung metastases, several of which might be actionable by targeted therapies.", "citation": "Kovaleva V, Geissler AL, Lutz L, Fritsch R, Makowiec F, Wiesemann S, Hopt UT, Passlick B, Werner M, Lassmann S. (2016). Spatio-temporal mutation profiles of case-matched colorectal carcinomas and their metastases reveal unique de novo mutations in metachronous lung metastases by targeted next generation sequencing. Molecular cancer. 15(1):63. http://doi.org/10.1186/s12943-016-0549-8. PMID: 27756406.", "score_list": [ 2.1628220819201704, 2.408448028460585 ], "ai_score_min": 2.1628220819201704, "ai_score_max": 2.408448028460585, "ai_score": 2.2856350551903777, "ai_reasoning": "Weak relevance. 'Spatio-temporal mutation profiles of case-matched ...' appears tangentially related to the research topic. Potential exclusion indicators: protocol.", "evidence": [ { "text": "Amplicon Cancer Panel RESULTS: By tNGS primary", "section": "abstract", "criterion": "Population", "supports": "exclude" }, { "text": "in APC, ATM, FBXW7, FGFR3, GNAQ, KIT,", "section": "abstract", "criterion": "Study Design", "supports": "exclude" }, { "text": "Spatio-temporal mutation profiles of case-matched colorectal", "section": "title", "criterion": "Population", "supports": "exclude" } ], "ai_decision": "include", "assigned_clusters": [ { "cluster_name": "Adult Patient Population", "cluster_type": "include", "cluster_description": "Papers focused on adult patient demographics with defined inclusion criteria", "related_criteria": "Population" }, { "cluster_name": "Biomarker Analysis Studies", "cluster_type": "include", "cluster_description": "Papers with molecular or biomarker focus and genetic data", "related_criteria": "Outcome" } ] }, { "id": "17", "title": "Next-generation sequencing in NSCLC and melanoma patients: a cost and budget impact analysis.", "abstract": "Next-generation sequencing (NGS) has reached the molecular diagnostic laboratories. Although the NGS technology aims to improve the effectiveness of therapies by selecting the most promising therapy, concerns are that NGS testing is expensive and that the 'benefits' are not yet in relation to these costs. In this study, we give an estimation of the costs and an institutional and national budget impact of various types of NGS tests in non-small-cell lung cancer (NSCLC) and melanoma patients within The Netherlands. First, an activity-based costing (ABC) analysis has been conducted on the costs of two examples of NGS panels (small- and medium-targeted gene panel (TGP)) based on data of The Netherlands Cancer Institute (NKI). Second, we performed a budget impact analysis (BIA) to estimate the current (2015) and future (2020) budget impact of NGS on molecular diagnostics for NSCLC and melanoma patients in The Netherlands. Literature, expert opinions, and a data set of patients within the NKI (", "citation": "van Amerongen RA, Ret\u00e8l VP, Coup\u00e9 VM, Nederlof PM, Vogel MJ, van Harten WH. (2016). Next-generation sequencing in NSCLC and melanoma patients: a cost and budget impact analysis. Ecancermedicalscience. 10:684. http://doi.org/10.3332/ecancer.2016.684. PMID: 27899957.", "score_list": [ 4.783292705996015, 4.364331846062185 ], "ai_score_min": 4.364331846062185, "ai_score_max": 4.783292705996015, "ai_score": 4.5738122760291, "ai_reasoning": "Strong candidate for inclusion. 'Next-generation sequencing in NSCLC and melanoma p...' directly addresses research criteria with clear methodology. Keywords suggesting inclusion: patient, therapy, study.", "evidence": [ { "text": "of NGS on molecular diagnostics for NSCLC and", "section": "abstract", "criterion": "Population", "supports": "include" }, { "text": "(NSCLC) and melanoma patients", "section": "abstract", "criterion": "Study Design", "supports": "include" }, { "text": "an institutional and national", "section": "abstract", "criterion": "Outcome", "supports": "include" }, { "text": "the effectiveness of therapies by selecting", "section": "abstract", "criterion": "Intervention", "supports": "include" }, { "text": "Next-generation sequencing in NSCLC and melanoma", "section": "title", "criterion": "Population", "supports": "include" } ], "ai_decision": "include", "assigned_clusters": [ { "cluster_name": "Treatment Efficacy Studies", "cluster_type": "include", "cluster_description": "Papers evaluating treatment outcomes and efficacy measures", "related_criteria": "Intervention" }, { "cluster_name": "Biomarker Analysis Studies", "cluster_type": "include", "cluster_description": "Papers with molecular or biomarker focus and genetic data", "related_criteria": "Outcome" } ] }, { "id": "18", "title": "Cost-effectiveness analysis in the Spanish setting of the PEAK trial of panitumumab plus mFOLFOX6 compared with bevacizumab plus mFOLFOX6 for first-line treatment of patients with wild-type RAS metastatic colorectal cancer.", "abstract": "OBJECTIVE: To assess the cost-effectiveness of panitumumab in combination with mFOLFOX6 (oxaliplatin, 5-fluorouracil, and leucovorin) vs bevacizumab in combination with mFOLFOX6 as first-line treatment of patients with wild-type RAS metastatic colorectal cancer (mCRC) in Spain. METHODS: A semi-Markov model was developed including the following health states: Progression free; Progressive disease: Treat with best supportive care; Progressive disease: Treat with subsequent active therapy; Attempted resection of metastases; Disease free after metastases resection; Progressive disease: after resection and relapse; and Death. Parametric survival analyses of patient-level progression free survival and overall survival data from the PEAK Phase II clinical trial were used to estimate health state transitions. Additional data from the PEAK trial were considered for the dose and duration of therapy, the use of subsequent therapy, the occurrence of adverse events, and the incidence and probability of time to metastasis resection. Utility weightings were calculated from patient-level data from panitumumab trials evaluating first-, second-, and third-line treatments. The study was performed from the Spanish National Health System (NHS) perspective including only direct costs. A life-time horizon was applied. Probabilistic sensitivity analyses and scenario sensitivity analyses were performed to assess the robustness of the model. RESULTS: Based on the PEAK trial, which demonstrated greater efficacy of panitumumab vs bevacizumab, both in combination with mFOLFOX6 first-line in wild-type RAS mCRC patients, the estimated incremental cost per life-year gained was \u20ac16,567 and the estimated incremental cost per quality-adjusted life year gained was \u20ac22,794. The sensitivity analyses showed the model was robust to alternative parameters and assumptions. LIMITATIONS: The analysis was based on a simulation model and, therefore, the results should be interpreted cautiously. CONCLUSIONS: Based on the PEAK Phase II clinical trial and taking into account Spanish costs, the results of the analysis showed that first-line treatment of mCRC with panitumumab + mFOLFOX6 could be considered a cost-effective option compared with bevacizumab + mFOLFOX6 for the Spanish NHS.", "citation": "Rivera F, Valladares M, Gea S, L\u00f3pez-Mart\u00ednez N. (2017). Cost-effectiveness analysis in the Spanish setting of the PEAK trial of panitumumab plus mFOLFOX6 compared with bevacizumab plus mFOLFOX6 for first-line treatment of patients with wild-type RAS metastatic colorectal cancer. Journal of medical economics. 20(6):574-584. http://doi.org/10.1080/13696998.2017.1285780. PMID: 28107090.", "score_list": [ 2.1204773123612037, 2.0227559381803766 ], "ai_score_min": 2.0227559381803766, "ai_score_max": 2.1204773123612037, "ai_score": 2.0716166252707904, "ai_reasoning": "Weak relevance. 'Cost-effectiveness analysis in the Spanish setting...' appears tangentially related to the research topic.", "evidence": [ { "text": "on the PEAK Phase II clinical trial", "section": "abstract", "criterion": "Population", "supports": "exclude" }, { "text": "compared with bevacizumab + mFOLFOX6 for", "section": "abstract", "criterion": "Study Design", "supports": "exclude" }, { "text": "Cost-effectiveness analysis in the Spanish setting", "section": "title", "criterion": "Population", "supports": "exclude" } ], "ai_decision": "include", "assigned_clusters": [ { "cluster_name": "Adult Patient Population", "cluster_type": "include", "cluster_description": "Papers focused on adult patient demographics with defined inclusion criteria", "related_criteria": "Population" } ] }, { "id": "19", "title": "Clinical applicability and cost of a 46-gene panel for genomic analysis of solid tumours: Retrospective validation and prospective audit in the UK National Health Service.", "abstract": "BACKGROUND: Single gene tests to predict whether cancers respond to specific targeted therapies are performed increasingly often. Advances in sequencing technology, collectively referred to as next generation sequencing (NGS), mean the entire cancer genome or parts of it can now be sequenced at speed with increased depth and sensitivity. However, translation of NGS into routine cancer care has been slow. Healthcare stakeholders are unclear about the clinical utility of NGS and are concerned it could be an expensive addition to cancer diagnostics, rather than an affordable alternative to single gene testing. METHODS AND FINDINGS: We validated a 46-gene hotspot cancer panel assay allowing multiple gene testing from small diagnostic biopsies. From 1 January 2013 to 31 December 2013, solid tumour samples (including non-small-cell lung carcinoma [NSCLC], colorectal carcinoma, and melanoma) were sequenced in the context of the UK National Health Service from 351 consecutively submitted prospective cases for which treating clinicians thought the patient had potential to benefit from more extensive genetic analysis. Following histological assessment, tumour-rich regions of formalin-fixed paraffin-embedded (FFPE) sections underwent macrodissection, DNA extraction, NGS, and analysis using a pipeline centred on Torrent Suite software. With a median turnaround time of seven working days, an integrated clinical report was produced indicating the variants detected, including those with potential diagnostic, prognostic, therapeutic, or clinical trial entry implications. Accompanying phenotypic data were collected, and a detailed cost analysis of the panel compared with single gene testing was undertaken to assess affordability for routine patient care. Panel sequencing was successful for 97% (342/351) of tumour samples in the prospective cohort and showed 100% concordance with known mutations (detected using cobas assays). At least one mutation was identified in 87% (296/342) of tumours. A locally actionable mutation (i.e., available targeted treatment or clinical trial) was identified in 122/351 patients (35%). Forty patients received targeted treatment, in 22/40 (55%) cases solely due to use of the panel. Examination of published data on the potential efficacy of targeted therapies showed theoretically actionable mutations (i.e., mutations for which targeted treatment was potentially appropriate) in 66% (71/107) and 39% (41/105) of melanoma and NSCLC patients, respectively. At a cost of \u00a3339 (US$449) per patient, the panel was less expensive locally than performing more than two or three single gene tests. Study limitations include the use of FFPE samples, which do not always provide high-quality DNA, and the use of \"real world\" data: submission of cases for sequencing did not always follow clinical guidelines, meaning that when mutations were detected, patients were not always eligible for targeted treatments on clinical grounds. CONCLUSIONS: This study demonstrates that more extensive tumour sequencing can identify mutations that could improve clinical decision-making in routine cancer care, potentially improving patient outcomes, at an affordable level for healthcare providers.", "citation": "Hamblin A, Wordsworth S, Fermont JM, Page S, Kaur K, Camps C, Kaisaki P, Gupta A, Talbot D, Middleton M, Henderson S, Cutts A, Vavoulis DV, Housby N, Tomlinson I, Taylor JC, Schuh A. (2017). Clinical applicability and cost of a 46-gene panel for genomic analysis of solid tumours: Retrospective validation and prospective audit in the UK National Health Service. PLoS medicine. 14(2):e1002230. http://doi.org/10.1371/journal.pmed.1002230. PMID: 28196074.", "score_list": [ 3.383345911694159, 3.630655561066002 ], "ai_score_min": 3.383345911694159, "ai_score_max": 3.630655561066002, "ai_score": 3.5070007363800806, "ai_reasoning": "Moderate relevance. 'Clinical applicability and cost of a 46-gene panel...' partially meets inclusion criteria but requires human review for final determination.", "evidence": [ { "text": "extraction, NGS, and analysis using a pipeline centred", "section": "abstract", "criterion": "Population", "supports": "include" }, { "text": "mutation was identified in 87% (296/342) of", "section": "abstract", "criterion": "Study Design", "supports": "include" }, { "text": "formalin-fixed paraffin-embedded (FFPE) sections underwent macrodissection, DNA", "section": "abstract", "criterion": "Outcome", "supports": "include" }, { "text": "Clinical applicability and cost of a", "section": "title", "criterion": "Population", "supports": "include" } ], "ai_decision": "include", "assigned_clusters": [ { "cluster_name": "Adult Patient Population", "cluster_type": "include", "cluster_description": "Papers focused on adult patient demographics with defined inclusion criteria", "related_criteria": "Population" }, { "cluster_name": "Biomarker Analysis Studies", "cluster_type": "include", "cluster_description": "Papers with molecular or biomarker focus and genetic data", "related_criteria": "Outcome" } ] }, { "id": "20", "title": "Genomic Profiling of Advanced Non-Small Cell Lung Cancer in Community Settings: Gaps and Opportunities.", "abstract": "BACKGROUND: National guidelines have advocated broad molecular profiling as a part of the standard diagnostic evaluation for advanced non-small cell lung cancer (NSCLC), with the goal of identifying driver mutations for which effective therapies or clinical trials are available. However, adherence to genomic testing guidelines could present challenges to community oncologists. PATIENTS AND METHODS: We performed a retrospective review of genomic testing patterns in patients with nonsquamous NSCLC treated by 89 oncologists at 15 sites throughout New Jersey and Maryland from January 2013 to December 2015. RESULTS: A total of 814 patients (89% with stage IV; 11% with stage IIIB) were identified in the COTA Inc database. Of the 814 patients, 479 (59%) met the guideline recommendations for EGFR (epidermal growth factor receptor) and ALK (anaplastic lymphoma kinase) biomarker testing; 63 (8%) underwent comprehensive genomic profiling for all 4 major types of alterations (point mutations, indels, fusions, and copy number amplifications). Gender, age, race, site of care (referral vs. community center), and practice size did not influence comprehensive genomic profiling frequency. Active smokers and patients who died within 30 days were tested less frequently (P < .05). Among those not tested for EGFR and ALK, 52% received chemotherapy without documented reasons for no testing, 32% did not receive antineoplastic therapy, and 13% had insufficient tissue for genotyping. CONCLUSION: Genomic testing presents multiple logistical challenges for the community-based oncologist, including coordination of sample handling, long turnaround times, test reimbursement, access to targeted therapies, insufficient tissue, and patient harm from the repeat biopsies necessary if the tissue sample is insufficient. Opportunities exist for improvement in guideline adherence, possibly through new technologies such as \"liquid biopsies,\" which obviates the need tissue biopsy samples in select settings.", "citation": "Gutierrez ME, Choi K, Lanman RB, Licitra EJ, Skrzypczak SM, Pe Benito R, Wu T, Arunajadai S, Kaur S, Harper H, Pecora AL, Schultz EV, Goldberg SL. (2017). Genomic Profiling of Advanced Non-Small Cell Lung Cancer in Community Settings: Gaps and Opportunities. Clinical lung cancer. 18(6):651-659. http://doi.org/10.1016/j.cllc.2017.04.004. PMID: 28479369.", "score_list": [ 3.251985432593456, 2.85855104168671 ], "ai_score_min": 2.85855104168671, "ai_score_max": 3.251985432593456, "ai_score": 3.055268237140083, "ai_reasoning": "Moderate relevance. 'Genomic Profiling of Advanced Non-Small Cell Lung ...' partially meets inclusion criteria but requires human review for final determination.", "evidence": [ { "text": "test reimbursement, access to", "section": "abstract", "criterion": "Population", "supports": "include" }, { "text": "ALK (anaplastic lymphoma kinase) biomarker testing;", "section": "abstract", "criterion": "Study Design", "supports": "include" }, { "text": "insufficient tissue for genotyping. CONCLUSION: Genomic testing presents", "section": "abstract", "criterion": "Outcome", "supports": "include" }, { "text": "Genomic Profiling of Advanced Non-Small Cell", "section": "title", "criterion": "Population", "supports": "include" } ], "ai_decision": "include", "assigned_clusters": [ { "cluster_name": "Adult Patient Population", "cluster_type": "include", "cluster_description": "Papers focused on adult patient demographics with defined inclusion criteria", "related_criteria": "Population" }, { "cluster_name": "Biomarker Analysis Studies", "cluster_type": "include", "cluster_description": "Papers with molecular or biomarker focus and genetic data", "related_criteria": "Outcome" } ] }, { "id": "21", "title": "Targeted next generation sequencing identifies somatic mutations and gene fusions in papillary thyroid carcinoma.", "abstract": "138 papillary thyroid carcinoma (PTC) samples were assessed for somatic mutation profile and fusion genes by targeted resequencing using a cancer panel (ThyGenCapTM) targeting 244 cancer-related genes and 20 potential fusion genes. At least one genetic alteration (including mutations and fusion genes) was observed in 118/138 (85.5%) samples. The most frequently mutated gene was BRAF V600E (57.2%). Moreover, we identified 11 fusion genes including eight previously reported ones and three novel fusion genes, UEVLD-RET, OSBPL9-BRAF, and SQSTM1-NTRK3. Alterations affecting the mitogen-activated protein kinase (MAPK) signaling pathway components were seen in 69.6% of the PTC cases and all of these driver mutations were mutually exclusive. Univariate analysis ascertained that the fusion genes were strongly associated with distinct clinicopathological characteristics, such as young age, local invasion, extensive metastasis, and disease stage. In conclusion, our approach facilitated simultaneous high-throughput detection of gene fusions and somatic mutations in PTC samples.", "citation": "Lu Z, Zhang Y, Feng D, Sheng J, Yang W, Liu B. (2017). Targeted next generation sequencing identifies somatic mutations and gene fusions in papillary thyroid carcinoma. Oncotarget. 8(28):45784-45792. http://doi.org/10.18632/oncotarget.17412. PMID: 28507274.", "score_list": [ 3.747664140262237, 3.540074442552993 ], "ai_score_min": 3.540074442552993, "ai_score_max": 3.747664140262237, "ai_score": 3.643869291407615, "ai_reasoning": "Moderate relevance. 'Targeted next generation sequencing identifies som...' partially meets inclusion criteria but requires human review for final determination.", "evidence": [ { "text": "exclusive. Univariate analysis ascertained that the fusion genes", "section": "abstract", "criterion": "Population", "supports": "include" }, { "text": "components were seen in 69.6% of the", "section": "abstract", "criterion": "Study Design", "supports": "include" }, { "text": "the PTC cases and all of", "section": "abstract", "criterion": "Outcome", "supports": "include" }, { "text": "Targeted next generation sequencing identifies somatic", "section": "title", "criterion": "Population", "supports": "include" } ], "ai_decision": "include", "assigned_clusters": [ { "cluster_name": "Biomarker Analysis Studies", "cluster_type": "include", "cluster_description": "Papers with molecular or biomarker focus and genetic data", "related_criteria": "Outcome" } ] }, { "id": "22", "title": "Comprehensive Analysis of the Discordance of EGFR Mutation Status between Tumor Tissues and Matched Circulating Tumor DNA in Advanced Non-Small Cell Lung Cancer.", "abstract": "INTRODUCTION: This study aimed to address the underlying reasons for and clinical significance of the discordant EGFR mutation (EGFRm) status between tumor tissue (TT) and circulating tumor DNA (ctDNA). METHODS: Three groups of EGFR tyrosine kinase inhibitor (EGFR TKI)-treated patients whose EGFRm status was determined by the amplification refractory mutation system (ARMS) were included (group A, TT-positive/ctDNA-positive EGFRm status; group B, TT-negative/ctDNA-positive EGFRm status; and group C, TT-positive/ctDNA-negative EGFRm status). Patients with discordant EGFRm status were reevaluated by droplet digital polymerase chain reaction (ddPCR) and next-generation sequencing. Meanwhile, surgical tumor specimens were microdissected for EGFRm detection by ddPCR. RESULTS: Of the 2463 patients with matched TT and ctDNA specimens, 1017 patients carried EGFRm in TT and/or ctDNA by the ARMS. Of these 1017 patients, 472 received EGFR TKIs, including 264, 28, and 180 in groups A, B, and C, respectively. The median progression-free survivals of those receiving EGFR TKIs across the three groups were similar (p = 0.062). Through ddPCR and next-generation sequencing of biopsy specimens (n = 22) and microdissected surgical specimens (n = 5), 27 patients in group B were identified as harboring EGFRm. After reevaluation by ddPCR, 64 patients in group C tested positive for EGFRm in their ctDNA. ctDNA as a screen for EGFRm then tissues as supplement (ctDNA\u2192TT pattern) had similar detection efficiency and saved about 30% of TT compared with TT for initial EGFRm detection followed by ctDNA (TT\u2192ctDNA pattern). CONCLUSIONS: Intratumor heterogeneity and the relatively low sensitivity of the ARMS contributed to discordant EGFRm status between TT specimens and ctDNA. The ctDNA\u2192TT pattern might be a rational clinical procedure for EGFRm determination.", "citation": "Wan R, Wang Z, Lee JJ, Wang S, Li Q, Tang F, Wang J, Sun Y, Bai H, Wang D, Zhao J, Duan J, Zhuo M, An T, Wu M, Chen Z, Yang Z, Wang J. (2017). Comprehensive Analysis of the Discordance of EGFR Mutation Status between Tumor Tissues and Matched Circulating Tumor DNA in Advanced Non-Small Cell Lung Cancer. Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer. 12(9):1376-1387. http://doi.org/10.1016/j.jtho.2017.05.011. PMID: 28552765.", "score_list": [ 3.3798637900744417, 3.192313686262357 ], "ai_score_min": 3.192313686262357, "ai_score_max": 3.3798637900744417, "ai_score": 3.2860887381683996, "ai_reasoning": "Moderate relevance. 'Comprehensive Analysis of the Discordance of EGFR ...' partially meets inclusion criteria but requires human review for final determination.", "evidence": [ { "text": "median progression-free survivals of those receiving EGFR", "section": "abstract", "criterion": "Population", "supports": "include" }, { "text": "(ddPCR) and next-generation sequencing.", "section": "abstract", "criterion": "Study Design", "supports": "include" }, { "text": "TT for initial EGFRm detection followed by", "section": "abstract", "criterion": "Outcome", "supports": "include" }, { "text": "Comprehensive Analysis of the Discordance of", "section": "title", "criterion": "Population", "supports": "include" } ], "ai_decision": "include", "assigned_clusters": [ { "cluster_name": "Adult Patient Population", "cluster_type": "include", "cluster_description": "Papers focused on adult patient demographics with defined inclusion criteria", "related_criteria": "Population" } ] }, { "id": "23", "title": "MSH2 Loss in Primary Prostate Cancer.", "abstract": "nan", "citation": "Guedes LB, Antonarakis ES, Schweizer MT, Mirkheshti N, Almutairi F, Park JC, Glavaris S, Hicks J, Eisenberger MA, De Marzo AM, Epstein JI, Isaacs WB, Eshleman JR, Pritchard CC, Lotan TL. (2017). MSH2 Loss in Primary Prostate Cancer. Clinical cancer research : an official journal of the American Association for Cancer Research. 23(22):6863-6874. http://doi.org/10.1158/1078-0432.CCR-17-0955. PMID: 28790115.", "score_list": [ 1.8051044974803914, 1.8113529791597334 ], "ai_score_min": 1.8051044974803914, "ai_score_max": 1.8113529791597334, "ai_score": 1.8082287383200624, "ai_reasoning": "Recommend exclusion. 'MSH2 Loss in Primary Prostate Cancer.' does not appear to meet core inclusion criteria.", "evidence": [ { "text": "MSH2 Loss in Primary Prostate Cancer.", "section": "title", "criterion": "Population", "supports": "exclude" } ], "ai_decision": "include", "assigned_clusters": [ { "cluster_name": "Methodology & Protocol Only", "cluster_type": "exclude", "cluster_description": "Papers focused on study design and methodology without clinical results", "related_criteria": "Study Design" } ] }, { "id": "24", "title": "Intratumoural evolutionary landscape of high-risk prostate cancer: the PROGENY study of genomic and immune parameters.", "abstract": "BACKGROUND: Intratumoural heterogeneity (ITH) is well recognised in prostate cancer (PC), but its role in high-risk disease is uncertain. A prospective, single-arm, translational study using targeted multiregion prostate biopsies was carried out to study genomic and T-cell ITH in clinically high-risk PC aiming to identify drivers and potential therapeutic strategies. PATIENTS AND METHODS: Forty-nine men with elevated prostate-specific antigen and multiparametric-magnetic resonance imaging detected PC underwent image-guided multiregion transperineal biopsy. Seventy-nine tumour regions from 25 patients with PC underwent sequencing, analysis of mutations, copy number and neoepitopes combined with tumour infiltrating T-cell subset quantification. RESULTS: We demonstrated extensive somatic nucleotide variation and somatic copy number alteration heterogeneity in high-risk PC. Overall, the mutational burden was low (0.93/Megabase), but two patients had hypermutation, with loss of mismatch repair (MMR) proteins, MSH2 and MSH6. Somatic copy number alteration burden was higher in patients with metastatic hormone-naive PC (mHNPC) than in those with high-risk localised PC (hrlPC), independent of Gleason grade. Mutations were rarely ubiquitous and mutational frequencies were similar for mHNPC and hrlPC patients. Enrichment of focal 3q26.2 and 3q21.3, regions containing putative metastasis drivers, was seen in mHNPC patients. We found evidence of parallel evolution with three separate clones containing activating mutations of \u03b2-catenin in a single patient. We demonstrated extensive intratumoural and intertumoural T-cell heterogeneity and high inflammatory infiltrate in the MMR-deficient (MMRD) patients and the patient with parallel evolution of \u03b2-catenin. Analysis of all patients with activating Wnt/\u03b2-catenin mutations demonstrated a low CD8+/FOXP3+ ratio, a potential surrogate marker of immune evasion. CONCLUSIONS: The PROGENY (PROstate cancer GENomic heterogeneitY) study provides a diagnostic platform suitable for studying tumour ITH. Genetic aberrations in clinically high-risk PC are associated with altered patterns of immune infiltrate in tumours. Activating mutations of Wnt/\u03b2-catenin signalling pathway or MMRD could be considered as potential biomarkers for immunomodulation therapies. CLINICAL TRIALS.GOV IDENTIFIER: NCT02022371.", "citation": "Linch M, Goh G, Hiley C, Shanmugabavan Y, McGranahan N, Rowan A, Wong YNS, King H, Furness A, Freeman A, Linares J, Akarca A, Herrero J, Rosenthal R, Harder N, Schmidt G, Wilson GA, Birkbak NJ, Mitter R, Dentro S, Cathcart P, Arya M, Johnston E, Scott R, Hung M, Emberton M, Attard G, Szallasi Z, Punwani S, Quezada SA, Marafioti T, Gerlinger M, Ahmed HU, Swanton C. (2017). Intratumoural evolutionary landscape of high-risk prostate cancer: the PROGENY study of genomic and immune parameters. Annals of oncology : official journal of the European Society for Medical Oncology. 28(10):2472-2480. http://doi.org/10.1093/annonc/mdx355. PMID: 28961847.", "score_list": [ 2.4504682232707204, 2.829070347269484 ], "ai_score_min": 2.4504682232707204, "ai_score_max": 2.829070347269484, "ai_score": 2.639769285270102, "ai_reasoning": "Weak relevance. 'Intratumoural evolutionary landscape of high-risk ...' appears tangentially related to the research topic.", "evidence": [ { "text": "a single patient. We demonstrated extensive intratumoural", "section": "abstract", "criterion": "Population", "supports": "exclude" }, { "text": "frequencies were similar for mHNPC", "section": "abstract", "criterion": "Study Design", "supports": "exclude" }, { "text": "Intratumoural evolutionary landscape of high-risk prostate", "section": "title", "criterion": "Population", "supports": "exclude" } ], "ai_decision": "include", "assigned_clusters": [ { "cluster_name": "Adult Patient Population", "cluster_type": "include", "cluster_description": "Papers focused on adult patient demographics with defined inclusion criteria", "related_criteria": "Population" }, { "cluster_name": "Biomarker Analysis Studies", "cluster_type": "include", "cluster_description": "Papers with molecular or biomarker focus and genetic data", "related_criteria": "Outcome" } ] }, { "id": "25", "title": "Decision support systems for incurable non-small cell lung cancer: a systematic review.", "abstract": "BACKGROUND: Individually tailored cancer treatment is essential to ensure optimal treatment and resource use. Treatments for incurable metastatic non-small cell lung cancer (NSCLC) are evolving rapidly, and decision support systems (DSS) for this patient population have been developed to balance benefits and harms for decision-making. The aim of this systematic review was to inventory DSS for stage IIIB/IV NSCLC patients. METHODS: A systematic literature search was performed in Pubmed, Embase and the Cochrane Library. DSS were described extensively, including their predictors, model performances (i.e., discriminative ability and calibration), levels of validation and user friendliness. RESULTS: The systematic search yielded 3531 articles. In total, 67 articles were included after additional reference tracking. The 39 identified DSS aim to predict overall survival and/or progression-free survival, but give no information about toxicity or cost-effectiveness. Various predictors were incorporated, such as performance status, serum and inflammatory markers, and patient and tumor characteristics. Some DSS were developed for the entire incurable NSCLC population, whereas others were specifically for patients with brain or spinal metastases. Few DSS had been validated externally using recent clinical data, and the discrimination and calibration were often poor. CONCLUSIONS: Many DSS have been developed for incurable NSCLC patients, but DSS are still lacking that are up-to-date with a good model performance, while covering the entire treatment spectrum. Future DSS should incorporate genetic and biological markers based on state-of-the-art evidence, and compare multiple treatment options to estimate survival, toxicity and cost-effectiveness.", "citation": "R\u00e9v\u00e9sz D, Engelhardt EG, Tamminga JJ, Schramel FMNH, Onwuteaka-Philipsen BD, van de Garde EMW, Steyerberg EW, Jansma EP, De Vet HCW, Coup\u00e9 VMH. (2017). Decision support systems for incurable non-small cell lung cancer: a systematic review. BMC medical informatics and decision making. 17(1):144. http://doi.org/10.1186/s12911-017-0542-1. PMID: 28969629.", "score_list": [ 3.5861322579649006, 3.633135339023064 ], "ai_score_min": 3.5861322579649006, "ai_score_max": 3.633135339023064, "ai_score": 3.6096337984939826, "ai_reasoning": "Moderate relevance. 'Decision support systems for incurable non-small c...' partially meets inclusion criteria but requires human review for final determination.", "evidence": [ { "text": "of this systematic review was", "section": "abstract", "criterion": "Population", "supports": "include" }, { "text": "should incorporate genetic and biological markers", "section": "abstract", "criterion": "Study Design", "supports": "include" }, { "text": "or cost-effectiveness. Various predictors were incorporated, such as", "section": "abstract", "criterion": "Outcome", "supports": "include" }, { "text": "Decision support systems for incurable non-small", "section": "title", "criterion": "Population", "supports": "include" } ], "ai_decision": "include", "assigned_clusters": [ { "cluster_name": "Adult Patient Population", "cluster_type": "include", "cluster_description": "Papers focused on adult patient demographics with defined inclusion criteria", "related_criteria": "Population" }, { "cluster_name": "Biomarker Analysis Studies", "cluster_type": "include", "cluster_description": "Papers with molecular or biomarker focus and genetic data", "related_criteria": "Outcome" } ] }, { "id": "26", "title": "Optimization of", "abstract": "Treatment with EGFR inhibitors is limited to patients with advanced/metastatic non-small cell lung cancer who have known", "citation": "Ilie M, Butori C, Lassalle S, Heeke S, Piton N, Sabourin JC, Tanga V, Washetine K, Long-Mira E, Maitre P, Yazbeck N, Bordone O, Lespinet V, Leroy S, Cohen C, Mouroux J, Marquette CH, Hofman V, Hofman P. (2017). Optimization of. Oncotarget. 8(61):103055-103062. http://doi.org/10.18632/oncotarget.21476. PMID: 29262544.", "score_list": [ 1.7706344116821575, 1.7390028682161045 ], "ai_score_min": 1.7390028682161045, "ai_score_max": 1.7706344116821575, "ai_score": 1.754818639949131, "ai_reasoning": "Recommend exclusion. 'Optimization of' does not appear to meet core inclusion criteria.", "evidence": [ { "text": "inhibitors is limited to patients with", "section": "abstract", "criterion": "Population", "supports": "exclude" }, { "text": "is limited to patients", "section": "abstract", "criterion": "Study Design", "supports": "exclude" } ], "ai_decision": "include", "assigned_clusters": [ { "cluster_name": "Methodology & Protocol Only", "cluster_type": "exclude", "cluster_description": "Papers focused on study design and methodology without clinical results", "related_criteria": "Study Design" } ] }, { "id": "27", "title": "Amplicon-based next-generation sequencing of plasma cell-free DNA for detection of driver and resistance mutations in advanced non-small cell lung cancer.", "abstract": "BACKGROUND: Genomic analysis of plasma cell-free DNA is transforming lung cancer care; however, available assays are limited by cost, turnaround time, and imperfect accuracy. Here, we study amplicon-based plasma next-generation sequencing (NGS), rather than hybrid-capture-based plasma NGS, hypothesizing this would allow sensitive detection and monitoring of driver and resistance mutations in advanced non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: Plasma samples from patients with NSCLC and a known targetable genotype (EGFR, ALK/ROS1, and other rare genotypes) were collected while on therapy and analyzed blinded to tumor genotype. Plasma NGS was carried out using enhanced tagged amplicon sequencing of hotspots and coding regions from 36 genes, as well as intronic coverage for detection of ALK/ROS1 fusions. Diagnostic accuracy was compared with plasma droplet digital PCR (ddPCR) and tumor genotype. RESULTS: A total of 168 specimens from 46 patients were studied. Matched plasma NGS and ddPCR across 120 variants from 80 samples revealed high concordance of allelic fraction (R2 = 0.95). Pretreatment, sensitivity of plasma NGS for the detection of EGFR driver mutations was 100% (30/30), compared with 87% for ddPCR (26/30). A full spectrum of rare driver oncogenic mutations could be detected including sensitive detection of ALK/ROS1 fusions (8/9 detected, 89%). Studying 25 patients positive for EGFR T790M that developed resistance to osimertinib, 15 resistance mechanisms could be detected including tertiary EGFR mutations (C797S, Q791P) and mutations or amplifications of non-EGFR genes, some of which could be detected pretreatment or months before progression. CONCLUSIONS: This blinded analysis demonstrates the ability of amplicon-based plasma NGS to detect a full range of targetable genotypes in NSCLC, including fusion genes, with high accuracy. The ability of plasma NGS to detect a range of preexisting and acquired resistance mechanisms highlights its potential value as an alternative to single mutation digital PCR-based plasma assays for personalizing treatment of TKI resistance in lung cancer.", "citation": "Guibert N, Hu Y, Feeney N, Kuang Y, Plagnol V, Jones G, Howarth K, Beeler JF, Paweletz CP, Oxnard GR. (2018). Amplicon-based next-generation sequencing of plasma cell-free DNA for detection of driver and resistance mutations in advanced non-small cell lung cancer. Annals of oncology : official journal of the European Society for Medical Oncology. 29(4):1049-1055. http://doi.org/10.1093/annonc/mdy005. PMID: 29325035.", "score_list": [ 1.8855646778503135, 2.0525564418504145 ], "ai_score_min": 1.8855646778503135, "ai_score_max": 2.0525564418504145, "ai_score": 1.969060559850364, "ai_reasoning": "Recommend exclusion. 'Amplicon-based next-generation sequencing of plasm...' does not appear to meet core inclusion criteria.", "evidence": [ { "text": "including fusion genes, with high accuracy. The ability", "section": "abstract", "criterion": "Population", "supports": "exclude" }, { "text": "enhanced tagged amplicon sequencing of", "section": "abstract", "criterion": "Study Design", "supports": "exclude" }, { "text": "Amplicon-based next-generation sequencing of plasma cell-free", "section": "title", "criterion": "Population", "supports": "exclude" } ], "ai_decision": "include", "assigned_clusters": [ { "cluster_name": "Methodology & Protocol Only", "cluster_type": "exclude", "cluster_description": "Papers focused on study design and methodology without clinical results", "related_criteria": "Study Design" } ] }, { "id": "28", "title": "Cost of cancer diagnosis using next-generation sequencing targeted gene panels in routine practice: a nationwide French study.", "abstract": "It is currently unclear if next-generation sequencing (NGS) technologies can be implemented in the diagnosis setting at an affordable cost. The aim of this study was to measure the total cost of performing NGS in clinical practice in France, in both germline and somatic cancer genetics.The study was performed on 15 French representative cancer molecular genetics laboratories performing NGS panels' tests. The production cost was estimated using a micro-costing method with resources consumed collected in situ in each laboratory from a healthcare provider perspective. In addition, we used a top-down methodology for specific post-sequencing steps including bioinformatics, technical validation, and biological validation. Additional non-specific costs were also included. Costs were detailed per step of the process (from the pre-analytical phase to delivery of results), and per cost driver (consumables, staff, equipment, maintenance, overheads). Sensitivity analyses were performed.The mean total cost of NGS for targeted gene panels was estimated to 607\u20ac (\u00b1207) in somatic genetics and 550\u20ac (\u00b1140) in germline oncogenetic analysis. Consumables were the highest cost driver of the sequencing process. The sensitivity analysis showed that a 25% reduction of consumables resulted in a 15% decrease in total NGS cost in somatic genetics, and 13% in germline analysis. Additional costs accounted for 30-32% of the total NGS costs.Beyond cost assessment considerations, the diffusion of NGS technologies will raise questions about their efficiency when compared to more targeted approaches, and their added value in a context of routine diagnosis.", "citation": "Marino P, Touzani R, Perrier L, Rouleau E, Kossi DS, Zhaomin Z, Charrier N, Goardon N, Preudhomme C, Durand-Zaleski I, Borget I, Baffert S. (2018). Cost of cancer diagnosis using next-generation sequencing targeted gene panels in routine practice: a nationwide French study. European journal of human genetics : EJHG. 26(3):314-323. http://doi.org/10.1038/s41431-017-0081-3. PMID: 29367707.", "score_list": [ 1.0, 1.1332815682586237 ], "ai_score_min": 1.0, "ai_score_max": 1.1332815682586237, "ai_score": 1.0666407841293117, "ai_reasoning": "Recommend exclusion. 