{ "job_id": "95d18d7e-12a8-4ade-a1e9-2ea9b19efe2c", "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": [ 4, 5 ], "min_score": 4, "max_score": 5, "mean_score": 4.5, "rating_reasoning": "This is a prospective genomic screening trial with sequencing and CNV assays in 428 metastatic cancers, reporting matched therapy and response outcomes, demonstrating feasibility and biomarker-guided treatment adoption; it meets multiple inclusion criteria (Interventions, Study size, Outcomes), justifying a high score.", "evidence": [ { "text": "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.", "section": "abstract", "criterion": "Interventions", "supports": "include" }, { "text": "Between November 2013 and August 2014, a total of 428 metastatic solid tumor patients were enrolled on to this study.", "section": "abstract", "criterion": "Study size", "supports": "include" }, { "text": "Of the 342 patients, 103 patients were matched to molecularly targeted agents in the context of clinical trials or clinical practice.", "section": "abstract", "criterion": "Outcomes", "supports": "include" } ], "included_cluster_list": "[\"Biomarker-Guided Therapy and Clinical Outcomes\", \"Comprehensive Genomic Profiling Technology Evaluation\", \"Substantial and Targeted Study Populations\"]", "excluded_cluster_list": null, "ai_decision": "include", "assigned_clusters": [ "Biomarker-Guided Therapy and Clinical Outcomes", "Comprehensive Genomic Profiling Technology Evaluation", "Substantial and Targeted Study Populations" ] }, { "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": [ 5, 5 ], "min_score": 5, "max_score": 5, "mean_score": 5.0, "rating_reasoning": "The study is an observational biomarker-guided therapy evaluation in advanced cancers using NGS, comparing matched vs. unmatched treatments with reported improved PFS/OS and response, aligning with biomarker-directed therapy and CGP utility criteria, and it has a substantial sample size and clear outcomes.", "evidence": [ { "text": "In this observational study, 347 patients with solid advanced cancers and next-generation sequencing (NGS) results were evaluated.", "section": "abstract", "criterion": "Study Design", "supports": "include" }, { "text": "Eight-seven patients (25%) were treated with a \"matched\" therapy, 93 (26.8%) with an \"unmatched\" therapy.", "section": "abstract", "criterion": "Interventions", "supports": "include" }, { "text": "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.", "section": "abstract", "criterion": "Outcomes", "supports": "include" } ], "included_cluster_list": "[\"Biomarker-Guided Therapy and Clinical Outcomes\", \"Substantial and Targeted Study Populations\"]", "excluded_cluster_list": null, "ai_decision": "include", "assigned_clusters": [ "Biomarker-Guided Therapy and Clinical Outcomes", "Substantial and Targeted Study Populations" ] }, { "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": [ 5, 5 ], "min_score": 5, "max_score": 5, "mean_score": 5.0, "rating_reasoning": "The study directly evaluates comprehensive genomic profiling (CGP) utility in advanced NSCLC, showing many cases with actionable EGFR mutations detected only by CGP after prior testing, and reports clinically meaningful outcomes from EGFR inhibitor therapy, aligning with key inclusion criteria (CGP utility, NSCLC, substantial cohort, outcomes).", "evidence": [ { "text": "From these, 400 cases harboring EGFR exon 19 deletions (\u0394ex19) were identified, and available clinical history was reviewed.", "section": "abstract", "criterion": "Study size", "supports": "include" }, { "text": "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.", "section": "abstract", "criterion": "Interventions", "supports": "include" }, { "text": "In a subset of these patients with available clinical outcome information, robust benefit from treatment with EGFR inhibitors was observed.", "section": "abstract", "criterion": "Outcomes", "supports": "include" } ], "included_cluster_list": "[\"Biomarker-Guided Therapy and Clinical Outcomes\", \"Comprehensive Genomic Profiling Technology Evaluation\", \"Substantial and Targeted Study Populations\"]", "excluded_cluster_list": null, "ai_decision": "include", "assigned_clusters": [ "Biomarker-Guided Therapy and Clinical Outcomes", "Comprehensive Genomic Profiling Technology Evaluation", "Substantial and Targeted Study Populations" ] }, { "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": [ 4, 1 ], "min_score": 1, "max_score": 4, "mean_score": 