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  "project": {
    "name": "ILL_ONC_1",
    "description": "Comprehensive genomic profiling/NGS in solid cancers."
  },
  "counts": {
    "papers": 121,
    "criteria": 50,
    "questions": 6,
    "indexer_records": 47,
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  "papers": [
    {
      "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."
    },
    {
      "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) ≥ 6 months/partial response (PR)/complete response (CR), 34.5% vs. 16.1%, (P ≤ 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 ≥1.3 compared with 19.3% of patients (11/57) in the unmatched group (P = 0.004 univariable and P ≥ 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 ≤ 0.2, (P = 0.040 in the Cox regression model). Matched versus unmatched patients had higher rates of SD ≥ 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. ©2016 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."
    },
    {
      "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 (Δex19) were identified, and available clinical history was reviewed. RESULTS: Pathology reports were available for 250 consecutive cases with classical EGFR Δex19 (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 Δex19 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 Δex19 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. ©2016 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."
    },
    {
      "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."
    },
    {
      "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."
    },
    {
      "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 ≥ 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."
    },
    {
      "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."
    },
    {
      "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 € 200, yielding an incremental cost-effectiveness ratio (ICER) of € 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 € 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."
    },
    {
      "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 €580 per patient. Strategy 2 resulted in the same health gains but increased costs by €10 773. In the probabilistic analysis, genotyping and dose reduction was the optimal strategy in approximately 100% of simulations at a threshold of €50 000 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."
    },
    {
      "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."
    },
    {
      "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(®) MS-MLPA(®) 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."
    },
    {
      "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."
    },
    {
      "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."
    },
    {
      "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, ⩽40 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."
    },
    {
      "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±105 versus 147±119, 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."
    },
    {
      "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."
    },
    {
      "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."
    },
    {
      "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. ©2016 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."
    },
    {
      "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."
    },
    {
      "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, Retèl VP, Coupé 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."
    },
    {
      "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 €16,567 and the estimated incremental cost per quality-adjusted life year gained was €22,794. 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, López-Martínez 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."
    },
    {
      "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 £339 (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."
    },
    {
      "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."
    },
    {
      "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."
    },
    {
      "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→TT pattern) had similar detection efficiency and saved about 30% of TT compared with TT for initial EGFRm detection followed by ctDNA (TT→ctDNA pattern). CONCLUSIONS: Intratumor heterogeneity and the relatively low sensitivity of the ARMS contributed to discordant EGFRm status between TT specimens and ctDNA. The ctDNA→TT 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."
    },
    {
      "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."
    },
    {
      "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 β-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 β-catenin. Analysis of all patients with activating Wnt/β-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/β-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."
    },
    {
      "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": "Révész D, Engelhardt EG, Tamminga JJ, Schramel FMNH, Onwuteaka-Philipsen BD, van de Garde EMW, Steyerberg EW, Jansma EP, De Vet HCW, Coupé 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."
    },
    {
      "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."
    },
    {
      "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."
    },
    {
      "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€ (±207) in somatic genetics and 550€ (±140) 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."
    },
    {
      "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."
    },
    {
      "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."
    },
    {
      "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 £50,000 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."
    },
    {
      "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."
    },
    {
      "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."
    },
    {
      "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."
    },
    {
      "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 £130,929 in the ITT, £72,053 in the KRAS wt and £44,185 in the RAS wt cohorts for cetuximab plus FOLFIRI compared with FOLFIRI alone. At a £50,000 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."
    },
    {
      "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."
    },
    {
      "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."
    },
    {
      "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."
    },
    {
      "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."
    },
    {
      "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."
    },
    {
      "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 €81,140 versus €94,705 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 €80,000. The Expected Value of Perfect Information (EVPI) amounted to €3 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": "Retèl 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."
    },
    {
      "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."
    },
    {
      "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."
    },
    {
      "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 (≥ 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 ≥ 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, Nordström T, Van Laere S, Rantalainen M, Rajan P, Egevad L, Ullén A, Yachnin J, Dirix L, Grönberg 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."
    },
    {
      "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."
    },
    {
      "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."
    },
    {
      "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."
    },
    {
      "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, Allgäuer M, Talla SB, von Winterfeld M, Herpel E, Goeppert B, Lier A, Winter H, Brummer T, Fröhling S, Faehling M, Fischer JR, Heußel 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."
    },
    {
      "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."
    },
    {
      "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."
    },
    {
      "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."
    },
    {
      "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."
    },
    {
      "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 ≤ HR ≥ 4.1; p ≤ 0.002), served as an independent indicator of poor prognosis in the four RP cohorts (1.96 ≤ HR ≥ 4.28; p ≤ 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-Echevarría 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."
    },
    {
      "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."
    },
    {
      "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 €1.13 billion to €2.27 billion based on epidemiological data, or from €0.91 billion to €1.82 billion based on sales volume data. In the first year only, the projected budgetary savings ranged from €58 million to €136 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 €0.91 billion and €2.27 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."
    },
    {
      "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 £637,000 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."
    },
    {
      "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."
    },
    {
      "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."
    },
    {
      "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, Pérez-Simó G, Llop M, Mancheño N, Ramos D, Juan I, Barragán E, Laiz B, Cases E, Ansótegui E, Gómez-Codina J, Aparicio J, Salvador C, Juan Ó, 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."
    },
    {
      "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, Guimarães 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."
    },
    {
      "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."
    },
    {
      "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."
    },
    {
      "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."
    },
    {
      "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."
    },
    {
      "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."
    },
    {
      "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 £30 000/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 £10 464/QALY (payer perspective) or £7216/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."
    },
    {
      "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."
    },
    {
      "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."
    },
    {
      "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× and 38×, 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."
    },
    {
      "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."
    },
    {
      "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, Mäkisalo H, Eide TJ, Weidemann S, Cheville JC, Mazza G, Hirschfield GM, Ponsioen CY, Bergquist A, Milkiewicz P, Lazaridis KN, Schramm C, Manns MP, Färkkilä 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."
    },
    {
      "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."
    },
    {
      "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 ≥10 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 × 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."
    },
    {
      "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."
    },
    {
      "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."
    },
    {
      "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."
    },
    {
      "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, Viñolas N, Rodríguez-Mues M, Cabrera C, Sánchez M, Vollmer I, Castillo S, Muñoz S, Sullivan IG, Rodriguez A, Garcia M, Alos S, Jares P, Martinez A, Prat A, Molina-Vila MÁ, 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."
    },
    {
      "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."
    },
    {
      "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": "Martínez-Sáez O, Chic N, Pascual T, Adamo B, Vidal M, González-Farré B, Sanfeliu E, Schettini F, Conte B, Brasó-Maristany F, Rodríguez A, Martínez D, Galván P, Rodríguez AB, Martinez A, Muñoz 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."
    },
    {
      "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."
    },
    {
      "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."
    },
    {
      "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."
    },
    {
      "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."
    },
    {
      "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."
    },
    {
      "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."