'Cost of cancer diagnosis using next-generation seq...' does not appear to meet core inclusion criteria.", "evidence": [ { "text": "was to measure the total", "section": "abstract", "criterion": "Population", "supports": "exclude" }, { "text": "panels' tests. The production cost was estimated", "section": "abstract", "criterion": "Study Design", "supports": "exclude" }, { "text": "Cost of cancer diagnosis using next-generation", "section": "title", "criterion": "Population", "supports": "exclude" } ], "ai_decision": "include", "assigned_clusters": [ { "cluster_name": "Methodology & Protocol Only", "cluster_type": "exclude", "cluster_description": "Papers focused on study design and methodology without clinical results", "related_criteria": "Study Design" } ] }, { "id": "29", "title": "Molecular profiling of lung cancer specimens and liquid biopsies using MALDI-TOF mass spectrometry.", "abstract": "BACKGROUND: Identification of predictive molecular alterations in lung adenocarcinoma is essential for accurate therapeutic decisions. Although several molecular approaches are available, a number of issues, including tumor heterogeneity, frequent material scarcity, and the large number of loci to be investigated, must be taken into account in selecting the most appropriate technique. MALDI-TOF mass spectrometry (MS), which allows multiplexed genotyping, has been adopted in routine diagnostics as a sensitive, reliable, fast, and cost-effective method. Our aim was to test the reliability of this approach in detecting targetable mutations in non-small cell lung cancer (NSCLC). In addition, we also analyzed low-quality samples, such as cytologic specimens, that often, are the unique source of starting material in lung cancer cases, to test the sensitivity of the system. METHODS: We designed a MS-based assay for testing 158 mutations in the EGFR, KRAS, BRAF, ALK, PIK3CA, ERBB2, DDR2, AKT, and MEK1 genes and applied it to 92 NSCLC specimens and 13 liquid biopsies from another subset of NSCLC patients. We also tested the sensitivity of the method to distinguish low represented mutations using serial dilutions of mutated DNA. RESULTS: Our panel is able to detect the most common NSCLC mutations and the frequency of the mutations observed in our cohort was comparable to literature data. The assay identifies mutated alleles at frequencies of 2.5-10%. In addition, we found that the amount of DNA template was irrelevant to efficiently uncover mutated alleles present at high frequency. However, when using less than 10 ng of DNA, the assay can detect mutations present in at least 10% of the alleles. Finally, using MS and a commercial kit for RT-PCR we tested liquid biopsy from 13 patients with identified mutations in cancers and detected the mutations in 4 (MS) and in 5 samples (RT-PCR). CONCLUSIONS: MS is a powerful method for the routine predictive tests of lung cancer also using low quality and scant tissues. Finally, after appropriate validation and improvement, MS could represent a promising and cost-effective strategy for monitoring the presence and percentage of the mutations also in non-invasive sampling.", "citation": "Bonaparte E, Pesenti C, Fontana L, Falcone R, Paganini L, Marzorati A, Ferrero S, Nosotti M, Mendogni P, Bareggi C, Sirchia SM, Tabano S, Bosari S, Miozzo M. (2018). Molecular profiling of lung cancer specimens and liquid biopsies using MALDI-TOF mass spectrometry. Diagnostic pathology. 13(1):4. http://doi.org/10.1186/s13000-017-0683-7. PMID: 29368620.", "score_list": [ 2.7682228022403463, 2.3641662561495655 ], "ai_score_min": 2.3641662561495655, "ai_score_max": 2.7682228022403463, "ai_score": 2.5661945291949557, "ai_reasoning": "Weak relevance. 'Molecular profiling of lung cancer specimens and l...' appears tangentially related to the research topic.", "evidence": [ { "text": "this approach in detecting targetable mutations", "section": "abstract", "criterion": "Population", "supports": "exclude" }, { "text": "is essential for accurate therapeutic", "section": "abstract", "criterion": "Study Design", "supports": "exclude" }, { "text": "Molecular profiling of lung cancer specimens", "section": "title", "criterion": "Population", "supports": "exclude" } ], "ai_decision": "include", "assigned_clusters": [ { "cluster_name": "Adult Patient Population", "cluster_type": "include", "cluster_description": "Papers focused on adult patient demographics with defined inclusion criteria", "related_criteria": "Population" }, { "cluster_name": "Biomarker Analysis Studies", "cluster_type": "include", "cluster_description": "Papers with molecular or biomarker focus and genetic data", "related_criteria": "Outcome" } ] }, { "id": "30", "title": "Prevalence of Mouse Mammary Tumor Virus (MMTV)-like sequences in human breast cancer tissues and adjacent normal breast tissues in Saudi Arabia.", "abstract": "BACKGROUND: Breast cancer is considered the most common cancer in women worldwide and is the leading cause of cancer mortality. Sequences similar to Mouse Mammary Tumor Virus (MMTV) were detected in human breast cancer in several studies from different geographical areas. However, the role played by this virus in breast cancer tumorigenesis is not completely understood. These MMTV-like sequences were found to be associated with breast cancer of more malignant types. The aim of this study is to determine the prevalence of MMTV-like envelope gene (env) positivity in breast cancer and non-cancerous breast tissue from Saudi Arabia. METHODS: Detection of MMTV-like env proviral sequences was done using newly designed primers for conventional polymerase chain reaction (PCR). One hundred nighty four samples were collected from 103 females with breast cancer in addition to 51 control breast tissue obtained from individuals without cancer. We additionally investigated the association of proviral positivity with age of the patients, grade of breast cancer and presence of lymph node metastasis. The results were confirmed by sequencing. RESULTS: The prevalence of MMTV-like env proviral positivity was 8.7% (9/103). MMTV env proviral sequences were detected in 5.9% (6/101) of breast cancer tissues and 9.7% (9/93) of non-cancerous adjacent tissues obtained from the same patients. None of the 51 control sample showed positive result for the MMTV env gene. No significant association was found between detection of the virus and the age of the patient, grade of the cancer or presence of metastasis. CONCLUSION: We document the presence of low frequency of MMTV env provirus sequence among breast cancer patients from Saudi Arabia. Further studies are needed to explore the role of the MMTV in breast cancer.", "citation": "Al Dossary R, Alkharsah KR, Kussaibi H. (2018). Prevalence of Mouse Mammary Tumor Virus (MMTV)-like sequences in human breast cancer tissues and adjacent normal breast tissues in Saudi Arabia. BMC cancer. 18(1):170. http://doi.org/10.1186/s12885-018-4074-6. PMID: 29426297.", "score_list": [ 2.926969379295674, 3.033813840121934 ], "ai_score_min": 2.926969379295674, "ai_score_max": 3.033813840121934, "ai_score": 2.9803916097088043, "ai_reasoning": "Weak relevance. 'Prevalence of Mouse Mammary Tumor Virus (MMTV)-lik...' appears tangentially related to the research topic.", "evidence": [ { "text": "No significant association was found between detection of", "section": "abstract", "criterion": "Population", "supports": "exclude" }, { "text": "prevalence of MMTV-like env proviral positivity", "section": "abstract", "criterion": "Study Design", "supports": "exclude" }, { "text": "Prevalence of Mouse Mammary Tumor Virus", "section": "title", "criterion": "Population", "supports": "exclude" } ], "ai_decision": "include", "assigned_clusters": [ { "cluster_name": "Adult Patient Population", "cluster_type": "include", "cluster_description": "Papers focused on adult patient demographics with defined inclusion criteria", "related_criteria": "Population" } ] }, { "id": "31", "title": "Economic Analysis of First-Line Treatment with Cetuximab or Panitumumab for RAS Wild-Type Metastatic Colorectal Cancer in England.", "abstract": "BACKGROUND: Combination therapies with cetuximab (Erbitux OBJECTIVE: The objective of the study was to estimate the cost effectiveness of these drugs in patients with previously untreated RAS wild-type (i.e. non-mutated) metastatic colorectal cancer, not eligible for liver resection at baseline, from the UK National Health Service and Personal Social Services perspective. METHODS: We constructed a partitioned survival model to evaluate the long-term costs and benefits of cetuximab and panitumumab combined with either FOLFOX (folinic acid, fluorouracil and oxaliplatin) or FOLFIRI (folinic acid, fluorouracil and irinotecan) vs. FOLFOX or FOLFIRI alone. The economic analysis was based on three randomised controlled trials. Costs and quality-adjusted life-years were discounted at 3.5% per annum. RESULTS: Based on the evidence available, both drugs fulfil the National Institute for Health and Care Excellence's end-of-life criteria. In the analysis, assuming discount prices for the drugs from patient access schemes agreed by the drug manufacturers with the Department of Health, predicted mean incremental cost-effectiveness ratios for cetuximab + FOLFOX, panitumumab + FOLFOX and cetuximab + FOLFIRI compared with chemotherapy alone appeared cost-effective at the National Institute for Health and Care Excellence's threshold of \u00a350,000 per quality-adjusted life-year gained, applicable to end-of-life treatments. CONCLUSION: Cetuximab and panitumumab were recommended by the National Institute for Health and Care Excellence for patients with previously untreated RAS wild-type metastatic colorectal cancer, not eligible for liver resection at baseline, for use within the National Health Service in England. Both treatments are available via the UK Cancer Drugs Fund.", "citation": "Tikhonova IA, Huxley N, Snowsill T, Crathorne L, Varley-Campbell J, Napier M, Hoyle M. (2018). Economic Analysis of First-Line Treatment with Cetuximab or Panitumumab for RAS Wild-Type Metastatic Colorectal Cancer in England. PharmacoEconomics. 36(7):837-851. http://doi.org/10.1007/s40273-018-0630-9. PMID: 29498000.", "score_list": [ 4.522552841860051, 4.91165576776907 ], "ai_score_min": 4.522552841860051, "ai_score_max": 4.91165576776907, "ai_score": 4.71710430481456, "ai_reasoning": "Strong candidate for inclusion. 'Economic Analysis of First-Line Treatment with Cet...' directly addresses research criteria with clear methodology. Keywords suggesting inclusion: treatment, patient, therapy.", "evidence": [ { "text": "baseline, from the UK National Health", "section": "abstract", "criterion": "Population", "supports": "include" }, { "text": "(Erbitux OBJECTIVE: The objective of the", "section": "abstract", "criterion": "Study Design", "supports": "include" }, { "text": "and cetuximab + FOLFIRI compared with", "section": "abstract", "criterion": "Outcome", "supports": "include" }, { "text": "by the National Institute for Health", "section": "abstract", "criterion": "Intervention", "supports": "include" }, { "text": "Economic Analysis of First-Line Treatment with", "section": "title", "criterion": "Population", "supports": "include" } ], "ai_decision": "include", "assigned_clusters": [ { "cluster_name": "Treatment Efficacy Studies", "cluster_type": "include", "cluster_description": "Papers evaluating treatment outcomes and efficacy measures", "related_criteria": "Intervention" } ] }, { "id": "32", "title": "Molecular Screening of Small Biopsy Samples Using Next-Generation Sequencing in Korean Patients with Advanced Non-small Cell Lung Cancer: Korean Lung Cancer Consortium (KLCC-13-01).", "abstract": "BACKGROUND: Non-small cell lung cancer (NSCLC) is a common type of cancer with poor prognosis. As individual cancers exhibit unique mutation patterns, identifying and characterizing gene mutations in NSCLC might help predict patient outcomes and guide treatment. The aim of this study was to evaluate the clinical adequacy of molecular testing using next-generation sequencing (NGS) for small biopsy samples and characterize the mutational landscape of Korean patients with advanced NSCLC. METHODS: DNA was extracted from small biopsy samples of 162 patients with advanced NSCLC. Targeted NGS of genomic alterations was conducted using Ion AmpliSeq Cancer Hotspot Panel v2. RESULTS: The median age of patients was 64 years (range, 32 to 83 years) and the majority had stage IV NSCLC at the time of cancer diagnosis (90%). Among the 162 patients, 161 patients (99.4%) had novel or hotspot mutations (range, 1 to 21 mutated genes). Mutations were found in 41 genes. Three of the most frequently mutated genes were CONCLUSIONS: These results suggest that targeted NGS using small biopsy samples is feasible and allows for the detection of both common and rare mutations in NSCLC.", "citation": "Ku BM, Heo MH, Kim JH, Cho BC, Cho EK, Min YJ, Lee KH, Sun JM, Lee SH, Ahn JS, Park K, Kim TJ, Lee HY, Kim H, Lee KJ, Ahn MJ. (2018). Molecular Screening of Small Biopsy Samples Using Next-Generation Sequencing in Korean Patients with Advanced Non-small Cell Lung Cancer: Korean Lung Cancer Consortium (KLCC-13-01). Journal of pathology and translational medicine. 52(3):148-156. http://doi.org/10.4132/jptm.2018.03.12. PMID: 29575851.", "score_list": [ 2.5292666123595606, 2.7639397133046004 ], "ai_score_min": 2.5292666123595606, "ai_score_max": 2.7639397133046004, "ai_score": 2.6466031628320805, "ai_reasoning": "Weak relevance. 'Molecular Screening of Small Biopsy Samples Using ...' appears tangentially related to the research topic.", "evidence": [ { "text": "161 patients (99.4%) had novel or hotspot", "section": "abstract", "criterion": "Population", "supports": "exclude" }, { "text": "using small biopsy samples is", "section": "abstract", "criterion": "Study Design", "supports": "exclude" }, { "text": "Molecular Screening of Small Biopsy Samples", "section": "title", "criterion": "Population", "supports": "exclude" } ], "ai_decision": "include", "assigned_clusters": [ { "cluster_name": "Adult Patient Population", "cluster_type": "include", "cluster_description": "Papers focused on adult patient demographics with defined inclusion criteria", "related_criteria": "Population" }, { "cluster_name": "Biomarker Analysis Studies", "cluster_type": "include", "cluster_description": "Papers with molecular or biomarker focus and genetic data", "related_criteria": "Outcome" } ] }, { "id": "33", "title": "Targeted next-generation-sequencing for reliable detection of targetable rearrangements in lung adenocarcinoma-a single center retrospective study.", "abstract": "Oncogenic rearrangements leading to targetable gene fusions are well-established cancer driver events in lung adenocarcinoma. Accurate and reliable detection of these gene fusions is crucial to select the appropriate targeted therapy for each patient. We compared the targeted next-generation-sequencing Oncomine Focus Assay (OFA; Thermo Fisher Scientific) with conventional ALK FISH and anti-Alk immunohistochemistry in a cohort of 52 lung adenocarcinomas (10 ALK rearranged, 18 non-ALK rearranged, and 24 untested cases). We found a sensitivity and specificity of 100% for detection of ALK rearrangements using the OFA panel. In addition, targeted next generation sequencing allowed us to analyze a set of 23 driver genes in a single assay. Besides EML4-ALK (11/52 cases), we detected EZR-ROS1 (1/52 cases), KIF5B-RET (1/52 cases) and MET-MET (4/52 cases) fusions. All EML4-ALK, EZR-ROS1 and KIF5B-RET fusions were confirmed by multiplexed targeted next generation sequencing assay (Oncomine Solid Tumor Fusion Transcript Kit, Thermo Fisher Scientific). All cases with EML4-ALK rearrangement were confirmed by Alk immunohistochemistry and all but one by ALK FISH. In our experience, targeted next-generation sequencing is a reliable and timesaving tool for multiplexed detection of targetable rearrangements. Therefore, targeted next-generation sequencing represents an efficient alternative to time-consuming single target assays currently used in molecular pathology.", "citation": "Velizheva NP, Rechsteiner MP, Valtcheva N, Freiberger SN, Wong CE, Vrugt B, Zhong Q, Wagner U, Moch H, Hillinger S, Schmitt-Opitz I, Soltermann A, Wild PJ, Tischler V. (2018). Targeted next-generation-sequencing for reliable detection of targetable rearrangements in lung adenocarcinoma-a single center retrospective study. Pathology, research and practice. 214(4):572-578. http://doi.org/10.1016/j.prp.2018.02.001. PMID: 29580750.", "score_list": [ 2.5580833403508287, 2.490395739340119 ], "ai_score_min": 2.490395739340119, "ai_score_max": 2.5580833403508287, "ai_score": 2.524239539845474, "ai_reasoning": "Weak relevance. 'Targeted next-generation-sequencing for reliable d...' appears tangentially related to the research topic.", "evidence": [ { "text": "to select the appropriate", "section": "abstract", "criterion": "Population", "supports": "exclude" }, { "text": "ALK rearrangements using the OFA panel.", "section": "abstract", "criterion": "Study Design", "supports": "exclude" }, { "text": "Targeted next-generation-sequencing for reliable detection of", "section": "title", "criterion": "Population", "supports": "exclude" } ], "ai_decision": "include", "assigned_clusters": [ { "cluster_name": "Adult Patient Population", "cluster_type": "include", "cluster_description": "Papers focused on adult patient demographics with defined inclusion criteria", "related_criteria": "Population" }, { "cluster_name": "Biomarker Analysis Studies", "cluster_type": "include", "cluster_description": "Papers with molecular or biomarker focus and genetic data", "related_criteria": "Outcome" } ] }, { "id": "34", "title": "Clinical Utility of Cell-Free DNA for the Detection of", "abstract": "0", "citation": "McCoach CE, Blakely CM, Banks KC, Levy B, Chue BM, Raymond VM, Le AT, Lee CE, Diaz J, Waqar SN, Purcell WT, Aisner DL, Davies KD, Lanman RB, Shaw AT, Doebele RC. (2018). Clinical Utility of Cell-Free DNA for the Detection of. Clinical cancer research : an official journal of the American Association for Cancer Research. 24(12):2758-2770. http://doi.org/10.1158/1078-0432.CCR-17-2588. PMID: 29599410.", "score_list": [ 2.5573402800458505, 2.9847525328143436 ], "ai_score_min": 2.5573402800458505, "ai_score_max": 2.9847525328143436, "ai_score": 2.771046406430097, "ai_reasoning": "Weak relevance. 'Clinical Utility of Cell-Free DNA for the Detectio...' appears tangentially related to the research topic.", "evidence": [ { "text": "Clinical Utility of Cell-Free DNA for", "section": "title", "criterion": "Population", "supports": "exclude" } ], "ai_decision": "include", "assigned_clusters": [ { "cluster_name": "Biomarker Analysis Studies", "cluster_type": "include", "cluster_description": "Papers with molecular or biomarker focus and genetic data", "related_criteria": "Outcome" } ] }, { "id": "35", "title": "Consequences of Biomarker Analysis on the Cost-Effectiveness of Cetuximab in Combination with FOLFIRI as a First-Line Treatment of Metastatic Colorectal Cancer: Personalised Medicine at Work.", "abstract": "BACKGROUND: Therapies may be more efficacious when targeting a patient subpopulation with specific attributes, thereby enhancing the cost-effectiveness of treatment. In the CRYSTAL study, patients with metastatic colorectal cancer (mCRC) were treated with cetuximab plus FOLFIRI or FOLFIRI alone until disease progression, unacceptable toxic effects or withdrawal of consent. OBJECTIVE: To determine if stratified use of cetuximab based on genetic biomarker detection improves cost-effectiveness. METHODS: We used individual patient data from CRYSTAL to compare the cost-effectiveness, cost per life-year (LY) and cost per quality-adjusted LY (QALY) gained of cetuximab plus FOLFIRI versus FOLFIRI alone in three cohorts of patients with mCRC: all randomised patients (intent-to-treat; ITT), tumours with no detectable mutations in codons 12 and 13 of exon 2 of the KRAS protein ('KRAS wt') and no detectable mutations in exons 2, 3 and 4 of KRAS and exons 2, 3 and 4 of NRAS ('RAS wt'). Survival analysis was conducted using RStudio, and a cost-utility model was modified to allow comparison of the three cohorts. RESULTS: The deterministic base-case ICER (cost per QALY gained) was \u00a3130,929 in the ITT, \u00a372,053 in the KRAS wt and \u00a344,185 in the RAS wt cohorts for cetuximab plus FOLFIRI compared with FOLFIRI alone. At a \u00a350,000 willingness-to-pay threshold, cetuximab plus FOLFIRI has a 2.8, 20 and 63% probability of being cost-effective for the ITT, KRAS wt and RAS wt cohorts, respectively, versus FOLFIRI alone. CONCLUSION: Screening for mutations in both KRAS and NRAS may provide the most cost-effective approach to patient selection.", "citation": "Harty G, Jarrett J, Jofre-Bonet M. (2018). Consequences of Biomarker Analysis on the Cost-Effectiveness of Cetuximab in Combination with FOLFIRI as a First-Line Treatment of Metastatic Colorectal Cancer: Personalised Medicine at Work. Applied health economics and health policy. 16(4):515-525. http://doi.org/10.1007/s40258-018-0395-5. PMID: 29948926.", "score_list": [ 1.6954944759215438, 1.4075197655616314 ], "ai_score_min": 1.4075197655616314, "ai_score_max": 1.6954944759215438, "ai_score": 1.5515071207415876, "ai_reasoning": "Recommend exclusion. 'Consequences of Biomarker Analysis on the Cost-Eff...' does not appear to meet core inclusion criteria.", "evidence": [ { "text": "mutations in exons 2, 3 and 4 of", "section": "abstract", "criterion": "Population", "supports": "exclude" }, { "text": "wt and \u00a344,185 in the", "section": "abstract", "criterion": "Study Design", "supports": "exclude" }, { "text": "Consequences of Biomarker Analysis on the", "section": "title", "criterion": "Population", "supports": "exclude" } ], "ai_decision": "include", "assigned_clusters": [ { "cluster_name": "Methodology & Protocol Only", "cluster_type": "exclude", "cluster_description": "Papers focused on study design and methodology without clinical results", "related_criteria": "Study Design" } ] }, { "id": "36", "title": "Targeted Next-Generation Sequencing in Men with Metastatic Prostate Cancer: a Pilot Study.", "abstract": "INTRODUCTION: Tumor profiling by targeted next-generation sequencing (tNGS) and personalized treatment based on these results is becoming increasingly common in patients with metastatic solid tumors, but it remains unclear whether this strategy results in benefit to patients with metastatic prostate cancer (mPCa). OBJECTIVE: To assess the clinical utility of tNGS in treatment decision-making for patients with mPCa. PATIENTS AND METHODS: Patients with available genomic profiling using tumor tissue (FoundationOne, F1) or cell-free DNA (FoundationACT, Guardant360) were included. Targetable genomic alterations (tGA) included a change in the copy number or mutations in DNA repair genes, mismatch repair genes, PTEN, cyclin-dependent kinases, ERBB2, BRAF, TSC, and the PIK3/mTOR pathway. RESULTS: The study included 66 patients, 86% of which had metastatic castration-resistant prostate cancer (mCRPC), and who had received a median of 3 (range 0-7) treatments prior to tNGS. The most frequent alterations were found in TP53 (42%), PTEN (35%), androgen receptor (AR) (30%), DNA repair (30%), PIK3CA signaling pathway (21%), cyclin-dependent kinases (15%), BRAF (9%), and MMR/MSI (6%) genes. Among the 45 (68%) tGA+ patients, tNGS influenced treatment in 13 (29%) [PARP inhibitor (n = 7), mTOR inhibitor (n = 4), anti-PD-1 (n = 2), anti-HER2 (n = 1)]. The median progression-free survival (PFS) was 4.1 months [95% confidence interval (CI), 2.8-5.4]. Among tGA+ patients who did not receive tNGS-based therapy, systemic treatment (n = 17) included chemotherapy (71%), new generation anti-androgen therapy (24%), and cabozantinib (6%); the median PFS was 4.3 months (95% CI, 2.6-6.0; p = 0.7 for tGA+ with personalized therapy vs. tGA+ without personalized therapy). CONCLUSION: In this cohort, the use of tNGS was feasible, detected frequent genomic alterations, and was used late in the disease course. Further studies and larger portfolios of targeted therapy trials are needed to maximize the benefit of tNGS in this population.", "citation": "Barata PC, Mendiratta P, Heald B, Klek S, Grivas P, Sohal DPS, Garcia JA. (2018). Targeted Next-Generation Sequencing in Men with Metastatic Prostate Cancer: a Pilot Study. Targeted oncology. 13(4):495-500. http://doi.org/10.1007/s11523-018-0576-z. PMID: 29974386.", "score_list": [ 1.5096166610635466, 1.635905799201274 ], "ai_score_min": 1.5096166610635466, "ai_score_max": 1.635905799201274, "ai_score": 1.5727612301324103, "ai_reasoning": "Recommend exclusion. 'Targeted Next-Generation Sequencing in Men with Me...' does not appear to meet core inclusion criteria.", "evidence": [ { "text": "(15%), BRAF (9%), and MMR/MSI (6%) genes.", "section": "abstract", "criterion": "Population", "supports": "exclude" }, { "text": "cyclin-dependent kinases, ERBB2, BRAF, TSC,", "section": "abstract", "criterion": "Study Design", "supports": "exclude" }, { "text": "Targeted Next-Generation Sequencing in Men with", "section": "title", "criterion": "Population", "supports": "exclude" } ], "ai_decision": "include", "assigned_clusters": [ { "cluster_name": "Methodology & Protocol Only", "cluster_type": "exclude", "cluster_description": "Papers focused on study design and methodology without clinical results", "related_criteria": "Study Design" } ] }, { "id": "37", "title": "Association of Broad-Based Genomic Sequencing With Survival Among Patients With Advanced Non-Small Cell Lung Cancer in the Community Oncology Setting.", "abstract": "IMPORTANCE: Broad-based genomic sequencing is being used more frequently for patients with advanced non-small cell lung cancer (NSCLC). However, little is known about the association between broad-based genomic sequencing and treatment selection or survival among patients with advanced NSCLC in a community oncology setting. OBJECTIVE: To compare clinical outcomes between patients with advanced NSCLC who received broad-based genomic sequencing vs a control group of patients who received routine testing for EGFR mutations and/or ALK rearrangements alone. DESIGN, SETTING, AND PARTICIPANTS: Retrospective cohort study of patients with chart-confirmed advanced NSCLC between January 1, 2011, and July 31, 2016, and who received care at 1 of 191 oncology practices across the United States using the Flatiron Health Database. Patients were diagnosed with stage IIIB/IV or unresectable nonsquamous NSCLC who received at least 1 line of antineoplastic treatment. EXPOSURES: Receipt of either broad-based genomic sequencing or routine testing (EGFR and/or ALK only). Broad-based genomic sequencing included any multigene panel sequencing assay examining more than 30 genes prior to third-line treatment. MAIN OUTCOMES AND MEASURES: Primary outcomes were 12-month mortality and overall survival from the start of first-line treatment. Secondary outcomes included frequency of genetic alterations and treatments received. RESULTS: Among 5688 individuals with advanced NSCLC (median age, 67 years [interquartile range, 41-85], 63.6% white, 80% with a history of smoking); 875 (15.4%) received broad-based genomic sequencing and 4813 (84.6%) received routine testing. Among patients who received broad-based genomic sequencing, 4.5% received targeted treatment based on testing results, 9.8% received routine EGFR/ALK targeted treatment, and 85.1% received no targeted treatment. Unadjusted mortality rates at 12 months were 49.2% for patients undergoing broad-based genomic sequencing and 35.9% for patients undergoing routine testing. Using an instrumental variable analysis, there was no significant association between broad-based genomic sequencing and 12-month mortality (predicted probability of death at 12 months, 41.1% for broad-based genomic sequencing vs 44.4% for routine testing; difference -3.6% [95% CI, -18.4% to 11.1%]; P = .63). The results were consistent in the propensity score-matched survival analysis (42.0% vs 45.1%; hazard ratio, 0.92 [95% CI, 0.73 to 1.11]; P = .40) vs unmatched cohort (hazard ratio, 0.69 [95% CI, 0.62 to 0.77]; log-rank P < .001). CONCLUSIONS AND RELEVANCE: Among patients with advanced non-small cell lung cancer receiving care in the community oncology setting, broad-based genomic sequencing directly informed treatment in a minority of patients and was not independently associated with better survival.", "citation": "Presley CJ, Tang D, Soulos PR, Chiang AC, Longtine JA, Adelson KB, Herbst RS, Zhu W, Nussbaum NC, Sorg RA, Agarwala V, Abernethy AP, Gross CP. (2018). Association of Broad-Based Genomic Sequencing With Survival Among Patients With Advanced Non-Small Cell Lung Cancer in the Community Oncology Setting. JAMA. 320(5):469-477. http://doi.org/10.1001/jama.2018.9824. PMID: 30088010.", "score_list": [ 3.778104635994796, 3.689737242389456 ], "ai_score_min": 3.689737242389456, "ai_score_max": 3.778104635994796, "ai_score": 3.733920939192126, "ai_reasoning": "Moderate relevance. 'Association of Broad-Based Genomic Sequencing With...' partially meets inclusion criteria but requires human review for final determination.", "evidence": [ { "text": "and July 31, 2016, and", "section": "abstract", "criterion": "Population", "supports": "include" }, { "text": "probability of death at 12 months,", "section": "abstract", "criterion": "Study Design", "supports": "include" }, { "text": "vs 45.1%; hazard ratio, 0.92 [95% CI, 0.73", "section": "abstract", "criterion": "Outcome", "supports": "include" }, { "text": "Association of Broad-Based Genomic Sequencing With", "section": "title", "criterion": "Population", "supports": "include" } ], "ai_decision": "include", "assigned_clusters": [ { "cluster_name": "Adult Patient Population", "cluster_type": "include", "cluster_description": "Papers focused on adult patient demographics with defined inclusion criteria", "related_criteria": "Population" }, { "cluster_name": "Biomarker Analysis Studies", "cluster_type": "include", "cluster_description": "Papers with molecular or biomarker focus and genetic data", "related_criteria": "Outcome" } ] }, { "id": "38", "title": "A method for treatment monitoring using circulating tumour DNA in cancer patients without targetable mutations.", "abstract": "BACKGROUND: The potentials of circulating tumour DNA (ctDNA) have been studied for non-invasive disease monitoring in patients with targetable mutations. However, the majority of cancer patients harbour no targetable mutations. A workflow including targeted next-generation sequencing (NGS) and droplet digital PCR (ddPCR) could be used for monitoring treatment in these patients. Thus, our aim was to evaluate the workflow for ctDNA monitoring in a cohort of non-small cell lung cancer patients. METHODS: Forty patients were prospectively included. Plasma samples were collected prior to and during treatment. NGS (Ion AmpliSeq Colon and Lung Cancer panel v2) was performed on ctDNA from pre-treatment samples. The identified mutations were monitored by ddPCR in consecutively collected samples. RESULTS: Mutations were detected in 21 patients. The most commonly mutated genes were CONCLUSION: ctDNA monitoring can be used for early detection of non-response in patients without targetable mutations, and therefore could supplement imaging data for treatment monitoring in this subset of patients.", "citation": "Demuth C, Winther-Larsen A, Madsen AT, Meldgaard P, Sorensen BS. (2018). A method for treatment monitoring using circulating tumour DNA in cancer patients without targetable mutations. Oncotarget. 9(57):31066-31076. http://doi.org/10.18632/oncotarget.25779. PMID: 30123427.", "score_list": [ 2.952718888120968, 3.0469956302873955 ], "ai_score_min": 2.952718888120968, "ai_score_max": 3.0469956302873955, "ai_score": 2.9998572592041817, "ai_reasoning": "Weak relevance. 'A method for treatment monitoring using circulatin...' appears tangentially related to the research topic.", "evidence": [ { "text": "monitoring treatment in these patients. Thus, our", "section": "abstract", "criterion": "Population", "supports": "exclude" }, { "text": "treatment monitoring in this", "section": "abstract", "criterion": "Study Design", "supports": "exclude" }, { "text": "A method for treatment monitoring using", "section": "title", "criterion": "Population", "supports": "exclude" } ], "ai_decision": "include", "assigned_clusters": [ { "cluster_name": "Adult Patient Population", "cluster_type": "include", "cluster_description": "Papers focused on adult patient demographics with defined inclusion criteria", "related_criteria": "Population" } ] }, { "id": "39", "title": "Prevalence of BRAF, NRAS and c-KIT mutations in Slovenian patients with advanced melanoma.", "abstract": "Background BRAF, NRAS and c-KIT mutations are characteristics of tumour tissues that influence on treatment decisions in metastatic melanoma patients. Mutation frequency and their correlation with histological characteristics in Slovenian population have not been investigated yet. Patients and methods In our retrospective analysis we analysed mutational status of BRAF, NRAS and c-KIT in 230 pathological samples of patients who were intended to be treated with systemic therapy due to metastatic disease at the Institute of Oncology Ljubljana between 2013 and 2016. We collected also histological characteristics of primary tumours and clinical data of patients and correlated them with mutational status of tumour samples. Results The study population consisted of 230 patients with a mean age 59 years (range 25-85). 141 (61.3%) were males and 89 (38.7%) females. BRAF mutations were identified in 129 (56.1%), NRAS in 31 (13.5%) and c-KIT in 3 (1.3%) tissue samples. Among the 129 patients with BRAF mutations, 114 (88.4%) patients had V600E mutation and 15 (11.6%) had V600K mutation. Patients with BRAF mutations tended to be younger at diagnosis (52 vs. 59 years, p < 0.05), patients with NRAS mutations older (61 vs. 55 years, p < 0.05). Number of c-KIT mutations were too low for any statistical correlation, but there was one out of 3 melanoma located in mucus membranes. Conclusions The analysis detected high rate of BRAF mutations, low NRAS mutations and low c-KIT mutations compared to previously published studies in Europe and North America. One of the main reasons for this observation is specific characteristics of study population.", "citation": "Moltara ME, Novakovic S, Boc M, Bucic M, Rebersek M, Zadnik V, Ocvirk J. (2018). Prevalence of BRAF, NRAS and c-KIT mutations in Slovenian patients with advanced melanoma. Radiology and oncology. 52(3):289-295. http://doi.org/10.2478/raon-2018-0017. PMID: 30210039.", "score_list": [ 4.093138698458829, 4.006723209880775 ], "ai_score_min": 4.006723209880775, "ai_score_max": 4.093138698458829, "ai_score": 4.0499309541698025, "ai_reasoning": "Strong candidate for inclusion. 'Prevalence of BRAF, NRAS and c-KIT mutations in Sl...' directly addresses research criteria with clear methodology. Keywords suggesting inclusion: treatment, patient, therapy.", "evidence": [ { "text": "NRAS in 31 (13.5%) and", "section": "abstract", "criterion": "Population", "supports": "include" }, { "text": "previously published studies in Europe and North America.", "section": "abstract", "criterion": "Study Design", "supports": "include" }, { "text": "metastatic disease at the Institute of Oncology", "section": "abstract", "criterion": "Outcome", "supports": "include" }, { "text": "any statistical correlation, but", "section": "abstract", "criterion": "Intervention", "supports": "include" }, { "text": "Prevalence of BRAF, NRAS and c-KIT", "section": "title", "criterion": "Population", "supports": "include" } ], "ai_decision": "include", "assigned_clusters": [ { "cluster_name": "Treatment Efficacy Studies", "cluster_type": "include", "cluster_description": "Papers evaluating treatment outcomes and efficacy measures", "related_criteria": "Intervention" } ] }, { "id": "40", "title": "Comparative mutational evaluation of multiple lung cancers by multiplex oncogene mutation analysis.", "abstract": "In patients presenting with synchronous or metachronous multiple lung cancer (MLC), it is important to distinguish between multiple primary lung cancer (MP) and intrapulmonary metastasis (IM). The present study was aimed at investigating the mutational profiles of synchronous/metachronous MLC and to compare the classification of paired tumors by multiplex gene mutation analysis with the histopathological evaluation. We carried out targeted sequencing of 20 lung cancer-related oncogenes using next-generation sequencing (NGS) in 82 tumors from 37 MLC patients who underwent surgical resection at our department. The patients were diagnosed as MP or IM cases based on the Martini and Melamed criteria, histopathological and gene mutational evaluations. Matching mutations between paired tumors was observed in 20 (54%) patients, who were diagnosed as IM cases by mutational evaluation. Patients who could not be clearly diagnosed by histopathological evaluation were classified as equivocal cases. Among the histopathological IM cases (n = 7), six (86%) were confirmed as IM cases also by mutational evaluation, and most of the paired tumors of these cases (n = 5) harbored multiple matching mutations. Among the histopathological MP cases (n = 17), mutational evaluation yielded a discordant diagnosis in eight (47%) cases. Of these, the paired tumors of four cases harbored multiple matching mutations, suggesting that the mutational diagnosis might be more suitable in these patients. Our findings suggest that multiplex mutational analysis could be a useful complementary tool for distinguishing between MP and IM in addition to histopathological evaluation.", "citation": "Takahashi Y, Shien K, Tomida S, Oda S, Matsubara T, Sato H, Suzawa K, Kurihara E, Ogoshi Y, Namba K, Yoshioka T, Torigoe H, Yamamoto H, Soh J, Toyooka S. (2018). Comparative mutational evaluation of multiple lung cancers by multiplex oncogene mutation analysis. Cancer science. 109(11):3634-3642. http://doi.org/10.1111/cas.13797. PMID: 30216592.", "score_list": [ 2.7200323985776245, 2.803445963139333 ], "ai_score_min": 2.7200323985776245, "ai_score_max": 2.803445963139333, "ai_score": 2.761739180858479, "ai_reasoning": "Weak relevance. 'Comparative mutational evaluation of multiple lung...' appears tangentially related to the research topic.", "evidence": [ { "text": "evaluation yielded a discordant", "section": "abstract", "criterion": "Population", "supports": "exclude" }, { "text": "could not be clearly diagnosed by", "section": "abstract", "criterion": "Study Design", "supports": "exclude" }, { "text": "Comparative mutational evaluation of multiple lung", "section": "title", "criterion": "Population", "supports": "exclude" } ], "ai_decision": "include", "assigned_clusters": [ { "cluster_name": "Adult Patient Population", "cluster_type": "include", "cluster_description": "Papers focused on adult patient demographics with defined inclusion criteria", "related_criteria": "Population" } ] }, { "id": "41", "title": "Early cost-effectiveness of tumor infiltrating lymphocytes (TIL) for second line treatment in advanced melanoma: a model-based economic evaluation.", "abstract": "BACKGROUND: An emerging immunotherapy is infusion of tumor infiltrating Lymphocytes (TIL), with objective response rates of around 50% versus 19% for ipilimumab. As an Advanced Therapeutic Medicinal Products (ATMP), TIL is highly personalized and complex therapy. It requests substantial upfront investments from the hospital in: expensive lab-equipment, staff expertise and training, as well as extremely tight hospital logistics. Therefore, an early health economic modelling study, as part of a Coverage with Evidence Development (CED) program, was performed. METHODS: We used a Markov decision model to estimate the expected costs and outcomes (quality-adjusted life years; QALYs) for TIL versus ipilimumab for second line treatment in metastatic melanoma patients from a Dutch health care perspective over a life long time horizon. Three mutually exclusive health states (stable disease (responders)), progressive disease and death) were modelled. To inform further research prioritization, Value of Information (VOI) analysis was performed. RESULTS: TIL is expected to generate more QALYs compared to ipilimumab (0.45 versus 0.38 respectively) at lower incremental cost (presently \u20ac81,140 versus \u20ac94,705 respectively) resulting in a dominant ICER (less costly and more effective). Based on current information TIL is dominating ipilimumab and has a probability of 86% for being cost effective at a cost/QALY threshold of \u20ac80,000. The Expected Value of Perfect Information (EVPI) amounted to \u20ac3 M. CONCLUSIONS: TIL is expected to have the highest probability of being cost-effective in second line treatment for advanced melanoma compared to ipilimumab. To reduce decision uncertainty, a clinical trial investigating e.g. costs and survival seems most valuable. This is currently being undertaken as part of a CED program in the Netherlands Cancer Institute, Amsterdam, the Netherlands, in collaboration with Denmark.", "citation": "Ret\u00e8l VP, Steuten LMG, Geukes Foppen MH, Mewes JC, Lindenberg MA, Haanen JBAG, van Harten WH. (2018). Early cost-effectiveness of tumor infiltrating lymphocytes (TIL) for second line treatment in advanced melanoma: a model-based economic evaluation. BMC cancer. 