2.5, "rating_reasoning": "Abstract indicates the article reviews existing knowledge and proposes a diagnostic algorithm rather than presenting original data or primary outcomes; framed as a narrative review rather than a primary study or systematic review.", "evidence": [ { "text": "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.", "section": "abstract", "criterion": "Study methodology", "supports": "exclude" }, { "text": "Finally, we propose a diagnostic algorithm for solid tumors to facilitate the identification of patients with TRK fusion cancer.", "section": "abstract", "criterion": "Study methodology", "supports": "exclude" } ], "included_cluster_list": "[\"Comprehensive Genomic Profiling Technology Evaluation\"]", "excluded_cluster_list": "[\"Outcomes Not Aligned with Review Scope\"]", "ai_decision": "include", "assigned_clusters": [ "Comprehensive Genomic Profiling Technology Evaluation" ] }, { "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": [ 5, 5 ], "min_score": 5, "max_score": 5, "mean_score": 5.0, "rating_reasoning": "The abstract reports on integration of CGP/NGS with clinical outcomes in diverse advanced cancers, including actionable alterations, treatment decisions, and observed clinical benefit, aligning with multiple criteria (Outcomes, Interventions, Study size, Publication date).", "evidence": [ { "text": "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.", "section": "abstract", "criterion": "Interventions", "supports": "include" }, { "text": "During the study period, NGS was attempted on tumors from 1138 patients and was successful in 1015 (89.2%)", "section": "abstract", "criterion": "Study size", "supports": "include" }, { "text": "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).", "section": "abstract", "criterion": "Outcomes", "supports": "include" } ], "included_cluster_list": "[\"Biomarker-Guided Therapy and Clinical Outcomes\"]", "excluded_cluster_list": null, "ai_decision": "include", "assigned_clusters": [ "Biomarker-Guided Therapy and Clinical Outcomes" ] }, { "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": [ 5, 5 ], "min_score": 5, "max_score": 5, "mean_score": 5.0, "rating_reasoning": "Direct diagnostic performance comparison of molecular MSI assays vs IHC in colorectal and endometrial cancers; reports AUC and sensitivity, aligning with testing technology and outcomes criteria.", "evidence": [ { "text": "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).", "section": "abstract", "criterion": "Outcomes", "supports": "include" }, { "text": "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.", "section": "abstract", "criterion": "Outcomes", "supports": "include" }, { "text": "PCR, Idylla and NGS show similar diagnostic performance for dMMR detection in colorectal and endometrial cancers.", "section": "abstract", "criterion": "Outcomes", "supports": "include" } ], "included_cluster_list": "[\"Direct Comparison of Diagnostic Assays\"]", "excluded_cluster_list": "[\"Inappropriate Intervention Assessed\", \"Outcomes Not Aligned with Review Scope\"]", "ai_decision": "include", "assigned_clusters": [ "Direct Comparison of Diagnostic Assays" ] }, { "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": [ 5, 4 ], "min_score": 4, "max_score": 5, "mean_score": 4.5, "rating_reasoning": "The study provides primary data on mutation detection in breast cancer using NGS and demonstrates feasibility to guide therapy, aligning with genomic testing utility, but it is a targeted panel study (not CGP) and lacks economic/outcome data, hence a high-but-not-perfect inclusion score (4.5).", "evidence": [ { "text": "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.", "section": "abstract", "criterion": "Interventions", "supports": "include" }, { "text": "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.", "section": "abstract", "criterion": "What is the clinical utility of comprehensive genome profiling (CGP)?", "supports": "include" }, { "text": "Rapid detection of genetic mutations in individual breast cancer patients by next-generation DNA sequencing.", "section": "title", "criterion": "Disease", "supports": "include" } ], "included_cluster_list": "[\"Biomarker Prevalence and Mutation Detection\"]", "excluded_cluster_list": "[\"Inappropriate Intervention Assessed\", \"Outcomes Not Aligned with Review Scope\"]", "ai_decision": "include", "assigned_clusters": [ "Biomarker Prevalence and Mutation Detection" ] }, { "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": [ 