    },
    {
      "id": "87",
      "title": "Genome‑wide copy number analysis of circulating tumor cells in breast cancer patients with liver metastasis.",
      "abstract": "The genome‑wide 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‑wide 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‑three breast cancer patients were selected for this study in which 23 newly diagnosed and 20 recurrent liver metastases were diagnosed by histopathology and 18F‑FDG PET/CT imaging. CTCs were counted from all patients using the CellSearch system and were confirmed by cytomorphology and three‑color 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 β‑defensin genes, which are significantly associated with anti‑angiogenesis 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‑wide 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."
    },
    {
      "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) (-€51,550), \"Pharmaceutical companies lowering the prices of ipilimumab\" (€11,420), \"Using TIL-therapy combined with ipilimumab\" (-€10,840), \"Automatic TIL production\" (€22,670), \"TIL more effective\" (€23,270), \"Less Interleukin-2\" (€20,370). 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, Retèl 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."
    },
    {
      "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."
    },
    {
      "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, Röcken 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."
    },
    {
      "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."
    },
    {
      "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."
    },
    {
      "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."
    },
    {
      "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."
    },
    {
      "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."
    },
    {
      "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 ∼30%. 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."
    },
    {
      "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."
    },
    {
      "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™ 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."
    },
    {
      "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."
    },
    {
      "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."
    },
    {
      "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 ≥ 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."
    },
    {
      "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™ Oncomine™ 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."
    },
    {
      "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."
    },
    {
      "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."
    },
    {
      "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."
    },
    {
      "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."
    },
    {
      "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, Dugué 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."
    },
    {
      "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."
    },
    {
      "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": "Özdoğan 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, Özatlı T, Kırca O, Çakır 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."
    },
    {
      "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-Barrón ZL, Cardona AF, Díaz-García D, Trejo Rosales R, Rojas L, Cruz-Rico G, Nagy R, Cabrera L, Vargas C, Saam J, Barrón 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."
    },
    {
      "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, Gönen 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."
    },
    {
      "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 Jiménez I, Tena I, Chirivella I, Richart-Aznar P, Segura A, Sánchez-Heras AB, Martinez-Dueñas 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."
    },
    {
      "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 ≤ 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."
    },
    {
      "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 ≥17 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."
    },
    {
      "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."
    },
    {
      "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 €80,000 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 (€1534 [incremental net monetary benefit -€1349]), and SoC followed by WGS resulted in fewer QALYs (-0.002) and more costs (€1059 [-€1194]) compared with SoC alone. WGS as a diagnostic test was only cost effective if it was priced at €2000 per patient and identified 2.7% more actionable patients than SoC alone. Treating these additional identified patients with new treatments costing >€4069 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, Retèl VP, Ramaekers BLT, Butter R, Mankor JM, Paats MS, Aerts JGJV, Mfumbilwa ZA, Roepman P, Coupé 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."
    },
    {
      "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."
    },
    {
      "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."
    },
    {
      "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, Dérangère 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."
    }
  ],
  "criteria": [
    {
      "name": "Disease",
      "type": "exclude",
      "value": "Other diseases"
    },
    {
      "name": "Disease",
      "type": "exclude",
      "value": "Early stage cancer"
    },
    {
      "name": "Population",
      "type": "exclude",
      "value": "Laboratory studies"
    },
    {
      "name": "Population",
      "type": "exclude",
      "value": "Animal studies"
    },
    {
      "name": "Population",
      "type": "exclude",
      "value": "Drug discovery studies"
    },
    {
      "name": "Outcomes",
      "type": "exclude",
      "value": "Cost and resource use in non-EU jurisdictions"
    },
    {
      "name": "Outcomes",
      "type": "exclude",
      "value": "Quality of life and health state utilities"
    },
    {
      "name": "Study methodology",
      "type": "exclude",
      "value": "Conference abstracts with little useful data"
    },
    {
      "name": "Study methodology",
      "type": "exclude",
      "value": "Narrative reviews, opinion-pieces, editorials, letters and other publications that are not primary research reports"
    },
    {
      "name": "Study size",
      "type": "exclude",
      "value": "Studies with <30 participants"
    },
    {
      "name": "Publication date",
      "type": "exclude",
      "value": "Studies published before 2015"
    },
    {
      "name": "Publication date",
      "type": "exclude",
      "value": "Conference abstracts published before 2019"
    },
    {
      "name": "Language",
      "type": "exclude",
      "value": "Full texts not in English"
    },
    {
      "name": "Disease",
      "type": "include",
      "value": "Non-small cell lung cancer"
    },
    {
      "name": "Disease",
      "type": "include",
      "value": "Colorectal cancer"
    },
    {
      "name": "Disease",
      "type": "include",
      "value": "Malignant melanoma"
    },
    {
      "name": "Disease",
      "type": "include",
      "value": "Ovarian cancer"
    },
    {
      "name": "Disease",
      "type": "include",
      "value": "Breast cancer"
    },
    {
      "name": "Disease",
      "type": "include",
      "value": "Bladder cancer"
    },
    {
      "name": "Disease",
      "type": "include",
      "value": "Cholangiocarcinoma"
    },
    {
      "name": "Disease",
      "type": "include",
      "value": "Prostate cancer"
    },
    {
      "name": "Disease",
      "type": "include",
      "value": "Thyroid cancer"
    },
    {
      "name": "Disease",
      "type": "include",
      "value": "Any cancer with one or more of the following biomarkers: MSI, TMB, NTRK, HRD/HRR, RET, ALK"
    },
    {
      "name": "Population",
      "type": "include",
      "value": "Adults or children with cancer"
    },
    {
      "name": "Interventions",
      "type": "include",
      "value": "Any relevant targeted or biomarker-directed therapy targeting the following genomic-based biomarkers (or others): ALK, ATM, BRAF, BRCA1/2, EGFR, ERBB2 gene amplification, EZH2, FGFR fusions, HRD/HRR, IDH1, KIT, KRAS/NRAS, MET, NTRK, PDGFR1, PIK3CA, RET, ROS1, SMARCB1, MSI-high, TMB-high"
    },
    {
      "name": "Interventions",