18(1):895. http://doi.org/10.1186/s12885-018-4788-5. PMID: 30219040.", "score_list": [ 3.6238189392230167, 3.4509966392533302 ], "ai_score_min": 3.4509966392533302, "ai_score_max": 3.6238189392230167, "ai_score": 3.5374077892381735, "ai_reasoning": "Moderate relevance. 'Early cost-effectiveness of tumor infiltrating lym...' partially meets inclusion criteria but requires human review for final determination.", "evidence": [ { "text": "expected to generate more QALYs compared to", "section": "abstract", "criterion": "Population", "supports": "include" }, { "text": "second line treatment in", "section": "abstract", "criterion": "Study Design", "supports": "include" }, { "text": "METHODS: We used a Markov decision", "section": "abstract", "criterion": "Outcome", "supports": "include" }, { "text": "Early cost-effectiveness of tumor infiltrating lymphocytes", "section": "title", "criterion": "Population", "supports": "include" } ], "ai_decision": "include", "assigned_clusters": [ { "cluster_name": "Adult Patient Population", "cluster_type": "include", "cluster_description": "Papers focused on adult patient demographics with defined inclusion criteria", "related_criteria": "Population" } ] }, { "id": "42", "title": "Do cancer biomarkers make targeted therapies cost-effective? A systematic review in metastatic colorectal cancer.", "abstract": "BACKGROUND: Recent advances in targeted therapies have raised expectations that the clinical application of biomarkers would improve patient's health outcomes and potentially save costs. However, the cost-effectiveness of biomarkers remains unclear irrespective of the cost-effectiveness of corresponding therapies. It is thus important to determine whether biomarkers for targeted therapies provide good value for money. This study systematically reviews economic evaluations of biomarkers for targeted therapies in metastatic colorectal cancer (mCRC) and assesses the cost-effectiveness of predictive biomarkers in mCRC. METHODS: A literature search was performed using Medline, Embase, EconLit, NHSEED. Papers published from 2000 until June 2018 were searched. All economic evaluations assessing biomarker-guided therapies with companion diagnostics in mCRC were searched. To make studies more comparable, cost-effectiveness results were synthesized as per biomarker tests and corresponding therapies. Methodological quality was assessed using the Quality of Health Economic Studies (QHES) instrument. RESULTS: Forty-six studies were included in this review. Of these, 17 studies evaluated the intrinsic value of cancer biomarkers, whereas the remaining studies focused on assessing the cost-effectiveness of corresponding drugs. Most studies indicated favourable cost-effectiveness of biomarkers for targeted therapies in mCRC. Some studies reported that biomarkers were cost-effective, while their corresponding therapies were not cost-effective. A considerable number of economic evaluations were conducted in pre-defined genetic populations and thus, often failed to fully capture the biomarker's clinical and economic values. The average QHES score was 73.6. CONCLUSION: Cancer biomarkers for targeted therapies in mCRC were mostly found to be cost-effective; otherwise, they at least improved the cost-effectiveness of targeted therapies by saving some costs. However, this did not necessarily make their corresponding therapies cost-effective. While companion biomarkers reduced therapy costs, the savings were not sufficient to make the corresponding agents cost-effective. Evaluation of biomarkers was often restricted to the cost of tests and did not consider their clinical values or biomarker prevalence.", "citation": "Seo MK, Cairns J. (2018). Do cancer biomarkers make targeted therapies cost-effective? A systematic review in metastatic colorectal cancer. PloS one. 13(9):e0204496. http://doi.org/10.1371/journal.pone.0204496. PMID: 30256829.", "score_list": [ 1.41474253416341, 1.2874832255663875 ], "ai_score_min": 1.2874832255663875, "ai_score_max": 1.41474253416341, "ai_score": 1.3511128798648988, "ai_reasoning": "Recommend exclusion. 'Do cancer biomarkers make targeted therapies cost-...' does not appear to meet core inclusion criteria. Exclusion keywords found: review.", "evidence": [ { "text": "searched. To make studies more comparable,", "section": "abstract", "criterion": "Population", "supports": "exclude" }, { "text": "biomarkers in mCRC. METHODS: A literature search", "section": "abstract", "criterion": "Study Design", "supports": "exclude" }, { "text": "Do cancer biomarkers make targeted therapies", "section": "title", "criterion": "Population", "supports": "exclude" } ], "ai_decision": "include", "assigned_clusters": [ { "cluster_name": "Review & Meta-Analysis (No Primary Data)", "cluster_type": "exclude", "cluster_description": "Secondary research synthesizing existing studies without new data", "related_criteria": "Study Design" } ] }, { "id": "43", "title": "Budget impact analysis of comprehensive genomic profiling in patients with advanced non-small cell lung cancer.", "abstract": "AIMS: Broad molecular profiling of patients with advanced non-small cell lung cancer (NSCLC) is strongly advised to optimize genomic matching with available targeted treatment options or investigational agents. Unlike conventional molecular diagnostic testing, or smaller hotspot panels, comprehensive genomic profiling (CGP) identifies genomic alterations across hundreds of clinically relevant cancer genes from a single tissue specimen. The present study sought to estimate the budget impact of increased use of CGP using a 324-gene panel (FoundationOne) vs non-CGP (represented by a mix of conventional molecular diagnostic testing and smaller NGS hotspot panels) and the number needed to test with CGP to gain 1 life year. MATERIALS AND METHODS: A decision analytic model was developed to assess the budget impact of increased CGP in advanced NSCLC from a US private payer perspective. Model inputs were based on published literature (epidemiology and treatment outcomes), real-world data (testing and rates, medical service costs), list prices for CGP and anti-cancer drugs, and assumptions for clinical trial participation. RESULTS: Among 2 million covered lives, 532 had advanced NSCLC; 266 underwent molecular diagnostic testing. An increase in CGP among those tested, from 2% to 10%, was associated with $0.02 per member per month budget impact, of which $0.013 was attributable to costs of prolonged drug treatment and survival and $0.005 to testing cost. Approximately 12 patients would need to be tested with CGP to add 1 life year. LIMITATIONS: The model incorporated certain assumptions to account for inputs with a limited evidence profile and simplify the possible post-CGP treatments. CONCLUSIONS: An increase in CGP utilization from 2% to 10% among patients with advanced NSCLC undergoing molecular diagnostic testing was associated with a modest budget impact, most of which was attributable to increased use of more effective treatments and prolonged survival.", "citation": "Signorovitch J, Zhou Z, Ryan J, Anhorn R, Chawla A. (2019). Budget impact analysis of comprehensive genomic profiling in patients with advanced non-small cell lung cancer. Journal of medical economics. 22(2):140-150. http://doi.org/10.1080/13696998.2018.1549056. PMID: 30430885.", "score_list": [ 1.6038690050928355, 1.7078369585220594 ], "ai_score_min": 1.6038690050928355, "ai_score_max": 1.7078369585220594, "ai_score": 1.6558529818074474, "ai_reasoning": "Recommend exclusion. 'Budget impact analysis of comprehensive genomic pr...' does not appear to meet core inclusion criteria.", "evidence": [ { "text": "of which was attributable to increased", "section": "abstract", "criterion": "Population", "supports": "exclude" }, { "text": "attributable to increased use of", "section": "abstract", "criterion": "Study Design", "supports": "exclude" }, { "text": "Budget impact analysis of comprehensive genomic", "section": "title", "criterion": "Population", "supports": "exclude" } ], "ai_decision": "include", "assigned_clusters": [ { "cluster_name": "Methodology & Protocol Only", "cluster_type": "exclude", "cluster_description": "Papers focused on study design and methodology without clinical results", "related_criteria": "Study Design" } ] }, { "id": "44", "title": "Cell-free DNA profiling of metastatic prostate cancer reveals microsatellite instability, structural rearrangements and clonal hematopoiesis.", "abstract": "BACKGROUND: There are multiple existing and emerging therapeutic avenues for metastatic prostate cancer, with a common denominator, which is the need for predictive biomarkers. Circulating tumor DNA (ctDNA) has the potential to cost-efficiently accelerate precision medicine trials to improve clinical efficacy and diminish costs and toxicity. However, comprehensive ctDNA profiling in metastatic prostate cancer to date has been limited. METHODS: A combination of targeted and low-pass whole genome sequencing was performed on plasma cell-free DNA and matched white blood cell germline DNA in 364 blood samples from 217 metastatic prostate cancer patients. RESULTS: ctDNA was detected in 85.9% of baseline samples, correlated to line of therapy and was mirrored by circulating tumor cell enumeration of synchronous blood samples. Comprehensive profiling of the androgen receptor (AR) revealed a continuous increase in the fraction of patients with intra-AR structural variation, from 15.4% during first-line metastatic castration-resistant prostate cancer therapy to 45.2% in fourth line, indicating a continuous evolution of AR during the course of the disease. Patients displayed frequent alterations in DNA repair deficiency genes (18.0%). Additionally, the microsatellite instability phenotype was identified in 3.81% of eligible samples (\u2265 0.1 ctDNA fraction). Sequencing of non-repetitive intronic and exonic regions of PTEN, RB1, and TP53 detected biallelic inactivation in 47.5%, 20.3%, and 44.1% of samples with \u2265 0.2 ctDNA fraction, respectively. Only one patient carried a clonal high-impact variant without a detectable second hit. Intronic high-impact structural variation was twice as common as exonic mutations in PTEN and RB1. Finally, 14.6% of patients presented false positive variants due to clonal hematopoiesis, commonly ignored in commercially available assays. CONCLUSIONS: ctDNA profiles appear to mirror the genomic landscape of metastatic prostate cancer tissue and may cost-efficiently provide somatic information in clinical trials designed to identify predictive biomarkers. However, intronic sequencing of the interrogated tumor suppressors challenges the ubiquitous focus on coding regions and is vital, together with profiling of synchronous white blood cells, to minimize erroneous assignments which in turn may confound results and impede true associations in clinical trials.", "citation": "Mayrhofer M, De Laere B, Whitington T, Van Oyen P, Ghysel C, Ampe J, Ost P, Demey W, Hoekx L, Schrijvers D, Brouwers B, Lybaert W, Everaert E, De Maeseneer D, Strijbos M, Bols A, Fransis K, Oeyen S, van Dam PJ, Van den Eynden G, Rutten A, Aly M, Nordstr\u00f6m T, Van Laere S, Rantalainen M, Rajan P, Egevad L, Ull\u00e9n A, Yachnin J, Dirix L, Gr\u00f6nberg H, Lindberg J. (2018). Cell-free DNA profiling of metastatic prostate cancer reveals microsatellite instability, structural rearrangements and clonal hematopoiesis. Genome medicine. 10(1):85. http://doi.org/10.1186/s13073-018-0595-5. PMID: 30458854.", "score_list": [ 2.8501985599844377, 2.453187346962358 ], "ai_score_min": 2.453187346962358, "ai_score_max": 2.8501985599844377, "ai_score": 2.6516929534733977, "ai_reasoning": "Weak relevance. 'Cell-free DNA profiling of metastatic prostate can...' appears tangentially related to the research topic.", "evidence": [ { "text": "to date has been", "section": "abstract", "criterion": "Population", "supports": "exclude" }, { "text": "blood cells, to minimize", "section": "abstract", "criterion": "Study Design", "supports": "exclude" }, { "text": "Cell-free DNA profiling of metastatic prostate", "section": "title", "criterion": "Population", "supports": "exclude" } ], "ai_decision": "include", "assigned_clusters": [ { "cluster_name": "Adult Patient Population", "cluster_type": "include", "cluster_description": "Papers focused on adult patient demographics with defined inclusion criteria", "related_criteria": "Population" }, { "cluster_name": "Biomarker Analysis Studies", "cluster_type": "include", "cluster_description": "Papers with molecular or biomarker focus and genetic data", "related_criteria": "Outcome" } ] }, { "id": "45", "title": "Pembrolizumab for Locally Advanced or Metastatic Urothelial Cancer Where Cisplatin is Unsuitable: An Evidence Review Group Perspective of a NICE Single Technology Appraisal.", "abstract": "As part of its Single Technology Appraisal (STA) process, the National Institute for Health and Care Excellence (NICE) invited the manufacturer (Merck Sharp & Dohme) of pembrolizumab (Keytruda", "citation": "Ren S, Squires H, Hock E, Kaltenthaler E, Rawdin A, Alifrangis C. (2019). Pembrolizumab for Locally Advanced or Metastatic Urothelial Cancer Where Cisplatin is Unsuitable: An Evidence Review Group Perspective of a NICE Single Technology Appraisal. PharmacoEconomics. 37(9):1073-1080. http://doi.org/10.1007/s40273-018-0750-2. PMID: 30547369.", "score_list": [ 1.9431423256164448, 2.1883776391722836 ], "ai_score_min": 1.9431423256164448, "ai_score_max": 2.1883776391722836, "ai_score": 2.065759982394364, "ai_reasoning": "Weak relevance. 'Pembrolizumab for Locally Advanced or Metastatic U...' appears tangentially related to the research topic. Potential exclusion indicators: review.", "evidence": [ { "text": "the manufacturer (Merck Sharp & Dohme)", "section": "abstract", "criterion": "Population", "supports": "exclude" }, { "text": "As part of its Single Technology", "section": "abstract", "criterion": "Study Design", "supports": "exclude" }, { "text": "Pembrolizumab for Locally Advanced or Metastatic", "section": "title", "criterion": "Population", "supports": "exclude" } ], "ai_decision": "include", "assigned_clusters": [ { "cluster_name": "Treatment Efficacy Studies", "cluster_type": "include", "cluster_description": "Papers evaluating treatment outcomes and efficacy measures", "related_criteria": "Intervention" }, { "cluster_name": "Methodology & Protocol Only", "cluster_type": "exclude", "cluster_description": "Papers focused on study design and methodology without clinical results", "related_criteria": "Study Design" } ] }, { "id": "46", "title": "Evaluation of microsatellite instability in tumor and tumor marginal samples of sporadic colorectal cancer using mononucleotide markers.", "abstract": "Microsatellite instability (MSI) is a unique molecular alteration that is due to a defective DNA mismatch repair (MMR) system. Approximately, 15-20 % of sporadic colorectal cancers (CRC) display MSI. Determination of MSI status in CRC has prognostic and predictive implications. Additionally, detecting MSI is used diagnostically for tumor detection and classification. The present study analyzed a panel of five mononucleotide markers, BAT-25, BAT-26, NR-21, NR-22 and NR-27, amplified in a single multiplex PCR reaction to evaluate MSI status in CRC patients. Genomic DNA from 50 CRC and paired adjacent normal tissues was used for PCR-based MSI analysis. Our finding showed microsatellite instability in 36 % of specimens. Instability with differences in allele lengths was observed in the tumoral DNA compared to the tumor-free margin DNA sample. The frequency of instability in NR-21, BAT-26 and BAT-25 markers were more than others; their frequency were 35.48 %, 29.03 %, and 22.58 %, respectively. In conclusion, the NR-21, BAT-26, and BAT-25 were the most useful markers for discriminating cancer tissue from normal, therefore these markers have demonstrated promising potential for determining MSI status in patients with sporadic colorectal cancer.", "citation": "Nouri Nojadeh J, Hashemzadeh S, Samadi Kafil H, Behrouz Sharif S, Eftekharsadat A, Ghasemnejad T, Ghojazadeh M, Sakhinia E. (2018). Evaluation of microsatellite instability in tumor and tumor marginal samples of sporadic colorectal cancer using mononucleotide markers. EXCLI journal. 17:945-951. http://doi.org/10.17179/excli2018-1455. PMID: 30564073.", "score_list": [ 3.804762415070393, 3.7273664680999836 ], "ai_score_min": 3.7273664680999836, "ai_score_max": 3.804762415070393, "ai_score": 3.766064441585188, "ai_reasoning": "Moderate relevance. 'Evaluation of microsatellite instability in tumor ...' partially meets inclusion criteria but requires human review for final determination.", "evidence": [ { "text": "BAT-26, and BAT-25 were the most", "section": "abstract", "criterion": "Population", "supports": "include" }, { "text": "frequency were 35.48 %, 29.03", "section": "abstract", "criterion": "Study Design", "supports": "include" }, { "text": "patients. Genomic DNA from 50", "section": "abstract", "criterion": "Outcome", "supports": "include" }, { "text": "Evaluation of microsatellite instability in tumor", "section": "title", "criterion": "Population", "supports": "include" } ], "ai_decision": "include", "assigned_clusters": [ { "cluster_name": "Adult Patient Population", "cluster_type": "include", "cluster_description": "Papers focused on adult patient demographics with defined inclusion criteria", "related_criteria": "Population" }, { "cluster_name": "Biomarker Analysis Studies", "cluster_type": "include", "cluster_description": "Papers with molecular or biomarker focus and genetic data", "related_criteria": "Outcome" } ] }, { "id": "47", "title": "Cohort versus patient level simulation for the economic evaluation of single versus combination immuno-oncology therapies in metastatic melanoma.", "abstract": "0", "citation": "Gibson EJ, Begum N, Koblbauer I, Dranitsaris G, Liew D, McEwan P, Yuan Y, Juarez-Garcia A, Tyas D, Pritchard C. (2019). Cohort versus patient level simulation for the economic evaluation of single versus combination immuno-oncology therapies in metastatic melanoma. Journal of medical economics. 22(6):531-544. http://doi.org/10.1080/13696998.2019.1569446. PMID: 30638416.", "score_list": [ 1.7073402800458506, 2.134752532814344 ], "ai_score_min": 1.7073402800458506, "ai_score_max": 2.134752532814344, "ai_score": 1.9210464064300972, "ai_reasoning": "Recommend exclusion. 'Cohort versus patient level simulation for the eco...' does not appear to meet core inclusion criteria.", "evidence": [ { "text": "Cohort versus patient level simulation for", "section": "title", "criterion": "Population", "supports": "exclude" } ], "ai_decision": "include", "assigned_clusters": [ { "cluster_name": "Methodology & Protocol Only", "cluster_type": "exclude", "cluster_description": "Papers focused on study design and methodology without clinical results", "related_criteria": "Study Design" } ] }, { "id": "48", "title": "Combined targeted DNA and RNA sequencing of advanced NSCLC in routine molecular diagnostics: Analysis of the first 3,000 Heidelberg cases.", "abstract": "Tyrosine kinase inhibitors currently confer the greatest survival gain for nonsmall cell lung cancer (NSCLC) patients with actionable genetic alterations. Simultaneously, the increasing number of targets and compounds poses the challenge of reliable, broad and timely molecular assays for the identification of patients likely to benefit from novel treatments. Here, we demonstrate the feasibility and clinical utility of comprehensive, NGS-based genetic profiling for routine workup of advanced NSCLC based on the first 3,000 patients analyzed in our department. Following automated extraction of DNA and RNA from formalin-fixed, paraffin-embedded tissue samples, parallel sequencing of DNA and RNA for detection of mutations and gene fusions, respectively, was performed using PCR-based enrichment with an ion semiconductor sequencing platform. Overall, 807 patients (27%) were eligible for currently approved, EGFR-/BRAF-/ALK- and ROS1-directed therapies, while 218 additional cases (7%) with MET, ERBB2 (HER2) and RET alterations could potentially benefit from experimental targeted compounds. In addition, routine capturing of comutations, e.g. TP53 (55%), KEAP1 (11%) and STK11 (11%), as well as the precise typing of fusion partners and involved exons in case of actionable translocations including ALK and ROS1, are prognostic and predictive tools currently gaining importance for further refinement of therapeutic and surveillance strategies. The reliability, low dropout rates (<5%), minimal tissue requirements, fast turnaround times (6 days on average) and lower costs of the diagnostic approach presented here compared to sequential single-gene testing, highlight its practicability in order to support individualized decisions in routine patient care, enrollment in molecularly stratified clinical trials, as well as translational research.", "citation": "Volckmar AL, Leichsenring J, Kirchner M, Christopoulos P, Neumann O, Budczies J, Morais de Oliveira CM, Rempel E, Buchhalter I, Brandt R, Allg\u00e4uer M, Talla SB, von Winterfeld M, Herpel E, Goeppert B, Lier A, Winter H, Brummer T, Fr\u00f6hling S, Faehling M, Fischer JR, Heu\u00dfel CP, Herth F, Lasitschka F, Schirmacher P, Thomas M, Endris V, Penzel R, Stenzinger A. (2019). Combined targeted DNA and RNA sequencing of advanced NSCLC in routine molecular diagnostics: Analysis of the first 3,000 Heidelberg cases. International journal of cancer. 145(3):649-661. http://doi.org/10.1002/ijc.32133. PMID: 30653256.", "score_list": [ 3.9067759894869694, 3.56901782889809 ], "ai_score_min": 3.56901782889809, "ai_score_max": 3.9067759894869694, "ai_score": 3.7378969091925294, "ai_reasoning": "Moderate relevance. 'Combined targeted DNA and RNA sequencing of advanc...' partially meets inclusion criteria but requires human review for final determination.", "evidence": [ { "text": "individualized decisions in routine", "section": "abstract", "criterion": "Population", "supports": "include" }, { "text": "In addition, routine capturing of comutations, e.g.", "section": "abstract", "criterion": "Study Design", "supports": "include" }, { "text": "and clinical utility of comprehensive, NGS-based genetic", "section": "abstract", "criterion": "Outcome", "supports": "include" }, { "text": "Combined targeted DNA and RNA sequencing", "section": "title", "criterion": "Population", "supports": "include" } ], "ai_decision": "include", "assigned_clusters": [ { "cluster_name": "Adult Patient Population", "cluster_type": "include", "cluster_description": "Papers focused on adult patient demographics with defined inclusion criteria", "related_criteria": "Population" }, { "cluster_name": "Biomarker Analysis Studies", "cluster_type": "include", "cluster_description": "Papers with molecular or biomarker focus and genetic data", "related_criteria": "Outcome" } ] }, { "id": "49", "title": "Molecular Profile of Advanced Non-Small Cell Lung Cancers in Octogenarians: The Door to Precision Medicine in Elderly Patients.", "abstract": "BACKGROUND: There is a pressing need to expand the evidence base in geriatric lung oncology. Most non-small cell lung cancers (NSCLCs) are diagnosed in the elderly, with approximately 15% of cases affecting octogenarians. Treatment-related decisions are challenging in this population, and the role of biologically driven therapies is still underrated. METHODS: A single-institution cohort of 76 NSCLCs from octogenarian patients was submitted to molecular analysis using a next-generation sequencing (NGS) multigene panel, fluorescence in situ hybridization (FISH) analyses, and immunohistochemistry for PD-L1 assessment. Treatment and clinical outcome data were available for 33 patients. RESULTS: Most cases ( CONCLUSIONS: This study highlights the utility of molecular profiling in all advanced-stage NSCLCs, regardless of the age at diagnosis, to drive personalized treatment. The prevalence of druggable alterations and the clinical benefits obtained by biologically-driven therapies in octogenarians were comparable to those of the younger NSCLC population.", "citation": "Fumagalli C, Catania C, Ranghiero A, Bosi C, Viale G, de Marinis F, Barberis M, Guerini-Rocco E. (2019). Molecular Profile of Advanced Non-Small Cell Lung Cancers in Octogenarians: The Door to Precision Medicine in Elderly Patients. Journal of clinical medicine. 8(1). http://doi.org/10.3390/jcm8010112. PMID: 30669267.", "score_list": [ 3.0264431537577434, 3.113747244620904 ], "ai_score_min": 3.0264431537577434, "ai_score_max": 3.113747244620904, "ai_score": 3.070095199189324, "ai_reasoning": "Moderate relevance. 'Molecular Profile of Advanced Non-Small Cell Lung ...' partially meets inclusion criteria but requires human review for final determination.", "evidence": [ { "text": "therapies in octogenarians were comparable to", "section": "abstract", "criterion": "Population", "supports": "include" }, { "text": "the role of biologically driven therapies is", "section": "abstract", "criterion": "Study Design", "supports": "include" }, { "text": "situ hybridization (FISH) analyses, and immunohistochemistry for PD-L1", "section": "abstract", "criterion": "Outcome", "supports": "include" }, { "text": "Molecular Profile of Advanced Non-Small Cell", "section": "title", "criterion": "Population", "supports": "include" } ], "ai_decision": "include", "assigned_clusters": [ { "cluster_name": "Adult Patient Population", "cluster_type": "include", "cluster_description": "Papers focused on adult patient demographics with defined inclusion criteria", "related_criteria": "Population" }, { "cluster_name": "Biomarker Analysis Studies", "cluster_type": "include", "cluster_description": "Papers with molecular or biomarker focus and genetic data", "related_criteria": "Outcome" } ] }, { "id": "50", "title": "Prevalence of Germline Variants in Prostate Cancer and Implications for Current Genetic Testing Guidelines.", "abstract": "IMPORTANCE: Prostate cancer is the third leading cause of cancer-related death in men in the United States. Although serious, most of these diagnoses are not terminal. Inherited risk for prostate cancer is associated with aggressive disease and poorer outcomes, indicating a critical need for increased genetic screening to identify disease-causing variants that can pinpoint individuals at increased risk for metastatic castration-resistant prostate cancer. OBJECTIVE: To identify positive (pathogenic, likely pathogenic, and increased risk) germline variants in a large prostate cancer cohort and to evaluate the usefulness of current practice guidelines in recognizing individuals at increased risk for prostate cancer who would benefit from diagnostic genetic testing. DESIGN, SETTING, AND PARTICIPANTS: Cross-sectional study of data from 3607 men with a personal history of prostate cancer who underwent germline genetic testing between 2013 and 2018 and were unselected for family history, stage of disease, or age at diagnosis. Referral-based testing was performed at a Clinical Laboratory Improvement Amendments/College of American Pathologists-certified diagnostic laboratory. All analysis took place between February 2017 and August 2018. MAIN OUTCOMES AND MEASURES: The frequency and distribution of positive germline variants, and the percentage of individuals with prostate cancer who met National Comprehensive Cancer Network (NCCN) guidelines for germline genetic testing. RESULTS: Of 3607 men (mean [SD] age at testing, 67 [9.51] years; mean age at diagnosis, 60 [9.05] years) with a personal diagnosis of prostate cancer who were referred for genetic testing, 620 (17.2%) had positive germline variants, of which only 30.7% were variants in BRCA1/2. Positive variants in HOXB13, a gene associated only with prostate cancer risk, were identified in 30 patients (4.5%). DNA mismatch repair variants with substantial known therapeutic implications were detected in 1.74% of variants in the total population tested. Examination of self-reported family histories indicated that 229 individuals (37%) with positive variants in this cohort would not have been approved for genetic testing using the NCCN genetic/familial breast and ovarian guidelines for patients with prostate cancer. CONCLUSIONS AND RELEVANCE: Current NCCN guidelines and Gleason scores cannot reliably stratify patients with prostate cancer for the presence or absence of pathogenic germline variants. Most positive genetic test results identified in this study have important management implications for patients and their families, which underscores the need to revisit current guidelines.", "citation": "Nicolosi P, Ledet E, Yang S, Michalski S, Freschi B, O'Leary E, Esplin ED, Nussbaum RL, Sartor O. (2019). Prevalence of Germline Variants in Prostate Cancer and Implications for Current Genetic Testing Guidelines. JAMA oncology. 5(4):523-528. http://doi.org/10.1001/jamaoncol.2018.6760. PMID: 30730552.", "score_list": [ 3.7763915547789093, 3.783710522201922 ], "ai_score_min": 3.7763915547789093, "ai_score_max": 3.783710522201922, "ai_score": 3.7800510384904156, "ai_reasoning": "Moderate relevance. 'Prevalence of Germline Variants in Prostate Cancer...' partially meets inclusion criteria but requires human review for final determination.", "evidence": [ { "text": "who were referred for genetic testing, 620 (17.2%)", "section": "abstract", "criterion": "Population", "supports": "include" }, { "text": "of current practice guidelines in recognizing individuals", "section": "abstract", "criterion": "Study Design", "supports": "include" }, { "text": "of which only 30.7% were variants in BRCA1/2.", "section": "abstract", "criterion": "Outcome", "supports": "include" }, { "text": "Prevalence of Germline Variants in Prostate", "section": "title", "criterion": "Population", "supports": "include" } ], "ai_decision": "include", "assigned_clusters": [ { "cluster_name": "Adult Patient Population", "cluster_type": "include", "cluster_description": "Papers focused on adult patient demographics with defined inclusion criteria", "related_criteria": "Population" }, { "cluster_name": "Biomarker Analysis Studies", "cluster_type": "include", "cluster_description": "Papers with molecular or biomarker focus and genetic data", "related_criteria": "Outcome" } ] }, { "id": "51", "title": "Multigene panel testing in unselected Israeli breast cancer cases: mutational spectrum and use of BRCA1/2 mutation prediction algorithms.", "abstract": "BACKGROUND: Studies assessing the contribution of non-BRCA1/2 gene mutations to inherited breast cancer (BC) predisposition consistently reported low (up to 4%) yield. The current study aimed at assessing the spectrum of non-BRCA mutations in unselected Israeli BC cases and the utility of BRCAPRO and Penn II models, as tools for prediction of detecting non-BRCA1/2 mutations in Israeli BC patients who tested negative for the predominant Jewish BRCA1/2 mutations. METHODS: All consecutive Jewish Israeli BC patients at the Sheba Medical center who tested negative for the predominant BRCA1/2 mutations and elected to perform multigene panel testing were included. For each patient probability of BRCA mutation detection was calculated by the Penn II algorithm and the BRCAPRO tool. RESULTS: Overall, 144 cases were included (median age at diagnosis was 48, range 20-73 years); 48% were Ashkenazim. One patient harbored a non-founder BRCA1 mutation (c.5434C>G; p.P1812A). Pathogenic/likely pathogenic (P/LP) mutations in non-BRCA1/2 genes were detected in additional 14/144 patients, including CHEK2 (n = 5), RAD51D (n = 2), MSH6 (n = 2), and one each in ATM, RET, TP53, NBN, and BAP1. Using a cutoff of 15% probability of BRCA mutation detection, both models accurately predicted the observed carrier rate of non-BRCA mutations. CONCLUSIONS: In unselected Jewish Israeli BC patients, the rate of detecting non-founder BRCA1/2 mutations is low, with CHEK2 mutations detected in 3.4% of cases. BRCA1/2 mutation prediction models may be utilized for selecting patients eligible for further multigene panel testing after exclusion of predominant BRCA1/2 mutations.", "citation": "Bernstein-Molho R, Singer A, Laitman Y, Netzer I, Zalmanoviz S, Friedman E. (2019). Multigene panel testing in unselected Israeli breast cancer cases: mutational spectrum and use of BRCA1/2 mutation prediction algorithms. Breast cancer research and treatment. 176(1):165-170. http://doi.org/10.1007/s10549-019-05228-6. PMID: 30980208.", "score_list": [ 2.3572873204004976, 2.3033467027989025 ], "ai_score_min": 2.3033467027989025, "ai_score_max": 2.3572873204004976, "ai_score": 2.3303170115997, "ai_reasoning": "Weak relevance. 'Multigene panel testing in unselected Israeli brea...' appears tangentially related to the research topic.", "evidence": [ { "text": "Pathogenic/likely pathogenic (P/LP) mutations in", "section": "abstract", "criterion": "Population", "supports": "exclude" }, { "text": "in 3.4% of cases. BRCA1/2 mutation", "section": "abstract", "criterion": "Study Design", "supports": "exclude" }, { "text": "Multigene panel testing in unselected Israeli", "section": "title", "criterion": "Population", "supports": "exclude" } ], "ai_decision": "include", "assigned_clusters": [ { "cluster_name": "Adult Patient Population", "cluster_type": "include", "cluster_description": "Papers focused on adult patient demographics with defined inclusion criteria", "related_criteria": "Population" } ] }, { "id": "52", "title": "High Yield of RNA Sequencing for Targetable Kinase Fusions in Lung Adenocarcinomas with No Mitogenic Driver Alteration Detected by DNA Sequencing and Low Tumor Mutation Burden.", "abstract": "PURPOSE: Targeted next-generation sequencing of DNA has become more widely used in the management of patients with lung adenocarcinoma; however, no clear mitogenic driver alteration is found in some cases. We evaluated the incremental benefit of targeted RNA sequencing (RNAseq) in the identification of gene fusions and EXPERIMENTAL DESIGN: Lung cancers driver negative by MSK-IMPACT underwent further analysis using a custom RNAseq panel (MSK-Fusion). Tumor mutation burden (TMB) was assessed as a potential prioritization criterion for targeted RNAseq. RESULTS: As part of prospective clinical genomic testing, we profiled 2,522 lung adenocarcinomas using MSK-IMPACT, which identified 195 (7.7%) fusions and 119 (4.7%) CONCLUSIONS: Targeted RNAseq assays should be used in all cases that appear driver negative by DNAseq assays to ensure comprehensive detection of actionable gene rearrangements. Furthermore, we observed a significant enrichment for fusions in DNAseq driver-negative samples with low TMB, supporting the prioritization of such cases for additional RNAseq.", "citation": "Benayed R, Offin M, Mullaney K, Sukhadia P, Rios K, Desmeules P, Ptashkin R, Won H, Chang J, Halpenny D, Schram AM, Rudin CM, Hyman DM, Arcila ME, Berger MF, Zehir A, Kris MG, Drilon A, Ladanyi M. (2019). High Yield of RNA Sequencing for Targetable Kinase Fusions in Lung Adenocarcinomas with No Mitogenic Driver Alteration Detected by DNA Sequencing and Low Tumor Mutation Burden. Clinical cancer research : an official journal of the American Association for Cancer Research. 25(15):4712-4722. http://doi.org/10.1158/1078-0432.CCR-19-0225. PMID: 31028088.", "score_list": [ 1.6468963652882518, 1.5286791912175104 ], "ai_score_min": 1.5286791912175104, "ai_score_max": 1.6468963652882518, "ai_score": 1.587787778252881, "ai_reasoning": "Recommend exclusion. 'High Yield of RNA Sequencing for Targetable Kinase...' does not appear to meet core inclusion criteria.", "evidence": [ { "text": "mutation burden (TMB) was assessed as a", "section": "abstract", "criterion": "Population", "supports": "exclude" }, { "text": "incremental benefit of targeted RNA sequencing", "section": "abstract", "criterion": "Study Design", "supports": "exclude" }, { "text": "High Yield of RNA Sequencing for", "section": "title", "criterion": "Population", "supports": "exclude" } ], "ai_decision": "include", "assigned_clusters": [ { "cluster_name": "Methodology & Protocol Only", "cluster_type": "exclude", "cluster_description": "Papers focused on study design and methodology without clinical results", "related_criteria": "Study Design" } ] }, { "id": "53", "title": "A TMEFF2-regulated cell cycle derived gene signature is prognostic of recurrence risk in prostate cancer.", "abstract": "BACKGROUND: The clinical behavior of prostate cancer (PCa) is variable, and while the majority of cases remain indolent, 10% of patients progress to deadly forms of the disease. Current clinical predictors used at the time of diagnosis have limitations to accurately establish progression risk. Here we describe the development of a tumor suppressor regulated, cell-cycle gene expression based prognostic signature for PCa, and validate its independent contribution to risk stratification in several radical prostatectomy (RP) patient cohorts. METHODS: We used RNA interference experiments in PCa cell lines to identify a gene expression based gene signature associated with Tmeff2, an androgen regulated, tumor suppressor gene whose expression shows remarkable heterogeneity in PCa. Gene expression was confirmed by qRT-PCR. Correlation of the signature with disease outcome (time to recurrence) was retrospectively evaluated in four geographically different cohorts of patients that underwent RP (834 samples), using multivariate logistical regression analysis. Multivariate analyses were adjusted for standard clinicopathological variables. Performance of the signature was compared to previously described gene expression based signatures using the SigCheck software. RESULTS: Low levels of TMEFF2 mRNA significantly (p < 0.0001) correlated with reduced disease-free survival (DFS) in patients from the Memorial Sloan Kettering Cancer Center (MSKCC) dataset. We identified a panel of 11 TMEFF2 regulated cell cycle related genes (TMCC11), with strong prognostic value. TMCC11 expression was significantly associated with time to recurrence after prostatectomy in four geographically different patient cohorts (2.9 \u2264 HR \u2265 4.1; p \u2264 0.002), served as an independent indicator of poor prognosis in the four RP cohorts (1.96 \u2264 HR \u2265 4.28; p \u2264 0.032) and improved the prognostic value of standard clinicopathological markers. The prognostic ability of TMCC11 panel exceeded previously published oncogenic gene signatures (p = 0.00017). CONCLUSIONS: This study provides evidence that the TMCC11 gene signature is a robust independent prognostic marker for PCa, reveals the value of using highly heterogeneously expressed genes, like Tmeff2, as guides to discover prognostic indicators, and suggests the possibility that low Tmeff2 expression marks a distinct subclass of PCa.", "citation": "Georgescu C, Corbin JM, Thibivilliers S, Webb ZD, Zhao YD, Koster J, Fung KM, Asch AS, Wren JD, Ruiz-Echevarr\u00eda MJ. (2019). A TMEFF2-regulated cell cycle derived gene signature is prognostic of recurrence risk in prostate cancer. BMC cancer. 19(1):423. http://doi.org/10.1186/s12885-019-5592-6. PMID: 31060542.", "score_list": [ 4.22412029874264, 4.3892454537404415 ], "ai_score_min": 4.22412029874264, "ai_score_max": 4.3892454537404415, "ai_score": 4.30668287624154, "ai_reasoning": "Strong candidate for inclusion. 