5, 5 ], "min_score": 5, "max_score": 5, "mean_score": 5.0, "rating_reasoning": "Directly evaluates a biomarker-guided, EGFR-directed first-line strategy in European setting with economic outcomes, English language, 2015 publication, and >30 participants implied via trial data usage; aligns with key questions on precision medicine, NSCLC, and economic impact.", "evidence": [ { "text": "Cost-Effectiveness of an Individualized First-Line Treatment Strategy Offering Erlotinib Based on EGFR Mutation Testing in Advanced Lung Adenocarcinoma Patients in Germany.", "section": "title", "criterion": "Interventions", "supports": "include" }, { "text": "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.", "section": "abstract", "criterion": "Study methodology", "supports": "include" }, { "text": "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.", "section": "abstract", "criterion": "Outcomes", "supports": "include" } ], "included_cluster_list": "[\"Biomarker-Guided Therapy and Clinical Outcomes\", \"Economic Evaluation of Biomarker-Directed Strategies\", \"European or English-Language and Recent Studies\", \"Substantial and Targeted Study Populations\"]", "excluded_cluster_list": null, "ai_decision": "include", "assigned_clusters": [ "Biomarker-Guided Therapy and Clinical Outcomes", "Economic Evaluation of Biomarker-Directed Strategies", "European or English-Language and Recent Studies", "Substantial and Targeted Study Populations" ] }, { "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": [ 5, 4 ], "min_score": 4, "max_score": 5, "mean_score": 4.5, "rating_reasoning": "Economic evaluation of a biomarker-directed test in colorectal cancer within a European setting; aligns with Economic impact and Study methodology, supporting inclusion, though limited to a single-gene test in Germany rather than broad CGP, slightly limiting generalizability.", "evidence": [ { "text": "The cost-effectiveness of UGT1A1 genotyping before colorectal cancer treatment with irinotecan from the perspective of the German statutory health insurance.", "section": "title", "criterion": "Economic impact", "supports": "include" }, { "text": "A decision-analytic Markov model with a life time horizon was developed.", "section": "abstract", "criterion": "Study methodology", "supports": "include" }, { "text": "Compared to no testing, it resulted in only marginal QALY increases (0.0002) but a cost reduction of \u20ac580 per patient.", "section": "abstract", "criterion": "Economic impact", "supports": "include" } ], "included_cluster_list": "[\"Economic Evaluation of Biomarker-Directed Strategies\", \"European or English-Language and Recent Studies\"]", "excluded_cluster_list": "[\"Inappropriate Intervention Assessed\"]", "ai_decision": "include", "assigned_clusters": [ "Economic Evaluation of Biomarker-Directed Strategies", "European or English-Language and Recent Studies" ] }, { "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": [ 5, 5 ], "min_score": 5, "max_score": 5, "mean_score": 5.0, "rating_reasoning": "High score driven by a large human CRC cohort, English report (2015), clear incidence data for ALK rearrangements, and demonstration of CGP-confirmed actionable targets with in vitro sensitivity to ALK inhibitors, indicating both clinical utility and biomarker-directed treatment potential.", "evidence": [ { "text": "ALK IHC is a viable screening strategy for identifying ALK rearrangement in CRC.", "section": "abstract", "criterion": "Clinical utility of CGP", "supports": "include" }, { "text": "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.", "section": "abstract", "criterion": "Incidence/ prevalence of cancers with targeted or genetic biomarker-directed therapies", "supports": "include" }, { "text": "Growth of a tumor cell line derived from this EML4-ALK CRC patient was inhibited by ALK inhibitors crizotinib and entrectinib.", "section": "abstract", "criterion": "Clinical utility of CGP", "supports": "include" } ], "included_cluster_list": "[\"Biomarker Prevalence and Mutation Detection\", \"Comprehensive Genomic Profiling Technology Evaluation\", \"Substantial and Targeted Study Populations\"]", "excluded_cluster_list": "[\"Inappropriate Intervention Assessed\", \"Outcomes Not Aligned with Review Scope\"]", "ai_decision": "include", "assigned_clusters": [ "Biomarker Prevalence and Mutation Detection", "Comprehensive Genomic Profiling Technology Evaluation", "Substantial and Targeted Study