      "type": "include",
      "value": "Genomic testing of individual genes and/or genome panels"
    },
    {
      "name": "Outcomes",
      "type": "include",
      "value": "Incidence/ prevalence of cancers with targeted or genetic biomarker-directed therapies"
    },
    {
      "name": "Outcomes",
      "type": "include",
      "value": "% of patients with cancer who have genetic biomarker detected"
    },
    {
      "name": "Outcomes",
      "type": "include",
      "value": "Adoption of precision medicine:"
    },
    {
      "name": "Outcomes",
      "type": "include",
      "value": "% on-label biomarker guided treatment"
    },
    {
      "name": "Outcomes",
      "type": "include",
      "value": "% off-label biomarker guided treatment"
    },
    {
      "name": "Outcomes",
      "type": "include",
      "value": "% clinical trial eligibility or enrolment for biomarker guided investigational treatment"
    },
    {
      "name": "Outcomes",
      "type": "include",
      "value": "Survival outcomes (PFS/OS)"
    },
    {
      "name": "Outcomes",
      "type": "include",
      "value": "Response rates (complete, partial response, stable disease, disease progression, overall response, objective response rate)"
    },
    {
      "name": "Outcomes",
      "type": "include",
      "value": "Disease control rate (CR, PR or SB for ≥6 months)"
    },
    {
      "name": "Outcomes",
      "type": "include",
      "value": "Burden of biopsy / repeat biopsy/ tissue conservation"
    },
    {
      "name": "Outcomes",
      "type": "include",
      "value": "Time to treatment initiation"
    },
    {
      "name": "Outcomes",
      "type": "include",
      "value": "Time to treatment failure"
    },
    {
      "name": "Outcomes",
      "type": "include",
      "value": "Costs of healthcare from payer perspective (including cost of dx testing specifically)"
    },
    {
      "name": "Outcomes",
      "type": "include",
      "value": "Healthcare resource use"
    },
    {
      "name": "Outcomes",
      "type": "include",
      "value": "Operational cost of test from lab perspective"
    },
    {
      "name": "Outcomes",
      "type": "include",
      "value": "Advantages of NGS methods for genome analysis vs other methods"
    },
    {
      "name": "Study methodology",
      "type": "include",
      "value": "Clinical trials"
    },
    {
      "name": "Study methodology",
      "type": "include",
      "value": "Observational studies"
    },
    {
      "name": "Study methodology",
      "type": "include",
      "value": "Economic evaluations"
    },
    {
      "name": "Study methodology",
      "type": "include",
      "value": "Systematic reviews and meta-analysis"
    },
    {
      "name": "Study size",
      "type": "include",
      "value": "Studies with >30 participants"
    },
    {
      "name": "Publication date",
      "type": "include",
      "value": "2015 to 2021"
    },
    {
      "name": "Publication date",
      "type": "include",
      "value": "Conference abstracts: 2019 onwards"
    },
    {
      "name": "Language",
      "type": "include",
      "value": "English language only"
    }
  ],
  "questions": [
    "What is the incidence and prevalence of advanced cancers in Europe and other key jurisdictions?\n-   Focus on France, Italy, Spain, Belgium, Switzerland, UK; also include data for rest of Europe and Brazil, Chile, Columbia, Mexico, Canada.",
    "What are EMA-approved and ESMO guideline-recommended biomarker-guided treatments in advanced cancer types?\n-   Focus on the use of genomic testing in non-small-cell lung cancer, colorectal cancer, malignant melanoma, ovarian cancer and breast cancer, to reflect the different number and type of biomarkers associated with each type of malignant disease",
    "What are the types of precision medicine approaches in advanced cancers in Europe (that is, finding treatments that are effective for specific genomic biomarkers in a solid tumor)?\n-   Targeted therapies for specific cancer types\n-   Tissue-agnostic (pan-cancer) therapies\n-   Multi-tumor type targeted therapies\n-   Biomarker-based immunotherapy approaches\n-   Emerging molecularly targeted therapies and ongoing clinical trials",
    "What are the unmet needs with current practice of genomic testing in advanced cancers in Europe?\n-   What are the existing technologies for genomic testing?\n-   What are the technology requirements for identification of specific types of genomic aberrations?\n-   What are the key unmet needs in genomic testing workup approaches in current clinical practice?\n-   What are the challenges faced by people trying to implement genomic testing for rate mutations?",
    "What is the clinical utility of comprehensive genome profiling (CGP)?\n-   How far does CGP offer broader coverage of medically necessary biomarkers than more traditional methods of identifying mutations, such as polymerase chain reaction (PCR), chromosomal microarray (CMA)  or small gene panel assays?\n-   Is the accuracy of CGP higher than traditional approaches in detecting biomarkers?\n-   Does the use of CGP improve patient outcomes, for example, do patients respond better to, or live longer with, therapies that target the patient's specific mutation?\n-   Does the use of CGP mean that fewer biopsy samples are needed?\n-   Does the use of CGP increase the number of patients who are eligible to be enrolled in clinical trials of new targeted therapies?",
    "Economic impact\n-   What is the budget impact of adopting CGP compared with traditional genetic testing?\n-   What is the cost-effectiveness of CGP?"
  ],
  "indexer_records": [
    {
      "ID": "20379",
      "Title": "Prognostic models for outcome prediction in patients with chronic obstructive pulmonary disease: systematic review and critical appraisal.",
      "Abstract": "OBJECTIVE: To map and assess prognostic models for outcome prediction in patients with chronic obstructive pulmonary disease (COPD). DESIGN: Systematic review. DATA SOURCES: PubMed until November 2018 and hand searched references from eligible articles. ELIGIBILITY CRITERIA FOR STUDY SELECTION: Studies developing, validating, or updating a prediction model in COPD patients and focusing on any potential clinical outcome. RESULTS: The systematic search yielded 228 eligible articles, describing the development of 408 prognostic models, the external validation of 38 models, and the validation of 20 prognostic models derived for diseases other than COPD. The 408 prognostic models were developed in three clinical settings: outpatients (n=239; 59%), patients admitted to hospital (n=155; 38%), and patients attending the emergency department (n=14; 3%). Among the 408 prognostic models, the most prevalent endpoints were mortality (n=209; 51%), risk for acute exacerbation of COPD (n=42; 10%), and risk for readmission after the index hospital admission (n=36; 9%). Overall, the most commonly used predictors were age (n=166; 41%), forced expiratory volume in one second (n=85; 21%), sex (n=74; 18%), body mass index (n=66; 16%), and smoking (n=65; 16%). Of the 408 prognostic models, 100 (25%) were internally validated and 91 (23%) examined the calibration of the developed model. For 286 (70%) models a model presentation was not available, and only 56 (14%) models were presented through the full equation. Model discrimination using the C statistic was available for 311 (76%) models. 38 models were externally validated, but in only 12 of these was the validation performed by a fully independent team. Only seven prognostic models with an overall low risk of bias according to PROBAST were identified. These models were ADO, B-AE-D, B-AE-D-C, extended ADO, updated ADO, updated BODE, and a model developed by Bertens et al. A meta-analysis of C statistics was performed for 12 prognostic models, and the summary estimates ranged from 0.611 to 0.769. CONCLUSIONS: This study constitutes a detailed mapping and assessment of the prognostic models for outcome prediction in COPD patients. The findings indicate several methodological pitfalls in their development and a low rate of external validation. Future research should focus on the improvement of existing models through update and external validation, as well as the assessment of the safety, clinical effectiveness, and cost effectiveness of the application of these prognostic models in clinical practice through impact studies. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42017069247."