'A TMEFF2-regulated cell cycle derived gene signatu...' directly addresses research criteria with clear methodology. Keywords suggesting inclusion: outcome, patient, results.", "evidence": [ { "text": "disease. Current clinical predictors", "section": "abstract", "criterion": "Population", "supports": "include" }, { "text": "genes, like Tmeff2, as guides to", "section": "abstract", "criterion": "Study Design", "supports": "include" }, { "text": "dataset. We identified a panel of", "section": "abstract", "criterion": "Outcome", "supports": "include" }, { "text": "prostate cancer (PCa) is variable,", "section": "abstract", "criterion": "Intervention", "supports": "include" }, { "text": "A TMEFF2-regulated cell cycle derived gene", "section": "title", "criterion": "Population", "supports": "include" } ], "ai_decision": "include", "assigned_clusters": [ { "cluster_name": "Treatment Efficacy Studies", "cluster_type": "include", "cluster_description": "Papers evaluating treatment outcomes and efficacy measures", "related_criteria": "Intervention" } ] }, { "id": "55", "title": "Evaluation of Cancer-Based Criteria for Use in Mainstream BRCA1 and BRCA2 Genetic Testing in Patients With Breast Cancer.", "abstract": "IMPORTANCE: Increasing BRCA1 and BRCA2 (collectively termed herein as BRCA) gene testing is required to improve cancer management and prevent BRCA-related cancers. OBJECTIVE: To evaluate mainstream genetic testing using cancer-based criteria in patients with cancer. DESIGN, SETTING, AND PARTICIPANTS: A quality improvement study and cost-effectiveness analysis of different BRCA testing selection criteria and access procedures to evaluate feasibility, acceptability, and mutation detection performance was conducted at the Royal Marsden National Health Service Foundation Trust as part of the Mainstreaming Cancer Genetics (MCG) Programme. Participants included 1184 patients with cancer who were undergoing genetic testing between September 1, 2013, and February 28, 2017. MAIN OUTCOMES AND MEASURES: Mutation rates, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratios were the primary outcomes. RESULTS: Of the 1184 patients (1158 women [97.8%]) meeting simple cancer-based criteria, 117 had a BRCA mutation (9.9%). The mutation rate was similar in retrospective United Kingdom (10.2% [235 of 2294]) and prospective Malaysian (9.7% [103 of 1061]) breast cancer studies. If traditional family history criteria had been used, more than 50% of the mutation-positive individuals would have been missed. Of the 117 mutation-positive individuals, 115 people (98.3%) attended their genetics appointment and cascade to relatives is underway in all appropriate families (85 of 85). Combining with the equivalent ovarian cancer study provides 5 simple cancer-based criteria for BRCA testing with a 10% mutation rate: (1) ovarian cancer; (2) breast cancer diagnosed when patients are 45 years or younger; (3) 2 primary breast cancers, both diagnosed when patients are 60 years or younger; (4) triple-negative breast cancer; and (5) male breast cancer. A sixth criterion-breast cancer plus a parent, sibling, or child with any of the other criteria-can be added to address family history. Criteria 1 through 5 are considered the MCG criteria, and criteria 1 through 6 are considered the MCGplus criteria. Testing using MCG or MCGplus criteria is cost-effective with cost-effectiveness ratios of $1330 per discounted QALYs and $1225 per discounted QALYs, respectively, and appears to lead to cancer and mortality reductions (MCG: 804 cancers, 161 deaths; MCGplus: 1020 cancers, 204 deaths per year over 50 years). Use of MCG or MCGplus criteria might allow detection of all BRCA mutations in patients with breast cancer in the United Kingdom through testing one-third of patients. Feedback questionnaires from 259 patients and 23 cancer team members (12 oncologists, 8 surgeons, and 3 nurse specialists) showed acceptability of the process with 100% of patients pleased they had genetic testing and 100% of cancer team members confident to approve patients for genetic testing. Use of MCGplus criteria also appeared to be time and resource efficient, requiring 95% fewer genetic consultations than the traditional process. CONCLUSIONS AND RELEVANCE: This study suggests that mainstream testing using simple, cancer-based criteria might be able to efficiently deliver consistent, cost-effective, patient-centered BRCA testing.", "citation": "Kemp Z, Turnbull A, Yost S, Seal S, Mahamdallie S, Poyastro-Pearson E, Warren-Perry M, Eccleston A, Tan MM, Teo SH, Turner N, Strydom A, George A, Rahman N. (2019). Evaluation of Cancer-Based Criteria for Use in Mainstream BRCA1 and BRCA2 Genetic Testing in Patients With Breast Cancer. JAMA network open. 2(5):e194428. http://doi.org/10.1001/jamanetworkopen.2019.4428. PMID: 31125106.", "score_list": [ 3.6794896609600083, 3.6296316817060754 ], "ai_score_min": 3.6296316817060754, "ai_score_max": 3.6794896609600083, "ai_score": 3.6545606713330416, "ai_reasoning": "Moderate relevance. 'Evaluation of Cancer-Based Criteria for Use in Mai...' partially meets inclusion criteria but requires human review for final determination.", "evidence": [ { "text": "cancer diagnosed when patients are 45 years or", "section": "abstract", "criterion": "Population", "supports": "include" }, { "text": "115 people (98.3%) attended their genetics appointment", "section": "abstract", "criterion": "Study Design", "supports": "include" }, { "text": "Testing using MCG or", "section": "abstract", "criterion": "Outcome", "supports": "include" }, { "text": "Evaluation of Cancer-Based Criteria for Use", "section": "title", "criterion": "Population", "supports": "include" } ], "ai_decision": "include", "assigned_clusters": [ { "cluster_name": "Adult Patient Population", "cluster_type": "include", "cluster_description": "Papers focused on adult patient demographics with defined inclusion criteria", "related_criteria": "Population" }, { "cluster_name": "Biomarker Analysis Studies", "cluster_type": "include", "cluster_description": "Papers with molecular or biomarker focus and genetic data", "related_criteria": "Outcome" } ] }, { "id": "56", "title": "Budget Impact of Switching to Biosimilar Trastuzumab (CT-P6) for the Treatment of Breast Cancer and Gastric Cancer in 28 European Countries.", "abstract": "BACKGROUND: As the economic burden of treating cancer patients has been soaring in European countries, performing a budget impact analysis is becoming one of the requirements for payers' application dossiers. OBJECTIVE: The objective of this study was to estimate the budgetary impact of introducing the biosimilar trastuzumab (CT-P6) from the payer's perspective and to determine the number of additional patients who could be treated with resulting savings in 28 European countries. METHODS: A budget impact model was developed to analyze the financial impact of switching from originator trastuzumab to biosimilar CT-P6 in the treatment of early and metastatic breast cancer and metastatic gastric cancer with a time horizon of 1-5 years. Budgetary savings and the number of patients potentially affected were measured based on epidemiological and sales volume data. The base-case analysis assumed that the price of CT-P6 is 70% of the originator price, the switching rate of originator to CT-P6 in the first year is 20%, and the annual growth in the switching rate for each subsequent year is 5%. RESULTS: For analyses using the base-case scenario following CT-P6 introduction, the total estimated budgetary savings over a 5-year period (depending on the scenario) ranged from \u20ac1.13 billion to \u20ac2.27 billion based on epidemiological data, or from \u20ac0.91 billion to \u20ac1.82 billion based on sales volume data. In the first year only, the projected budgetary savings ranged from \u20ac58 million to \u20ac136 million, and the number of additional patients who could be treated using the savings ranged from 3503 to 7078 by sensitivity analysis. CONCLUSIONS: The conducted budget impact analysis assessing a switch from originator trastuzumab to biosimilar CT-P6 in 28 European countries indicates that budget savings could be between \u20ac0.91 billion and \u20ac2.27 billion over the next 5 years. These savings could be used to help improve patient access to local biologics in their respective countries while simultaneously strengthening the overall public health landscape across the European Union.", "citation": "Lee SM, Jung JH, Suh D, Jung YS, Yoo SL, Kim DW, Kim JA, Suh DC. (2019). Budget Impact of Switching to Biosimilar Trastuzumab (CT-P6) for the Treatment of Breast Cancer and Gastric Cancer in 28 European Countries. BioDrugs : clinical immunotherapeutics, biopharmaceuticals and gene therapy. 33(4):423-436. http://doi.org/10.1007/s40259-019-00359-0. PMID: 31201616.", "score_list": [ 1.4237195422674676, 1.7209062657217118 ], "ai_score_min": 1.4237195422674676, "ai_score_max": 1.7209062657217118, "ai_score": 1.5723129039945896, "ai_reasoning": "Recommend exclusion. 'Budget Impact of Switching to Biosimilar Trastuzum...' does not appear to meet core inclusion criteria.", "evidence": [ { "text": "each subsequent year is 5%. RESULTS: For analyses", "section": "abstract", "criterion": "Population", "supports": "exclude" }, { "text": "of treating cancer patients has been soaring", "section": "abstract", "criterion": "Study Design", "supports": "exclude" }, { "text": "Budget Impact of Switching to Biosimilar", "section": "title", "criterion": "Population", "supports": "exclude" } ], "ai_decision": "include", "assigned_clusters": [ { "cluster_name": "Methodology & Protocol Only", "cluster_type": "exclude", "cluster_description": "Papers focused on study design and methodology without clinical results", "related_criteria": "Study Design" } ] }, { "id": "57", "title": "Context-Specific Economic Evaluation for Molecular Pathology Tests: An Application in Colorectal Cancer in the West of Scotland.", "abstract": "OBJECTIVES: The cost-effectiveness of molecular pathology testing is highly context dependent. The field is fast-moving, and national health technology assessment may not be relevant or timely for local decision makers. This study illustrates a method of context-specific economic evaluation that can be carried out in a limited timescale without extensive resources. METHODS: We established a multi-disciplinary group including an oncologist, pathologists and a health economist. We set out diagnostic and treatment pathways and costs using registry data, health technology assessments, guidelines, audit data, and estimates from the group. Sensitivity analysis varied input parameters across plausible ranges. The evaluation setting was the West of Scotland and UK NHS perspective was adopted. The evaluation was assessed against the AdHopHTA checklist for hospital-based health technology assessment. RESULTS: A context-specific economic evaluation could be carried out on a timely basis using limited resources. The evaluation met all relevant criteria in the AdHopHTA checklist. Health outcomes were expected to be at least equal to the current strategy. Annual cost savings of \u00a3637,000 were estimated resulting primarily from a reduction in the proportion of patients receiving intravenous infusional chemotherapy regimens. The result was not sensitive to any parameter. The data driving the main cost saving came from a small clinical audit. We recommended this finding was confirmed in a larger population. CONCLUSIONS: The method could be used to evaluate testing changes elsewhere. The results of the case study may be transferable to other jurisdictions where the organization of cancer services is fragmented.", "citation": "Bouttell J, Tan YY, Creed D, McGaffin G, Hawkins N, McLaughlin R, Smith G, Westwood P, Williams N, Graham J. (2019). Context-Specific Economic Evaluation for Molecular Pathology Tests: An Application in Colorectal Cancer in the West of Scotland. International journal of technology assessment in health care. 35(4):327-333. http://doi.org/10.1017/S026646231900045X. PMID: 31292015.", "score_list": [ 1.5025337120765387, 1.5071086258896176 ], "ai_score_min": 1.5025337120765387, "ai_score_max": 1.5071086258896176, "ai_score": 1.5048211689830782, "ai_reasoning": "Recommend exclusion. 'Context-Specific Economic Evaluation for Molecular...' does not appear to meet core inclusion criteria. Exclusion keywords found: guideline.", "evidence": [ { "text": "small clinical audit. We", "section": "abstract", "criterion": "Population", "supports": "exclude" }, { "text": "We set out diagnostic", "section": "abstract", "criterion": "Study Design", "supports": "exclude" }, { "text": "Context-Specific Economic Evaluation for Molecular Pathology", "section": "title", "criterion": "Population", "supports": "exclude" } ], "ai_decision": "include", "assigned_clusters": [ { "cluster_name": "Methodology & Protocol Only", "cluster_type": "exclude", "cluster_description": "Papers focused on study design and methodology without clinical results", "related_criteria": "Study Design" } ] }, { "id": "58", "title": "Treatment with Next-Generation ALK Inhibitors Fuels Plasma", "abstract": "PURPOSE: Acquired resistance to next-generation ALK tyrosine kinase inhibitors (TKIs) is often driven by secondary EXPERIMENTAL DESIGN: We analyzed 106 plasma specimens from 84 patients with advanced RESULTS: By genotyping plasma, we detected an CONCLUSIONS:", "citation": "Dagogo-Jack I, Rooney M, Lin JJ, Nagy RJ, Yeap BY, Hubbeling H, Chin E, Ackil J, Farago AF, Hata AN, Lennerz JK, Gainor JF, Lanman RB, Shaw AT. (2019). Treatment with Next-Generation ALK Inhibitors Fuels Plasma. Clinical cancer research : an official journal of the American Association for Cancer Research. 25(22):6662-6670. http://doi.org/10.1158/1078-0432.CCR-19-1436. PMID: 31358542.", "score_list": [ 3.3209903664518188, 3.1918666701951315 ], "ai_score_min": 3.1918666701951315, "ai_score_max": 3.3209903664518188, "ai_score": 3.2564285183234754, "ai_reasoning": "Moderate relevance. 'Treatment with Next-Generation ALK Inhibitors Fuel...' partially meets inclusion criteria but requires human review for final determination.", "evidence": [ { "text": "patients with advanced RESULTS: By genotyping", "section": "abstract", "criterion": "Population", "supports": "include" }, { "text": "(TKIs) is often driven by", "section": "abstract", "criterion": "Study Design", "supports": "include" }, { "text": "by secondary EXPERIMENTAL DESIGN: We analyzed", "section": "abstract", "criterion": "Outcome", "supports": "include" }, { "text": "Treatment with Next-Generation ALK Inhibitors Fuels", "section": "title", "criterion": "Population", "supports": "include" } ], "ai_decision": "include", "assigned_clusters": [ { "cluster_name": "Adult Patient Population", "cluster_type": "include", "cluster_description": "Papers focused on adult patient demographics with defined inclusion criteria", "related_criteria": "Population" } ] }, { "id": "59", "title": "A systematic review of the international prevalence of", "abstract": "A systematic review was conducted, summarizing international", "citation": "Armstrong N, Ryder S, Forbes C, Ross J, Quek RG. (2019). A systematic review of the international prevalence of. Clinical epidemiology. 11:543-561. http://doi.org/10.2147/CLEP.S206949. PMID: 31372057.", "score_list": [ 1.1796561397958596, 1.0 ], "ai_score_min": 1.0, "ai_score_max": 1.1796561397958596, "ai_score": 1.08982806989793, "ai_reasoning": "Recommend exclusion. 'A systematic review of the international prevalenc...' does not appear to meet core inclusion criteria. Exclusion keywords found: review.", "evidence": [ { "text": "systematic review was conducted, summarizing international", "section": "abstract", "criterion": "Population", "supports": "exclude" }, { "text": "systematic review was conducted, summarizing international", "section": "abstract", "criterion": "Study Design", "supports": "exclude" }, { "text": "A systematic review of the international", "section": "title", "criterion": "Population", "supports": "exclude" } ], "ai_decision": "include", "assigned_clusters": [ { "cluster_name": "Review & Meta-Analysis (No Primary Data)", "cluster_type": "exclude", "cluster_description": "Secondary research synthesizing existing studies without new data", "related_criteria": "Study Design" } ] }, { "id": "60", "title": "Development, Implementation and Assessment of Molecular Diagnostics by Next Generation Sequencing in Personalized Treatment of Cancer: Experience of a Public Reference Healthcare Hospital.", "abstract": "The establishment of precision medicine in cancer patients requires the study of several biomarkers. Single-gene testing approaches are limited by sample availability and turnaround time. Next generation sequencing (NGS) provides an alternative for detecting genetic alterations in several genes with low sample requirements. Here we show the implementation to routine diagnostics of a NGS assay under International Organization for Standardization (UNE-EN ISO 15189:2013) accreditation. For this purpose, 106 non-small cell lung cancer (NSCLC) and 102 metastatic colorectal cancer (mCRC) specimens were selected for NGS analysis with Oncomine Solid Tumor (ThermoFisher). In NSCLC the most prevalently mutated gene was", "citation": "Simarro J, Murria R, P\u00e9rez-Sim\u00f3 G, Llop M, Manche\u00f1o N, Ramos D, Juan I, Barrag\u00e1n E, Laiz B, Cases E, Ans\u00f3tegui E, G\u00f3mez-Codina J, Aparicio J, Salvador C, Juan \u00d3, Palanca S. (2019). Development, Implementation and Assessment of Molecular Diagnostics by Next Generation Sequencing in Personalized Treatment of Cancer: Experience of a Public Reference Healthcare Hospital. Cancers. 11(8). http://doi.org/10.3390/cancers11081196. PMID: 31426418.", "score_list": [ 4.670769319053549, 4.392441385398507 ], "ai_score_min": 4.392441385398507, "ai_score_max": 4.670769319053549, "ai_score": 4.531605352226028, "ai_reasoning": "Strong candidate for inclusion. 'Development, Implementation and Assessment of Mole...' directly addresses research criteria with clear methodology. Keywords suggesting inclusion: treatment, patient, study.", "evidence": [ { "text": "turnaround time. Next generation", "section": "abstract", "criterion": "Population", "supports": "include" }, { "text": "of precision medicine in cancer", "section": "abstract", "criterion": "Study Design", "supports": "include" }, { "text": "this purpose, 106 non-small cell lung cancer", "section": "abstract", "criterion": "Outcome", "supports": "include" }, { "text": "Solid Tumor (ThermoFisher). In", "section": "abstract", "criterion": "Intervention", "supports": "include" }, { "text": "Development, Implementation and Assessment of Molecular", "section": "title", "criterion": "Population", "supports": "include" } ], "ai_decision": "include", "assigned_clusters": [ { "cluster_name": "Treatment Efficacy Studies", "cluster_type": "include", "cluster_description": "Papers evaluating treatment outcomes and efficacy measures", "related_criteria": "Intervention" }, { "cluster_name": "Biomarker Analysis Studies", "cluster_type": "include", "cluster_description": "Papers with molecular or biomarker focus and genetic data", "related_criteria": "Outcome" } ] }, { "id": "61", "title": "Targeted Gene Next-Generation Sequencing Panel in Patients with Advanced Lung Adenocarcinoma: Paving the Way for Clinical Implementation.", "abstract": "Identification of targetable molecular changes is essential for selecting appropriate treatment in patients with advanced lung adenocarcinoma.", "citation": "Fernandes MGO, Jacob M, Martins N, Moura CS, Guimar\u00e3es S, Reis JP, Justino A, Pina MJ, Cirnes L, Sousa C, Pinto J, Marques JA, Machado JC, Hespanhol V, Costa JL. (2019). Targeted Gene Next-Generation Sequencing Panel in Patients with Advanced Lung Adenocarcinoma: Paving the Way for Clinical Implementation. Cancers. 11(9). http://doi.org/10.3390/cancers11091229. PMID: 31443496.", "score_list": [ 2.0189095658470158, 1.9814665183916034 ], "ai_score_min": 1.9814665183916034, "ai_score_max": 2.0189095658470158, "ai_score": 2.0001880421193095, "ai_reasoning": "Weak relevance. 'Targeted Gene Next-Generation Sequencing Panel in ...' appears tangentially related to the research topic.", "evidence": [ { "text": "in patients with advanced", "section": "abstract", "criterion": "Population", "supports": "exclude" }, { "text": "essential for selecting appropriate treatment in patients with", "section": "abstract", "criterion": "Study Design", "supports": "exclude" }, { "text": "Targeted Gene Next-Generation Sequencing Panel in", "section": "title", "criterion": "Population", "supports": "exclude" } ], "ai_decision": "include", "assigned_clusters": [ { "cluster_name": "Adult Patient Population", "cluster_type": "include", "cluster_description": "Papers focused on adult patient demographics with defined inclusion criteria", "related_criteria": "Population" }, { "cluster_name": "Biomarker Analysis Studies", "cluster_type": "include", "cluster_description": "Papers with molecular or biomarker focus and genetic data", "related_criteria": "Outcome" } ] }, { "id": "62", "title": "Biomarkers of Targeted Therapy and Immuno-Oncology in Cancers Metastatic to the Breast.", "abstract": "The breast is a rare site for metastases, and their molecular characteristics have not been studied yet. Intrinsic molecular genetics, cancer characteristics, and breast tissue immune responses in diverse metastases to the breast have not been previously studied. We identified 64 patients with cancers metastatic to the breast: 51 carcinomas and 13 melanomas. Programmed death ligand 1 (PD-L1), steroid receptors, and HER2/neu expressions were evaluated using immunohistochemistry. Gene sequencing, copy number alterations, microsatellite instability, and tumor mutational burden were performed using next-generation sequencing platforms. The 3 most common primary sites for metastatic carcinomas were lung (37%), ovary (29%), and fallopian tubes/peritoneum (14%). TP53 mutations were commonly (50%) observed among the carcinoma cases, while other mutations were characteristic for the primary cancers (VHL in renal, BRCA1 in the fallopian tube, and BRAF in melanomas). High tumor mutational burden was detected in 5/14 carcinomas and 3/7 melanomas. Tumor cell PD-L1 expression was detected in 6 carcinomas, but not in any of the melanomas, whereas immune cells' expression of PD-L1 was seen in 17 carcinomas and 6 melanomas. Estrogen receptor status was positive in 13/49 carcinomas including 12 adenocarcinomas originating from the ovary and fallopian tube or peritoneum and 1 duodenal neuroendocrine carcinoma. No carcinoma was HER2/neu positive. Intrinsic genetic characteristics of the metastases to the breast followed the pattern commonly seen in primary tumors. Biomarkers of potential benefit to immune checkpoint inhibition therapy were limited to PD-L1-positive non-small cell lung cancer. No common characteristics of the heterogeneous group of tumor metastases to this organ were identified.", "citation": "Vranic S, Senarathne W, Stafford P, Poorman K, Pockaj BA, Gatalica Z. (2020). Biomarkers of Targeted Therapy and Immuno-Oncology in Cancers Metastatic to the Breast. Applied immunohistochemistry & molecular morphology : AIMM. 28(9):661-668. http://doi.org/10.1097/PAI.0000000000000808. PMID: 31517642.", "score_list": [ 2.946395572899254, 2.7491431071018146 ], "ai_score_min": 2.7491431071018146, "ai_score_max": 2.946395572899254, "ai_score": 2.8477693400005344, "ai_reasoning": "Weak relevance. 'Biomarkers of Targeted Therapy and Immuno-Oncology...' appears tangentially related to the research topic.", "evidence": [ { "text": "tissue immune responses in diverse", "section": "abstract", "criterion": "Population", "supports": "exclude" }, { "text": "in 5/14 carcinomas and", "section": "abstract", "criterion": "Study Design", "supports": "exclude" }, { "text": "Biomarkers of Targeted Therapy and Immuno-Oncology", "section": "title", "criterion": "Population", "supports": "exclude" } ], "ai_decision": "include", "assigned_clusters": [ { "cluster_name": "Adult Patient Population", "cluster_type": "include", "cluster_description": "Papers focused on adult patient demographics with defined inclusion criteria", "related_criteria": "Population" }, { "cluster_name": "Biomarker Analysis Studies", "cluster_type": "include", "cluster_description": "Papers with molecular or biomarker focus and genetic data", "related_criteria": "Outcome" } ] }, { "id": "63", "title": "Microsatellite instability detection using a large next-generation sequencing cancer panel across diverse tumour types.", "abstract": "AIM: Microsatellite instability (MSI), a hallmark of DNA mismatch repair deficiency, is a key molecular biomarker with multiple clinical implications including the selection of patients for immunotherapy, identifying patients who may have Lynch syndrome and predicting prognosis in patients with colorectal tumours. Next-generation sequencing (NGS) provides the opportunity to interrogate large numbers of microsatellite loci concurrently with genomic variants. We sought to develop a method to detect MSI that would not require paired normal tissue and would leverage the sequence data obtained from a broad range of tumours tested using our 467-gene NGS Columbia Combined Cancer Panel (CCCP). METHODS: Altered mononucleotide and dinucleotide microsatellite loci across the CCCP region of interest were evaluated in clinical samples encompassing a diverse range of tumour types. The number of altered loci was used to develop a decision tree classifier model trained on the retrospectively collected cohort of 107 clinical cases sequenced by the CCCP assay. RESULTS: The classifier was able to correctly classify all cases and was then used to analyse a test set of clinical cases (n=112) and was able to correctly predict their MSI status with 100% sensitivity and specificity. Analysis of recurrently altered loci identified alterations in genes involved in DNA repair, signalling and transcriptional regulation pathways, many of which have been implicated in MSI tumours. CONCLUSION: This study highlights the utility of this approach, which should be applicable to laboratories performing similar testing.", "citation": "Pang J, Gindin T, Mansukhani M, Fernandes H, Hsiao S. (2020). Microsatellite instability detection using a large next-generation sequencing cancer panel across diverse tumour types. Journal of clinical pathology. 73(2):83-89. http://doi.org/10.1136/jclinpath-2019-206136. PMID: 31530574.", "score_list": [ 1.4921012519140888, 1.1667061422511535 ], "ai_score_min": 1.1667061422511535, "ai_score_max": 1.4921012519140888, "ai_score": 1.329403697082621, "ai_reasoning": "Recommend exclusion. 'Microsatellite instability detection using a large...' does not appear to meet core inclusion criteria.", "evidence": [ { "text": "the utility of this approach, which", "section": "abstract", "criterion": "Population", "supports": "exclude" }, { "text": "highlights the utility of this approach,", "section": "abstract", "criterion": "Study Design", "supports": "exclude" }, { "text": "Microsatellite instability detection using a large", "section": "title", "criterion": "Population", "supports": "exclude" } ], "ai_decision": "include", "assigned_clusters": [ { "cluster_name": "Methodology & Protocol Only", "cluster_type": "exclude", "cluster_description": "Papers focused on study design and methodology without clinical results", "related_criteria": "Study Design" } ] }, { "id": "64", "title": "Tumor-derived DNA from pleural effusion supernatant as a promising alternative to tumor tissue in genomic profiling of advanced lung cancer.", "abstract": "Pleural effusion (PE) is commonly observed in advanced lung cancer and was suggested to contain both cell-free tumor DNA and tumor cells. Molecular profiling of PE represents a minimally invasive approach of detecting tumor driver mutations for clinical decision making, especially when tumor tissues are not available. The objective of this study is to investigate the efficacy and precision of detecting gene alterations in PE samples to address the feasibility in clinical use.", "citation": "Tong L, Ding N, Tong X, Li J, Zhang Y, Wang X, Xu X, Ye M, Li C, Wu X, Bao H, Zhang X, Hong Q, Song Y, Shao YW, Bai C, Zhou J, Hu J. (2019). Tumor-derived DNA from pleural effusion supernatant as a promising alternative to tumor tissue in genomic profiling of advanced lung cancer. Theranostics. 9(19):5532-5541. http://doi.org/10.7150/thno.34070. PMID: 31534501.", "score_list": [ 1.0411342756386235, 1.0773083191245996 ], "ai_score_min": 1.0411342756386235, "ai_score_max": 1.0773083191245996, "ai_score": 1.0592212973816115, "ai_reasoning": "Recommend exclusion. 'Tumor-derived DNA from pleural effusion supernatan...' does not appear to meet core inclusion criteria.", "evidence": [ { "text": "precision of detecting gene alterations in PE", "section": "abstract", "criterion": "Population", "supports": "exclude" }, { "text": "Pleural effusion (PE) is commonly observed", "section": "abstract", "criterion": "Study Design", "supports": "exclude" }, { "text": "Tumor-derived DNA from pleural effusion supernatant", "section": "title", "criterion": "Population", "supports": "exclude" } ], "ai_decision": "include", "assigned_clusters": [ { "cluster_name": "Methodology & Protocol Only", "cluster_type": "exclude", "cluster_description": "Papers focused on study design and methodology without clinical results", "related_criteria": "Study Design" } ] }, { "id": "65", "title": "Integrating a Next Generation Sequencing Panel into Clinical Practice in Ovarian Cancer.", "abstract": "PURPOSE: Few efforts have been made to integrate a next generation sequencing (NGS) panel into standard clinical treatment of ovarian cancer. The aim of this study was to investigate the clinical utility of NGS and to identify clinically impactful information beyond targetable alterations. MATERIALS AND METHODS: We conducted a retrospective review of 84 patients with ovarian cancer who underwent NGS between March 1, 2017, and July 31, 2018, at the Yonsei Cancer Hospital. We extracted DNA from formalin-fixed, paraffin-embedded tissue samples of ovarian cancer. The TruSight Tumor 170 gene panel was used to prepare libraries, and the MiSeq instrument was used for NGS. RESULTS: Of the 84 patients, 55 (65.1%) had high-grade serous carcinomas. Seventy-three (86.7%) patients underwent NGS at the time of diagnosis, and 11 (13.3%) underwent NGS upon relapse. The most common genetic alterations were in CONCLUSION: Implementation of NGS may help in identifying patients who might benefit from targeted treatment therapies and genetic counseling.", "citation": "Lee YJ, Kim D, Kim HS, Na K, Lee JY, Nam EJ, Kim SW, Kim S, Kim YT. (2019). Integrating a Next Generation Sequencing Panel into Clinical Practice in Ovarian Cancer. Yonsei medical journal. 60(10):914-923. http://doi.org/10.3349/ymj.2019.60.10.914. PMID: 31538426.", "score_list": [ 2.1882275609276403, 2.279477455961784 ], "ai_score_min": 2.1882275609276403, "ai_score_max": 2.279477455961784, "ai_score": 2.233852508444712, "ai_reasoning": "Weak relevance. 'Integrating a Next Generation Sequencing Panel int...' appears tangentially related to the research topic. Potential exclusion indicators: review.", "evidence": [ { "text": "from targeted treatment therapies and", "section": "abstract", "criterion": "Population", "supports": "exclude" }, { "text": "and to identify clinically", "section": "abstract", "criterion": "Study Design", "supports": "exclude" }, { "text": "Integrating a Next Generation Sequencing Panel", "section": "title", "criterion": "Population", "supports": "exclude" } ], "ai_decision": "include", "assigned_clusters": [ { "cluster_name": "Adult Patient Population", "cluster_type": "include", "cluster_description": "Papers focused on adult patient demographics with defined inclusion criteria", "related_criteria": "Population" }, { "cluster_name": "Biomarker Analysis Studies", "cluster_type": "include", "cluster_description": "Papers with molecular or biomarker focus and genetic data", "related_criteria": "Outcome" } ] }, { "id": "66", "title": "Mutational Profile in Vulvar, Vaginal, and Urethral Melanomas: Review of 37 Cases With Focus on Primary Tumor Site.", "abstract": "Melanomas of female genital tract are rare tumors with poor prognosis. While BRAF-V600E is the most common pathogenic mutation seen in cutaneous sun-exposed melanomas, mucosal and anogenital melanomas usually lack BRAF mutations and instead they harbor KIT alterations. The American Joint Committee on Cancer staging guideline (AJCC eighth edition) recommends using cutaneous melanoma guidelines for vulvar melanoma staging and does not provide any recommendations for vaginal melanoma staging. The aim of this study is to investigate the mutational status of invasive melanomas arising from different anatomic sites in lower female genital tract (vulvar hair-bearing skin, glabrous skin, vagina and urethra) in a group of 37 patients. Tumors were analyzed using a DNA targeted next-generation sequencing panel covering the 21 most common genes and mutation hotspots in melanomas. The most common genetic alterations in invasive melanomas of lower female genital tract are KIT (32%), TP53 (22%), and NF1 (19%). Overall 66% (21/32) of cases showed a pathogenic alteration in at least one of the MAPK pathway genes. No statistical significance seen between different primary tumor sites and the frequency of the oncogenic mutations, nor were any significant differences found by mutation status. Only one case of urethral melanoma showed a BRAF non-V600E mutation (D594G). Our results suggest a similar molecular pathogenesis and overall survival in melanomas arising from lower female genital tract, irrespective of their exact location in the urogenital area. Future classifications of melanoma should consider grouping vulvar melanomas with mucosal rather than cutaneous melanomas.", "citation": "Zarei S, Voss JS, Jin L, Jenkins SM, Bryce AH, Erickson LA, Bell DA, Kipp BR, Flotte TJ. (2020). Mutational Profile in Vulvar, Vaginal, and Urethral Melanomas: Review of 37 Cases With Focus on Primary Tumor Site. International journal of gynecological pathology : official journal of the International Society of Gynecological Pathologists. 39(6):587-594. http://doi.org/10.1097/PGP.0000000000000636. PMID: 31567539.", "score_list": [ 3.2771614624991554, 3.609228809305463 ], "ai_score_min": 3.2771614624991554, "ai_score_max": 3.609228809305463, "ai_score": 3.443195135902309, "ai_reasoning": "Moderate relevance. 'Mutational Profile in Vulvar, Vaginal, and Urethra...' partially meets inclusion criteria but requires human review for final determination.", "evidence": [ { "text": "of cases showed a pathogenic alteration in at", "section": "abstract", "criterion": "Population", "supports": "include" }, { "text": "37 patients. Tumors were analyzed using a DNA", "section": "abstract", "criterion": "Study Design", "supports": "include" }, { "text": "melanomas usually lack BRAF mutations and", "section": "abstract", "criterion": "Outcome", "supports": "include" }, { "text": "Mutational Profile in Vulvar, Vaginal, and", "section": "title", "criterion": "Population", "supports": "include" } ], "ai_decision": "include", "assigned_clusters": [ { "cluster_name": "Adult Patient Population", "cluster_type": "include", "cluster_description": "Papers focused on adult patient demographics with defined inclusion criteria", "related_criteria": "Population" }, { "cluster_name": "Biomarker Analysis Studies", "cluster_type": "include", "cluster_description": "Papers with molecular or biomarker focus and genetic data", "related_criteria": "Outcome" } ] }, { "id": "67", "title": "A Cost-effectiveness Analysis of Multigene Testing for All Patients With Breast Cancer.", "abstract": "IMPORTANCE: Moving to multigene testing for all women with breast cancer (BC) could identify many more mutation carriers who can benefit from precision prevention. However, the cost-effectiveness of this approach remains unaddressed. OBJECTIVE: To estimate incremental lifetime effects, costs, and cost-effectiveness of multigene testing of all patients with BC compared with the current practice of genetic testing (BRCA) based on family history (FH) or clinical criteria. DESIGN, SETTING, AND PARTICIPANTS: This cost-effectiveness microsimulation modeling study compared lifetime costs and effects of high-risk BRCA1/BRCA2/PALB2 (multigene) testing of all unselected patients with BC (strategy A) with BRCA1/BRCA2 testing based on FH or clinical criteria (strategy B) in United Kingdom (UK) and US populations. Data were obtained from 11 836 patients in population-based BC cohorts (regardless of FH) recruited to 4 large research studies. Data were collected and analyzed from January 1, 2018, through June 8, 2019. The time horizon is lifetime. Payer and societal perspectives are presented. Probabilistic and 1-way sensitivity analyses evaluate model uncertainty. INTERVENTIONS: In strategy A, all women with BC underwent BRCA1/BRCA2/PALB2 testing. In strategy B, only women with BC fulfilling FH or clinical criteria underwent BRCA testing. Affected BRCA/PALB2 carriers could undertake contralateral preventive mastectomy; BRCA carriers could choose risk-reducing salpingo-oophorectomy (RRSO). Relatives of mutation carriers underwent cascade testing. Unaffected relative carriers could undergo magnetic resonance imaging or mammography screening, chemoprevention, or risk-reducing mastectomy for BC risk and RRSO for ovarian cancer (OC) risk. MAIN OUTCOMES AND MEASURES: Incremental cost-effectiveness ratio (ICER) was calculated as incremental cost per quality-adjusted life-year (QALY) gained and compared with standard \u00a330 000/QALY and $100 000/QALY UK and US thresholds, respectively. Incidence of OC, BC, excess deaths due to heart disease, and the overall population effects were estimated. RESULTS: BRCA1/BRCA2/PALB2 multigene testing for all patients detected with BC annually would cost \u00a310 464/QALY (payer perspective) or \u00a37216/QALY (societal perspective) in the United Kingdom or $65 661/QALY (payer perspective) or $61 618/QALY (societal perspective) in the United States compared with current BRCA testing based on clinical criteria or FH. This is well below UK and US cost-effectiveness thresholds. In probabilistic sensitivity analysis, unselected multigene testing remained cost-effective for 98% to 99% of UK and 64% to 68% of US health system simulations. One year's unselected multigene testing could prevent 2101 cases of BC and OC and 633 deaths in the United Kingdom and 9733 cases of BC and OC and 2406 deaths in the United States. Correspondingly, 8 excess deaths due to heart disease occurred in the United Kingdom and 35 in the United States annually. CONCLUSIONS AND RELEVANCE: This study found unselected, high-risk multigene testing for all patients with BC to be extremely cost-effective compared with testing based on FH or clinical criteria for UK and US health systems. These findings support changing current policy to expand genetic testing to all women with BC.", "citation": "Sun L, Brentnall A, Patel S, Buist DSM, Bowles EJA, Evans DGR, Eccles D, Hopper J, Li S, Southey M, Duffy S, Cuzick J, Dos Santos Silva I, Miners A, Sadique Z, Yang L, Legood R, Manchanda R. (2019). A Cost-effectiveness Analysis of Multigene Testing for All Patients With Breast Cancer. JAMA oncology. 5(12):1718-1730. http://doi.org/10.1001/jamaoncol.2019.3323. PMID: 31580391.", "score_list": [ 2.549633351495596, 2.6391890242218783 ], "ai_score_min": 2.549633351495596, "ai_score_max": 2.6391890242218783, "ai_score": 2.594411187858737, "ai_reasoning": "Weak relevance. 