Populations" ] }, { "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": [ 4, 5 ], "min_score": 4, "max_score": 5, "mean_score": 4.5, "rating_reasoning": "The study provides concrete biomarker incidence data in colorectal cancer (MSI with KRAS mutation), uses standard genomic testing (PCR) to detect mutations, and involves a substantial sample size within the targeted cancer types, aligning with biomarker testing and epidemiology goals within the date range.", "evidence": [ { "text": "A total of 530 colorectal cancers were studied for MSI and KRAS gene mutation.", "section": "abstract", "criterion": "Study size", "supports": "include" }, { "text": "Fourteen (2.6%) cancers with both MSI and a KRAS mutation were identified, and all cancers were BRAF wild type.", "section": "abstract", "criterion": "Incidence/ prevalence of cancers with targeted or genetic biomarker-directed therapies", "supports": "include" }, { "text": "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.", "section": "abstract", "criterion": "Interventions", "supports": "include" } ], "included_cluster_list": "[\"Biomarker Prevalence and Mutation Detection\", \"Substantial and Targeted Study Populations\"]", "excluded_cluster_list": "[\"Inappropriate Intervention Assessed\", \"Outcomes Not Aligned with Review Scope\"]", "ai_decision": "include", "assigned_clusters": [ "Biomarker Prevalence and Mutation Detection", "Substantial and Targeted Study Populations" ] }, { "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": [ 5, 4 ], "min_score": 4, "max_score": 5, "mean_score": 4.5, "rating_reasoning": "The study uses a targeted gene panel to profile mutations in brain metastases from breast cancer, reporting mutation prevalence and actionable alterations, aligning with outcomes on biomarker detection and genomic testing, though it focuses on non-EU data and does not show clinical outcomes.", "evidence": [ { "text": "Mutational profiling of brain metastasis from breast cancer: matched pair analysis of targeted sequencing between brain metastasis and primary breast cancer", "section": "title", "criterion": "Interventions", "supports": "include" }, { "text": "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.", "section": "abstract", "criterion": "Interventions", "supports": "include" }, { "text": "In a total of 42 BCBM samples, 32 (76.2%) harbored at least one mutation (median 1, range 0-7 mutations).", "section": "abstract", "criterion": "Outcomes", "supports": "include" } ], "included_cluster_list": "[\"Biomarker Prevalence and Mutation Detection\", \"Substantial and Targeted Study Populations\"]", "excluded_cluster_list": "[\"Inappropriate Intervention Assessed\", \"Outcomes Not Aligned with Review Scope\"]", "ai_decision": "include", "assigned_clusters": [ "Biomarker Prevalence and Mutation Detection", "Substantial and Targeted Study Populations" ] }, { "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": [ 1, 1 ], "min_score": 1, "max_score": 1, "mean_score": 1.0, "rating_reasoning": "The study reports a diagnostic test method for non-invasive bladder cancer detection, not a biomarker-guided therapy or CGP utility in advanced cancers, hence it falls outside the review\u2019s scope of precision medicine interventions and outcomes.", "evidence": [ { "text": "Multiplex PCR and Next Generation Sequencing for the Non-Invasive Detection of Bladder Cancer.", "section": "title", "criterion": "Interventions", "supports": "exclude" }, { "text": "This simple, cost-effective approach could be used for the non-invasive surveillance of patients with non-muscle-invasive bladder cancers harbouring these mutations.", "section": "abstract", "criterion": "Interventions", "supports": "exclude" }, { "text": "BACKGROUND: Highly sensitive and specific urine-based tests to detect either primary or recurrent bladder cancer have proved elusive to date.", "section": "abstract", "criterion": "Interventions", "supports": "exclude" } ], "included_cluster_list": "[\"Direct Comparison of Diagnostic Assays\"]", "excluded_cluster_list": "[\"Inappropriate Intervention Assessed\"]", "ai_decision": "exclude", "assigned_clusters": [ "Inappropriate Intervention Assessed" ] }, { "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": [ 4, 2 ], "min_score": 2, "max_score": 4, "mean_score": 3.0, "rating_reasoning": "Unsure because the study demonstrates multi-gene panel testing and mutation detection in breast/ovarian cancer, but lacks Europe-focused data and explicit treatment outcomes or