    },
    {
      "ID": "20380",
      "Title": "Mortality of workers certified by pneumoconiosis medical panels as having asbestosis.",
      "Abstract": "A mortality study has been carried out at the London, Cardiff, or Swansea Pneumoconiosis Medical Panels between 1952 and 1976 on people certified as suffering from asbestosis. The main analysis was of 665 men, 283 of whom had died. Of the deaths, 39% were from lung cancer, 9% mesothelioma, and 20% asbestosis. The observed mortality was compared with expectation based on the death rates for England and Wales. For all causes the observed number of deaths was 2.6 times expectation and for lung cancer 9.1 times expectation. After 10 years from first certification half of the men had died compared with an expectation of one in four. The excess death rates were apparent in the first year after certification and were still operating after 10 years on those who survived until then. The main factor influencing the mortality was the clinical state of the men at the time of certification, as indicated by the percentage disability awarded; the excess lung cancer rate and the mesothelioma and asbestosis rates all increased with percentage disability. Those awarded only 10% or 20% benefit were still at risk from all the three asbestos-related causes. For a man certified at age 55 it was estimated that his life expectation would be reduced by 3, 5, 8, or 12 years according to whether his rate of disablement benefit was 10%, 20%, 30% or 40% , or 50% or more respectively."
    },
    {
      "ID": "20381",
      "Title": "Predicting COPD 1-year mortality using prognostic predictors routinely measured in primary care.",
      "Abstract": "BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a major cause of mortality. Patients with advanced disease often have a poor quality of life, such that guidelines recommend providing palliative care in their last year of life. Uptake and use of palliative care in advanced COPD is low; difficulty in predicting 1-year mortality is thought to be a major contributing factor. METHODS: We identified two primary care COPD cohorts using UK electronic healthcare records (Clinical Practice Research Datalink). The first cohort was randomised equally into training and test sets. An external dataset was drawn from a second cohort. A risk model to predict mortality within 12 months was derived from the training set using backwards elimination Cox regression. The model was given the acronym BARC based on putative prognostic factors including body mass index and blood results (B), age (A), respiratory variables (airflow obstruction, exacerbations, smoking) (R) and comorbidities (C). The BARC index predictive performance was validated in the test set and external dataset by assessing calibration and discrimination. The observed and expected probabilities of death were assessed for increasing quartiles of mortality risk (very low risk, low risk, moderate risk, high risk). The BARC index was compared to the established index scores body mass index, obstructive, dyspnoea and exacerbations (BODEx), dyspnoea, obstruction, smoking and exacerbations (DOSE) and age, dyspnoea and obstruction (ADO). RESULTS: Fifty-four thousand nine hundred ninety patients were eligible from the first cohort and 4931 from the second cohort. Eighteen variables were included in the BARC, including age, airflow obstruction, body mass index, smoking, exacerbations and comorbidities. The risk model had acceptable predictive performance (test set: C-index = 0.79, 95% CI 0.78-0.81, D-statistic = 1.87, 95% CI 1.77-1.96, calibration slope = 0.95, 95% CI 0.9-0.99; external dataset: C-index = 0.67, 95% CI 0.65-0.7, D-statistic = 0.98, 95% CI 0.8-1.2, calibration slope = 0.54, 95% CI 0.45-0.64) and acceptable accuracy predicting the probability of death (probability of death in 1 year, n high-risk group, test set: expected = 0.31, observed = 0.30; external dataset: expected = 0.22, observed = 0.27). The BARC compared favourably to existing index scores that can also be applied without specialist respiratory variables (area under the curve: BARC = 0.78, 95% CI 0.76-0.79; BODEx = 0.48, 95% CI 0.45-0.51; DOSE = 0.60, 95% CI 0.57-0.61; ADO = 0.68, 95% CI 0.66-0.69, external dataset: BARC = 0.70, 95% CI 0.67-0.72; BODEx = 0.41, 95% CI 0.38-0.45; DOSE = 0.52, 95% CI 0.49-0.55; ADO = 0.57, 95% CI 0.54-0.60). CONCLUSION: The BARC index performed better than existing tools in predicting 1-year mortality. Critically, the risk score only requires routinely collected non-specialist information which, therefore, could help identify patients seen in primary care that may benefit from palliative care."
    },
    {
      "ID": "20382",
      "Title": "Mortality from lung cancer among silicotic patients in Sardinia: an update study with 10 more years of follow up.",
      "Abstract": "OBJECTIVES: To evaluate the association between silica, silicosis and lung cancer, the mortality of 724 patients with silicosis, first diagnosed by standard chest x ray film between 1964 and 1970, has been analysed by a cohort study extended to 31 December 1997. METHODS: Smoking and detailed occupational histories were available for each member of the cohort as well as the estimated lifetime exposure to respirable silica dust and radon daughters. Two independent readers blindly classified standard radiographs according to the 12 point International Labour Organisation (ILO) scale. Lung function tests meeting the American Thoracic Society's criteria were available for 665 patients. Standardised mortality ratios (SMRs) for selected causes of death were based on the age specific Sardinian regional death rates. RESULTS: The mortality for all causes was significantly higher than expected (SMR 1.35, 95% confidence interval (95% CI) 1.24 to 1.46) mainly due to tuberculosis (SMR 22.0) and to non-malignant chronic respiratory diseases (NMCRD) (SMR 6.03). All cancer deaths were within the expected numbers (SMR 0.93; 95% CI 0.76 to 1.14). The SMR for lung cancer was 1.37 (95% CI 0.98 to 1.91, 34 observed), increasing to 1.65 (95% CI 0.98 to 2.77) allowing for 20 years of latency since the first diagnosis of silicosis. Although mortality from NMCRD was strongly associated to the severity of radiological silicosis and to the extent of the cumulative exposure to silica, SMR for lung cancer was weakly related to the ILO categories and to the cumulative exposure to silica dust only after 20 years of lag interval. A significant excess of deaths from lung cancer (SMR 2.35) was found among silicotic patients previously employed in underground metal mines characterised by a relatively high airborne concentration of radon daughters and among ever smokers who showed an airflow obstruction at the time of the first diagnosis of silicosis (SMR 3.29). Mortality for lung cancer related to exposure was evaluated with both the Cox's proportional hazards modelling within the entire cohort and a nested case-control study (34 cases of lung cancer and 136 matched controls). Both multivariate analyses did not show any significant association with cumulative exposure to silica or severity of silicosis, but confirmed the association between mortality for lung cancer and relatively high exposure to radon, smoking, and airflow obstruction as significant covariates. CONCLUSIONS: The findings indicate that the slightly increased mortality for lung cancer in this cohort of silicotic patients was significantly associated with other risk factors-such as cigarette smoking, airflow obstruction, and estimated exposure to radon daughters in underground mines-rather than to the severity of radiological silicosis or to the cumulative exposure to crystalline silica dust itself."