'A Cost-effectiveness Analysis of Multigene Testing...' appears tangentially related to the research topic.", "evidence": [ { "text": "screening, chemoprevention, or risk-reducing mastectomy for BC", "section": "abstract", "criterion": "Population", "supports": "exclude" }, { "text": "the United States annually. CONCLUSIONS", "section": "abstract", "criterion": "Study Design", "supports": "exclude" }, { "text": "A Cost-effectiveness Analysis of Multigene Testing", "section": "title", "criterion": "Population", "supports": "exclude" } ], "ai_decision": "include", "assigned_clusters": [ { "cluster_name": "Adult Patient Population", "cluster_type": "include", "cluster_description": "Papers focused on adult patient demographics with defined inclusion criteria", "related_criteria": "Population" }, { "cluster_name": "Biomarker Analysis Studies", "cluster_type": "include", "cluster_description": "Papers with molecular or biomarker focus and genetic data", "related_criteria": "Outcome" } ] }, { "id": "68", "title": "Clinical Utility of a Fully Automated Microsatellite Instability Test with Minimal Hands-on Time.", "abstract": "BACKGROUND: Microsatellite instability (MSI) analysis is becoming increasingly important in many types of tumor including colorectal cancer (CRC). The commonly used MSI tests are either time-consuming or labor-intensive. A fully automated MSI test, the Idylla MSI assay, has recently been introduced. However, its diagnostic performance has not been extensively validated in clinical CRC samples. METHODS: We evaluated 133 samples whose MSI status had been rigorously validated by standard polymerase chain reaction (PCR), clinical nextgeneration sequencing (NGS) cancer panel test, or both. We evaluated the diagnostic performance of the Idylla MSI assay in terms of sensitivity, specificity, and positive and negative predictive values, as well as various sample requirements, such as minimum tumor purity and the quality of paraffin blocks. RESULTS: Compared with the gold standard results confirmed through both PCR MSI test and NGS, the Idylla MSI assay showed 99.05% accuracy (104/105), 100% sensitivity (11/11), 98.94% specificity (93/94), 91.67% positive predictive value (11/12), and 100% negative predictive value (93/93). In addition, the Idylla MSI assay did not require macro-dissection in most samples and reliably detected MSI-high in samples with approximately 10% tumor purity. The total turnaround time was about 150 minutes and the hands-on time was less than 2 minutes. CONCLUSIONS: The Idylla MSI assay shows good diagnostic performance that is sufficient for its implementation in the clinic to determine the MSI status of at least the CRC samples. In addition, the fully automated procedure requires only a few slices of formalin-fixed paraffin-embedded tissue and might greatly save time and labor.", "citation": "Lee M, Chun SM, Sung CO, Kim SY, Kim TW, Jang SJ, Kim J. (2019). Clinical Utility of a Fully Automated Microsatellite Instability Test with Minimal Hands-on Time. Journal of pathology and translational medicine. 53(6):386-392. http://doi.org/10.4132/jptm.2019.09.25. PMID: 31606978.", "score_list": [ 2.5408445388722405, 2.530662933781744 ], "ai_score_min": 2.530662933781744, "ai_score_max": 2.5408445388722405, "ai_score": 2.535753736326992, "ai_reasoning": "Weak relevance. 'Clinical Utility of a Fully Automated Microsatelli...' appears tangentially related to the research topic.", "evidence": [ { "text": "specificity (93/94), 91.67% positive predictive value (11/12), and", "section": "abstract", "criterion": "Population", "supports": "exclude" }, { "text": "many types of tumor", "section": "abstract", "criterion": "Study Design", "supports": "exclude" }, { "text": "Clinical Utility of a Fully Automated", "section": "title", "criterion": "Population", "supports": "exclude" } ], "ai_decision": "include", "assigned_clusters": [ { "cluster_name": "Methodology & Protocol Only", "cluster_type": "exclude", "cluster_description": "Papers focused on study design and methodology without clinical results", "related_criteria": "Study Design" } ] }, { "id": "69", "title": "New Insights into the Epidemiology of Prostate Cancer in Ontario.", "abstract": "The epidemiology of prostate cancer (PC) continues to change. We evaluated the changes in incidence, in average age at diagnosis, and in survival from 1992 to 2015 in Ontario. We compared the cumulative incidence of PC-specific and non PC-specific mortality using two algorithms for cause of death: Method 1 assigned deaths from \"other cancers\" to non PC-specific causes, and Method 2 assigned these cases to PC-specific mortality. There were 188,714 cases diagnosed with PC between 1992 and 2015 in Ontario. The average age at diagnosis declined from 1992 to 2008 by 0.26 year (3.1 months) annually (", "citation": "Abrahamyan L, Huszti E, Bremner KE, Pechlivanoglou P, Mitsakakis N, Krahn M. (2019). New Insights into the Epidemiology of Prostate Cancer in Ontario. Cancer investigation. 37(10):513-523. http://doi.org/10.1080/07357907.2019.1682154. PMID: 31617759.", "score_list": [ 2.2806629135642376, 2.2066758558866564 ], "ai_score_min": 2.2066758558866564, "ai_score_max": 2.2806629135642376, "ai_score": 2.2436693847254467, "ai_reasoning": "Weak relevance. 'New Insights into the Epidemiology of Prostate Can...' appears tangentially related to the research topic.", "evidence": [ { "text": "in Ontario. The average age", "section": "abstract", "criterion": "Population", "supports": "exclude" }, { "text": "for cause of death: Method", "section": "abstract", "criterion": "Study Design", "supports": "exclude" }, { "text": "New Insights into the Epidemiology of", "section": "title", "criterion": "Population", "supports": "exclude" } ], "ai_decision": "include", "assigned_clusters": [ { "cluster_name": "Adult Patient Population", "cluster_type": "include", "cluster_description": "Papers focused on adult patient demographics with defined inclusion criteria", "related_criteria": "Population" }, { "cluster_name": "Biomarker Analysis Studies", "cluster_type": "include", "cluster_description": "Papers with molecular or biomarker focus and genetic data", "related_criteria": "Outcome" } ] }, { "id": "70", "title": "Pan-cancer whole-genome analyses of metastatic solid tumours.", "abstract": "Metastatic cancer is a major cause of death and is associated with poor treatment efficacy. A better understanding of the characteristics of late-stage cancer is required to help adapt personalized treatments, reduce overtreatment and improve outcomes. Here we describe the largest, to our knowledge, pan-cancer study of metastatic solid tumour genomes, including whole-genome sequencing data for 2,520 pairs of tumour and normal tissue, analysed at median depths of 106\u00d7 and 38\u00d7, respectively, and surveying more than 70 million somatic variants. The characteristic mutations of metastatic lesions varied widely, with mutations that reflect those of the primary tumour types, and with high rates of whole-genome duplication events (56%). Individual metastatic lesions were relatively homogeneous, with the vast majority (96%) of driver mutations being clonal and up to 80% of tumour-suppressor genes being inactivated bi-allelically by different mutational mechanisms. Although metastatic tumour genomes showed similar mutational landscape and driver genes to primary tumours, we find characteristics that could contribute to responsiveness to therapy or resistance in individual patients. We implement an approach for the review of clinically relevant associations and their potential for actionability. For 62% of patients, we identify genetic variants that may be used to stratify patients towards therapies that either have been approved or are in clinical trials. This demonstrates the importance of comprehensive genomic tumour profiling for precision medicine in cancer.", "citation": "Priestley P, Baber J, Lolkema MP, Steeghs N, de Bruijn E, Shale C, Duyvesteyn K, Haidari S, van Hoeck A, Onstenk W, Roepman P, Voda M, Bloemendal HJ, Tjan-Heijnen VCG, van Herpen CML, Labots M, Witteveen PO, Smit EF, Sleijfer S, Voest EE, Cuppen E. (2019). Pan-cancer whole-genome analyses of metastatic solid tumours. Nature. 575(7781):210-216. http://doi.org/10.1038/s41586-019-1689-y. PMID: 31645765.", "score_list": [ 3.462643894151169, 3.1568269020367974 ], "ai_score_min": 3.1568269020367974, "ai_score_max": 3.462643894151169, "ai_score": 3.3097353980939834, "ai_reasoning": "Moderate relevance. 'Pan-cancer whole-genome analyses of metastatic sol...' partially meets inclusion criteria but requires human review for final determination.", "evidence": [ { "text": "that could contribute to responsiveness to therapy", "section": "abstract", "criterion": "Population", "supports": "include" }, { "text": "and surveying more than 70 million", "section": "abstract", "criterion": "Study Design", "supports": "include" }, { "text": "with high rates of", "section": "abstract", "criterion": "Outcome", "supports": "include" }, { "text": "Pan-cancer whole-genome analyses of metastatic solid", "section": "title", "criterion": "Population", "supports": "include" } ], "ai_decision": "include", "assigned_clusters": [ { "cluster_name": "Adult Patient Population", "cluster_type": "include", "cluster_description": "Papers focused on adult patient demographics with defined inclusion criteria", "related_criteria": "Population" }, { "cluster_name": "Biomarker Analysis Studies", "cluster_type": "include", "cluster_description": "Papers with molecular or biomarker focus and genetic data", "related_criteria": "Outcome" } ] }, { "id": "71", "title": "Detection of Targetable Genetic Alterations in Korean Lung Cancer Patients: A Comparison Study of Single-Gene Assays and Targeted Next-Generation Sequencing.", "abstract": "PURPOSE: Epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), and ROS proto-oncogene 1 (ROS1) are 'must-test' biomarkers in the molecular diagnostics of advanced-stage lung cancer patients. Although single-gene assays are currently considered the gold standard for these genes, next-generation sequencing (NGS) tests are being introduced to clinical practices. We compared the results of current diagnostics and aimed to suggest timely effective guidance for their clinical use. MATERIALS AND METHODS: Patients with lung cancer who received both conventional single-gene assays and subsequent targeted NGS testing were enrolled, and the results of their tests were compared. RESULTS: A total of 241 patients were enrolled, and the EGFR real-time polymerase chain reaction, ALK fluorescence in situ hybridization (FISH), and ROS1 FISH assays exhibited 92.9%, 99.6%, and 99.5% concordance with the NGS tests, respectively. The discordant cases were mostly false-negatives of the single-gene assays, probably due to technical limitation. Of 158 cases previously designated as wild-type, EGFR, ALK, and ROS1 alterations were identified in 10.1%, 1.9%, and 1.3%, respectively, and other targetable alterations were identified in 36.1% of the cases. Of patients with additionally identified actionable alterations, 32.6% (31/95) received matched therapy with a clinical benefit of 48.4% (15/31). CONCLUSION: Even though the conventional and NGS methods were concordant in the majority of cases, NGS testing still revealed a considerable number of additional EGFR, ALK, and ROS1 alterations, as well as other targetable alterations, in Korean advanced-stage lung cancer patients. Given the high frequency of EGFR and other targetable mutations identified in the present study, NGS testing is highly recommended in the diagnosis of Korean lung cancer patients.", "citation": "Park E, Shim HS. (2020). Detection of Targetable Genetic Alterations in Korean Lung Cancer Patients: A Comparison Study of Single-Gene Assays and Targeted Next-Generation Sequencing. Cancer research and treatment. 52(2):543-551. http://doi.org/10.4143/crt.2019.305. PMID: 31726498.", "score_list": [ 2.7748026370099024, 3.005944724671471 ], "ai_score_min": 2.7748026370099024, "ai_score_max": 3.005944724671471, "ai_score": 2.8903736808406864, "ai_reasoning": "Weak relevance. 'Detection of Targetable Genetic Alterations in Kor...' appears tangentially related to the research topic.", "evidence": [ { "text": "1.3%, respectively, and other targetable", "section": "abstract", "criterion": "Population", "supports": "exclude" }, { "text": "compared. RESULTS: A total of", "section": "abstract", "criterion": "Study Design", "supports": "exclude" }, { "text": "Detection of Targetable Genetic Alterations in", "section": "title", "criterion": "Population", "supports": "exclude" } ], "ai_decision": "include", "assigned_clusters": [ { "cluster_name": "Adult Patient Population", "cluster_type": "include", "cluster_description": "Papers focused on adult patient demographics with defined inclusion criteria", "related_criteria": "Population" }, { "cluster_name": "Biomarker Analysis Studies", "cluster_type": "include", "cluster_description": "Papers with molecular or biomarker focus and genetic data", "related_criteria": "Outcome" } ] }, { "id": "72", "title": "Genomic Characterization of Cholangiocarcinoma in Primary Sclerosing Cholangitis Reveals Therapeutic Opportunities.", "abstract": "BACKGROUND AND AIMS: Lifetime risk of biliary tract cancer (BTC) in primary sclerosing cholangitis (PSC) may exceed 20%, and BTC is currently the leading cause of death in patients with PSC. To open new avenues for management, we aimed to delineate clinically relevant genomic and pathological features of a large panel of PSC-associated BTC (PSC-BTC). APPROACH AND RESULTS: We analyzed formalin-fixed, paraffin-embedded tumor tissue from 186 patients with PSC-BTC from 11 centers in eight countries with all anatomical locations included. We performed tumor DNA sequencing at 42 clinically relevant genetic loci to detect mutations, translocations, and copy number variations, along with histomorphological and immunohistochemical characterization. Regardless of the anatomical localization, PSC-BTC exhibited a uniform molecular and histological characteristic similar to extrahepatic cholangiocarcinoma. We detected a high frequency of genomic alterations typical of extrahepatic cholangiocarcinoma, such as TP53 (35.5%), KRAS (28.0%), CDKN2A (14.5%), and SMAD4 (11.3%), as well as potentially druggable mutations (e.g., HER2/ERBB2). We found a high frequency of nontypical/nonductal histomorphological subtypes (55.2%) and of the usually rare BTC precursor lesion, intraductal papillary neoplasia (18.3%). CONCLUSIONS: Genomic alterations in PSC-BTC include a significant number of putative actionable therapeutic targets. Notably, PSC-BTC shows a distinct extrahepatic morpho-molecular phenotype, independent of the anatomical location of the tumor. These findings advance our understanding of PSC-associated cholangiocarcinogenesis and provide strong incentives for clinical trials to test genome-based personalized treatment strategies in PSC-BTC.", "citation": "Goeppert B, Folseraas T, Roessler S, Kloor M, Volckmar AL, Endris V, Buchhalter I, Stenzinger A, Grzyb K, Grimsrud MM, Gornicka B, von Seth E, Reynolds GM, Franke A, Gotthardt DN, Mehrabi A, Cheung A, Verheij J, Arola J, M\u00e4kisalo H, Eide TJ, Weidemann S, Cheville JC, Mazza G, Hirschfield GM, Ponsioen CY, Bergquist A, Milkiewicz P, Lazaridis KN, Schramm C, Manns MP, F\u00e4rkkil\u00e4 M, Vogel A, Boberg KM, Schirmacher P, Karlsen TH. (2020). Genomic Characterization of Cholangiocarcinoma in Primary Sclerosing Cholangitis Reveals Therapeutic Opportunities. Hepatology (Baltimore, Md.). 72(4):1253-1266. http://doi.org/10.1002/hep.31110. PMID: 31925805.", "score_list": [ 1.4827852930502343, 1.0838515234564157 ], "ai_score_min": 1.0838515234564157, "ai_score_max": 1.4827852930502343, "ai_score": 1.2833184082533249, "ai_reasoning": "Recommend exclusion. 'Genomic Characterization of Cholangiocarcinoma in ...' does not appear to meet core inclusion criteria.", "evidence": [ { "text": "therapeutic targets. Notably, PSC-BTC shows a distinct extrahepatic", "section": "abstract", "criterion": "Population", "supports": "exclude" }, { "text": "putative actionable therapeutic targets. Notably,", "section": "abstract", "criterion": "Study Design", "supports": "exclude" }, { "text": "Genomic Characterization of Cholangiocarcinoma in Primary", "section": "title", "criterion": "Population", "supports": "exclude" } ], "ai_decision": "include", "assigned_clusters": [ { "cluster_name": "Methodology & Protocol Only", "cluster_type": "exclude", "cluster_description": "Papers focused on study design and methodology without clinical results", "related_criteria": "Study Design" } ] }, { "id": "73", "title": "The Value of Next-Generation Sequencing for Treatment in Non-Small Cell Lung Cancer Patients: The Observational, Real-World Evidence in China.", "abstract": "BACKGROUND: Great success has been made in the targeting therapy of advanced non-small cell lung cancer (NSCLC). Nowadays, next generation sequencing (NGS) is acquirable and affordable in developed area of China. Using this feasible and accurate method of detecting therapeutic genes would help to select optimal treatments to extend patients survival. Here, we identified somatic mutations by NGS and analyzed the value for treatment of NSCLC in a real-world clinical setting. METHODS: NGS was carried out on biopsy samples obtained from 66 advanced unresectable NSCLC patients who had not received any treatment. 23 patients received liquid biopsy after failure of first-line targeted treatment. The mutation profiling as well as associations between mutations and clinicopathological characters was analyzed. The study also assessed the values of NGS for choosing treatment options and predicting prognosis in NSCLC patients. RESULTS: 152 somatic mutations were identified in 45 (68.18%) tissue samples. The most frequently mutated genes were CONCLUSIONS: The observational study from real-world demonstrated that using NGS in routine clinical detection may be useful in guiding the therapy decisions and benefit more Chinese NSCLC patients.", "citation": "Zhang Y, Shen WX, Zhou LN, Tang M, Tan Y, Feng CX, Li P, Wang LQ, Chen MB. (2020). The Value of Next-Generation Sequencing for Treatment in Non-Small Cell Lung Cancer Patients: The Observational, Real-World Evidence in China. BioMed research international. 2020:9387167. http://doi.org/10.1155/2020/9387167. PMID: 32047821.", "score_list": [ 4.477910767775447, 4.462712564199455 ], "ai_score_min": 4.462712564199455, "ai_score_max": 4.477910767775447, "ai_score": 4.470311665987451, "ai_reasoning": "Strong candidate for inclusion. 'The Value of Next-Generation Sequencing for Treatm...' directly addresses research criteria with clear methodology. Keywords suggesting inclusion: treatment, patient, therapy.", "evidence": [ { "text": "for choosing treatment options and predicting", "section": "abstract", "criterion": "Population", "supports": "include" }, { "text": "(NSCLC). Nowadays, next generation sequencing", "section": "abstract", "criterion": "Study Design", "supports": "include" }, { "text": "affordable in developed area of China. Using", "section": "abstract", "criterion": "Outcome", "supports": "include" }, { "text": "clinical detection may be useful in guiding the", "section": "abstract", "criterion": "Intervention", "supports": "include" }, { "text": "The Value of Next-Generation Sequencing for", "section": "title", "criterion": "Population", "supports": "include" } ], "ai_decision": "include", "assigned_clusters": [ { "cluster_name": "Treatment Efficacy Studies", "cluster_type": "include", "cluster_description": "Papers evaluating treatment outcomes and efficacy measures", "related_criteria": "Intervention" } ] }, { "id": "74", "title": "Prevalence and mutational determinants of high tumor mutation burden in breast cancer.", "abstract": "BACKGROUND: High tumor mutation burden (TMB) can benefit immunotherapy for multiple tumor types, but the prevalence of hypermutated breast cancer is not well described. The aim of this study was to evaluate the frequency, mutational patterns, and genomic profile of hypermutated breast cancer. PATIENTS AND METHODS: We used de-identified data from individuals with primary or metastatic breast cancer from six different publicly available genomic studies. The prevalence of hypermutated breast cancer was determined among 3969 patients' samples that underwent whole exome sequencing or gene panel sequencing. The samples were classified as having high TMB if they had \u226510 mutations per megabase (mut/Mb). An additional eight patients were identified from a Dana-Farber Cancer Institute cohort for inclusion in the hypermutated cohort. Among the patients with high TMB, the mutational patterns and genomic profiles were determined. A subset of patients was treated with regimens containing PD-1 inhibitors. RESULTS: The median TMB was 2.63 mut/Mb. The median TMB significantly varied according to the tumor subtype (HR-/HER2- >HER2+ >HR+/HER2-, P < 0.05) and sample type (metastatic > primary, P = 2.2 \u00d7 10 CONCLUSION: Hypermutation occurs in 5% of all breast cancers with enrichment in metastatic tumors. Different mutational signatures are present in this population with APOBEC activity being the most common dominant process. Preliminary data suggest that hypermutated breast cancers are more likely to benefit from PD-1 inhibitors.", "citation": "Barroso-Sousa R, Jain E, Cohen O, Kim D, Buendia-Buendia J, Winer E, Lin N, Tolaney SM, Wagle N. (2020). Prevalence and mutational determinants of high tumor mutation burden in breast cancer. Annals of oncology : official journal of the European Society for Medical Oncology. 31(3):387-394. http://doi.org/10.1016/j.annonc.2019.11.010. PMID: 32067680.", "score_list": [ 3.3368048796996863, 3.071472645296673 ], "ai_score_min": 3.071472645296673, "ai_score_max": 3.3368048796996863, "ai_score": 3.2041387624981796, "ai_reasoning": "Moderate relevance. 'Prevalence and mutational determinants of high tum...' partially meets inclusion criteria but requires human review for final determination.", "evidence": [ { "text": "individuals with primary or metastatic breast", "section": "abstract", "criterion": "Population", "supports": "include" }, { "text": "profile of hypermutated breast cancer. PATIENTS AND", "section": "abstract", "criterion": "Study Design", "supports": "include" }, { "text": "individuals with primary or", "section": "abstract", "criterion": "Outcome", "supports": "include" }, { "text": "Prevalence and mutational determinants of high", "section": "title", "criterion": "Population", "supports": "include" } ], "ai_decision": "include", "assigned_clusters": [ { "cluster_name": "Adult Patient Population", "cluster_type": "include", "cluster_description": "Papers focused on adult patient demographics with defined inclusion criteria", "related_criteria": "Population" } ] }, { "id": "75", "title": "Detection of Molecular Signatures of Homologous Recombination Deficiency in Prostate Cancer with or without BRCA1/2 Mutations.", "abstract": "PURPOSE: Prostate cancers with mutations in genes involved in homologous recombination (HR), most commonly BRCA2, respond favorably to PARP inhibition and platinum-based chemotherapy. We investigated whether other prostate tumors that do not harbor deleterious mutations in these particular genes can similarly be deficient in HR, likely rendering those sensitive to HR-directed therapies. EXPERIMENTAL DESIGN: Homologous recombination deficiency (HRD) levels can be estimated using various mutational signatures derived from next-generation sequencing data. We used this approach on whole-genome sequencing (WGS; RESULTS: Known BRCA-deficient samples showed all previously described HRD-associated mutational signatures in the WGS data. HRD-associated mutational signatures were also detected in a subset of patients who did not harbor germline or somatic mutations in BRCA1/2 or other HR-related genes. Similar results, albeit with lower sensitivity and accuracy, were also obtained from WES data. CONCLUSIONS: These findings may expand the number of cases likely to respond to PARP inhibitor treatment. On the basis of the HR-associated mutational signatures, 5% to 8% of localized prostate cancer cases may be good candidates for PARP-inhibitor treatment (including those with BRCA1/2 mutations).", "citation": "Sztupinszki Z, Diossy M, Krzystanek M, Borcsok J, Pomerantz MM, Tisza V, Spisak S, Rusz O, Csabai I, Freedman ML, Szallasi Z. (2020). Detection of Molecular Signatures of Homologous Recombination Deficiency in Prostate Cancer with or without BRCA1/2 Mutations. Clinical cancer research : an official journal of the American Association for Cancer Research. 26(11):2673-2680. http://doi.org/10.1158/1078-0432.CCR-19-2135. PMID: 32071115.", "score_list": [ 1.1671239468459387, 1.6535379538484658 ], "ai_score_min": 1.1671239468459387, "ai_score_max": 1.6535379538484658, "ai_score": 1.4103309503472024, "ai_reasoning": "Recommend exclusion. 'Detection of Molecular Signatures of Homologous Re...' does not appear to meet core inclusion criteria.", "evidence": [ { "text": "signatures in the WGS data. HRD-associated mutational signatures", "section": "abstract", "criterion": "Population", "supports": "exclude" }, { "text": "of cases likely to", "section": "abstract", "criterion": "Study Design", "supports": "exclude" }, { "text": "Detection of Molecular Signatures of Homologous", "section": "title", "criterion": "Population", "supports": "exclude" } ], "ai_decision": "include", "assigned_clusters": [ { "cluster_name": "Methodology & Protocol Only", "cluster_type": "exclude", "cluster_description": "Papers focused on study design and methodology without clinical results", "related_criteria": "Study Design" } ] }, { "id": "76", "title": "Genetic Characterization of Molecular Targets in Korean Patients with Gastrointestinal Stromal Tumors.", "abstract": "PURPOSE: Gastrointestinal stromal tumors (GISTs) frequently harbor activating gene mutations in either MATERIALS AND METHODS: Using the OFA that enables rapid and simultaneous detection of hotspots, single nucleotide variants (SNVs), insertion and deletions (Indels), copy number variants (CNVs), and gene fusions across 52 genes relevant to solid tumors, targeted NGS was performed using genomic DNA extracted from formalin-fixed and paraffin-embedded samples of 30 GISTs. RESULTS: Forty-three hotspot/other likely pathogenic variants (33 SNVs, 8 Indels, and 2 amplifications) in 16 genes were identified in 26 of the 30 GISTs. CONCLUSIONS: Our study confirmed the advantage of using targeted NGS with a cancer gene panel to efficiently identify mutations associated with GISTs. These findings may provide a molecular genetic basis for developing new drugs targeting these gene mutations for GIST therapy.", "citation": "Park J, Yoo HM, Sul HJ, Shin S, Lee SW, Kim JG. (2020). Genetic Characterization of Molecular Targets in Korean Patients with Gastrointestinal Stromal Tumors. Journal of gastric cancer. 20(1):29-40. http://doi.org/10.5230/jgc.2020.20.e2. PMID: 32269842.", "score_list": [ 1.7498562096502002, 1.976549197035305 ], "ai_score_min": 1.7498562096502002, "ai_score_max": 1.976549197035305, "ai_score": 1.8632027033427527, "ai_reasoning": "Recommend exclusion. 'Genetic Characterization of Molecular Targets in K...' does not appear to meet core inclusion criteria.", "evidence": [ { "text": "targeted NGS with a cancer gene panel", "section": "abstract", "criterion": "Population", "supports": "exclude" }, { "text": "amplifications) in 16 genes were identified", "section": "abstract", "criterion": "Study Design", "supports": "exclude" }, { "text": "Genetic Characterization of Molecular Targets in", "section": "title", "criterion": "Population", "supports": "exclude" } ], "ai_decision": "include", "assigned_clusters": [ { "cluster_name": "Methodology & Protocol Only", "cluster_type": "exclude", "cluster_description": "Papers focused on study design and methodology without clinical results", "related_criteria": "Study Design" } ] }, { "id": "77", "title": "Spectrum of driver mutations and clinical impact of circulating tumor DNA analysis in non-small cell lung cancer: Analysis of over 8000 cases.", "abstract": "BACKGROUND: Circulating cell-free tumor DNA (ctDNA)-based mutation profiling, if sufficiently sensitive and comprehensive, can efficiently identify genomic targets in advanced lung adenocarcinoma. Therefore, the authors investigated the accuracy and clinical utility of a commercially available digital next-generation sequencing platform in a large series of patients with non-small cell lung cancer (NSCLC). METHODS: Plasma-based comprehensive genomic profiling results from 8388 consecutively tested patients with advanced NSCLC were analyzed. Driver and resistance mutations were examined with regard to their distribution, frequency, co-occurrence, and mutual exclusivity. RESULTS: Somatic alterations were detected in 86% of samples. The median variant allele fraction was 0.43% (range, 0.03%-97.62%). Activating alterations in actionable oncogenes were identified in 48% of patients, including EGFR (26.4%), MET (6.1%), and BRAF (2.8%) alterations and fusions (ALK, RET, and ROS1) in 2.3%. Treatment-induced resistance mutations were common in this cohort, including driver-dependent and driver-independent alterations. In the subset of patients who had progressive disease during EGFR therapy, 64% had known or putative resistance alterations detected in plasma. Subset analysis revealed that ctDNA increased the identification of driver mutations by 65% over standard-of-care, tissue-based testing at diagnosis. A pooled data analysis on this plasma-based assay demonstrated that targeted therapy response rates were equivalent to those reported from tissue analysis. CONCLUSIONS: Comprehensive ctDNA analysis detected the presence of therapeutically targetable driver and resistance mutations at the frequencies and distributions predicted for the study population. These findings add support for comprehensive ctDNA testing in patients who are incompletely tested at the time of diagnosis and as a primary option at the time of progression on targeted therapies.", "citation": "Mack PC, Banks KC, Espenschied CR, Burich RA, Zill OA, Lee CE, Riess JW, Mortimer SA, Talasaz A, Lanman RB, Gandara DR. (2020). Spectrum of driver mutations and clinical impact of circulating tumor DNA analysis in non-small cell lung cancer: Analysis of over 8000 cases. Cancer. 126(14):3219-3228. http://doi.org/10.1002/cncr.32876. PMID: 32365229.", "score_list": [ 2.1582180000173863, 2.0410543557971192 ], "ai_score_min": 2.0410543557971192, "ai_score_max": 2.1582180000173863, "ai_score": 2.0996361779072528, "ai_reasoning": "Weak relevance. 'Spectrum of driver mutations and clinical impact o...' appears tangentially related to the research topic.", "evidence": [ { "text": "of diagnosis and as", "section": "abstract", "criterion": "Population", "supports": "exclude" }, { "text": "in this cohort, including driver-dependent and", "section": "abstract", "criterion": "Study Design", "supports": "exclude" }, { "text": "Spectrum of driver mutations and clinical", "section": "title", "criterion": "Population", "supports": "exclude" } ], "ai_decision": "include", "assigned_clusters": [ { "cluster_name": "Adult Patient Population", "cluster_type": "include", "cluster_description": "Papers focused on adult patient demographics with defined inclusion criteria", "related_criteria": "Population" } ] }, { "id": "78", "title": "Usefulness of Two Independent DNA and RNA Tissue-Based Multiplex Assays for the Routine Care of Advanced NSCLC Patients.", "abstract": "Personalized medicine is nowadays a paradigm in lung cancer management, offering important benefits to patients. This study aimed to test the feasibility and utility of embedding two multiplexed genomic platforms as the routine workup of advanced non-squamous non-small cell lung cancer (NSCLC) patients. Two parallel multiplexed approaches were performed based on DNA sequencing and direct digital detection of RNA with nCounter", "citation": "Marin E, Teixido C, Carmona-Rocha E, Reyes R, Arcocha A, Vi\u00f1olas N, Rodr\u00edguez-Mues M, Cabrera C, S\u00e1nchez M, Vollmer I, Castillo S, Mu\u00f1oz S, Sullivan IG, Rodriguez A, Garcia M, Alos S, Jares P, Martinez A, Prat A, Molina-Vila M\u00c1, Reguart N. (2020). Usefulness of Two Independent DNA and RNA Tissue-Based Multiplex Assays for the Routine Care of Advanced NSCLC Patients. Cancers. 12(5). http://doi.org/10.3390/cancers12051124. PMID: 32365867.", "score_list": [ 2.9221038251261398, 2.834906916585662 ], "ai_score_min": 2.834906916585662, "ai_score_max": 2.9221038251261398, "ai_score": 2.878505370855901, "ai_reasoning": "Weak relevance. 'Usefulness of Two Independent DNA and RNA Tissue-B...' appears tangentially related to the research topic.", "evidence": [ { "text": "paradigm in lung cancer management,", "section": "abstract", "criterion": "Population", "supports": "exclude" }, { "text": "digital detection of RNA", "section": "abstract", "criterion": "Study Design", "supports": "exclude" }, { "text": "Usefulness of Two Independent DNA and", "section": "title", "criterion": "Population", "supports": "exclude" } ], "ai_decision": "include", "assigned_clusters": [ { "cluster_name": "Adult Patient Population", "cluster_type": "include", "cluster_description": "Papers focused on adult patient demographics with defined inclusion criteria", "related_criteria": "Population" } ] }, { "id": "79", "title": "Predictive value of tumor genetic alteration profiling for chemotherapy and EGFR-TKI treatment in advanced NSCLC.", "abstract": "Previous studies have suggested that a variety of tumor driver genetic alterations affected the treatment efficacy of chemotherapy and epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) in advanced non-small cell lung cancer (NSCLC). The present study aimed to investigate the association between the tumor genetic alteration landscape and the treatment outcome of first-line chemotherapy and EGFR-TKIs in advanced NSCLC. A total of 94 patients with advanced NSCLC were recruited. All patients received first-line chemotherapy and/or EGFR-TKIs (either first- or second-generation EGFR-TKI, or third-generation EGFR-TKI) alone or sequentially. Prior to chemotherapy and/or EGFR-TKI treatment, plasma, effusion and/or tumor tissues from the included patients were subjected to next-generation sequencing, targeting 59 genes. The results indicated that the positive genetic alteration status prior to first-line chemotherapy was associated with prolonged progression-free survival (PFS) time compared with the negative status [9.1 vs. 4.0 months; hazard ratio (HR)=6.68; 95% CI, 2.25-19.82; P=0.001). Furthermore, patients with EGFR activating mutation harboring concomitant alterations exhibited a shorter PFS (11.1 vs. 7.4 months; HR=2.14; 95% CI, 1.03-4.44; P=0.04) and overall survival (OS) time [not reached (NR) vs. 32.8 months; HR=4.30; 95% CI, 1.41-13.16; P=0.01] than those without concomitant alterations, with first- and second-generation EGFR-TKI treatment. Similarly, patients with T79M mutation harboring concomitant alterations exhibited a shorter PFS (15.6 vs. 3.6 months; HR=9.48; 95% CI, 2.29-39.28; P=0.002) and OS time (NR vs. 32.8 months; HR=4.85; 95% CI, 1.16-20.29; P=0.03) with osimertinib treatment. Taken together, the results demonstrated that positive genetic alteration status predicted greater efficacy of first-line chemotherapy, while concomitant genetic alterations were associated with poor treatment outcome for first- or second-generation EGFR-TKI and third-generation EGFR-TKI treatment.", "citation": "Jiang W, Zeng A, Ning R, Zhao W, Su C, Wang H, Zhou S, Yu Q. (2020). Predictive value of tumor genetic alteration profiling for chemotherapy and EGFR-TKI treatment in advanced NSCLC. Oncology letters. 19(6):3859-3870. http://doi.org/10.3892/ol.2020.11502. PMID: 32382334.", "score_list": [ 4.1017933707131045, 4.039566642805727 ], "ai_score_min": 4.039566642805727, "ai_score_max": 4.1017933707131045, "ai_score": 4.0706800067594155, "ai_reasoning": "Strong candidate for inclusion. 'Predictive value of tumor genetic alteration profi...' directly addresses research criteria with clear methodology. Keywords suggesting inclusion: efficacy, outcome, treatment.", "evidence": [ { "text": "mutation harboring concomitant alterations exhibited a", "section": "abstract", "criterion": "Population", "supports": "include" }, { "text": "Taken together, the results", "section": "abstract", "criterion": "Study Design", "supports": "include" }, { "text": "with the negative status [9.1 vs.", "section": "abstract", "criterion": "Outcome", "supports": "include" }, { "text": "months; HR=4.30; 95% CI, 1.41-13.16; P=0.01] than", "section": "abstract", "criterion": "Intervention", "supports": "include" }, { "text": "Predictive value of tumor genetic alteration", "section": "title", "criterion": "Population", "supports": "include" } ], "ai_decision": "include", "assigned_clusters": [ { "cluster_name": "Treatment Efficacy Studies", "cluster_type": "include", "cluster_description": "Papers evaluating treatment outcomes and efficacy measures", "related_criteria": "Intervention" } ] }, { "id": "80", "title": "Frequency and spectrum of PIK3CA somatic mutations in breast cancer.", "abstract": "PURPOSE: The therascreen PIK3CA mutation assay and the alpha-specific PI3K inhibitor alpelisib are FDA-approved for identifying and treating patients with advanced PIK3CA-mutated (PIK3CAmut) breast cancer (BC). However, it is currently unknown to what extend this assay detects most PIK3CA mutations in BC. This information is critical as patients and clinicians are using this and other genomic assays to indicate alpelisib. METHODS: Data from 6338 patients with BC was explored across 10 publicly available studies. The primary objective was to evaluate the proportion and distribution of PIK3CA mutations in BC. Secondary objectives were (1) to evaluate in silico the spectrum of PIK3CA mutations in BC that would be captured by the therascreen panel; (2) to evaluate the proportion and distribution of PIK3CA mutations in hormone receptor-positive/HER2-negative (HR+/HER2-), HER2+, and triple-negative BC (TNBC); and (3) to explore the identification of PIK3CA mutations in a cohort of 48 HR+/HER2- advanced BC patients by the Guardant B360 circulating tumor DNA (ctDNA) assay. RESULTS: Patients with PIK3CAmut tumors represented 35.7% (2261/6338). Five PIK3CA mutations comprised 73% of all PIK3CA mutations: H1047R (35%), E545K (17%), E542K (11%), N345K (6%), and H1047L (4%). Therascreen gene list would capture 72% of all PIK3CA mutations and 80% of patients with a known PIK3CAmut BC. Among patients with double PIK3CAmut tumors (12% of all PIK3CAmut), the therascreen panel would capture 78% as harboring 1 single PIK3CA mutation, 17% as PIK3CAmut undetected, and 5% as PIK3CA double-mut. PIK3CA mutation rates were lower in TNBC (16%) compared to HR+/HER2 (42%) and HER2+ (31%) BC; however, the distribution of the 4 main PIK3CA mutations across subtypes was similar. Finally, 28% of PIK3CA mutations identified in ctDNA in 48 patients with advanced HR+/HER2- BC were not part of the therascreen panel. CONCLUSION: PIK3CA mutations in BC are heterogenous and ~ 20% of patients with a known PIK3CA mutation, and 95% with a known double PIK3CAmut tumor, would not be captured by the therascreen panel. Finally, the clinical utility of PIK3CA mutations not present in the therascreen companion diagnostic assay or identified by other sequencing-based assays needs further investigation.", "citation": "Mart\u00ednez-S\u00e1ez O, Chic N, Pascual T, Adamo B, Vidal M, Gonz\u00e1lez-Farr\u00e9 B, Sanfeliu E, Schettini F, Conte B, Bras\u00f3-Maristany F, Rodr\u00edguez A, Mart\u00ednez D, Galv\u00e1n P, Rodr\u00edguez AB, Martinez A, Mu\u00f1oz M, Prat A. (2020). Frequency and spectrum of PIK3CA somatic mutations in breast cancer. Breast cancer research : BCR. 22(1):45. http://doi.org/10.1186/s13058-020-01284-9. PMID: 32404150.", "score_list": [ 1.6154626187642867, 1.3244529022797122 ], "ai_score_min": 1.3244529022797122, "ai_score_max": 1.6154626187642867, "ai_score": 1.4699577605219996, "ai_reasoning": "Recommend exclusion. 