guideline-directed therapy implications.", "evidence": [ { "text": "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.", "section": "title", "criterion": "Interventions", "supports": "include" }, { "text": "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.", "section": "abstract", "criterion": "Interventions", "supports": "include" }, { "text": "We were able to detect pathogenic mutations in 51 (36.2%) cases, out of which 19 were novel mutations.", "section": "abstract", "criterion": "Outcomes", "supports": "include" }, { "text": "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.", "section": "abstract", "criterion": "Interventions", "supports": "include" } ], "included_cluster_list": "[\"Biomarker Prevalence and Mutation Detection\", \"Comprehensive Genomic Profiling Technology Evaluation\"]", "excluded_cluster_list": "[\"Inappropriate Intervention Assessed\", \"Outcomes Not Aligned with Review Scope\"]", "ai_decision": "include", "assigned_clusters": [ "Biomarker Prevalence and Mutation Detection", "Comprehensive Genomic Profiling Technology Evaluation" ] }, { "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": [ 5, 1 ], "min_score": 1, "max_score": 5, "mean_score": 3.0, "rating_reasoning": "Provides biomarker prevalence data (SOX9 mutations in CRC) and molecular associations via NGS, but offers no direct clinical utility, treatment guidance, or European/CGP-focused outcomes, leading to an uncertain overall fit for the review criteria.", "evidence": [ { "text": "Next generation sequencing data (MSK-IMPACT) from CRC patients was used to interrogate SOX9, KRAS, NRAS, BRAF, TP53, APC, and PIK3CA.", "section": "abstract", "criterion": "Study methodology", "supports": "include" }, { "text": "SOX9 was mutated in 38 of 353 (10.7%) CRC, of which 82% were frameshift or nonsense.", "section": "abstract", "criterion": "Outcomes", "supports": "include" }, { "text": "SOX9 is overexpressed in CRC, including those with recurrent distal truncating mutations.", "section": "abstract", "criterion": "Outcomes", "supports": "include" } ], "included_cluster_list": "[\"Biomarker Prevalence and Mutation Detection\"]", "excluded_cluster_list": "[\"Outcomes Not Aligned with Review Scope\"]", "ai_decision": "include", "assigned_clusters": [ "Biomarker Prevalence and Mutation Detection" ] }, { "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": [ 4, 5 ], "min_score": 4, "max_score": 5, "mean_score": 4.5, "rating_reasoning": "This is a European economic evaluation of a biomarker-directed breast cancer therapy, reporting costs and ICER from a payer perspective, aligning with the Economic impact and biomarker-guided treatment criteria; published within 2015\u20132021 and in English.", "evidence": [ { "text": "Palbociclib plus letrozole cannot be considered cost-effective for the first-line treatment of patients with metastatic breast cancer in the Swiss healthcare system.", "section": "abstract", "criterion": "Economic evaluations", "supports": "include" }, { "text": "Here we examined the cost-effectiveness of this regimen for the Swiss healthcare system.", "section": "abstract", "criterion": "Economic evaluations", "supports": "include" }, { "text": "Costs were assessed from the Swiss healthcare system perspective.", "section": "abstract", "criterion": "Economic evaluations", "supports": "include" } ], "included_cluster_list": "[\"Economic Evaluation of Biomarker-Directed Strategies\", \"European or English-Language and Recent Studies\"]", "excluded_cluster_list": "[\"Outcomes Not Aligned with Review Scope\"]", "ai_decision": "include", "assigned_clusters": [ "Economic Evaluation of Biomarker-Directed Strategies", "European or English-Language and Recent Studies" ] }, { "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": [ 1, 1 ], "min_score": 1, "max_score": 1, "mean_score": 1.0, "rating_reasoning": "The paper studies early-stage, localized prostate cancer (active surveillance, Gleason 6) rather than advanced cancers, using biomarkers in urine rather than genome-wide profiling for targeted therapy; no Europe-focused data or downstream advanced-disease outcomes are reported, making it outside the specified scope.", "evidence": [ { "text": "PURPOSE: Patients with prostate cancer on active surveillance are monitored by repeat prostate specific antigen measurements, digital rectal examinations and prostate biopsies.", "section": "abstract", "criterion": "Population", "supports": "exclude" }, { "text": "153 men on