    },
    {
      "ID": "20383",
      "Title": "The bronchiectasis severity index. An international derivation and validation study.",
      "Abstract": "RATIONALE: There are no risk stratification tools for morbidity and mortality in bronchiectasis. Identifying patients at risk of exacerbations, hospital admissions, and mortality is vital for future research. OBJECTIVES: This study describes the derivation and validation of the Bronchiectasis Severity Index (BSI). METHODS: Derivation of the BSI used data from a prospective cohort study (Edinburgh, UK, 2008-2012) enrolling 608 patients. Cox proportional hazard regression was used to identify independent predictors of mortality and hospitalization over 4-year follow-up. The score was validated in independent cohorts from Dundee, UK (n = 218); Leuven, Belgium (n = 253); Monza, Italy (n = 105); and Newcastle, UK (n = 126). MEASUREMENTS AND MAIN RESULTS: Independent predictors of future hospitalization were prior hospital admissions, Medical Research Council dyspnea score greater than or equal to 4, FEV1 < 30% predicted, Pseudomonas aeruginosa colonization, colonization with other pathogenic organisms, and three or more lobes involved on high-resolution computed tomography. Independent predictors of mortality were older age, low FEV1, lower body mass index, prior hospitalization, and three or more exacerbations in the year before the study. The derived BSI predicted mortality and hospitalization: area under the receiver operator characteristic curve (AUC) 0.80 (95% confidence interval, 0.74-0.86) for mortality and AUC 0.88 (95% confidence interval, 0.84-0.91) for hospitalization, respectively. There was a clear difference in exacerbation frequency and quality of life using the St. George's Respiratory Questionnaire between patients classified as low, intermediate, and high risk by the score (P < 0.0001 for all comparisons). In the validation cohorts, the AUC for mortality ranged from 0.81 to 0.84 and for hospitalization from 0.80 to 0.88. CONCLUSIONS: The BSI is a useful clinical predictive tool that identifies patients at risk of future mortality, hospitalization, and exacerbations across healthcare systems."
    },
    {
      "ID": "20384",
      "Title": "Compensation, radiographic changes, and survival in applicants for asbestosis compensation.",
      "Abstract": "The survival of 354 claimants for compensation for pulmonary asbestosis among former workers of the Wittenoom crocidolite mine and mill in Western Australia has been examined. There were 118 deaths up to December 1982. The median time between start of work and claim for compensation was 17 years. The standardised mortality ratio (SMR) for deaths from all causes was 2.65 (p less than 0.0001). The SMR for pneumoconiosis was 177.2 (p less than 0.0001), bronchitis and emphysema 2.6 (p = 0.04), tuberculosis 44.6 (p less than 0.0001), respiratory cancer (including five deaths from malignant pleural mesothelioma) 6.4 (p less than 0.0001), gastrointestinal cancer 1.6 (p = 0.22), all other cancers 1.6 (p = 0.17), heart disease 1.4 (p = 0.07), and all other causes 2.18 (p = 0.004). Plain chest radiographs taken within two years of claiming compensation were found for 238 subjects and were categorised independently by two observers according to the International Labour Organisation criteria without knowledge of exposure or compensation details. Profusion of radiographic opacities, age at claiming compensation, work in the Wittenoom mill, and degree of disability awarded by the pneumoconiosis medical board were significant predictors of survival, but total estimated exposure to asbestos was not. Radiographic profusion and degree of disability were, however, predictable by total exposure. The median survival from claim for compensation was 17 years in subjects with ILO category 1 pneumoconiosis, 12 years in category 2, and three years in category 3."
    },
    {
      "ID": "20385",
      "Title": "The modified BODE index: validation with mortality in COPD.",
      "Abstract": "Peak oxygen uptake (V'(O(2))) remains the gold standard measurement of exercise capacity and has been associated with survival. A modified BODE (body mass index, airflow obstruction, dyspnoea, exercise capacity) index replacing the 6-min walk distance (6MWD) with V'(O(2)) as % predicted (mBODE%) has been developed and found to have excellent correlation with the conventional BODE index. The objectives of the present study were to compare the ability of the conventional BODE and the mBODE% to predict mortality in 444 patients with chronic obstructive pulmonary disease (COPD) followed for a mean+/-SD period of 71+/-34 months. Anthropometrics, spirometry, lung volumes, comorbidity, cardiopulmonary cyclo-ergometry test and 6MWD were determined at entry. The mean BODE indices for the cohort were: BODE 4.1+/-2 and mBODE% 5.5+/-2. Both indices were significantly correlated with mortality. Logistic regression analysis with COPD survival as the dependent variable identified the BODE index, Charlson's and exercise capacity (in W) as variables associated with this outcome. In conclusion, the conventional BODE index, which uses the 6-min walk distance, predicts mortality in chronic obstructive pulmonary disease as well as the modified index using peak oxygen uptake. The results support the use of the simpler index, which includes the 6-min walk distance in the comprehensive evaluation of patients with chronic obstructive pulmonary disease."
    },
    {
      "ID": "20386",
      "Title": "Mortality in cases of asbestosis diagnosed by a pneumoconiosis medical panel.",
      "Abstract": "One hundred and fifty five male cases of asbestosis certified by the London Pneumoconiosis Medical Panel during 1968-74 were followed up during 1978-9, 4-11 (mean 7.5) years after certification. Fifty nine patients had died, 23 (39%) from lung cancer, 6 (10%) from mesothelioma, and 11 (19%) from other respiratory causes. The number of observed deaths was 2.25 times greater than expected and 7.4 times greater than expected for lung cancer. Adenocarcinoma was the commonest histological type but other cell types were also increased. Finger clubbing (p less than 0.01) and percentage of predicted FEV1 (p less than 0.01) were of value in predicting death, but increasing profusion of small opacities greater than 1/0 (ILO/U-C international classification of radiographs of pneumoconiosis, 1971), duration of exposure to asbestos, time from first exposure to asbestos, and percentage of predicted vital capacity and transfer factor did not predict death."
    },
    {
      "ID": "20387",
      "Title": "Obstructive sleep apnea, COPD, the overlap syndrome, and mortality: results from the 2005-2008 National Health and Nutrition Examination Survey.",
      "Abstract": "OBJECTIVE: The aim of this study was to investigate the role of obstructive sleep apnea (OSA) on all-cause mortality in patients with COPD. METHODS: Data for this cross-sectional study were obtained from the National Health and Nutrition Examination Survey (NHANES) data (year 2005-2008). Eligible subjects were ≥20 years who had no COPD or OSA (n=9,237), had only OSA (n=366), had only COPD (n=695), and had OSA/COPD overlap syndrome (n=90). Univariate and multivariate analyses were used to evaluate factors associated with overall mortality. RESULTS: Multivariate analysis found that the COPD and OSA/COPD overlap syndrome groups had significantly higher chance of all-cause mortality than the group of subjects who did not have OSA or COPD (adjusted hazard ratio [HR] =1.5 for the COPD group and 2.4 for the overlap syndrome group) ( CONCLUSION: The present study found that COPD and OSA/COPD overlap syndrome were associated with higher all-cause mortality compared with patients without either disease and that OSA did not significantly increase mortality in patients with COPD."