'Frequency and spectrum of PIK3CA somatic mutations...' does not appear to meet core inclusion criteria.", "evidence": [ { "text": "(12% of all PIK3CAmut), the", "section": "abstract", "criterion": "Population", "supports": "exclude" }, { "text": "BC. This information is critical as patients", "section": "abstract", "criterion": "Study Design", "supports": "exclude" }, { "text": "Frequency and spectrum of PIK3CA somatic", "section": "title", "criterion": "Population", "supports": "exclude" } ], "ai_decision": "include", "assigned_clusters": [ { "cluster_name": "Methodology & Protocol Only", "cluster_type": "exclude", "cluster_description": "Papers focused on study design and methodology without clinical results", "related_criteria": "Study Design" } ] }, { "id": "81", "title": "Detection of Fusion Genes Using a Targeted RNA Sequencing Panel in Gastrointestinal and Rare Cancers.", "abstract": "Successful identification and targeting of oncogenic gene fusion is a major breakthrough in cancer treatment. Here, we investigate the therapeutic implications and feasibility of using a targeted RNA sequencing panel to identify fusion genes in gastrointestinal and rare cancers. From February through December 2017, patients with gastrointestinal, hepatobiliary, gynecologic, sarcoma, or rare cancers were recruited for a clinical sequencing project at Samsung Medical Center (NCT #02593578). The median age of the patients was 58 years (range, 31-81 years), and the male-to-female ratio was 1.3 : 1. A total of 118 patients passed the quality control process for a next-generation sequencing- (NGS-) based targeted sequencing assay. The NGS-based targeted sequencing assay was performed to detect gene fusions in 36-53 cancer-implicated genes. The following cancer types were included in this study: 28 colorectal cancers, 27 biliary tract cancers, 25 gastric cancers, 18 soft tissue sarcomas, 9 pancreatic cancers, 6 ovarian cancers, and 9 other rare cancers. Strong fusion was detected in 25 samples (21.2%). We found that 5.9% (7/118) of patients had known targetable fusion genes involving", "citation": "Lee SJ, Hong JY, Kim K, Kim KM, Kang SY, Lee T, Kim ST, Park SH, Park YS, Lim HY, Kang WK, Lee J, Park JO. (2020). Detection of Fusion Genes Using a Targeted RNA Sequencing Panel in Gastrointestinal and Rare Cancers. Journal of oncology. 2020:4659062. http://doi.org/10.1155/2020/4659062. PMID: 32411236.", "score_list": [ 2.6515215113900936, 2.3727223181909523 ], "ai_score_min": 2.3727223181909523, "ai_score_max": 2.6515215113900936, "ai_score": 2.512121914790523, "ai_reasoning": "Weak relevance. 'Detection of Fusion Genes Using a Targeted RNA Seq...' appears tangentially related to the research topic.", "evidence": [ { "text": "patients with gastrointestinal, hepatobiliary, gynecologic, sarcoma, or", "section": "abstract", "criterion": "Population", "supports": "exclude" }, { "text": "5.9% (7/118) of patients had known targetable fusion", "section": "abstract", "criterion": "Study Design", "supports": "exclude" }, { "text": "Detection of Fusion Genes Using a", "section": "title", "criterion": "Population", "supports": "exclude" } ], "ai_decision": "include", "assigned_clusters": [ { "cluster_name": "Adult Patient Population", "cluster_type": "include", "cluster_description": "Papers focused on adult patient demographics with defined inclusion criteria", "related_criteria": "Population" } ] }, { "id": "82", "title": "Molecular and clinicopathological features of colorectal adenocarcinoma with enteroblastic differentiation.", "abstract": "BACKGROUND: Colorectal adenocarcinoma with enteroblastic differentiation (CAED) is a rare subtype of colorectal malignancy with expression of enteroblastic markers (glypican 3, SALL4, AFP); however, the clinicopathological and epidemiological features are not fully elucidated. AIMS: The aims of this study were to elucidate and establish the molecular and clinicopathological characteristics of CAED. MATERIALS AND METHODS: In addition to three cases recently diagnosed as CAED, colorectal carcinoma (CRC) with expression of enteroblastic markers were selected by using immunohistochemistry (IHC) on tissue microarrays of 988 advanced CRC. We employed next-generation sequencing (NGS) and Sanger sequencing for the detection of genetic alterations. IHC for p53 and HER2, HER2-FISH and MSI status was also investigated. Survival analyses for clinicopathological parameters were performed using Kaplan-Meier methods. RESULTS: Thirty-nine cases (4.0%) were positive for at least one enteroblastic marker. Histological evaluation of the total of 42 cases revealed that 10 contained tumour cells with clear cytoplasm. Enteroblastic marker-positive cases had aggressive behaviour and poor prognosis. NGS revealed TP53 as the most frequently mutated gene. The rate of HER2-positive cases and MSI-H cases was 9.5% (four of 42) and 12.2% (five of 41), respectively. Among these 42 cases, there were no molecular and clinicopathological differences according to the presence of tumour cells with clear cytoplasm. CONCLUSIONS: Enteroblastic marker-positive CRC could be grouped together as CAED regardless of clear cell cytoplasm. Using this definition, the frequency of CAED is 4.0% and has a poorer prognosis than that for conventional CRCs. HER2 targeted therapy would be a meaningful treatment for CAED, and CAEDs contain both MSI-H and MSI-stable CRCs, although the MSS phenotype is dominant.", "citation": "Yamashiro Y, Saito T, Hayashi T, Murakami T, Yanai Y, Tsuyama S, Suehara Y, Takamochi K, Yao T. (2020). Molecular and clinicopathological features of colorectal adenocarcinoma with enteroblastic differentiation. Histopathology. 77(3):492-502. http://doi.org/10.1111/his.14158. PMID: 32438490.", "score_list": [ 4.280926801570517, 4.229413458600271 ], "ai_score_min": 4.229413458600271, "ai_score_max": 4.280926801570517, "ai_score": 4.255170130085394, "ai_reasoning": "Strong candidate for inclusion. 'Molecular and clinicopathological features of colo...' directly addresses research criteria with clear methodology. Keywords suggesting inclusion: treatment, therapy, results.", "evidence": [ { "text": "a poorer prognosis than that for conventional", "section": "abstract", "criterion": "Population", "supports": "include" }, { "text": "Sanger sequencing for the detection of genetic alterations.", "section": "abstract", "criterion": "Study Design", "supports": "include" }, { "text": "HER2, HER2-FISH and MSI status", "section": "abstract", "criterion": "Outcome", "supports": "include" }, { "text": "the frequency of CAED is 4.0% and", "section": "abstract", "criterion": "Intervention", "supports": "include" }, { "text": "Molecular and clinicopathological features of colorectal", "section": "title", "criterion": "Population", "supports": "include" } ], "ai_decision": "include", "assigned_clusters": [ { "cluster_name": "Treatment Efficacy Studies", "cluster_type": "include", "cluster_description": "Papers evaluating treatment outcomes and efficacy measures", "related_criteria": "Intervention" }, { "cluster_name": "Biomarker Analysis Studies", "cluster_type": "include", "cluster_description": "Papers with molecular or biomarker focus and genetic data", "related_criteria": "Outcome" } ] }, { "id": "83", "title": "Non-amplification genetic alterations of", "abstract": "AIMS: The present study investigated the incidence and spectrum of human epidermal growth factor receptor 2 (HER2) mutations, associated clinicopathological characteristics and the co-occurrence of METHODS: All patients with advanced lung adenocarcinoma (LUAD) who underwent broad genomic profiling by next generation sequencing (NGS) from 2015 to 2019 were included in the study. RESULTS: Fifty-four (37.2%) out of the 145 cases harboured tier 1 driver mutations comprising CONCLUSIONS: There is a relatively higher occurrence of", "citation": "Mehta A, Nathany S, Tripathi R, Sharma SK, Saifi M, Batra U. (2021). Non-amplification genetic alterations of. Journal of clinical pathology. 74(2):106-110. http://doi.org/10.1136/jclinpath-2020-206730. PMID: 32527755.", "score_list": [ 2.1589126631788065, 2.1293275083594554 ], "ai_score_min": 2.1293275083594554, "ai_score_max": 2.1589126631788065, "ai_score": 2.144120085769131, "ai_reasoning": "Weak relevance. 'Non-amplification genetic alterations of' appears tangentially related to the research topic.", "evidence": [ { "text": "epidermal growth factor receptor 2 (HER2) mutations, associated", "section": "abstract", "criterion": "Population", "supports": "exclude" }, { "text": "sequencing (NGS) from 2015 to 2019 were", "section": "abstract", "criterion": "Study Design", "supports": "exclude" }, { "text": "Non-amplification genetic alterations of", "section": "title", "criterion": "Population", "supports": "exclude" } ], "ai_decision": "include", "assigned_clusters": [ { "cluster_name": "Adult Patient Population", "cluster_type": "include", "cluster_description": "Papers focused on adult patient demographics with defined inclusion criteria", "related_criteria": "Population" } ] }, { "id": "84", "title": "Assessment of Nine Driver Gene Mutations in Surgically Resected Samples from Patients with Non-Small-Cell Lung Cancer.", "abstract": "BACKGROUND: The mutational profile of oncogenic driver genes play an important role in non-small-cell lung cancer (NSCLC). The need of a testing panel capable of comprehensively determining patient genotypes in limited amounts of material has increased since the recent association of nine core oncogenic driver genes as tumor predictive biomarkers. METHODS: Surgically resected samples from 214 NSCLC patients (168 patients with adenocarcinomas and 46 with squamous cell cancers) were included. A multiplexed PCR-based assay was developed to simultaneously test 118 hotspot mutations and fusions in nine driver genes. RESULTS: The sensitivity of the kit was 1% for gene mutation and 450 copies for gene fusion. Genetic alterations were detected in 143 (66.8%) patients by the assay. The three most common alterations identified were EGFR mutations (50.9%), KRAS mutations (8.4%) and ALK fusions (4.7%). Eight (3.7%) patients harbored concurrent mutations, and the most common partners were EGFR mutations which were observed in the eight patients. No associations between survival and EGFR, KRAS, and ALK status were observed. Patients with two or more alterations exhibited shorter DFS compared to those with single mutations ( CONCLUSION: These findings suggest this multiplex gene panel testing technique can be efficiently used to detect nine driver genes in a limited number of specimens. This methodology would have the potential to save both specimens and time compared to the combination of all assays by other methods.", "citation": "Wang S, Qu X, Cao L, Hu X, Hou K, Liu Y, Che X. (2020). Assessment of Nine Driver Gene Mutations in Surgically Resected Samples from Patients with Non-Small-Cell Lung Cancer. Cancer management and research. 12:4029-4038. http://doi.org/10.2147/CMAR.S250822. PMID: 32581578.", "score_list": [ 3.1315787691599657, 2.9891485899239436 ], "ai_score_min": 2.9891485899239436, "ai_score_max": 3.1315787691599657, "ai_score": 3.060363679541955, "ai_reasoning": "Moderate relevance. 'Assessment of Nine Driver Gene Mutations in Surgic...' partially meets inclusion criteria but requires human review for final determination.", "evidence": [ { "text": "NSCLC patients (168 patients", "section": "abstract", "criterion": "Population", "supports": "include" }, { "text": "were included. A multiplexed PCR-based assay", "section": "abstract", "criterion": "Study Design", "supports": "include" }, { "text": "squamous cell cancers) were included. A multiplexed PCR-based", "section": "abstract", "criterion": "Outcome", "supports": "include" }, { "text": "Assessment of Nine Driver Gene Mutations", "section": "title", "criterion": "Population", "supports": "include" } ], "ai_decision": "include", "assigned_clusters": [ { "cluster_name": "Adult Patient Population", "cluster_type": "include", "cluster_description": "Papers focused on adult patient demographics with defined inclusion criteria", "related_criteria": "Population" }, { "cluster_name": "Biomarker Analysis Studies", "cluster_type": "include", "cluster_description": "Papers with molecular or biomarker focus and genetic data", "related_criteria": "Outcome" } ] }, { "id": "85", "title": "Tumor Mutational Burden and PD-L1 Expression in Non-Small-Cell Lung Cancer (NSCLC) in Southwestern China.", "abstract": "PURPOSE: To explore the impact between the tumor mutational burden (TMB) and programmed death ligand-1 (PD-L1) expression on NSCLC in the Yunnan region of southwestern China. PATIENTS AND METHODS: Seventy-one NSCLC specimens that were pathologically confirmed were collected at first. The TMB and driver genetic alterations were evaluated accordingly by next-generation sequencing (NGS). Afterwards, clinical parameters and tumor PD-L1 expressions were collected. Finally, the relationship between TMB, PD-L1 expression and clinical outcome was evaluated. RESULTS: The median TMB was 5 (0.6-49) mutations/Mb by our NGS panel and the majority of patients (63/71, 88.7%) did not receive immunotherapy. The progression-free survival (PFS) was longer in TMB-low patients versus TMB-high ones (median 18.0 vs. 9.0 months, hazard ratio = 0.34, 95% confidence interval 0.14 to 0.84, CONCLUSION: TMB was a valid and independent prognostic biomarker for NSCLC patients' clinical outcome and comprehensive screening of TMB based on NGS is recommended for individualized treatment strategies in Yunnan population.", "citation": "Ma Y, Li Q, Du Y, Chen W, Zhao G, Liu X, Ye L, Li H, Wang X, Liu J, Shen Z, Ma L, Zhou Y. (2020). Tumor Mutational Burden and PD-L1 Expression in Non-Small-Cell Lung Cancer (NSCLC) in Southwestern China. OncoTargets and therapy. 13:5191-5198. http://doi.org/10.2147/OTT.S255947. PMID: 32606739.", "score_list": [ 3.015614941481596, 2.7593288091632897 ], "ai_score_min": 2.7593288091632897, "ai_score_max": 3.015614941481596, "ai_score": 2.8874718753224426, "ai_reasoning": "Weak relevance. 'Tumor Mutational Burden and PD-L1 Expression in No...' appears tangentially related to the research topic.", "evidence": [ { "text": "88.7%) did not receive immunotherapy.", "section": "abstract", "criterion": "Population", "supports": "exclude" }, { "text": "were collected. Finally, the relationship between", "section": "abstract", "criterion": "Study Design", "supports": "exclude" }, { "text": "Tumor Mutational Burden and PD-L1 Expression", "section": "title", "criterion": "Population", "supports": "exclude" } ], "ai_decision": "include", "assigned_clusters": [ { "cluster_name": "Adult Patient Population", "cluster_type": "include", "cluster_description": "Papers focused on adult patient demographics with defined inclusion criteria", "related_criteria": "Population" }, { "cluster_name": "Biomarker Analysis Studies", "cluster_type": "include", "cluster_description": "Papers with molecular or biomarker focus and genetic data", "related_criteria": "Outcome" } ] }, { "id": "86", "title": "Next-generation sequencing analysis of endometrial screening liquid-based cytology specimens: a comparative study to tissue specimens.", "abstract": "BACKGROUND: Liquid-based cytology (LBC) is now a widely used method for cytologic screening and cancer diagnosis. Since the cells are fixed with alcohol-based fixatives, and the specimens are stored in a liquid condition, LBC specimens are suitable for genetic analyses. METHODS: Here, we established a small cancer gene panel, including 60 genes and 17 microsatellite markers for next-generation sequencing, and applied to residual LBC specimens obtained by endometrial cancer screening to compare with corresponding formalin-fixed paraffin-embedded (FFPE) tissues. RESULTS: A total of 49 FFPE and LBC specimens (n = 24) were analyzed, revealing characteristic mutations for endometrial cancer, including PTEN, CTNNB1, PIK3CA, and PIK3R1 mutations. Eight cases had higher scores for both tumor mutation burden (TMB) and microsatellite instability (MSI), which agree with defective mismatch repair (MMR) protein expression. Paired endometrial LBC, and biopsied and/or resected FFPE tissues from 7 cases, presented almost identical mutations, TMB, and MSI profiles in all cases. CONCLUSION: These findings demonstrate that our ad hoc cancer gene panel enabled the detection of therapeutically actionable gene mutations in endometrial LBC and FFPE specimens. Endometrial cancer LBC specimens offer an alternative and affordable source of molecular testing materials.", "citation": "Akahane T, Kitazono I, Yanazume S, Kamio M, Togami S, Sakamoto I, Nohara S, Yokoyama S, Kobayashi H, Hiraki T, Suzuki S, Ueno S, Tanimoto A. (2020). Next-generation sequencing analysis of endometrial screening liquid-based cytology specimens: a comparative study to tissue specimens. BMC medical genomics. 13(1):101. http://doi.org/10.1186/s12920-020-00753-6. PMID: 32652986.", "score_list": [ 3.62466384488558, 3.44390592174211 ], "ai_score_min": 3.44390592174211, "ai_score_max": 3.62466384488558, "ai_score": 3.534284883313845, "ai_reasoning": "Moderate relevance. 'Next-generation sequencing analysis of endometrial...' partially meets inclusion criteria but requires human review for final determination.", "evidence": [ { "text": "FFPE and LBC specimens (n", "section": "abstract", "criterion": "Population", "supports": "include" }, { "text": "all cases. CONCLUSION: These findings demonstrate", "section": "abstract", "criterion": "Study Design", "supports": "include" }, { "text": "mutations in endometrial LBC", "section": "abstract", "criterion": "Outcome", "supports": "include" }, { "text": "Next-generation sequencing analysis of endometrial screening", "section": "title", "criterion": "Population", "supports": "include" } ], "ai_decision": "include", "assigned_clusters": [ { "cluster_name": "Biomarker Analysis Studies", "cluster_type": "include", "cluster_description": "Papers with molecular or biomarker focus and genetic data", "related_criteria": "Outcome" } ] }, { "id": "87", "title": "Genome\u2011wide copy number analysis of circulating tumor cells in breast cancer patients with liver metastasis.", "abstract": "The genome\u2011wide copy number analysis of circulating tumor cells (CTCs) provides a promising prognostic biomarker for survival in breast cancer liver metastasis (BCLM) patients. The present study aimed to confirm the prognostic value of the presence of CTCs in BCLM patients. We previously developed an assay for the genome\u2011wide pattern differences in copy number variations (CNVs) as an adjunct test for the routine imaging and histopathologic diagnosis methods to distinguish newly diagnosed liver metastases and recurrent liver metastases. Forty\u2011three breast cancer patients were selected for this study in which 23 newly diagnosed and 20 recurrent liver metastases were diagnosed by histopathology and 18F\u2011FDG PET/CT imaging. CTCs were counted from all patients using the CellSearch system and were confirmed by cytomorphology and three\u2011color immunocytochemistry. Genomic DNA of single CTCs was amplified using multiple annealing and looping based amplification cycles (MALBAC). Then, we compared the CTC numbers of newly diagnosed and recurrent BCLM patients using Illumina platforms. A high CTC frequency (>15 CTCs/7.5 ml blood) was found to be correlated with disease severity and metastatic progression, which suggests the value for CTCs in the diagnosis of BCLM in comparison with pathohistology and PET/CT imaging (P>0.05). Moreover, CTCs isolated from BCLM patients remained an independent prognostic detection factor associated with overall survival (P=0.0041). Comparison between newly diagnosed and recurrent liver metastases revealed different frequencies of CNVs (P>0.05). Notably, the CNV pattern of isolated CTCs of recurrent BCLM patients was similar to recurrent liver metastases (nearly 82% of the gain/loss regions). Functional enrichment analysis identified 25 genes as a CNV signature of BCLM. Among them, were defensin and \u03b2\u2011defensin genes, which are significantly associated with anti\u2011angiogenesis and immunomodulation signaling pathways. High CTC frequencies are effective in the evaluation and differentiation between newly diagnosed liver metastases from recurrent liver metastases. Future clinical studies will be necessary to fully determine the prognostic potential of CTC cluster signatures in patients with BCLM.", "citation": "Zou L, Imani S, Maghsoudloo M, Shasaltaneh MD, Gao L, Zhou J, Wen Q, Liu S, Zhang L, Chen G. (2020). Genome\u2011wide copy number analysis of circulating tumor cells in breast cancer patients with liver metastasis. Oncology reports. 44(3):1075-1093. http://doi.org/10.3892/or.2020.7650. PMID: 32705227.", "score_list": [ 4.222637761098002, 4.275622236531572 ], "ai_score_min": 4.222637761098002, "ai_score_max": 4.275622236531572, "ai_score": 4.249129998814787, "ai_reasoning": "Strong candidate for inclusion. 'Genome\u2011wide copy number analysis of circulating tu...' directly addresses research criteria with clear methodology. Keywords suggesting inclusion: patient, study.", "evidence": [ { "text": "CTCs was amplified using", "section": "abstract", "criterion": "Population", "supports": "include" }, { "text": "genes, which are significantly associated with anti\u2011angiogenesis and", "section": "abstract", "criterion": "Study Design", "supports": "include" }, { "text": "newly diagnosed and 20", "section": "abstract", "criterion": "Outcome", "supports": "include" }, { "text": "prognostic value of the presence", "section": "abstract", "criterion": "Intervention", "supports": "include" }, { "text": "Genome\u2011wide copy number analysis of circulating", "section": "title", "criterion": "Population", "supports": "include" } ], "ai_decision": "include", "assigned_clusters": [ { "cluster_name": "Treatment Efficacy Studies", "cluster_type": "include", "cluster_description": "Papers evaluating treatment outcomes and efficacy measures", "related_criteria": "Intervention" }, { "cluster_name": "Biomarker Analysis Studies", "cluster_type": "include", "cluster_description": "Papers with molecular or biomarker focus and genetic data", "related_criteria": "Outcome" } ] }, { "id": "88", "title": "Evaluating different adoption scenarios for TIL-therapy and the influence on its (early) cost-effectiveness.", "abstract": "BACKGROUND: Treatment with tumor-Infiltrating Lymphocytes (TIL) is an innovative therapy for advanced melanoma with promising clinical phase I/II study results and likely beneficial cost-effectiveness. As a randomized controlled trial on the effectiveness of TIL therapy in advanced melanoma compared to ipilimumab is still ongoing, adoption of TIL therapy by the field is confronted with uncertainty. To deal with this, scenario drafting can be used to identify potential barriers and enables the subsequent anticipation on these barriers. This study aims to inform adoption decisions of TIL by evaluating various scenarios and evaluate their effect on the cost-effectiveness. METHODS: First, 14 adoption scenarios for TIL-therapy were drafted using a Delphi approach with a group of involved experts. Second, the likelihood of the scenarios taking place within 5 years was surveyed among international experts using a web-based questionnaire. Third, based on the questionnaire results and recent literature, scenarios were labeled as being either \"likely\" or \"-unlikely\". Finally, the cost-effectiveness of TIL treatment involving the \"likely\" scored scenarios was calculated. RESULTS: Twenty-nine experts from 12 countries completed the questionnaire. The scenarios showed an average likelihood ranging from 29 to 58%, indicating that future developments of TIL-therapy were surrounded with quite some uncertainty. Eight of the 14 scenarios were labeled as \"likely\". The net monetary benefit per patient is presented as a measure of cost-effectiveness, where a positive value means that a scenario is cost-effective. For six of these scenarios the cost-effectiveness was calculated: \"Commercialization of TIL production\" (the price was assumed to be 3 times the manufacturing costs in the academic setting) (-\u20ac51,550), \"Pharmaceutical companies lowering the prices of ipilimumab\" (\u20ac11,420), \"Using TIL-therapy combined with ipilimumab\" (-\u20ac10,840), \"Automatic TIL production\" (\u20ac22,670), \"TIL more effective\" (\u20ac23,270), \"Less Interleukin-2\" (\u20ac20,370). CONCLUSIONS: Incorporating possible future developments, TIL-therapy was calculated to be cost-effective compared to ipilimumab in the majority of \"likely\" scenarios. These scenarios could function as facilitators for adoption. Contrary, TIL therapy was expected to not be cost-effective when sold at commercial prices, or when combined with ipilimumab. These scenarios should be considered in the adoption decision as these may act as crucial barriers.", "citation": "Lindenberg M, Ret\u00e8l V, Rohaan M, van den Berg J, Haanen J, van Harten W. (2020). Evaluating different adoption scenarios for TIL-therapy and the influence on its (early) cost-effectiveness. BMC cancer. 20(1):712. http://doi.org/10.1186/s12885-020-07166-9. PMID: 32736535.", "score_list": [ 3.2096600841292244, 3.2458259127103806 ], "ai_score_min": 3.2096600841292244, "ai_score_max": 3.2458259127103806, "ai_score": 3.2277429984198025, "ai_reasoning": "Moderate relevance. 'Evaluating different adoption scenarios for TIL-th...' partially meets inclusion criteria but requires human review for final determination.", "evidence": [ { "text": "a scenario is cost-effective. For six of", "section": "abstract", "criterion": "Population", "supports": "include" }, { "text": "29 to 58%, indicating that future developments", "section": "abstract", "criterion": "Study Design", "supports": "include" }, { "text": "is an innovative therapy for advanced", "section": "abstract", "criterion": "Outcome", "supports": "include" }, { "text": "Evaluating different adoption scenarios for TIL-therapy", "section": "title", "criterion": "Population", "supports": "include" } ], "ai_decision": "include", "assigned_clusters": [ { "cluster_name": "Adult Patient Population", "cluster_type": "include", "cluster_description": "Papers focused on adult patient demographics with defined inclusion criteria", "related_criteria": "Population" } ] }, { "id": "89", "title": "Mutation analysis and genomic imbalances of cells found in effusion fluids from patients with ovarian cancer.", "abstract": "Ovarian carcinomas and carcinosarcomas often cause malignant effusions, an accumulation within serous cavities of fluid containing cancer cells. Few studies have focused on the molecular alterations and genetic mechanisms behind effusion formation. The present study investigated the mutation status of", "citation": "Brunetti M, Panagopoulos I, Kostolomov I, Davidson B, Heim S, Micci F. (2020). Mutation analysis and genomic imbalances of cells found in effusion fluids from patients with ovarian cancer. Oncology letters. 20(3):2273-2279. http://doi.org/10.3892/ol.2020.11782. PMID: 32782545.", "score_list": [ 2.8724320004255848, 2.5505859210210335 ], "ai_score_min": 2.5505859210210335, "ai_score_max": 2.8724320004255848, "ai_score": 2.711508960723309, "ai_reasoning": "Weak relevance. 'Mutation analysis and genomic imbalances of cells ...' appears tangentially related to the research topic.", "evidence": [ { "text": "often cause malignant effusions, an accumulation within", "section": "abstract", "criterion": "Population", "supports": "exclude" }, { "text": "cause malignant effusions, an accumulation within serous cavities", "section": "abstract", "criterion": "Study Design", "supports": "exclude" }, { "text": "Mutation analysis and genomic imbalances of", "section": "title", "criterion": "Population", "supports": "exclude" } ], "ai_decision": "include", "assigned_clusters": [ { "cluster_name": "Biomarker Analysis Studies", "cluster_type": "include", "cluster_description": "Papers with molecular or biomarker focus and genetic data", "related_criteria": "Outcome" } ] }, { "id": "90", "title": "Distinct Mutation Patterns Reveal Melanoma Subtypes and Influence Immunotherapy Response in Advanced Melanoma Patients.", "abstract": "The detection of somatic driver mutations by next-generation sequencing (NGS) is becoming increasingly important in the care of advanced melanoma patients. In our study, we evaluated the NGS results of 82 melanoma patients from clinical routine in 2017. Besides determining the tumor mutational burden (TMB) and annotation of all genetic driver alterations, we investigated their potential as a predictor for resistance to immune checkpoint inhibitors (ICI) and as a distinguishing feature between melanoma subtypes. Melanomas of unknown primary had a similar mutation pattern and TMB to cutaneous melanoma, which hints at its cutaneous origin. Besides the typical hotspot mutation in", "citation": "Hilke FJ, Sinnberg T, Gschwind A, Niessner H, Demidov G, Amaral T, Ossowski S, Bonzheim I, R\u00f6cken M, Riess O, Garbe C, Schroeder C, Forschner A. (2020). Distinct Mutation Patterns Reveal Melanoma Subtypes and Influence Immunotherapy Response in Advanced Melanoma Patients. Cancers. 12(9). http://doi.org/10.3390/cancers12092359. PMID: 32825510.", "score_list": [ 2.2013726762933254, 2.612410243461603 ], "ai_score_min": 2.2013726762933254, "ai_score_max": 2.612410243461603, "ai_score": 2.406891459877464, "ai_reasoning": "Weak relevance. 'Distinct Mutation Patterns Reveal Melanoma Subtype...' appears tangentially related to the research topic.", "evidence": [ { "text": "results of 82 melanoma", "section": "abstract", "criterion": "Population", "supports": "exclude" }, { "text": "to immune checkpoint inhibitors (ICI) and", "section": "abstract", "criterion": "Study Design", "supports": "exclude" }, { "text": "Distinct Mutation Patterns Reveal Melanoma Subtypes", "section": "title", "criterion": "Population", "supports": "exclude" } ], "ai_decision": "include", "assigned_clusters": [ { "cluster_name": "Adult Patient Population", "cluster_type": "include", "cluster_description": "Papers focused on adult patient demographics with defined inclusion criteria", "related_criteria": "Population" }, { "cluster_name": "Biomarker Analysis Studies", "cluster_type": "include", "cluster_description": "Papers with molecular or biomarker focus and genetic data", "related_criteria": "Outcome" } ] }, { "id": "91", "title": "Molecular Profiling in Daily Clinical Practice: Practicalities in Advanced Cholangiocarcinoma and Other Biliary Tract Cancers.", "abstract": "BACKGROUND: Molecular profiling is becoming increasingly relevant in the management of patients with advanced cancer; to identify targetable aberrations and prognostic markers to enable a precision medicine strategy. METHODS: Eligible patients were those diagnosed with advanced biliary tract cancer (BTC) including intrahepatic (iCCA) and extrahepatic cholangiocarcinoma (eCCA), gallbladder cancer (GBC), and ampullary carcinoma (Amp) who underwent molecular profiling between April 2017 and June 2020 based on analysis of either tumour samples (FoundationOne CDx RESULTS: A total of 149 samples from 104 individual patients diagnosed with advanced BTC were identified and eligible for this analysis: 68.2% iCCA, 100% advanced stage; 94.2% received palliative therapy. The rate of sample failure was 26.8% for tissue and 15.4% for ctDNA; CONCLUSIONS: Molecular profiling is of use for identification of novel therapeutic strategies for patients with advanced BTC (mainly iCCA). One in four archived tissue samples may have insufficient tumour content for molecular profiling; ctDNA-based approaches may overcome these obstacles.", "citation": "Lamarca A, Kapacee Z, Breeze M, Bell C, Belcher D, Staiger H, Taylor C, McNamara MG, Hubner RA, Valle JW. (2020). Molecular Profiling in Daily Clinical Practice: Practicalities in Advanced Cholangiocarcinoma and Other Biliary Tract Cancers. Journal of clinical medicine. 9(9). http://doi.org/10.3390/jcm9092854. PMID: 32899345.", "score_list": [ 2.4263947394623555, 2.9678813346737507 ], "ai_score_min": 2.4263947394623555, "ai_score_max": 2.9678813346737507, "ai_score": 2.6971380370680533, "ai_reasoning": "Weak relevance. 'Molecular Profiling in Daily Clinical Practice: Pr...' appears tangentially related to the research topic.", "evidence": [ { "text": "with advanced BTC (mainly iCCA). One", "section": "abstract", "criterion": "Population", "supports": "exclude" }, { "text": "cancer (GBC), and ampullary carcinoma", "section": "abstract", "criterion": "Study Design", "supports": "exclude" }, { "text": "Molecular Profiling in Daily Clinical Practice:", "section": "title", "criterion": "Population", "supports": "exclude" } ], "ai_decision": "include", "assigned_clusters": [ { "cluster_name": "Adult Patient Population", "cluster_type": "include", "cluster_description": "Papers focused on adult patient demographics with defined inclusion criteria", "related_criteria": "Population" }, { "cluster_name": "Biomarker Analysis Studies", "cluster_type": "include", "cluster_description": "Papers with molecular or biomarker focus and genetic data", "related_criteria": "Outcome" } ] }, { "id": "92", "title": "Multidisciplinary Care for Melanoma of Unknown Primary: Experience in the Era of Molecular Profiling.", "abstract": "BACKGROUND: Melanoma of unknown primary (MUP) accounts for approximately 3% of melanoma diagnoses. This study sought to evaluate treatment and outcomes for a modern MUP cohort. METHODS: A retrospective review of MUP was performed at a tertiary referral cancer center. RESULTS: Of 815 melanoma patients, 67 (8.2%) had MUP. Men were more likely to have MUP than women (67% vs. 55%; p = 0.04). The most common sites of MUP were lymph nodes (28%), visceral solid organs (25%), brain (16%), and skin/subcutaneous tissues (10%). Of the patients who underwent tumor genomic profiling, 52% harbored pathogenic BRAF mutations. Of the 24 patients who underwent multi-gene panel testing, all had pathogenic mutations and 21 (88%) had mutations in addition to or exclusive of BRAF, including 11 patients (46%) with telomerase reverse transcriptase promoter mutations. Checkpoint inhibitors (39%) and BRAF-MEK inhibitors (7%) were the most common first-line treatments. Upfront surgical resection was used for 25% of the MUP patients, and 12 of these resections were for curative intent. During a median follow-up period of 22.1 months, the median overall survival (OS) was not met for the patients with MUP isolated to lymph nodes. At 56.8 months, 75% of these patients were alive. The median OS was 37.4 months for skin/soft tissue MUP, 33.3 months for single solid organ viscera MUP, and 29.8 months for metastatic brain MUP. CONCLUSION: Multigene panel testing identified pathogenic mutations in all tested MUP patients and frequently identified targets outside BRAF. Despite advanced stage, aggressive multimodal therapy for MUP can be associated with 5-year OS and should be pursued for appropriate candidates.", "citation": "De Andrade JP, Wong P, O'Leary MP, Parekh V, Amini A, Schoellhammer HF, Margolin KA, Afkhami M, Melstrom LG. (2020). Multidisciplinary Care for Melanoma of Unknown Primary: Experience in the Era of Molecular Profiling. Annals of surgical oncology. 27(13):5240-5247. http://doi.org/10.1245/s10434-020-09112-2. PMID: 32909128.", "score_list": [ 3.6141528137400165, 3.5926069501900106 ], "ai_score_min": 3.5926069501900106, "ai_score_max": 3.6141528137400165, "ai_score": 3.6033798819650134, "ai_reasoning": "Moderate relevance. 'Multidisciplinary Care for Melanoma of Unknown Pri...' partially meets inclusion criteria but requires human review for final determination.", "evidence": [ { "text": "MUP cohort. METHODS: A retrospective review of MUP", "section": "abstract", "criterion": "Population", "supports": "include" }, { "text": "and 21 (88%) had", "section": "abstract", "criterion": "Study Design", "supports": "include" }, { "text": "inhibitors (7%) were the most", "section": "abstract", "criterion": "Outcome", "supports": "include" }, { "text": "Multidisciplinary Care for Melanoma of Unknown", "section": "title", "criterion": "Population", "supports": "include" } ], "ai_decision": "include", "assigned_clusters": [ { "cluster_name": "Adult Patient Population", "cluster_type": "include", "cluster_description": "Papers focused on adult patient demographics with defined inclusion criteria", "related_criteria": "Population" } ] }, { "id": "93", "title": "Prevalence of Phosphatidylinositol-3-Kinase (PI3K) Pathway Alterations and Co-alteration of Other Molecular Markers in Breast Cancer.", "abstract": "0", "citation": "Khoury K, Tan AR, Elliott A, Xiu J, Gatalica Z, Heeke AL, Isaacs C, Pohlmann PR, Schwartzberg LS, Simon M, Korn WM, Swain SM, Lynce F. (2020). Prevalence of Phosphatidylinositol-3-Kinase (PI3K) Pathway Alterations and Co-alteration of Other Molecular Markers in Breast Cancer. Frontiers in oncology. 10:1475. http://doi.org/10.3389/fonc.2020.01475. PMID: 32983983.", "score_list": [ 3.12234028004585, 3.5497525328143436 ], "ai_score_min": 3.12234028004585, "ai_score_max": 3.5497525328143436, "ai_score": 3.3360464064300968, "ai_reasoning": "Moderate relevance. 'Prevalence of Phosphatidylinositol-3-Kinase (PI3K)...' partially meets inclusion criteria but requires human review for final determination.", "evidence": [ { "text": "Prevalence of Phosphatidylinositol-3-Kinase (PI3K) Pathway Alterations", "section": "title", "criterion": "Population", "supports": "include" } ], "ai_decision": "include", "assigned_clusters": [ { "cluster_name": "Biomarker Analysis Studies", "cluster_type": "include", "cluster_description": "Papers with molecular or biomarker focus and genetic data", "related_criteria": "Outcome" } ] }, { "id": "94", "title": "Integrated DNA and RNA sequencing reveals targetable alterations in metastatic pediatric papillary thyroid carcinoma.", "abstract": "BACKGROUND: Pediatric papillary thyroid carcinoma (PTC) is clinically and biologically distinct from adult PTC. We sequenced a cohort of clinically annotated pediatric PTC cases enriched for high-risk tumors to identify genetic alterations of relevance for diagnosis and therapy. METHODS: Tumor DNA and RNA were extracted from FFPE tissue and subjected to next-generation sequencing (NGS) library preparation using a custom 124-gene hybridization capture panel and the 75-gene Archer Oncology Research Panel, respectively. NGS libraries were sequenced on an Illumina MiSeq. RESULTS: Thirty-six pediatric PTC cases were analyzed. Metastases were frequently observed to cervical lymph nodes (29/36, 81%), with pulmonary metastases less commonly found (10/36, 28%). Relapsed or refractory disease occurred in 18 patients (18/36, 50%). DNA sequencing revealed targetable mutations in 8 of 31 tumors tested (26%), most commonly BRAF p.V600E (n = 6). RNA sequencing identified targetable fusions in 13 of 25 tumors tested (52%): RET (n = 8), NTRK3 (n = 4), and BRAF. Mutually exclusive targetable alterations were discovered in 15 of the 20 tumors (75%) with both DNA and RNA analyzed. Fusion-positive PTC was associated with multifocal disease, higher tumor staging, and higher American Thyroid Association risk levels. Both BRAF V600E mutations and gene fusions were correlated with the presence of cervical metastases. CONCLUSIONS: Targetable alterations were identified in 75% of pediatric PTC cases with both DNA and RNA evaluated. Inclusion of RNA sequencing for detection of fusion genes is critical for evaluation of these tumors. Patients with fusion-positive tumors were more likely to have features of high-risk disease.", "citation": "Potter SL, Reuther J, Chandramohan R, Gandhi I, Hollingsworth F, Sayeed H, Voicu H, Kakkar N, Baksi KS, Sarabia SF, Lopez ME, Chelius DC, Athanassaki ID, Mahajan P, Venkatramani R, Quintanilla NM, Lopez-Terrada DH, Roy A, Parsons DW. (2021). Integrated DNA and RNA sequencing reveals targetable alterations in metastatic pediatric papillary thyroid carcinoma. Pediatric blood & cancer. 68(1):e28741. http://doi.org/10.1002/pbc.28741. PMID: 33009870.", "score_list": [ 3.7118303172597407, 3.402952310069047 ], "ai_score_min": 3.402952310069047, "ai_score_max": 3.7118303172597407, "ai_score": 3.557391313664394, "ai_reasoning": "Moderate relevance. 'Integrated DNA and RNA sequencing reveals targetab...' partially meets inclusion criteria but requires human review for final determination.", "evidence": [ { "text": "cases enriched for high-risk", "section": "abstract", "criterion": "Population", "supports": "include" }, { "text": "likely to have features of high-risk disease.", "section": "abstract", "criterion": "Study Design", "supports": "include" }, { "text": "(n = 4), and", "section": "abstract", "criterion": "Outcome", "supports": "include" }, { "text": "Integrated DNA and RNA sequencing reveals", "section": "title", "criterion": "Population", "supports": "include" } ], "ai_decision": "include", "assigned_clusters": [ { "cluster_name": "Adult Patient Population", "cluster_type": "include", "cluster_description": "Papers focused on adult patient demographics with defined inclusion criteria", "related_criteria": "Population" }, { "cluster_name": "Biomarker Analysis Studies", "cluster_type": "include", "cluster_description": "Papers with molecular or biomarker focus and genetic data", "related_criteria": "Outcome" } ] }, { "id": "95", "title": "The genomic landscape of metastatic histologic special types of invasive breast cancer.", "abstract": "Histologic special types of breast cancer (BC) account for ~20% of BCs. Large sequencing studies of metastatic BC have focused on invasive ductal carcinomas of no special type (IDC-NSTs). We sought to define the repertoire of somatic genetic alterations of metastatic histologic special types of BC. We reanalyzed targeted capture sequencing data of 309 special types of BC, including metastatic and primary invasive lobular carcinomas (ILCs;", "citation": "Pareja F, Ferrando L, Lee SSK, Beca F, Selenica P, Brown DN, Farmanbar A, Da Cruz Paula A, Vahdatinia M, Zhang H, Zoppoli G, Wen HY, Brogi E, Robson ME, Razavi P, Chandarlapaty S, Weigelt B, Reis-Filho JS. (2020). The genomic landscape of metastatic histologic special types of invasive breast cancer. NPJ breast cancer. 