active surveillance who were diagnosed with Gleason score 6 disease.", "section": "abstract", "criterion": "Disease", "supports": "exclude" }, { "text": "Urinary DNA Methylation Biomarkers for Noninvasive Prediction of Aggressive Disease in Patients with Prostate Cancer on Active Surveillance.", "section": "title", "criterion": "Interventions", "supports": "exclude" } ], "included_cluster_list": "[\"Biomarker Prevalence and Mutation Detection\", \"Comprehensive Genomic Profiling Technology Evaluation\", \"European or English-Language and Recent Studies\", \"Substantial and Targeted Study Populations\"]", "excluded_cluster_list": "[\"Disease Stage Not Relevant\", \"Inappropriate Intervention Assessed\", \"Outcomes Not Aligned with Review Scope\"]", "ai_decision": "exclude", "assigned_clusters": [ "Disease Stage Not Relevant", "Inappropriate Intervention Assessed", "Outcomes Not Aligned with Review Scope" ] }, { "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": [ 5, 5 ], "min_score": 5, "max_score": 5, "mean_score": 5.0, "rating_reasoning": "The paper directly assesses a clinic-ready targeted NGS panel to predict response to PD-1 blockade in melanoma, reports objective outcomes by mutation burden, and argues for clinical utility of CGP in guiding immunotherapy, meeting multiple inclusion criteria.", "evidence": [ { "text": "Targeted Next Generation Sequencing Identifies Markers of Response to PD-1 Blockade.", "section": "title", "criterion": "Interventions", "supports": "include" }, { "text": "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.", "section": "abstract", "criterion": "Outcomes", "supports": "include" }, { "text": "This approach may provide a clinically feasible predictor of response to anti-PD-1/PD-L1.", "section": "abstract", "criterion": "Outcomes", "supports": "include" } ], "included_cluster_list": "[\"Biomarker-Guided Therapy and Clinical Outcomes\", \"Comprehensive Genomic Profiling Technology Evaluation\"]", "excluded_cluster_list": null, "ai_decision": "include", "assigned_clusters": [ "Biomarker-Guided Therapy and Clinical Outcomes", "Comprehensive Genomic Profiling Technology Evaluation" ] }, { "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, 1 ], "min_score": 1, "max_score": 2, "mean_score": 1.5, "rating_reasoning": "Low score rationale: paper provides genomic profiling data in colorectal cancer using targeted NGS but does not report clinical utility outcomes, guideline-directed biomarker treatments, or economic impact, limiting direct applicability to the review questions.", "evidence": [ { "text": "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.", "section": "title", "criterion": "Interventions", "supports": "include" }, { "text": "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.", "section": "abstract", "criterion": "Interventions", "supports": "include" }, { "text": "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.", "section": "abstract", "criterion": "Study methodology", "supports": "include" } ], "included_cluster_list": "[\"Biomarker Prevalence and Mutation Detection\"]", "excluded_cluster_list": "[\"Inappropriate Intervention Assessed\", \"Outcomes Not Aligned with Review Scope\"]", "ai_decision": "include", "assigned_clusters": [ "Biomarker Prevalence and Mutation Detection" ] }, { "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": [ 5, 5 ], "min_score": 5, "max_score": 5, "mean_score": 5.0, "rating_reasoning": "The study is an economic evaluation of NGS/CGP in NSCLC and melanoma, within Europe (Netherlands), addressing budget impact and costs, aligning with the Economic impact criterion and the target disease set, dated post-2015.", "evidence": [ { "text": "Next-generation sequencing (NGS) has reached the molecular diagnostic laboratories.", "section": "abstract", "criterion": "Economic impact", "supports": "include" }, { "text": "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.", "section": "abstract", "criterion": "Economic impact", "supports": "include" }, { "text": "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.", "section": "abstract", "criterion": "Economic impact", "supports": "include" } ], "included_cluster_list": "[\"Economic Evaluation of Biomarker-Directed Strategies\", \"European or English-Language and Recent Studies\"]", "excluded_cluster_list": "[\"Outcomes Not Aligned with Review Scope\"]", "ai_decision": "include", "assigned_clusters": [ "Economic Evaluation of Biomarker-Directed Strategies", "European or