    },
    {
      "ID": "20388",
      "Title": "Predicting mortality in bronchiectasis using bronchiectasis severity index and FACED scores: a 19-year cohort study.",
      "Abstract": "The clinical course of bronchiectasis is unpredictable, posing a challenge both in clinical practice and in research. Two mortality prediction scores, the bronchiectasis severity index (BSI) and FACED scores, have recently been developed. The aim of this study was to assess the ability of these scores to predict long-term mortality and to compare the two scores.The study was a single-centre retrospective cohort analysis consisting of 91 subjects originally recruited in 1994. BSI and FACED scores were calculated at the time of enrolment and long-term mortality ascertained. Data was available for 74 patients with a median of 18.8 years of follow-up.Both scoring systems had similar predictive power for 5-year mortality (area under receiver operator characteristic curve (AUC) 0.79 for BSI and 0.8 for FACED). Both scores were able to predict 15-year mortality with the FACED score showing slightly superior predictive power (AUC 0.82 versus 0.69, p=0.0495).This study provides further validation of the FACED and BSI scores for the prediction of mortality in bronchiectasis and demonstrates their utility over a longer period than originally described. Whilst both scores had excellent predictive power, the FACED score was superior for 15-year mortality."
    },
    {
      "ID": "20389",
      "Title": "Distribution, temporal stability and association with all-cause mortality of the 2017 GOLD groups in the ECLIPSE cohort.",
      "Abstract": "BACKGROUND: In 2017, the Global Initiative for Chronic Obstructive Lung Disease (GOLD) proposed a new classification of patients with chronic obstructive pulmonary disease (COPD). MATERIAL AND METHODS: We contrasted the distribution of COPD patients according to GOLD 2017 and 2011 classifications, the temporal stability of the 2017 groups during 3 years follow-up and their association with all-cause mortality in the ECLIPSE cohort. RESULTS: We found that GOLD 2017: (1) switched a substantial proportion of GOLD 2011C and D patients to A and B groups at recruitment; (2) about half of A, B and D patients remained in the same group at the end of follow-up, whereas 74% of C patients (the smallest group of all) changed, either because exacerbation rate decreased or dyspnea increased; and, (3) all-cause mortality by group was not significantly different between GOLD 2011 and 2017. Of note, mortality in B (16%) and D patients (18%) was similar, both with similar severity of airflow limitation, the best individual mortality risk factor. CONCLUSIONS: These results illustrate the cross-sectional and longitudinal effects of excluding FEV1 from GOLD 2017, and highlight both the clinical relevance of symptom assessment in the management of COPD and the prognostic capacity of FEV1."
    },
    {
      "ID": "20390",
      "Title": "Temporal Patterns of Exposure to Asbestos and Risk of Asbestosis: An Analysis of a Cohort of Asbestos Textile Workers.",
      "Abstract": "OBJECTIVE: The aim of the study was to assess the risk of asbestosis death based on the temporal pattern of exposure to asbestos. METHODS: We followed up a cohort of asbestos textile workers, employed in 1946 to 1984, until November 2013. We measured the duration of the employment, the time since last employment (TSLE), the age, and the year of first employment. Hazard ratios (HR) were estimated through multivariable Cox regression models. RESULTS: We observed 51 asbestosis deaths among 1823 workers. The HR of asbestosis death increased with exposure duration (HR 2.4 for ≥15 years compared with <5 years, P trend = 0.014) and declined with TSLE (HR 0.3 for ≥25 compared with <5 years, P = 0.004). The risk of asbestosis mortality strongly declined for exposure starting after 1968. CONCLUSIONS: The risk of asbestosis death strongly declines in the decades after cessation of the exposure."
    },
    {
      "ID": "20391",
      "Title": "Respiratory-related death in individuals with incident asthma and COPD: a competing risk analysis.",
      "Abstract": "BACKGROUND: Distinguishing between mortality attributed to respiratory causes and other causes among people with asthma, COPD, and asthma-COPD overlap (ACO) is important. This study used electronic health records in England to estimate excess risk of death from respiratory-related causes after accounting for other causes of death. METHODS: We used linked Clinical Practice Research Datalink (CPRD) primary care and Office for National Statistics mortality data to identify adults with asthma and COPD from 2005 to 2015. Causes of death were ascertained using death certificates. Hazard ratios (HR) and excess risk of death were estimated using Fine-Gray competing risk models and adjusting for age, sex, smoking status, body mass index and socioeconomic status. RESULTS: 65,021 people with asthma and 45,649 with COPD in the CPRD dataset were frequency matched 5:1 with people without the disease on age, sex and general practice. Only 14 in 100,000 people with asthma are predicted to experience a respiratory-related death up to 10 years post-diagnosis, whereas in COPD this is 98 in 100,000. Asthma is associated with an 0.01% excess incidence of respiratory related mortality whereas COPD is associated with an 0.07% excess. Among people with asthma-COPD overlap (N = 22,145) we observed an increased risk of respiratory-related death compared to those with asthma alone (HR = 1.30; 95% CI 1.21-1.40) but not COPD alone (HR = 0.89; 95% CI 0.83-0.94). CONCLUSIONS: Asthma and COPD are associated with an increased risk of respiratory-related death after accounting for other causes; however, diagnosis of COPD carries a much higher probability. ACO is associated with a lower risk compared to COPD alone but higher risk compared to asthma alone."
    },
    {
      "ID": "20392",
      "Title": "Mortality risk attributable to classification of chronic obstructive pulmonary disease and reduced lung function: A 21-year longitudinal cohort study.",
      "Abstract": "AIM: The mortality risk attributable to the classifications of chronic obstructive pulmonary disease (COPD) remains unclear. We investigated the associations of mortality with COPD classifications and reduced lung function in a large longitudinal cohort in Taiwan. METHODS: A total of 388,401 adults (≥25 years of age) were recruited between 1996 and 2016 underwent 834,491 medical examinations including spirometry. We used the Global Initiative for Chronic Obstructive Lung Disease (GOLD) to establish the COPD classifications. A time-dependent Cox regression model was used to investigate the associations between the morality risk and COPD classifications. We also examined the associations between mortality and lung function. RESULTS: The mean age of the participants was 42.1 years, and the median follow-up duration was 16.2 years. We identified 28,283 natural-cause deaths, and the mortality rate was 4.7 per 1,000 person-years. The hazard ratios (HRs) [95%confidence interval (95%CI)] of mortality in the participants with restrictive spirometry pattern and COPD GOLD Ⅰ-Ⅳ were 1.31 (1.27-1.35), 1.18 (1.00-1.39), 1.43 (1.35-1.51), 1.78 (1.66-1.90), and 2.13 (1.94-2.34), respectively, with reference to the participants with normal lung function. The natural-cause mortality risk increased by 33% [HR(95%CI): 1.33 (1.28-1.39)] for participants with COPD. Reduced lung function was also associated with a higher mortality risk. CONCLUSIONS: A more advanced classification of COPD was associated with a greater increase in the mortality risk. Our study suggests that early detection of COPD and slowing the disease progress in patients with COPD are crucial for mortality prevention."