6:53. http://doi.org/10.1038/s41523-020-00195-4. PMID: 33083532.", "score_list": [ 4.103203440874681, 4.363441213540157 ], "ai_score_min": 4.103203440874681, "ai_score_max": 4.363441213540157, "ai_score": 4.23332232720742, "ai_reasoning": "Strong candidate for inclusion. 'The genomic landscape of metastatic histologic spe...' directly addresses research criteria with clear methodology.", "evidence": [ { "text": "type (IDC-NSTs). We sought to", "section": "abstract", "criterion": "Population", "supports": "include" }, { "text": "of 309 special types of BC,", "section": "abstract", "criterion": "Study Design", "supports": "include" }, { "text": "309 special types of BC, including", "section": "abstract", "criterion": "Outcome", "supports": "include" }, { "text": "of metastatic histologic special types of BC.", "section": "abstract", "criterion": "Intervention", "supports": "include" }, { "text": "The genomic landscape of metastatic histologic", "section": "title", "criterion": "Population", "supports": "include" } ], "ai_decision": "include", "assigned_clusters": [ { "cluster_name": "Treatment Efficacy Studies", "cluster_type": "include", "cluster_description": "Papers evaluating treatment outcomes and efficacy measures", "related_criteria": "Intervention" } ] }, { "id": "96", "title": "Integration of whole-exome and anchored PCR-based next generation sequencing significantly increases detection of actionable alterations in precision oncology.", "abstract": "BACKGROUND: Frequency of clinically relevant mutations in solid tumors by targeted and whole-exome sequencing is \u223c30%. Transcriptome analysis complements detection of actionable gene fusions in advanced cancer patients. Goal of this study was to determine the added value of anchored multiplex PCR (AMP)-based next-generation sequencing (NGS) assay to identify further potential drug targets, when coupled with whole-exome sequencing (WES). METHODS: Selected series of fifty-six samples from 55 patients enrolled in our precision medicine study were interrogated by WES and AMP-based NGS. RNA-seq was performed in 19 cases. Clinically relevant and actionable alterations detected by three methods were integrated and analyzed. RESULTS: AMP-based NGS detected 48 fusions in 31 samples (55.4%); 31.25% (15/48) were classified as targetable based on published literature. WES revealed 29 samples (51.8%) harbored targetable alterations. TMB-high and MSI-high status were observed in 12.7% and 1.8% of cases. RNA-seq from 19 samples identified 8 targetable fusions (42.1%), also captured by AMP-based NGS. When number of actionable fusions detected by AMP-based NGS were added to WES targetable alterations, 66.1% of samples had potential drug targets. When both WES and RNA-seq were analyzed, 57.8% of samples had targetable alterations. CONCLUSIONS: This study highlights importance of an integrative genomic approach for precision oncology, including use of different NGS platforms with complementary features. Integrating RNA data (whole transcriptome or AMP-based NGS) significantly enhances detection of potential targets in cancer patients. In absence of fresh frozen tissue, AMP-based NGS is a robust method to detect actionable fusions using low-input RNA from archival tissue.", "citation": "Beg S, Bareja R, Ohara K, Eng KW, Wilkes DC, Pisapia DJ, Zoughbi WA, Kudman S, Zhang W, Rao R, Manohar J, Kane T, Sigouros M, Xiang JZ, Khani F, Robinson BD, Faltas BM, Sternberg CN, Sboner A, Beltran H, Elemento O, Mosquera JM. (2021). Integration of whole-exome and anchored PCR-based next generation sequencing significantly increases detection of actionable alterations in precision oncology. Translational oncology. 14(1):100944. http://doi.org/10.1016/j.tranon.2020.100944. PMID: 33190043.", "score_list": [ 1.8534299793120033, 1.8096355027261184 ], "ai_score_min": 1.8096355027261184, "ai_score_max": 1.8534299793120033, "ai_score": 1.831532741019061, "ai_reasoning": "Recommend exclusion. 'Integration of whole-exome and anchored PCR-based ...' does not appear to meet core inclusion criteria.", "evidence": [ { "text": "of actionable fusions detected by", "section": "abstract", "criterion": "Population", "supports": "exclude" }, { "text": "were classified as targetable based on published literature.", "section": "abstract", "criterion": "Study Design", "supports": "exclude" }, { "text": "Integration of whole-exome and anchored PCR-based", "section": "title", "criterion": "Population", "supports": "exclude" } ], "ai_decision": "include", "assigned_clusters": [ { "cluster_name": "Methodology & Protocol Only", "cluster_type": "exclude", "cluster_description": "Papers focused on study design and methodology without clinical results", "related_criteria": "Study Design" } ] }, { "id": "97", "title": "A genomic signature for accurate classification and prediction of clinical outcomes in cancer patients treated with immune checkpoint blockade immunotherapy.", "abstract": "Tumor mutational burden (TMB) is associated with clinical response to immunotherapy, but application has been limited to a subset of cancer patients. We hypothesized that advanced machine-learning and proper modeling could identify mutations that classify patients most likely to derive clinical benefits. Training data: Two sets of public whole-exome sequencing (WES) data for metastatic melanoma. Validation data: One set of public non-small cell lung cancer (NSCLC) data. Least Absolute Shrinkage and Selection Operator (LASSO) machine-learning and proper modeling were used to identify a set of mutations (biomarker) with maximum predictive accuracy (measured by AUROC). Kaplan-Meier and log-rank methods were used to test prediction of overall survival. The initial model considered 2139 mutations. After pruning, 161 mutations (11%) were retained. An optimal threshold of 0.41 divided patients into high-weight (HW) or low-weight (LW) TMB groups. Classification for HW-TMB was 100% (AUROC = 1.0) on melanoma learning/testing data; HW-TMB was a prognostic marker for longer overall survival. In validation data, HW-TMB was associated with survival (p = 0.0057) and predicted 6-month clinical benefit (AUROC = 0.83) in NSCLC. In conclusion, we developed and validated a 161-mutation genomic signature with \"outstanding\" 100% accuracy to classify melanoma patients by likelihood of response to immunotherapy. This biomarker can be adapted for clinical practice to improve cancer treatment and care.", "citation": "Lu M, Wu KH, Trudeau S, Jiang M, Zhao J, Fan E. (2020). A genomic signature for accurate classification and prediction of clinical outcomes in cancer patients treated with immune checkpoint blockade immunotherapy. Scientific reports. 10(1):20575. http://doi.org/10.1038/s41598-020-77653-3. PMID: 33239757.", "score_list": [ 1.4951611936849707, 1.2823902276266566 ], "ai_score_min": 1.2823902276266566, "ai_score_max": 1.4951611936849707, "ai_score": 1.3887757106558136, "ai_reasoning": "Recommend exclusion. 'A genomic signature for accurate classification an...' does not appear to meet core inclusion criteria.", "evidence": [ { "text": "AUROC). Kaplan-Meier and log-rank methods were used", "section": "abstract", "criterion": "Population", "supports": "exclude" }, { "text": "Operator (LASSO) machine-learning and proper", "section": "abstract", "criterion": "Study Design", "supports": "exclude" }, { "text": "A genomic signature for accurate classification", "section": "title", "criterion": "Population", "supports": "exclude" } ], "ai_decision": "include", "assigned_clusters": [ { "cluster_name": "Methodology & Protocol Only", "cluster_type": "exclude", "cluster_description": "Papers focused on study design and methodology without clinical results", "related_criteria": "Study Design" } ] }, { "id": "98", "title": "Comprehensive molecular profiling broadens treatment options for breast cancer patients.", "abstract": "Precision oncology with next generation sequencing (NGS) using tumor tissue with or without blood has begun in Japan. Tumor molecular profiling tests are available, including the OncoGuide\u2122 NCC Oncopanel System and FoundationOne", "citation": "Kawaji H, Kubo M, Yamashita N, Yamamoto H, Kai M, Kajihara A, Yamada M, Kurata K, Kaneshiro K, Harada Y, Hayashi S, Shimazaki A, Mori H, Akiyoshi S, Oki E, Oda Y, Baba E, Mori M, Nakamura M. (2021). Comprehensive molecular profiling broadens treatment options for breast cancer patients. Cancer medicine. 10(2):529-539. http://doi.org/10.1002/cam4.3619. PMID: 33274848.", "score_list": [ 3.678206042167165, 3.1608342541544525 ], "ai_score_min": 3.1608342541544525, "ai_score_max": 3.678206042167165, "ai_score": 3.419520148160809, "ai_reasoning": "Moderate relevance. 'Comprehensive molecular profiling broadens treatme...' partially meets inclusion criteria but requires human review for final determination.", "evidence": [ { "text": "sequencing (NGS) using tumor tissue with or", "section": "abstract", "criterion": "Population", "supports": "include" }, { "text": "in Japan. Tumor molecular profiling tests", "section": "abstract", "criterion": "Study Design", "supports": "include" }, { "text": "using tumor tissue with or", "section": "abstract", "criterion": "Outcome", "supports": "include" }, { "text": "Comprehensive molecular profiling broadens treatment options", "section": "title", "criterion": "Population", "supports": "include" } ], "ai_decision": "include", "assigned_clusters": [ { "cluster_name": "Biomarker Analysis Studies", "cluster_type": "include", "cluster_description": "Papers with molecular or biomarker focus and genetic data", "related_criteria": "Outcome" } ] }, { "id": "99", "title": "Molecular profiling of advanced non-small cell lung cancer in the era of immunotherapy approach: a multicenter Italian observational prospective study of biomarker screening in daily clinical practice.", "abstract": "AIMS: Heterogeneous implementation of molecular tests in current diagnostic algorithm at a European and international level is emerging as a major issue for efficient lung cancer molecular profiling. METHODS: From May 2017 until October 2017, N=1612 patients referring to 13 Italian institutions were selected, at advanced stage non-small cell lung cancer (NSCLC), and prospectively evaluated. Principal endpoints were: the percentage of diagnoses performed on cytological and histological material, the proportion of requests for epidermal growth factor receptor (EGFR) mutational status, and resistance mutations detected on tissue and/or liquid biopsy samples after first-generation or second-generation tyrosine kinase inhibitors, the proportion of requests for anaplastic lymphoma kinase (ALK) gene rearrangements, ROS proto-oncogene 1 (ROS1) and Kirsten Rat Sarcoma (KRAS) determinations, the proportion of requests for programmed death-ligand1 (PD-L1) evaluation and, finally, the different assays used for the detection of EGFR mutations, ALK and ROS1 gene rearrangements and PD-L1 expression. RESULTS: Of 1325 patients finally included, only 50.8% requests were related to driver mutations with target agents already available in first-line at that preplanned time, while 49.2% were associated with PD-L1, ROS1, KRAS and others. Multiplex genomic assays (such as next-generation sequencing) were considered by all participating centres. CONCLUSIONS: To the best of our knowledge, this is the first study in a 'real-life daily practice' involving both pathologists and oncologists evaluating routinely workflow and trends towards improvements in molecular requests. Collected data aim to describe the applied algorithms and evolution of molecular screening for stage IV NSCLC in clinical practice.", "citation": "Vavala T, Malapelle U, Veggiani C, Ludovini V, Papotti M, Leone A, Graziano P, Minari R, Bono F, Sapino A, Manotti L, Troncone G, Pisapia P, Girlando S, Buffoni L, Righi L, Colantonio I, Bertetto O, Novello S. (2022). Molecular profiling of advanced non-small cell lung cancer in the era of immunotherapy approach: a multicenter Italian observational prospective study of biomarker screening in daily clinical practice. Journal of clinical pathology. 75(4):234-240. http://doi.org/10.1136/jclinpath-2020-207339. PMID: 33509945.", "score_list": [ 2.830346815831805, 2.5003057796837704 ], "ai_score_min": 2.5003057796837704, "ai_score_max": 2.830346815831805, "ai_score": 2.6653262977577876, "ai_reasoning": "Weak relevance. 'Molecular profiling of advanced non-small cell lun...' appears tangentially related to the research topic.", "evidence": [ { "text": "of EGFR mutations, ALK and", "section": "abstract", "criterion": "Population", "supports": "exclude" }, { "text": "only 50.8% requests were", "section": "abstract", "criterion": "Study Design", "supports": "exclude" }, { "text": "Molecular profiling of advanced non-small cell", "section": "title", "criterion": "Population", "supports": "exclude" } ], "ai_decision": "include", "assigned_clusters": [ { "cluster_name": "Adult Patient Population", "cluster_type": "include", "cluster_description": "Papers focused on adult patient demographics with defined inclusion criteria", "related_criteria": "Population" }, { "cluster_name": "Biomarker Analysis Studies", "cluster_type": "include", "cluster_description": "Papers with molecular or biomarker focus and genetic data", "related_criteria": "Outcome" } ] }, { "id": "100", "title": "Development and validation of a multigene variant profiling assay to guide targeted and immuno therapy selection in solid tumors.", "abstract": "We present data on analytical validation of the multigene variant profiling assay (CellDx) to provide actionable indications for selection of targeted and immune checkpoint inhibitor (ICI) therapy in solid tumors. CellDx includes Next Generation Sequencing (NGS) profiling of gene variants in a targeted 452-gene panel as well as status of total Tumor Mutation Burden (TMB), Microsatellite instability (MSI), Mismatch Repair (MMR) and Programmed Cell Death-Ligand 1 (PD-L1) respectively. Validation parameters included accuracy, sensitivity, specificity and reproducibility for detection of Single Nucleotide Alterations (SNAs), Copy Number Alterations (CNAs), Insertions and Deletions (Indels), Gene fusions, MSI and PDL1. Cumulative analytical sensitivity and specificity of the assay were 99.03 (95% CI: 96.54-99.88) and 99.23% (95% CI: 98.54% - 99.65%) respectively with 99.20% overall Accuracy (95% CI: 98.57% - 99.60%) and 99.7% Precision based on evaluation of 116 reference samples. The clinical performance of CellDx was evaluated in a subsequent analysis of 299 clinical samples where 861 unique mutations were detected of which 791 were oncogenic and 47 were actionable. Indications in MMR, MSI and TMB for selection of ICI therapies were also detected in the clinical samples. The high specificity, sensitivity, accuracy and reproducibility of the CellDx assay is suitable for clinical application for guiding selection of targeted and immunotherapy agents in patients with solid organ tumors.", "citation": "Akolkar D, Patil D, Srivastava N, Patil R, Datta V, Apurwa S, Yashwante N, Dhasarathan R, Gosavi R, John J, Khan S, Jadhav N, Mene P, Ahire D, Pawar S, Bodke H, Sahoo S, Nile A, Saindane D, Darokar H, Devhare P, Srinivasan A, Datar R. (2021). Development and validation of a multigene variant profiling assay to guide targeted and immuno therapy selection in solid tumors. PloS one. 16(2):e0246048. http://doi.org/10.1371/journal.pone.0246048. PMID: 33556149.", "score_list": [ 4.353479438478148, 4.347584973394267 ], "ai_score_min": 4.347584973394267, "ai_score_max": 4.353479438478148, "ai_score": 4.350532205936208, "ai_reasoning": "Strong candidate for inclusion. 'Development and validation of a multigene variant ...' directly addresses research criteria with clear methodology. Keywords suggesting inclusion: patient, therapy.", "evidence": [ { "text": "in the clinical samples. The high specificity,", "section": "abstract", "criterion": "Population", "supports": "include" }, { "text": "for selection of targeted", "section": "abstract", "criterion": "Study Design", "supports": "include" }, { "text": "panel as well as status of total Tumor", "section": "abstract", "criterion": "Outcome", "supports": "include" }, { "text": "98.54% - 99.65%) respectively", "section": "abstract", "criterion": "Intervention", "supports": "include" }, { "text": "Development and validation of a multigene", "section": "title", "criterion": "Population", "supports": "include" } ], "ai_decision": "include", "assigned_clusters": [ { "cluster_name": "Treatment Efficacy Studies", "cluster_type": "include", "cluster_description": "Papers evaluating treatment outcomes and efficacy measures", "related_criteria": "Intervention" } ] }, { "id": "101", "title": "Clinical Value of EGFR Copy Number Gain Determined by Amplicon-Based Targeted Next Generation Sequencing in Patients with EGFR-Mutated NSCLC.", "abstract": "BACKGROUND: The clinical relevance of epidermal growth factor receptor (EGFR) copy number gain in patients with EGFR mutated advanced non-small cell lung cancer on first-line tyrosine kinase inhibitor treatment has not been fully elucidated. OBJECTIVE: We aimed to estimate EGFR copy number gain using amplicon-based next generation sequencing data and explored its prognostic value. PATIENTS AND METHODS: Next generation sequencing data were obtained for 1566 patients with non-small cell lung cancer. EGFR copy number gain was defined based on an increase in EGFR read counts relative to internal reference amplicons and normal controls in combination with a modified z-score \u2265 3.5. Clinical follow-up data were available for 60 patients treated with first-line EGFR-tyrosine kinase inhibitors. RESULTS: Specificity and sensitivity of next generation sequencing-based EGFR copy number estimations were above 90%. EGFR copy number gain was observed in 27.9% of EGFR mutant cases and in 7.4% of EGFR wild-type cases. EGFR gain was not associated with progression-free survival but showed a significant effect on overall survival with an adjusted hazard ratio of 3.14 (95% confidence interval 1.46-6.78, p = 0.003). Besides EGFR copy number gain, osimertinib in second or subsequent lines of treatment and the presence of T790M at relapse revealed significant effects in a multivariate analysis with adjusted hazard ratio of 0.43 (95% confidence interval 0.20-0.91, p = 0.028) and 0.24 (95% confidence interval 0.1-0.59, p = 0.001), respectively. CONCLUSIONS: Pre-treatment EGFR copy number gain determined by amplicon-based next generation sequencing data predicts worse overall survival in EGFR-mutated patients treated with first-line EGFR-tyrosine kinase inhibitors. T790M at relapse and subsequent treatment with osimertinib predict longer overall survival.", "citation": "Wei J, Meng P, Terpstra MM, van Rijk A, Tamminga M, Scherpen F, Ter Elst A, Alimohamed MZ, Johansson LF, Stigt J, Gijtenbeek RPG, van Putten J, Hiltermann TJN, Groen HJM, Kok K, van der Wekken AJ, van den Berg A. (2021). Clinical Value of EGFR Copy Number Gain Determined by Amplicon-Based Targeted Next Generation Sequencing in Patients with EGFR-Mutated NSCLC. Targeted oncology. 16(2):215-226. http://doi.org/10.1007/s11523-021-00798-2. PMID: 33606136.", "score_list": [ 1.396214994441586, 1.2330013332416043 ], "ai_score_min": 1.2330013332416043, "ai_score_max": 1.396214994441586, "ai_score": 1.3146081638415952, "ai_reasoning": "Recommend exclusion. 'Clinical Value of EGFR Copy Number Gain Determined...' does not appear to meet core inclusion criteria.", "evidence": [ { "text": "The clinical relevance of epidermal growth factor receptor", "section": "abstract", "criterion": "Population", "supports": "exclude" }, { "text": "growth factor receptor (EGFR) copy number gain in", "section": "abstract", "criterion": "Study Design", "supports": "exclude" }, { "text": "Clinical Value of EGFR Copy Number", "section": "title", "criterion": "Population", "supports": "exclude" } ], "ai_decision": "include", "assigned_clusters": [ { "cluster_name": "Methodology & Protocol Only", "cluster_type": "exclude", "cluster_description": "Papers focused on study design and methodology without clinical results", "related_criteria": "Study Design" } ] }, { "id": "103", "title": "Comprehensive molecular profiling of Taiwanese breast cancers revealed potential therapeutic targets: prevalence of actionable mutations among 380 targeted sequencing analyses.", "abstract": "BACKGROUND: Breast cancer is one of the leading causes of cancer-related deaths in women, and there is a demand in developing an Asian-based genetic profiling database for breast cancer in improving the treatment response. This study aimed to determine molecular alternations and identify potential therapeutic targets by analyzing the genetic profiling from a cohort of Taiwanese breast cancers using a commercialized next-generation sequencing (NGS) targeted panel. METHODS: The study population comprised a broad spectrum of breast cancer patients in Taiwan, including Group 1: planned to receive first-line surgery and followed by adjuvant therapy, or early relapse within three years, Group 2: planned to receive first-line neoadjuvant therapy and followed by surgery, and Group 3: de novo stage IV, or stage IV with recurrence beyond three years. Molecular profiles were determined using Thermo Fisher\u2122 Oncomine\u2122 Comprehensive Assay version 3 (TMO comprehensive assay) from Formalin-Fixed Paraffin-Embedded (FFPE) tissues. Level of actionability was evaluated with the ESMO Scale of clinical actionability of molecular targets (ESCAT). RESULTS: A total of 380 TMO comprehensive assays were conducted on 372 patients, and we presented targeted sequencing analyses of Tier I: alteration-drug match associated with improved outcome in clinical trials including ERBB2 amplification, BRCA1/2 germline mutation, PIK3CA mutation, and NTRK translocation, and Tier II: antitumor activity associated with the matched alteration-drug but lack of prospective outcome data including PTEN loss, ESR1 mutation, AKT1 mutation, and ERBB2 mutation, and Tier III: matched drug-alteration that led to clinical benefit in another tumor type including MDM2 amplification, and ERBB3 mutation. Among them, 249 (66%) showed at least one actionable alternation based on the ESCAT criteria. The most frequent impacted genes (all variants combined within each sample) were PIK3CA (38%), followed by ERBB2 (23%), ESR1 (10%), AKT1 (6%), and BRCA2 (5%), and the remaining rare variants (less than 5% of assayed cohort) were BRCA1 (3%), MDM2 (2.2%), and ERBB3 (1.1%). CONCLUSION: Targeted sequencing of actionable genes is believed to provide clinical applicability and substantial benefits for Taiwanese breast cancer patients. A valid scale of clinical actionability should be adopted for precision medicine practice under multidisciplinary molecular tumor board.", "citation": "Huang CC, Tsai YF, Liu CY, Chao TC, Lien PJ, Lin YS, Feng CJ, Chiu JH, Hsu CY, Tseng LM. (2021). Comprehensive molecular profiling of Taiwanese breast cancers revealed potential therapeutic targets: prevalence of actionable mutations among 380 targeted sequencing analyses. BMC cancer. 21(1):199. http://doi.org/10.1186/s12885-021-07931-4. PMID: 33632156.", "score_list": [ 2.653178489514825, 2.599341506367831 ], "ai_score_min": 2.599341506367831, "ai_score_max": 2.653178489514825, "ai_score": 2.626259997941328, "ai_reasoning": "Weak relevance. 'Comprehensive molecular profiling of Taiwanese bre...' appears tangentially related to the research topic.", "evidence": [ { "text": "using a commercialized next-generation sequencing (NGS) targeted", "section": "abstract", "criterion": "Population", "supports": "exclude" }, { "text": "BRCA1 (3%), MDM2 (2.2%), and ERBB3", "section": "abstract", "criterion": "Study Design", "supports": "exclude" }, { "text": "Comprehensive molecular profiling of Taiwanese breast", "section": "title", "criterion": "Population", "supports": "exclude" } ], "ai_decision": "include", "assigned_clusters": [ { "cluster_name": "Adult Patient Population", "cluster_type": "include", "cluster_description": "Papers focused on adult patient demographics with defined inclusion criteria", "related_criteria": "Population" }, { "cluster_name": "Biomarker Analysis Studies", "cluster_type": "include", "cluster_description": "Papers with molecular or biomarker focus and genetic data", "related_criteria": "Outcome" } ] }, { "id": "104", "title": "Thai patients who fulfilled NCCN criteria for breast/ovarian cancer genetic assessment demonstrated high prevalence of germline mutations in cancer susceptibility genes: implication to Asian population testing.", "abstract": "BACKGROUND: Germline genetic mutation plays a significant role in breast cancer susceptibility. The strength of such predisposition varies among ethnic groups across the globe, and clinical data from Asian population to develop a strategic approach to who should undergo a genetic test are lacking. METHODS: We performed a multigene test with next generation sequencing in Thai patients whose clinical history fulfilled NCCN criteria for breast/ovarian cancer genetic assessment, consists of 306 breast cancer patients, 62 ovarian cancer patients, 14 pancreatic cancer patients and 7 prostate cancer patients. Genetic test result and clinical history were then checked with each NCCN criteria to determined detection rate for each indication. RESULTS: There were 83 pathogenic/likely pathogenic (P/LP) variants identified in 104 patients, 44 of these P/LP variants were novel. We reported a high rate of germline P/LP variants in breast cancer (24%), ovarian cancer (37%), pancreatic cancer (14%), and prostate cancer (29%). Germline P/LP variants in BRCA1 and BRCA2 accounted for 80% of P/LP variants found in breast cancer and 57% of P/LP variants found in ovarian cancer. The detection rate of patients who fulfilled NCCN 2019 guideline for genetic/familial high-risk assessment of breast and ovarian cancers was 22-40%. CONCLUSION: Overall, the data from this study strongly support the consideration of multigene panel test as a diagnostic tool for patients with inherited cancer susceptibility in Thailand and Asian population. Implementation of the NCCN guideline is applicable, some modification may be needed to be more suitable for Asian population.", "citation": "Lertwilaiwittaya P, Roothumnong E, Nakthong P, Dungort P, Meesamarnpong C, Tansa-Nga W, Pongsuktavorn K, Wiboonthanasarn S, Tititumjariya W, Thongnoppakhun W, Chanprasert S, Limwongse C, Pithukpakorn M. (2021). Thai patients who fulfilled NCCN criteria for breast/ovarian cancer genetic assessment demonstrated high prevalence of germline mutations in cancer susceptibility genes: implication to Asian population testing. Breast cancer research and treatment. 188(1):237-248. http://doi.org/10.1007/s10549-021-06152-4. PMID: 33649982.", "score_list": [ 2.673718497383024, 2.749734643734295 ], "ai_score_min": 2.673718497383024, "ai_score_max": 2.749734643734295, "ai_score": 2.7117265705586595, "ai_reasoning": "Weak relevance. 'Thai patients who fulfilled NCCN criteria for brea...' appears tangentially related to the research topic. Potential exclusion indicators: guideline.", "evidence": [ { "text": "predisposition varies among ethnic groups across the", "section": "abstract", "criterion": "Population", "supports": "exclude" }, { "text": "to who should undergo a genetic test are", "section": "abstract", "criterion": "Study Design", "supports": "exclude" }, { "text": "Thai patients who fulfilled NCCN criteria", "section": "title", "criterion": "Population", "supports": "exclude" } ], "ai_decision": "include", "assigned_clusters": [ { "cluster_name": "Adult Patient Population", "cluster_type": "include", "cluster_description": "Papers focused on adult patient demographics with defined inclusion criteria", "related_criteria": "Population" }, { "cluster_name": "Biomarker Analysis Studies", "cluster_type": "include", "cluster_description": "Papers with molecular or biomarker focus and genetic data", "related_criteria": "Outcome" } ] }, { "id": "105", "title": "Improvement of EGFR Testing over the Last Decade and Impact of Delaying TKI Initiation.", "abstract": "BACKGROUND: Epidermal growth factor receptor (EGFR) is the most common oncogenic mutation in lung adenocarcinoma and tyrosine kinase inhibitors (TKIs) have been considered standard treatment for more than a decade. However, time to initiation of TKIs (TTIT) from diagnosis is often delayed and represents a challenge for clinicians. We aimed to assess the impact of TTIT on clinical outcomes and complications. METHOD: TTIT was defined as the time between confirmed advanced diagnosis and the initiation of a TKI. Complications during this pre-TKI period were retrospectively collected from all patients with EGFR-mutant non small cell lung cancer (NSCLC) in our institution. RESULTS: 102 patients were diagnosed with EGFR mutated NSCLC between 2006 and 2019. The median PFS and OS were 12.9 and 22.5 months, respectively. TTIT was 5.7 months (95% CI 3.4-8) with a significant decrease in the latter years of this cohort. During the pre-TKI period, 23 patients received chemotherapy as first line treatment, of which 5 developed severe adverse events and 3 were not fit to receive TKI thereafter. Additionally, 29 patients had rapid clinical deterioration before initiation of first line TKI and 16 had to be hospitalized. Among the patients presenting a performance status deterioration, their prognosis was markedly affected compared to the remainder of the cohort ( CONCLUSION: Our real-world evidence study supports the concept that a delay to treat EGFR mutant NSCLC with TKIs is associated with adverse events, patient progression, hospitalization, and decreased overall survival. Rapid molecular diagnosis, including access to ctDNA technology may circumvent these deleterious delays.", "citation": "Blanc-Durand F, Florescu M, Tehfe M, Routy B, Alameddine R, Tran-Thanh D, Blais N. (2021). Improvement of EGFR Testing over the Last Decade and Impact of Delaying TKI Initiation. Current oncology (Toronto, Ont.). 28(2):1045-1055. http://doi.org/10.3390/curroncol28020102. PMID: 33652831.", "score_list": [ 1.2893693086775526, 1.2617014379972953 ], "ai_score_min": 1.2617014379972953, "ai_score_max": 1.2893693086775526, "ai_score": 1.275535373337424, "ai_reasoning": "Recommend exclusion. 'Improvement of EGFR Testing over the Last Decade a...' does not appear to meet core inclusion criteria.", "evidence": [ { "text": "the concept that a delay to treat", "section": "abstract", "criterion": "Population", "supports": "exclude" }, { "text": "between 2006 and 2019. The median PFS", "section": "abstract", "criterion": "Study Design", "supports": "exclude" }, { "text": "Improvement of EGFR Testing over the", "section": "title", "criterion": "Population", "supports": "exclude" } ], "ai_decision": "include", "assigned_clusters": [ { "cluster_name": "Methodology & Protocol Only", "cluster_type": "exclude", "cluster_description": "Papers focused on study design and methodology without clinical results", "related_criteria": "Study Design" } ] }, { "id": "106", "title": "Genomic Analyses for Predictors of Response to Chemoradiation in Stage III Non-Small Cell Lung Cancer.", "abstract": "BACKGROUND: Radiation with platinum-based chemotherapy is the standard of care for unresectable stage III non-small cell lung cancer (NSCLC). Despite aggressive treatment, progression-free survival and overall survival remain poor. It is unclear whether any tumor genetic mutations are associated with response to chemoradiation therapy. METHODS: We retrospectively reviewed clinical outcomes of patients with stage III NSCLC treated with definitive radiation who had undergone tumor molecular profiling through a next-generation DNA sequencing platform. Cox proportional hazards model was used to investigate associations between clinical outcomes and genetic mutations detected by next-generation sequencing. RESULTS: 110 patients were identified with stage III NSCLC and underwent definitive radiation between 2013 and 2017 and tumor molecular profiling. Concurrent or sequential chemotherapy was given in 104 patients (95%). Unbiased genomic analyses revealed a significant association between CONCLUSIONS: This study coupled multiplexed targeted sequencing with clinical outcome and identified mutations in", "citation": "Luo LY, Samstein RM, Dick-Godfrey R, Sidiqi B, Wang C, Oro F, Sonnick M, Paik PK, Chaft JE, Shaverdian N, Gomez DR, Rimner A, Wu AJ. (2021). Genomic Analyses for Predictors of Response to Chemoradiation in Stage III Non-Small Cell Lung Cancer. Advances in radiation oncology. 6(1):100615. http://doi.org/10.1016/j.adro.2020.10.027. PMID: 33665490.", "score_list": [ 2.5882135614917052, 2.340324396771393 ], "ai_score_min": 2.340324396771393, "ai_score_max": 2.5882135614917052, "ai_score": 2.464268979131549, "ai_reasoning": "Weak relevance. 'Genomic Analyses for Predictors of Response to Che...' appears tangentially related to the research topic. Potential exclusion indicators: review.", "evidence": [ { "text": "was given in 104 patients (95%). Unbiased", "section": "abstract", "criterion": "Population", "supports": "exclude" }, { "text": "It is unclear whether any tumor genetic", "section": "abstract", "criterion": "Study Design", "supports": "exclude" }, { "text": "Genomic Analyses for Predictors of Response", "section": "title", "criterion": "Population", "supports": "exclude" } ], "ai_decision": "include", "assigned_clusters": [ { "cluster_name": "Adult Patient Population", "cluster_type": "include", "cluster_description": "Papers focused on adult patient demographics with defined inclusion criteria", "related_criteria": "Population" }, { "cluster_name": "Biomarker Analysis Studies", "cluster_type": "include", "cluster_description": "Papers with molecular or biomarker focus and genetic data", "related_criteria": "Outcome" } ] }, { "id": "107", "title": "IHC versus FISH versus NGS to detect ALK gene rearrangement in NSCLC: all questions answered?", "abstract": "AIMS: Anaplastic lymphoma kinase ( METHODS: We analysed the concordance between IHC using D5F3 monoclonal antibody, FISH (break-apart) and NGS using a custom panel containing 71 different RESULTS: Among 71 cases included in this study, FISH was evaluable in 58 cases. The concordance of ALK IHC with FISH was 75.9% and that with NGS was 84.5%. The sensitivities of FISH and NGS were 75.6% and 87.5%, respectively. The median progression-free survival of ALK IHC-positive and FISH-negative group was 5.5 months and that of both positive was 9.97 months. CONCLUSION: Although NGS offers a better throughput and visualisation, IHC still remains the quintessential screening tool in upfront diagnosis of ALK rearranged NSCLC.", "citation": "Batra U, Nathany S, Sharma M, Pasricha S, Bansal A, Jain P, Mehta A. (2022). IHC versus FISH versus NGS to detect ALK gene rearrangement in NSCLC: all questions answered?. Journal of clinical pathology. 75(6):405-409. http://doi.org/10.1136/jclinpath-2021-207408. PMID: 33753563.", "score_list": [ 3.8952519966703907, 3.6389771304363068 ], "ai_score_min": 3.6389771304363068, "ai_score_max": 3.8952519966703907, "ai_score": 3.7671145635533487, "ai_reasoning": "Moderate relevance. 'IHC versus FISH versus NGS to detect ALK gene rear...' partially meets inclusion criteria but requires human review for final determination.", "evidence": [ { "text": "FISH (break-apart) and NGS using a custom panel", "section": "abstract", "criterion": "Population", "supports": "include" }, { "text": "still remains the quintessential", "section": "abstract", "criterion": "Study Design", "supports": "include" }, { "text": "The median progression-free survival of", "section": "abstract", "criterion": "Outcome", "supports": "include" }, { "text": "IHC versus FISH versus NGS to", "section": "title", "criterion": "Population", "supports": "include" } ], "ai_decision": "include", "assigned_clusters": [ { "cluster_name": "Methodology & Protocol Only", "cluster_type": "exclude", "cluster_description": "Papers focused on study design and methodology without clinical results", "related_criteria": "Study Design" } ] }, { "id": "108", "title": "Rare Germline Pathogenic Variants Identified by Multigene Panel Testing and the Risk of Aggressive Prostate Cancer.", "abstract": "While gene panel sequencing is becoming widely used for cancer risk prediction, its clinical utility with respect to predicting aggressive prostate cancer (PrCa) is limited by our current understanding of the genetic risk factors associated with predisposition to this potentially lethal disease phenotype. This study included 837 men diagnosed with aggressive PrCa and 7261 controls (unaffected men and men who did not meet criteria for aggressive PrCa). Rare germline pathogenic variants (including likely pathogenic variants) were identified by targeted sequencing of 26 known or putative cancer predisposition genes. We found that 85 (10%) men with aggressive PrCa and 265 (4%) controls carried a pathogenic variant (", "citation": "Nguyen-Dumont T, Dowty JG, MacInnis RJ, Steen JA, Riaz M, Dugu\u00e9 PA, Renault AL, Hammet F, Mahmoodi M, Theys D, Tsimiklis H, Severi G, Bolton D, Lacaze P, Sebra R, Schadt E, McNeil J, Giles GG, Milne RL, Southey MC. (2021). Rare Germline Pathogenic Variants Identified by Multigene Panel Testing and the Risk of Aggressive Prostate Cancer. Cancers. 13(7). http://doi.org/10.3390/cancers13071495. PMID: 33804961.", "score_list": [ 2.2534078606112122, 2.1576800490615238 ], "ai_score_min": 2.1576800490615238, "ai_score_max": 2.2534078606112122, "ai_score": 2.205543954836368, "ai_reasoning": "Weak relevance. 'Rare Germline Pathogenic Variants Identified by Mu...' appears tangentially related to the research topic.", "evidence": [ { "text": "study included 837 men diagnosed with", "section": "abstract", "criterion": "Population", "supports": "exclude" }, { "text": "with aggressive PrCa and", "section": "abstract", "criterion": "Study Design", "supports": "exclude" }, { "text": "Rare Germline Pathogenic Variants Identified by", "section": "title", "criterion": "Population", "supports": "exclude" } ], "ai_decision": "include", "assigned_clusters": [ { "cluster_name": "Biomarker Analysis Studies", "cluster_type": "include", "cluster_description": "Papers with molecular or biomarker focus and genetic data", "related_criteria": "Outcome" } ] }, { "id": "109", "title": "SMARCA4 and Other SWItch/Sucrose NonFermentable Family Genomic Alterations in NSCLC: Clinicopathologic Characteristics and Outcomes to Immune Checkpoint Inhibition.", "abstract": "INTRODUCTION: The SWItch/Sucrose Nonfermentable (SWI/SNF) chromatin remodeling complex acts as a regulatory component of transcription, and inactivating mutations (muts) within the complex are implicated in genomic instability, higher tumor mutational burden, and an aggressive cancer phenotype. Whether SMARCA4 and other SWI/SNF alterations are independent prognostic factors or associated with clinical outcomes to immune checkpoint inhibitors (ICIs) in NSCLC remains unclear. METHODS: We collected clinicopathologic and genomic data from patients with NSCLC who underwent targeted next-generation sequencing at the Dana-Farber Cancer Institute. Tumors were characterized on the basis of the presence or absence of muts across a set of six SWI/SNF genes (ARID1A, ARID1B, ARID2, PBRM1, SMARCA4, and SMARCB1). RESULTS: Of 2689 patients with NSCLC, 20.6% (N = 555) had SWI/SNF genomic alterations. Compared with SWI/SNF wild-type (wt) NSCLC, patients with SWI/SNF-mutant NSCLCs had a lower prevalence of concurrent targetable driver muts (33.2% versus 22.2%; p < 0.001), a higher tumor mutational burden (median 8.5 versus 12.2 muts/megabase; p < 0.001), and a shorter median overall survival (mOS) from the time of advanced disease diagnosis (25.0 versus 19.3 mo, p = 0.01); the detrimental effect in OS seemed to be largely driven by SMARCA4 muts (mOS: 25.0 for SMARCA4 wt versus 15.6 mo for SMARCA4 mutant; p < 0.001). Among 532 patients who received ICIs, 25.5% (N = 136) harbored SWI/SNF muts. From the start of immunotherapy, there was no difference in objective response rate (ORR = 19.9% versus 25.0%, p = 0.2), median progression-free survival (mPFS = 3.0 versus 3.0 mo, hazard ratio [HR] = 0.96 [95% confidence interval [CI] = 0.77-1.18], p = 0.7), or mOS (13.1 versus 9.5 mo, HR = 0.81 [95% CI: 0.64-1.02], p = 0.07) in SWI/SNF-wt versus SWI/SNF-mutant NSCLC, respectively. Nevertheless, among KRAS-mutant NSCLCs treated with ICIs (N = 176), a concurrent SWI/SNF mut (N = 39) conferred a numerically lower ORR (21.9% versus 12.8%, p = 0.2), a significantly shorter mPFS (4.1 versus 1.8 mo, HR = 0.57 [95% CI: 0.38-0.84], p = 0.005), and a significantly shorter mOS (15.5 versus 8.2 mo, HR = 0.56 [95% CI: 0.36-0.86], p = 0.008). The deleterious effect on immunotherapy outcomes in KRAS-mutant NSCLC was most pronounced in the SMARCA4-mutant subset (N = 17), with a lower ORR (22% versus 0%, p = 0.03), a significantly shorter mPFS (4.1 versus 1.4 mo, HR = 0.25 [95% CI: 0.14-0.42], p < 0.001), and a significantly shorter mOS (15.1 versus 3.0 mo, HR = 0.29 [95% CI: 0.17-0.50], p < 0.001) compared with SMARCA4-wt KRAS-mutant NSCLCs. CONCLUSIONS: Although there were no associations between SWI/SNF mut status and immunotherapy efficacy in the overall NSCLC cohort, the presence of a SMARCA4 alteration may confer a worse outcome to immunotherapy among KRAS-mutant NSCLCs.", "citation": "Alessi JV, Ricciuti B, Spurr LF, Gupta H, Li YY, Glass C, Nishino M, Cherniack AD, Lindsay J, Sharma B, Felt KD, Rodig SJ, Cheng ML, Sholl LM, Awad MM. (2021). SMARCA4 and Other SWItch/Sucrose NonFermentable Family Genomic Alterations in NSCLC: Clinicopathologic Characteristics and Outcomes to Immune Checkpoint Inhibition. Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer. 16(7):1176-1187. http://doi.org/10.1016/j.jtho.2021.03.024. PMID: 33845210.", "score_list": [ 3.464668118112111, 3.53722540029827 ], "ai_score_min": 3.464668118112111, "ai_score_max": 3.53722540029827, "ai_score": 3.50094675920519, "ai_reasoning": "Moderate relevance. 'SMARCA4 and Other SWItch/Sucrose NonFermentable Fa...' partially meets inclusion criteria but requires human review for final determination.", "evidence": [ { "text": "immunotherapy, there was no difference", "section": "abstract", "criterion": "Population", "supports": "include" }, { "text": "versus 19.3 mo, p = 0.01); the", "section": "abstract", "criterion": "Study Design", "supports": "include" }, { "text": "at the Dana-Farber Cancer Institute. Tumors were", "section": "abstract", "criterion": "Outcome", "supports": "include" }, { "text": "SMARCA4 and Other SWItch/Sucrose NonFermentable Family", "section": "title", "criterion": "Population", "supports": "include" } ], "ai_decision": "include", "assigned_clusters": [ { "cluster_name": "Adult Patient Population", "cluster_type": "include", "cluster_description": "Papers focused on adult patient demographics with defined inclusion criteria", "related_criteria": "Population" } ] }, { "id": "110", "title": "Comprehensive tumor molecular profile analysis in clinical practice.", "abstract": "BACKGROUND: Tumor molecular profile analysis by Next Generation Sequencing technology is currently widely applied in clinical practice and has enabled the detection of predictive biomarkers of response to targeted treatment. In parallel with targeted therapies, immunotherapies are also evolving, revolutionizing cancer therapy, with Programmed Death-ligand 1 (PD-L1), Microsatellite instability (MSI), and Tumor Mutational Burden (TMB) analysis being the biomarkers employed most commonly. METHODS: In the present study, tumor molecular profile analysis was performed using a 161 gene NGS panel, containing the majority of clinically significant genes for cancer treatment selection. A variety of tumor types have been analyzed, including aggressive and hard to treat cancers such as pancreatic cancer. Besides, the clinical utility of immunotherapy biomarkers (TMB, MSI, PD-L1), was also studied. RESULTS: Molecular profile analysis was conducted in 610 cancer patients, while in 393 of them a at least one biomarker for immunotherapy response was requested. An actionable alteration was detected in 77.87% of the patients. 54.75% of them received information related to on-label or off-label treatment (Tiers 1A.1, 1A.2, 2B, and 2C.1) and 21.31% received a variant that could be used for clinical trial inclusion. The addition to immunotherapy biomarker to targeted biomarkers' analysis in 191 cases increased the number of patients with an on-label treatment recommendation by 22.92%, while an option for on-label or off-label treatment was provided in 71.35% of the cases. CONCLUSIONS: Tumor molecular profile analysis using NGS is a first-tier method for a variety of tumor types and provides important information for decision making in the treatment of cancer patients. Importantly, simultaneous analysis for targeted therapy and immunotherapy biomarkers could lead to better tumor characterization and offer actionable information in the majority of patients. Furthermore, our data suggest that one in two patients may be eligible for on-label ICI treatment based on biomarker analysis. However, appropriate interpretation of results from such analysis is essential for implementation in clinical practice and accurate refinement of treatment strategy.", "citation": "\u00d6zdo\u011fan M, Papadopoulou E, Tsoulos N, Tsantikidi A, Mariatou VM, Tsaousis G, Kapeni E, Bourkoula E, Fotiou D, Kapetsis G, Boukovinas I, Touroutoglou N, Fassas A, Adamidis A, Kosmidis P, Trafalis D, Galani E, Lypas G, Orhan B, Tansan S, \u00d6zatl\u0131 T, K\u0131rca O, \u00c7ak\u0131r O, Nasioulas G. (2021). Comprehensive tumor molecular profile analysis in clinical practice. BMC medical genomics. 14(1):105. http://doi.org/10.1186/s12920-021-00952-9. PMID: 33853586.", "score_list": [ 2.9138479836475986, 2.7407195302552396 ], "ai_score_min": 2.7407195302552396, "ai_score_max": 2.9138479836475986, "ai_score": 2.8272837569514193, "ai_reasoning": "Weak relevance. 'Comprehensive tumor molecular profile analysis in ...' appears tangentially related to the research topic. Potential exclusion indicators: recommendation.", "evidence": [ { "text": "analysis by Next Generation", "section": "abstract", "criterion": "Population", "supports": "exclude" }, { "text": "610 cancer patients, while in", "section": "abstract", "criterion": "Study Design", "supports": "exclude" }, { "text": "Comprehensive tumor molecular profile analysis in", "section": "title", "criterion": "Population", "supports": "exclude" } ], "ai_decision": "include", "assigned_clusters": [ { "cluster_name": "Adult Patient Population", "cluster_type": "include", "cluster_description": "Papers focused on adult patient demographics with defined inclusion criteria", "related_criteria": "Population" }, { "cluster_name": "Biomarker Analysis Studies", "cluster_type": "include", "cluster_description": "Papers with molecular or biomarker focus and genetic data", "related_criteria": "Outcome" } ] }, { "id": "111", "title": "Cell-Free Circulating Tumor DNA Improves Standard Genotyping of Non-Small-Cell Lung Cancer and Increases Detection of Targetable Alterations in a Selected Hispanic Cohort.", "abstract": "BACKGROUND: Several studies have shown that the non-small-cell lung cancer (NSCLC) genomic background among Hispanics differs from other populations. The finding of low-frequency genomic alterations in cell-free DNA (cfDNA) can increase diagnostic accuracy and could improve treatment in NSCLC. METHODS: Data from 54 Hispanic patients with advanced NSCLC with high clinical suspicion for ALK, EGFR, and ROS1 mutations were collected (including young age, female sex, and non-smokers). cfDNA was extracted from plasma and analyzed using a commercial next-generation sequencing test (Guardant360) which detects genomic alterations in 74 genes. RESULTS: The median age was 56 years (range 31-83). Most patients were female (661.1%) and never smokers (72.3%). Among the patients included, 96% (52/54) had cfDNA detectable alterations with a mean number of 3.37 cfDNA alterations per test (range 1-10). cfDNA was able to detect some genomic alterations previously undetected by tissue biopsy. Among patients with insufficient or unavailable tissue to perform testing, mutations in EGFR and ALK which led to a change in therapy were determined using cfDNA in 28.8 and 3.8% of cases, respectively. Among patients with cfDNA alterations, 46.1% (n = 24) were switched to a targeted therapy with a median progression-free survival of 11.1 months (95% CI 7.6-14.6) and an overall survival of 40.3 months (95% CI 27.1-53.6). Concurrent genetic mutations with TP53 and KRAS negatively impacted the prognosis. CONCLUSIONS: In a selected population of NSCLC Hispanic patients, comprehensive cfDNA analysis allowed a treatment change in 46.1% of the cases. Guardant360 allows the identification of genomic alterations to improve treatment selection and increase prognosis.", "citation": "Zatarain-Barr\u00f3n ZL, Cardona AF, D\u00edaz-Garc\u00eda D, Trejo Rosales R, Rojas L, Cruz-Rico G, Nagy R, Cabrera L, Vargas C, Saam J, Barr\u00f3n F, Arrieta O. (2021). Cell-Free Circulating Tumor DNA Improves Standard Genotyping of Non-Small-Cell Lung Cancer and Increases Detection of Targetable Alterations in a Selected Hispanic Cohort. Oncology. 99(8):539-546. http://doi.org/10.1159/000514648. PMID: 33902046.", "score_list": [ 2.299737298330644, 2.0609472857715674 ], "ai_score_min": 2.0609472857715674, "ai_score_max": 2.299737298330644, "ai_score": 2.1803422920511055, "ai_reasoning": "Weak relevance. 'Cell-Free Circulating Tumor DNA Improves Standard ...' appears tangentially related to the research topic.", "evidence": [ { "text": "METHODS: Data from 54", "section": "abstract", "criterion": "Population", "supports": "exclude" }, { "text": "survival of 11.1 months (95% CI 7.6-14.6) and", "section": "abstract", "criterion": "Study Design", "supports": "exclude" }, { "text": "Cell-Free Circulating Tumor DNA Improves Standard", "section": "title", "criterion": "Population", "supports": "exclude" } ], "ai_decision": "include", "assigned_clusters": [ { "cluster_name": "Adult Patient Population", "cluster_type": "include", "cluster_description": "Papers focused on adult patient demographics with defined inclusion criteria", "related_criteria": "Population" }, { "cluster_name": "Biomarker Analysis Studies", "cluster_type": "include", "cluster_description": "Papers with molecular or biomarker focus and genetic data", "related_criteria": "Outcome" } ] }, { "id": "112", "title": "Intrahepatic Cholangiocarcinoma with Lymph Node Metastasis: Treatment-Related Outcomes and the Role of Tumor Genomics in Patient Selection.", "abstract": "PURPOSE: Lymph node metastasis (LNM) drastically reduces survival after resection of intrahepatic cholangiocarcinoma (IHC). Optimal treatment is ill defined, and it is unclear whether tumor mutational profiling can support treatment decisions. EXPERIMENTAL DESIGN: Patients with liver-limited IHC with or without LNM treated with resection ( RESULTS: For node-negative patients, resection was associated with the longest median overall survival [OS, 59.9 months; 95% confidence interval (CI), 47.2-74.31], followed by HAIC (24.9 months; 95% CI, 20.3-29.6), and SYS (13.7 months; 95% CI, 8.9-15.9; CONCLUSIONS: There was no difference in OS for patients with node-positive IHC treated by resection versus HAIC, and both treatments had better survival than SYS alone. The presence of high-risk genetic alterations provides valuable prognostic information that may help guide treatment.", "citation": "Jolissaint JS, Soares KC, Seier KP, Kundra R, G\u00f6nen M, Shin PJ, Boerner T, Sigel C, Madupuri R, Vakiani E, Cercek A, Harding JJ, Kemeny NE, Connell LC, Balachandran VP, D'Angelica MI, Drebin JA, Kingham TP, Wei AC, Jarnagin WR. (2021). Intrahepatic Cholangiocarcinoma with Lymph Node Metastasis: Treatment-Related Outcomes and the Role of Tumor Genomics in Patient Selection. Clinical cancer research : an official journal of the American Association for Cancer Research. 27(14):4101-4108. http://doi.org/10.1158/1078-0432.CCR-21-0412. PMID: 33963001.", "score_list": [ 1.957713281190732, 1.9872930977624597 ], "ai_score_min": 1.957713281190732, "ai_score_max": 1.9872930977624597, "ai_score": 1.9725031894765959, "ai_reasoning": "Recommend exclusion. 'Intrahepatic Cholangiocarcinoma with Lymph Node Me...' does not appear to meet core inclusion criteria.", "evidence": [ { "text": "IHC treated by resection", "section": "abstract", "criterion": "Population", "supports": "exclude" }, { "text": "(24.9 months; 95% CI, 20.3-29.6),", "section": "abstract", "criterion": "Study Design", "supports": "exclude" }, { "text": "Intrahepatic Cholangiocarcinoma with Lymph Node Metastasis:", "section": "title", "criterion": "Population", "supports": "exclude" } ], "ai_decision": "include", "assigned_clusters": [ { "cluster_name": "Methodology & Protocol Only", "cluster_type": "exclude", "cluster_description": "Papers focused on study design and methodology without clinical results", "related_criteria": "Study Design" } ] }, { "id": "114", "title": "Prevalence and Clinicopathological Characteristics of Moderate and High-Penetrance Genes in Non-BRCA1/2 Breast Cancer High-Risk Spanish Families.", "abstract": "(1) Background: Over the last decade, genetic counseling clinics have moved from single-gene sequencing to multigene panel sequencing. Multiple genes related to a moderate risk of breast cancer (BC) have emerged, although many questions remain regarding the risks and clinical features associated with these genes. (2) Methods: Ninety-six BC index cases (ICs) with high-risk features for hereditary breast and ovarian cancer (HBOC) and with a previous uninformative result for", "citation": "Fonfria M, de Juan Jim\u00e9nez I, Tena I, Chirivella I, Richart-Aznar P, Segura A, S\u00e1nchez-Heras AB, Martinez-Due\u00f1as E. (2021). Prevalence and Clinicopathological Characteristics of Moderate and High-Penetrance Genes in Non-BRCA1/2 Breast Cancer High-Risk Spanish Families. Journal of personalized medicine. 11(6). http://doi.org/10.3390/jpm11060548. PMID: 34204722.", "score_list": [ 4.245542482914743, 4.2054188920420135 ], "ai_score_min": 4.2054188920420135, "ai_score_max": 4.245542482914743, "ai_score": 4.225480687478378, "ai_reasoning": "Strong candidate for inclusion. 'Prevalence and Clinicopathological Characteristics...' directly addresses research criteria with clear methodology.", "evidence": [ { "text": "genetic counseling clinics have", "section": "abstract", "criterion": "Population", "supports": "include" }, { "text": "sequencing. Multiple genes related to a moderate risk", "section": "abstract", "criterion": "Study Design", "supports": "include" }, { "text": "clinics have moved from", "section": "abstract", "criterion": "Outcome", "supports": "include" }, { "text": "regarding the risks and", "section": "abstract", "criterion": "Intervention", "supports": "include" }, { "text": "Prevalence and Clinicopathological Characteristics of Moderate", "section": "title", "criterion": "Population", "supports": "include" } ], "ai_decision": "include", "assigned_clusters": [ { "cluster_name": "Treatment Efficacy Studies", "cluster_type": "include", "cluster_description": "Papers evaluating treatment outcomes and efficacy measures", "related_criteria": "Intervention" } ] }, { "id": "115", "title": "Tumor Mutation Burden Prediction Model in Egyptian Breast Cancer patients based on Next Generation Sequencing.", "abstract": "OBJECTIVES: This study aimed to identify the tumor mutation burden (TMB) value in Egyptian breast cancer (BC) patients. Moreover, to find the best TMB prediction model based on the expression of estrogen (ER), progesterone (PR), human epidermal growth factor receptor 2 (HER-2), and proliferation index Ki-67. METHODS: The Ion AmpliSeq Comprehensive Cancer Panel was used to determine TMB value of 58 Egyptian BC tumor tissues. Different machine learning models were used to select the optimal classification model for prediction of TMB level according to patient's receptor status. RESULTS: The measured TMB value was between 0 and 8.12/Mb. Positive expression of ER and PR was significantly associated with TMB \u2264 1.25 [(OR =0.35, 95% CI: 0.04-2.98), (OR = 0.17, 95% CI= 0.02-0.44)] respectively. Ki-67 expression positive was significantly associated with TMB >1.25 than those who were Ki-67 expression negative (OR = 9.33, 95% CI= 2.07-42.18). However, no significant differences were observed between HER2 positive and HER2 negative groups. The optimized logistic regression model was TMB = -27.5 -1.82 ER - 0.73 PR + 0.826 HER2 + 2.08 Ki-67. CONCLUSION: Our findings revealed that TMB value can be predicted based on the expression level of ER, PR, HER-2, and Ki-67.", "citation": "Nassar A, Lymona AM, Lotfy MM, Youssef ASE, Mohanad M, Manie TM, Youssef MMG, Farahat IG, Zekri AN. (2021). Tumor Mutation Burden Prediction Model in Egyptian Breast Cancer patients based on Next Generation Sequencing. Asian Pacific journal of cancer prevention : APJCP. 22(7):2053-2059. http://doi.org/10.31557/APJCP.2021.22.7.2053. PMID: 34319027.", "score_list": [ 4.320973172380092, 3.832052125394219 ], "ai_score_min": 3.832052125394219, "ai_score_max": 4.320973172380092, "ai_score": 4.076512648887156, "ai_reasoning": "Strong candidate for inclusion. 'Tumor Mutation Burden Prediction Model in Egyptian...' directly addresses research criteria with clear methodology. Keywords suggesting inclusion: patient, results, study.", "evidence": [ { "text": "be predicted based on the expression", "section": "abstract", "criterion": "Population", "supports": "include" }, { "text": "can be predicted based on", "section": "abstract", "criterion": "Study Design", "supports": "include" }, { "text": "regression model was TMB =", "section": "abstract", "criterion": "Outcome", "supports": "include" }, { "text": "Ki-67. METHODS: The Ion AmpliSeq Comprehensive Cancer Panel", "section": "abstract", "criterion": "Intervention", "supports": "include" }, { "text": "Tumor Mutation Burden Prediction Model in", "section": "title", "criterion": "Population", "supports": "include" } ], "ai_decision": "include", "assigned_clusters": [ { "cluster_name": "Treatment Efficacy Studies", "cluster_type": "include", "cluster_description": "Papers evaluating treatment outcomes and efficacy measures", "related_criteria": "Intervention" } ] }, { "id": "116", "title": "Tumour mutational burden, microsatellite instability, and actionable alterations in metastatic colorectal cancer: Next-generation sequencing results of TRIBE2 study.", "abstract": "BACKGROUND: We performed a comprehensive genomic profiling of tumour samples from metastatic colorectal cancer (mCRC) patients enrolled in the TRIBE2 study to assess the concordance among different techniques to evaluate mismatch repair (MMR) and microsatellite instability (MSI) status, to characterize tumours according to the tumour mutational burden (TMB) and explore the clinical relevance of different TMB cutpoints, and to investigate the prevalence of alterations actionable with targeted approaches or immune checkpoint inhibitors. MATERIAL AND METHODS: Tumour samples of 296 (44%) of 679 enrolled patients underwent 592-gene DNA next-generation sequencing (NGS). MMR status was assessed by immunohistochemistry (MMR-IHC), and MSI status was assessed by NGS (MSI-NGS). TMB was defined as low, intermediate, or high if <7, 7-16, or \u226517 mutations/megabase (mut/Mb) were found. The performance of TMB to predict MSI status was tested by receiver operating characteristic (ROC) curve. Actionable alterations included BRAF V600E, KRAS G12C, POLE mutations, HER2 amplification and mutations, and MSI-H. RESULTS: Of 216 paired cases, concordance between MMR-IHC and MSI-NGS was 98.6%. Among 11 TMB-high tumours, eight (73%) were MSI-H and three (27%) were microsatellite stable and harboured POLE or MSH6 mutations. High TMB had a trend for a better outcome than low/intermediate TMB (hazard ratio for overall survival 0.45, 95% confidence interval 0.28-1.33; P = 0.106). No interaction effect between TMB and treatment arm was observed. Seventeen mut/Mb was identified as the optimal threshold of TMB for predicting MSI status. Actionable alterations were found in 62 (21%) of 296 patients. CONCLUSIONS: Genomic profiling provides an overview of the genomic landscape of mCRC in a single analysis, including actionable targets and markers of immune sensitivity.", "citation": "Antoniotti C, Korn WM, Marmorino F, Rossini D, Lonardi S, Masi G, Randon G, Conca V, Boccaccino A, Tomasello G, Passardi A, Swensen J, Ugolini C, Oberley M, Tamburini E, Casagrande M, Domenyuk V, Fontanini G, Giordano M, Abraham J, Spetzler D, Falcone A, Lenz HJ, Cremolini C. (2021). Tumour mutational burden, microsatellite instability, and actionable alterations in metastatic colorectal cancer: Next-generation sequencing results of TRIBE2 study. European journal of cancer (Oxford, England : 1990). 155:73-84. http://doi.org/10.1016/j.ejca.2021.06.037. PMID: 34365081.", "score_list": [ 4.17109056586473, 3.970505595580387 ], "ai_score_min": 3.970505595580387, "ai_score_max": 4.17109056586473, "ai_score": 4.070798080722558, "ai_reasoning": "Strong candidate for inclusion. 'Tumour mutational burden, microsatellite instabili...' directly addresses research criteria with clear methodology. Keywords suggesting inclusion: outcome, treatment, patient.", "evidence": [ { "text": "techniques to evaluate mismatch repair", "section": "abstract", "criterion": "Population", "supports": "include" }, { "text": "mutational burden (TMB) and", "section": "abstract", "criterion": "Study Design", "supports": "include" }, { "text": "curve. Actionable alterations included BRAF V600E, KRAS G12C,", "section": "abstract", "criterion": "Outcome", "supports": "include" }, { "text": "and MSI-H. RESULTS: Of", "section": "abstract", "criterion": "Intervention", "supports": "include" }, { "text": "Tumour mutational burden, microsatellite instability, and", "section": "title", "criterion": "Population", "supports": "include" } ], "ai_decision": "include", "assigned_clusters": [ { "cluster_name": "Treatment Efficacy Studies", "cluster_type": "include", "cluster_description": "Papers evaluating treatment outcomes and efficacy measures", "related_criteria": "Intervention" } ] }, { "id": "117", "title": "High chromosome instability identified by low-pass whole-genome sequencing assay is associated with TP53 copy loss and worse prognosis in BRCA1 germline mutation breast cancer.", "abstract": "BACKGROUND: Though BRCA1 mutation is the most susceptible factor of breast cancer, its prognostic value is disputable. Here in this study, we use a novel method which based on whole-genome analysis to evaluate the chromosome instability (CIN) value and identified the potential relationship between CIN and prognosis of breast cancer patients with germline-BRCA1 mutation. MATERIALS AND METHODS: Sanger sequencing or a 98-gene panel sequencing assay was used to screen for BRCA1 germline small mutations in 1151 breast cancer patients with high-risk factors. MLPA assay was employed to screen BRCA1 large genomic rearrangements in familial breast cancer patients with BRCA1 negative for small mutations. Thirty-two samples with unique BRCA1 germline mutation patterns were further subjected to CIN evaluation by LPWGS (low-pass whole-genome sequencing) technology. RESULTS: Firstly, 113 patients with germline BRCA1 mutations were screened from the cohort. Further CIN analysis by the LPWGS assay indicated that CIN was independent from the mutation location or type of BRCA1. Patients with high CIN status had shorter disease-free survival rates (DFS) (HR = 6.54, 95% CI 1.30-32.98, P = 0.034). The TP53 copy loss was also characterized by LPWGS assay. The rates of TP53 copy loss in CIN high and CIN low groups were 85.71% (12/14) and 16.67% (3/18), respectively. CONCLUSION: CIN-high is a prognostic factor correlated with shorter DFS and was independent with the germline BRCA1 mutation pattern. Higher CIN values were significantly correlated with TP53 copy loss in breast cancer patients with germline BRCA1 mutation. Our results revealed a reliable molecular parameter for distinguishing patients with poor prognosis from the BRCA1-mutated breast cancer patients.", "citation": "Zhu L, Pan JN, Qian Z, Ye WW, Wang XJ, Cao WM. (2022). High chromosome instability identified by low-pass whole-genome sequencing assay is associated with TP53 copy loss and worse prognosis in BRCA1 germline mutation breast cancer. Breast cancer (Tokyo, Japan). 29(1):103-113. http://doi.org/10.1007/s12282-021-01286-1. PMID: 34403063.", "score_list": [ 2.2093410507111133, 2.3382062335451814 ], "ai_score_min": 2.2093410507111133, "ai_score_max": 2.3382062335451814, "ai_score": 2.2737736421281474, "ai_reasoning": "Weak relevance. 'High chromosome instability identified by low-pass...' appears tangentially related to the research topic.", "evidence": [ { "text": "BRCA1 large genomic rearrangements in", "section": "abstract", "criterion": "Population", "supports": "exclude" }, { "text": "relationship between CIN and prognosis", "section": "abstract", "criterion": "Study Design", "supports": "exclude" }, { "text": "High chromosome instability identified by low-pass", "section": "title", "criterion": "Population", "supports": "exclude" } ], "ai_decision": "include", "assigned_clusters": [ { "cluster_name": "Adult Patient Population", "cluster_type": "include", "cluster_description": "Papers focused on adult patient demographics with defined inclusion criteria", "related_criteria": "Population" }, { "cluster_name": "Biomarker Analysis Studies", "cluster_type": "include", "cluster_description": "Papers with molecular or biomarker focus and genetic data", "related_criteria": "Outcome" } ] }, { "id": "118", "title": "Early Cost Effectiveness of Whole-Genome Sequencing as a Clinical Diagnostic Test for Patients with Inoperable Stage IIIB,C/IV Non-squamous Non-small-Cell Lung Cancer.", "abstract": "BACKGROUND: Advanced non-small-cell lung cancer (NSCLC) harbours many genetic aberrations that can be targeted with systemic treatments. Whole-genome sequencing (WGS) can simultaneously detect these (and possibly new) molecular targets. However, the exact added clinical value of WGS is unknown. OBJECTIVE: The objective of this study was to determine the early cost effectiveness of using WGS in diagnostic strategies compared with currently used molecular diagnostics for patients with inoperable stage IIIB,C/IV non-squamous NSCLC from a Dutch healthcare perspective. METHODS: A decision tree represented the diagnostic pathway, and a cohort state transition model represented disease progression. Three diagnostic strategies were modelled: standard of care (SoC) alone, WGS as a diagnostic test, and SoC followed by WGS. Treatment effectiveness was based on a systematic review. Probabilistic cost-effectiveness analyses were performed, and threshold analyses (using \u20ac80,000 per quality-adjusted life-year [QALY]) was used to explore the early cost effectiveness of WGS. RESULTS: WGS as a diagnostic test resulted in more QALYs (0.002) and costs (\u20ac1534 [incremental net monetary benefit -\u20ac1349]), and SoC followed by WGS resulted in fewer QALYs (-0.002) and more costs (\u20ac1059 [-\u20ac1194]) compared with SoC alone. WGS as a diagnostic test was only cost effective if it was priced at \u20ac2000 per patient and identified 2.7% more actionable patients than SoC alone. Treating these additional identified patients with new treatments costing >\u20ac4069 per month decreased the probability of cost effectiveness. CONCLUSIONS: Our analysis suggests that providing WGS as a diagnostic test is cost effective compared with SoC followed by WGS and SoC alone if costs for WGS decrease and additional patients with actionable targets are identified. This cost-effectiveness model can be used to incorporate new findings iteratively and to support ongoing decision making regarding the use of WGS in this rapidly evolving field.", "citation": "Simons MJHG, Ret\u00e8l VP, Ramaekers BLT, Butter R, Mankor JM, Paats MS, Aerts JGJV, Mfumbilwa ZA, Roepman P, Coup\u00e9 VMH, Uyl-de Groot CA, van Harten WH, Joore MA. (2021). Early Cost Effectiveness of Whole-Genome Sequencing as a Clinical Diagnostic Test for Patients with Inoperable Stage IIIB,C/IV Non-squamous Non-small-Cell Lung Cancer. PharmacoEconomics. 39(12):1429-1442. http://doi.org/10.1007/s40273-021-01073-y. PMID: 34405371.", "score_list": [ 1.8259329244175657, 1.5376066206438594 ], "ai_score_min": 1.5376066206438594, "ai_score_max": 1.8259329244175657, "ai_score": 1.6817697725307126, "ai_reasoning": "Recommend exclusion. 'Early Cost Effectiveness of Whole-Genome Sequencin...' does not appear to meet core inclusion criteria. Exclusion keywords found: review.", "evidence": [ { "text": "resulted in fewer QALYs (-0.002) and more costs", "section": "abstract", "criterion": "Population", "supports": "exclude" }, { "text": "to determine the early cost", "section": "abstract", "criterion": "Study Design", "supports": "exclude" }, { "text": "Early Cost Effectiveness of Whole-Genome Sequencing", "section": "title", "criterion": "Population", "supports": "exclude" } ], "ai_decision": "include", "assigned_clusters": [ { "cluster_name": "Review & Meta-Analysis (No Primary Data)", "cluster_type": "exclude", "cluster_description": "Secondary research synthesizing existing studies without new data", "related_criteria": "Study Design" } ] }, { "id": "119", "title": "Molecular Landscape of Therapy-related Myeloid Neoplasms in Patients Previously Treated for Gynecologic and Breast Cancers.", "abstract": "Definition of therapy-related myeloid neoplasms (TRMN) is only based on clinical history of exposure to leukemogenic therapy. No specific molecular classification combining therapy-related acute myeloid leukemia and therapy-related myelodysplastic syndromes has been proposed. We aimed to describe the molecular landscape of TRMN at diagnosis, among 77 patients with previous gynecologic and breast cancer with a dedicated next-generation sequencing panel covering 74 genes. We investigated the impact of clonal hematopoiesis of indeterminate potential-associated mutations (CHIP-AMs defined as presence at TRMN stage of mutations described in CHIP with a frequency >1%) on overall survival (OS) and the clinical relevance of a modified genetic ontogeny-based classifier that categorized patients in 3 subgroups. The most frequently mutated genes were", "citation": "Khalife-Hachem S, Saleh K, Pasquier F, Willekens C, Tarabay A, Antoun L, Grinda T, Castilla-Llorente C, Duchmann M, Quivoron C, Auger N, Saada V, Delaloge S, Leary A, Renneville A, Antony-Debre I, Rosselli F, De Botton S, Salviat F, Marzac C, Micol JB. (2021). Molecular Landscape of Therapy-related Myeloid Neoplasms in Patients Previously Treated for Gynecologic and Breast Cancers. HemaSphere. 5(9):e632. http://doi.org/10.1097/HS9.0000000000000632. PMID: 34423258.", "score_list": [ 2.6472878513421696, 2.638825771191111 ], "ai_score_min": 2.638825771191111, "ai_score_max": 2.6472878513421696, "ai_score": 2.64305681126664, "ai_reasoning": "Weak relevance. 'Molecular Landscape of Therapy-related Myeloid Neo...' appears tangentially related to the research topic.", "evidence": [ { "text": "with a frequency >1%) on overall", "section": "abstract", "criterion": "Population", "supports": "exclude" }, { "text": "myelodysplastic syndromes has been proposed. We aimed", "section": "abstract", "criterion": "Study Design", "supports": "exclude" }, { "text": "Molecular Landscape of Therapy-related Myeloid Neoplasms", "section": "title", "criterion": "Population", "supports": "exclude" } ], "ai_decision": "include", "assigned_clusters": [ { "cluster_name": "Adult Patient Population", "cluster_type": "include", "cluster_description": "Papers focused on adult patient demographics with defined inclusion criteria", "related_criteria": "Population" }, { "cluster_name": "Biomarker Analysis Studies", "cluster_type": "include", "cluster_description": "Papers with molecular or biomarker focus and genetic data", "related_criteria": "Outcome" } ] }, { "id": "120", "title": "Implementation of Next Generation Sequencing-Based Liquid Biopsy for Clinical Molecular Diagnostics in Non-Small Cell Lung Cancer (NSCLC) Patients.", "abstract": "Genetic screening of somatic mutations in circulating free DNA (cfDNA) opens up new opportunities for personalized medicine. In this study, we aim to illustrate the implementation of NGS-based liquid biopsy in clinical practice for the detection of somatic alterations in selected genes. Our work is particularly relevant for the diagnosis and treatment of NSCLC. Beginning in 2020, we implemented the use of Roche's Avenio ctDNA expanded panel in our diagnostic routine. In this study, we retrospectively review NGS-based clinical genetic tests performed in our laboratory, focusing on key analytical parameters. Avenio ctDNA kits demonstrated 100% sensitivity in detecting single nucleotide variants (SNVs) at >0.5% variant allele frequency (VAF), and high consistency in reproducibility. Since 2020, we performed cfDNA genotyping test in 86 NSCLC patients, and we successfully sequenced 96.5% (83/86) of samples. We observed consistency in sequencing performance based upon sequencing depth and on-target rate. At least one gene variant was identified in 52 samples (63%), and one or more actionable variants were detected in 21 out of 83 (25%) of analysed patients. We demonstrated the feasibility of implementing an NGS-based liquid biopsy assay for routine genetic characterization of metastatic NSCLC patients.", "citation": "Zulato E, Tosello V, Nardo G, Bonanno L, Del Bianco P, Indraccolo S. (2021). Implementation of Next Generation Sequencing-Based Liquid Biopsy for Clinical Molecular Diagnostics in Non-Small Cell Lung Cancer (NSCLC) Patients. Diagnostics (Basel, Switzerland). 11(8). http://doi.org/10.3390/diagnostics11081468. PMID: 34441402.", "score_list": [ 3.408438269900218, 3.0897543547232154 ], "ai_score_min": 3.0897543547232154, "ai_score_max": 3.408438269900218, "ai_score": 3.2490963123117167, "ai_reasoning": "Moderate relevance. 'Implementation of Next Generation Sequencing-Based...' partially meets inclusion criteria but requires human review for final determination.", "evidence": [ { "text": "observed consistency in sequencing performance based upon sequencing", "section": "abstract", "criterion": "Population", "supports": "include" }, { "text": "We observed consistency in sequencing", "section": "abstract", "criterion": "Study Design", "supports": "include" }, { "text": "variant was identified in 52", "section": "abstract", "criterion": "Outcome", "supports": "include" }, { "text": "Implementation of Next Generation Sequencing-Based Liquid", "section": "title", "criterion": "Population", "supports": "include" } ], "ai_decision": "include", "assigned_clusters": [ { "cluster_name": "Adult Patient Population", "cluster_type": "include", "cluster_description": "Papers focused on adult patient demographics with defined inclusion criteria", "related_criteria": "Population" }, { "cluster_name": "Biomarker Analysis Studies", "cluster_type": "include", "cluster_description": "Papers with molecular or biomarker focus and genetic data", "related_criteria": "Outcome" } ] }, { "id": "121", "title": "Does large NGS panel analysed using exome tumour sequencing improve the management of advanced non-small-cell lung cancers?", "abstract": "INTRODUCTION: Non-small-cell lung cancer (NSCLC) is one of the most common and deadly cancers. Several molecular drivers of oncogene addiction are now known to be strong predictive biomarkers for target therapies. Advances in large Next Generation Sequencing (LNGS) have improved the ability to detect potentially targetable mutations. However, the integration of LNGS into clinical management in an individualized manner remains challenging. METHODS: In this single-center observational study we included all patients with advanced NSCLC who underwent LNGS. Somatic and germline exome analysis was performed with a restriction on 323 cancer related genes. Variants were classified and Molecular Tumour Board (MTB) made therapeutic propositions. RESULTS: We performed LNGS analysis in 281 patients with advanced NSCLC between March 2015 and January 2018. Technical failure occurred in only 3% of cases. Three hundred and fifty-six targetable mutations were detected. At least one targetable mutation was found in 209 patients. For all these patients, the MTB was able to recommend treatment with a targeted agent based on the evaluation of the tumour's genetic profile and treatment history. Twenty-nine patients (13.9%) were subsequently treated with an MTB-recommended targeted therapy. We did not observe any improvement in terms of clinical benefit for these patients. CONCLUSIONS: In this case series, we show that including LNGS into routine clinical management was feasible but does not appear to provide clinical benefit in the management of patients with advanced NSCLC.", "citation": "Niogret J, Dalens L, Truntzer C, Chevrier S, Favier L, Lagrange A, Coudert B, Fraisse C, Foucher P, Zouak A, Westeel V, Goussot V, D\u00e9rang\u00e8re V, Albuisson J, Arnould L, Boidot R, Kaderbhai CG, Ghiringhelli F. (2021). Does large NGS panel analysed using exome tumour sequencing improve the management of advanced non-small-cell lung cancers?. Lung cancer (Amsterdam, Netherlands). 161:98-107. http://doi.org/10.1016/j.lungcan.2021.08.013. PMID: 34560426.", "score_list": [ 1.5453133968259338, 1.5248776551395449 ], "ai_score_min": 1.5248776551395449, "ai_score_max": 1.5453133968259338, "ai_score": 1.5350955259827392, "ai_reasoning": "Recommend exclusion. 'Does large NGS panel analysed using exome tumour s...' does not appear to meet core inclusion criteria.", "evidence": [ { "text": "lung cancer (NSCLC) is one of the most", "section": "abstract", "criterion": "Population", "supports": "exclude" }, { "text": "therapy. We did not", "section": "abstract", "criterion": "Study Design", "supports": "exclude" }, { "text": "Does large NGS panel analysed using", "section": "title", "criterion": "Population", "supports": "exclude" } ], "ai_decision": "include", "assigned_clusters": [ { "cluster_name": "Methodology & Protocol Only", "cluster_type": "exclude", "cluster_description": "Papers focused on study design and methodology without clinical results", "related_criteria": "Study Design" } ] } ], "clusters": [ { "cluster_name": "Treatment Efficacy Studies", "cluster_type": "include", "cluster_description": "Papers evaluating treatment outcomes and efficacy measures", "related_criteria": "Intervention" }, { "cluster_name": "Methodology & Protocol Only", "cluster_type": "exclude", "cluster_description": "Papers focused on study design and methodology without clinical results", "related_criteria": "Study Design" }, { "cluster_name": "Adult Patient Population", "cluster_type": "include", "cluster_description": "Papers focused on adult patient demographics with defined inclusion criteria", "related_criteria": "Population" }, { "cluster_name": "Biomarker Analysis Studies", "cluster_type": "include", "cluster_description": "Papers with molecular or biomarker focus and genetic data", "related_criteria": "Outcome" }, { "cluster_name": "Review & Meta-Analysis (No Primary Data)", "cluster_type": "exclude", "cluster_description": "Secondary research synthesizing existing studies without new data", "related_criteria": "Study Design" } ], "error": null, "error_category": null, "error_retryable": null, "model_version": "gpt-5-nano", "config": { "model": "gpt-5-nano", "repetitions": 2, "threshold": 1.0, "clusters_type": null, "mock": true, "papers_count": 121, "criteria_count": 50 }, "stage_timings": { "Scoring papers": 33.0, "Generating explanations": 21.0, "Creating thematic clusters": 0.0, "Assigning papers to clusters": 11.0 }, "duration_ms": 65, "estimated_cost_usd": 0.028193, "created_at": "2026-04-24T13:36:23.291736+00:00", "completed_at": "2026-04-24T13:36:23.360257+00:00" }