English-Language and Recent Studies" ] } ], "clusters": [ { "cluster_type": "include", "cluster_name": "Biomarker-Guided Therapy and Clinical Outcomes", "cluster_description": "Studies evaluating the use of comprehensive genomic profiling (CGP), next-generation sequencing (NGS), or biomarker-guided testing to inform therapy choices in cancer, reporting on matched therapy, response rates, progression-free survival, or overall survival as direct outcomes of biomarker-directed treatment.", "related_criteria": "Outcomes" }, { "cluster_type": "include", "cluster_name": "Comprehensive Genomic Profiling Technology Evaluation", "cluster_description": "Papers focusing on the feasibility, performance, or comparative utility of CGP or NGS technologies (including detection of actionable mutations or comparison with prior/alternative testing methods) in real-world patient populations with cancer.", "related_criteria": "Interventions" }, { "cluster_type": "include", "cluster_name": "Economic Evaluation of Biomarker-Directed Strategies", "cluster_description": "Studies conducting cost-effectiveness, cost-utility, or budget impact analyses of biomarker-guided therapies or molecular testing in oncology, with reporting of costs, ICER, or economic outcomes relevant to decision-makers (typically in European/English contexts and post-2015).", "related_criteria": "Study methodology" }, { "cluster_type": "include", "cluster_name": "Substantial and Targeted Study Populations", "cluster_description": "Inclusion of studies with large or disease-specific (e.g., colorectal, breast, NSCLC, melanoma, ovarian, metastatic cancers) cohorts that provide prevalence, incidence, or outcome data for biomarker testing within those cancers, ensuring statistical reliability and disease relevance.", "related_criteria": "Study size" }, { "cluster_type": "include", "cluster_name": "Biomarker Prevalence and Mutation Detection", "cluster_description": "Papers primarily reporting the frequency, associations, or epidemiology of specific mutations or biomarkers (e.g., EGFR, ALK, KRAS, MSI, SOX9) in cancer populations, often using targeted NGS or PCR. These inform the landscape of actionable alterations but may lack direct clinical outcome data.", "related_criteria": "Disease" }, { "cluster_type": "include", "cluster_name": "Direct Comparison of Diagnostic Assays", "cluster_description": "Studies directly comparing the diagnostic performance (e.g., sensitivity, specificity, AUC) of different molecular or immunohistochemical biomarker testing methods for cancer diagnosis or molecular classification.", "related_criteria": "Interventions" }, { "cluster_type": "include", "cluster_name": "European or English-Language and Recent Studies", "cluster_description": "Papers prioritized for their relevance to the European clinical or health economic context, written in English, and published within a defined recent period (e.g., post-2015), to enhance applicability and contemporary relevance.", "related_criteria": "Publication date" }, { "cluster_type": "exclude", "cluster_name": "Disease Stage Not Relevant", "cluster_description": "Studies focused on early-stage or localized cancers rather than advanced or metastatic disease were excluded as they do not address the review question pertinent to advanced cancer management.", "related_criteria": "Disease" }, { "cluster_type": "exclude", "cluster_name": "Inappropriate Intervention Assessed", "cluster_description": "Papers evaluating only diagnostic, prognostic, or surveillance tests (e.g., non-interventional biomarker tests) or non-genome-wide profiling, instead of comprehensive genomic profiling or biomarker-guided therapy, were excluded.", "related_criteria": "Interventions" }, { "cluster_type": "exclude", "cluster_name": "Outcomes Not Aligned with Review Scope", "cluster_description": "Studies that did not report on downstream outcomes related to precision medicine interventions, such as targeted therapy efficacy or utility derived from CGP in advanced cancer, were excluded.", "related_criteria": "Outcomes" } ], "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": false, "papers_count": 20, "criteria_count": 50 }, "stage_timings": { "Scoring papers": 39304.0, "Generating explanations": 62695.0, "Clustering themes": 12199.0, "Assigning clusters": 49661.0, "Complete": 0.0 }, "duration_ms": 163859, "estimated_cost_usd": 0.00466, "created_at": "2026-04-24T13:36:23.418758+00:00", "completed_at": "2026-04-24T13:39:07.281268+00:00" }