    },
    {
      "ID": "20393",
      "Title": "Asbestosis and mesothelioma among British asbestos workers (1971-2005).",
      "Abstract": "BACKGROUND: Ascertainment of asbestosis and mesothelioma from underlying cause of death underestimates the burden of these diseases. The aims of this study were to estimate the true frequency of asbestosis and mesothelioma among asbestos workers in Great Britain (GB), and to identify factors associated with the risk of death with these diseases. METHODS: The GB Asbestos Survey was established in 1971 to monitor long-term health outcomes among workers covered by regulations to control asbestos at work. Asbestosis and mesothelioma cases were defined by multiple cause of death, and were ascertained by identifying asbestos workers on the GB Asbestosis and Mesothelioma Registers. Standardized mortality ratios (SMRs) were calculated; the risks of asbestosis and mesothelioma were modeled with Poisson regression analysis. Deaths to the end of 2005 were included. RESULTS: There were 15,557 deaths between 1971 and 2005 among the 98,912 workers. Altogether 477 asbestosis and 649 mesothelioma cases were identified. The SMR for all causes was 1.42, for asbestosis 51.3, and for mesothelioma 13.5. In multiply adjusted analysis, age, sex, job, and birth cohort were significantly associated with asbestosis and mesothelioma. For asbestosis year of first exposure, and for mesothelioma latency, were also statistically significant. CONCLUSIONS: The asbestos workers experienced high mortality from all causes, asbestosis, and mesothelioma. There was some evidence that the risk of asbestosis and mesothelioma was lower in later birth cohorts and among those first occupationally exposed to asbestos more recently. Due to the long latency of both diseases, further follow-up is required to confirm these trends."
    },
    {
      "ID": "20394",
      "Title": "Adults with current asthma but not former asthma have higher all-cause and cardiovascular mortality: a population-based prospective cohort study.",
      "Abstract": "Higher mortality in asthmatics has been shown previously. However, evidence on different asthma phenotypes on long-term mortality risk is limited. The aim was to evaluate the impact of asthma phenotypes on mortality in general population. Data from the National Health and Nutrition Examination Survey from 2001-2002 to 2013-2014 linked mortality files through December 31, 2015, were used (N = 37,015). Cox proportional hazards regression was used to estimate the risk of all-cause and cause-specific mortality adjusting for sociodemographic characteristics, smoking, body mass index, and chronic conditions. During the mean follow-up time of 7.5 years, 4326 participants died from a variety of causes. Current asthma, but not former asthma was associated with increased all-cause mortality (current asthma: HR = 1.37; 95% CI 1.20-1.58; Former asthma: HR = 0.93; 95% CI 0.73-1.18); as well as mortality from cardiovascular disease (HR"
    },
    {
      "ID": "20395",
      "Title": "Early Predictors of Mortality in Patients with COPD, in Relation to Respiratory and Non-Respiratory Causes of Death - A National Register Study.",
      "Abstract": "BACKGROUND: Both single factors and composite measures have been suggested to predict mortality in patients with chronic obstructive pulmonary disease (COPD) and there is a need to analyze the relative importance of each variable. OBJECTIVE: To explore the predictors of mortality for patients with COPD in relation to respiratory, cardiac, and malignant causes, as well as all causes of death. METHODS: After merging the Swedish Respiratory Tract Register (SRTR) and the Swedish Cause of Death Register, patients with respiratory, cardiac, and other causes of death were identified. Demographic and clinical variables from the deceased patients' first registration with the SRTR were compared. Three univariable and multivariable Cox proportional hazards regression analyses were conducted for different causes of death, with time from first registration to either death or a fixed end date as dependent variable, and variables regarding demographics, respiration, and comorbidities as independent variables. RESULTS: In the multivariable Cox models, mortality for patients with all causes of death was predicted by older age 1.79 (CI 1.41, 2.27), lower percentage of predicted forced expiratory volume in 1 second (FEV CONCLUSION: Obstruction predicted mortality in all models and dyspnea in two models and needs to be addressed. Comorbidity with heart disease could further worsen the COPD patient's prognosis and should be treated by a multidisciplinary team of professional specialists."
    },
    {
      "ID": "20396",
      "Title": "Asthma, airflow limitation and mortality risk in the general population.",
      "Abstract": "Asthma and chronic obstructive pulmonary disease co-exist in a significant proportion of patients. Whether asthma increases mortality risk among subjects with airflow limitation remains controversial. We used data from 2121 adult participants in the population-based Tucson Epidemiological Study of Airway Obstructive Disease cohort. At enrolment (1972-1973), participants completed questionnaires and lung function tests. Participants were categorised into four groups based on the combination of airflow limitation (AL; forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) <70%) and physician-confirmed asthma at baseline. Vital status as of January 2011 was assessed through the National Death Index. Cox proportional hazards models were used to test differences in mortality risk across the four airflow limitation/asthma groups. In multivariate Cox models, the AL+/asthma+ group had a 114% increased mortality risk during follow-up compared with the AL-/asthma- group (adjusted HR 2.14; 95% CI 1.64-2.79). The corresponding hazard ratios were 1.09 (95% CI 0.89-1.34) and 1.34 (95% CI 1.14-1.57) for the AL-/asthma+ and AL+/asthma- groups, respectively. Among subjects with airflow limitation, asthma was associated with increased mortality risk (HR 1.58, 95% CI 1.17-2.12). However, this increased risk was substantially reduced and no longer significant after further adjustment for baseline FEV1 levels. Similar results were obtained when airflow limitation was defined as FEV1/FVC less than the lower limit of normal. In a population-based cohort, subjects with concomitant airflow limitation and asthma had an increased risk of dying, which was mainly related to their baseline lung function deficits."
    },
    {
      "ID": "20397",
      "Title": "External Validation Of The Updated ADO Score In COPD Patients From The Birmingham COPD Cohort.",
      "Abstract": "BACKGROUND: Reviews suggest that the ADO score is the most discriminatory prognostic score for predicting mortality among chronic obstructive pulmonary disease (COPD) patients, but a full evaluation and external validation within primary care settings is critical before implementation. OBJECTIVES: To validate the ADO score in prevalent and screen-detected primary care COPD cases at 3 years and at shorter time periods. PATIENTS AND METHODS: One thousand eight hundred and ninety-two COPD cases were recruited between 2012 and 2014 from 71 United Kingdom general practices as part of the Birmingham COPD Cohort study. Cases were either on the practice COPD register or screen-detected. We validated the ADO score for predicting 3-year mortality with 1-year and 2-year mortality as secondary endpoints using discrimination (area-under-the-curve (AUC)) and calibration plots. RESULTS: One hundred and fifty-four deaths occurred within 3 years. The ADO score was discriminatory for predicting 3-year mortality (AUC= 0.74; 95% CI: 0.69-0.79). Similar performance was found for 1- (AUC= 0.73; 0.66-0.80) and 2-year mortality (0.72; 0.67-0.76). The ADO score showed reasonable calibration for predicting 3-year mortality (calibration slope 0.95; 0.70-1.19) but over-predicted in cases with higher predicted risks of mortality at 1 (0.79; 0.45-1.13) and 2-year (0.79; 0.57-1.01) mortality. DISCUSSION: The ADO score showed promising discrimination in predicting 3-year mortality in a primary care population including screen-detected cases. It may need to be recalibrated if it is used to provide risk predictions for 1- or 2-year mortality since, in these time-periods, over-prediction was evident, especially in cases with higher predicted mortality risks."
    },
    {
      "ID": "20398",
      "Title": "Concurrent physician-diagnosed asthma and chronic obstructive pulmonary disease: A population study of prevalence, incidence and mortality.",
      "Abstract": "OBJECTIVE: We conducted a population-based cohort study to estimate trends in prevalence, incidence, and mortality of concurrent physician-diagnosed asthma and chronic obstructive pulmonary disease (COPD). STUDY DESIGN AND SETTING: Two validated health administrative case definitions were used to identify asthma and COPD among all individuals aged 35 years and older living in Ontario, Canada. Annual asthma, COPD, and concurrent asthma and COPD prevalence, incidence, and mortality, standardized for age and sex, were estimated, and compared from 2002 to 2012, using generalized linear models. RESULTS: Standardized prevalence of concurrent asthma and COPD increased by 10.5%, from 2.9% in 2002 to 3.2% in 2012 overall, but more prominently in women compared to men. Overall, standardized incidence decreased by16%, from 2.5 to 2.1 per 1000 individuals, but increased significantly in young adults. All-cause mortality among patients with concurrent asthma and COPD decreased by 11.2%, from 2.6% to 2.2%. Being diagnosed with both diseases was significantly associated with higher all-cause mortality compared to asthma (OR = 1.56, 95% CI: 1.50-1.58), but not compared to COPD (OR = 0.97, 0.96-0.98), except in young adults aged 35 to 49 years where people with asthma and COPD had higher mortality (OR = 1.21, 1.15-1.27). CONCLUSIONS: In a large North American population, the burden of concurrent physician-diagnosed asthma and COPD is increasing, particularly in women and young adults."
    },
    {
      "ID": "20399",
      "Title": "Mortality and its predictive factors in participants with asthma: a 26-year follow-up.",
      "Abstract": "BACKGROUND: The long-term impact of asthma on mortality remains uncertain. This study aimed to assess mortality and its predictors over 26 years in asthmatic participants compared to those with or without other respiratory symptoms. METHODS: This longitudinal cohort study included participants recruited from the general Swedish population, followed from 1990 to 2016. The younger (30-39 years, n = 938) and older (60-69 years, at baseline, n = 1020) groups were divided into asthma, other and no respiratory symptoms. Baseline data included spirometry, allergy testing, smoking status, and quality of life. Survival analyses were conducted using Kaplan-Meier and Cox proportional hazards models. RESULTS: At 26-years follow-up the survival rates were 34 % and 95 % for asthmatics in the older and younger age groups, respectively. Asthma was not found to be a statistically significant independent predictor of mortality when compared to non-asthmatics in either age group (older group HR 95 % CI: 0.94 (0.77-1.15); younger group: 1.39 (0.63-3.09). Significant mortality predictors included increasing age ((1.13 (1.10-1.16)), male sex (1.73 (1.44-2.07), smoking (2.01 (1.65-2.44), lower forced expiratory volume in 1 s (FEV CONCLUSION: Asthma was not a strong independent predictor of mortality in either age group, whereas age, male sex, other respiratory symptoms, smoking, and lower FEV"
    },
    {
      "ID": "20400",
      "Title": "Meta-analysis of silicosis and lung cancer.",
      "Abstract": "OBJECTIVES: This study examined the association between silicosis and lung cancer in a systematic review (and meta-analysis) of the epidemiologic literature, with special reference to the methodological quality of observational studies. METHODS: We searched Medline, Toxline, BIOSIS and Embase (1966-May 2004) for original articles published in any language and systematically reviewed the bibliographies of the retrieved articles. Observational studies (cohort and case-control studies) were selected if they reported a measure of association [standardized mortality ratio (SMR), relative risk or odds ratio] relating lung cancer to silicosis. RESULTS: Thirty-one studies (27 cohort studies, 4 case-control studies) met the inclusion criteria of the meta-analysis. Without any adjustment for smoking, the meta-analysis of the cohort studies indicated that the common SMR was 2.45 [95% confidence interval (95% CI) 1.63-3.66; homogeneity P<0.0001]. When the results of the cohorts for which mortality data were adjusted for smoking were pooled, the common SMR was 1.60 (95% CI 1.33-1.93; homogeneity P=0.52). In a \"dose-response\" analysis, the profusion of small and large opacities found in chest X-rays correlated with the risk of death from lung cancer. Overall, the case-control studies were more conservative in their conclusions. CONCLUSIONS: Because of biases inherent to observational studies, it is likely that the risk of lung cancer among silicosis patients is overestimated in the current literature. There is nevertheless evidence, from data restricted to never-smokers and from a \"dose-response\" analysis, that silicosis and lung cancer are associated."
    },
    {
      "ID": "20401",
      "Title": "Up-to-date on mortality in COPD - report from the OLIN COPD study.",
      "Abstract": "BACKGROUND: The poor recognition and related underdiagnosis of COPD contributes to an underestimation of mortality in subjects with COPD. Data derived from population studies can advance our understanding of the true burden of COPD. The objective of this report was to evaluate the impact of COPD on mortality and its predictors in a cohort of subjects with and without COPD recruited during the twenty first century. METHODS: All subjects with COPD (n = 993) defined according to the GOLD spirometric criteria, FEV1/FVC < 0.70, and gender- and age-matched subjects without airway obstruction, non-COPD (n = 993), were identified in a clinical follow-up survey of the Obstructive Lung Disease in Northern Sweden (OLIN) Studies cohorts in 2002-2004. Mortality was observed until the end of year 2007. Baseline data from examination at recruitment were used in the risk factor analyses; age, smoking status, lung function (FEV1 % predicted) and reported heart disease. RESULTS: The mortality was significantly higher among subjects with COPD, 10.9%, compared to subjects without COPD, 5.8% (p < 0.001). Mortality was associated with higher age, being a current smoker, male gender, and COPD. Replacing COPD with FEV1 % predicted in the multivariate model resulted in the decreasing level of FEV1 being a significant risk factor for death, while heart disease was not a significant risk factor for death in any of the models. CONCLUSIONS: In this cohort COPD and decreased FEV1 were significant risk factors for death when adjusted for age, gender, smoking habits and reported heart disease."
    },
    {
      "ID": "20402",
      "Title": "Retrospective mortality cohort study of Italian workers compensated for silicosis.",
      "Abstract": "OBJECTIVES: To estimate cause specific mortality in a large cohort of Italian workers compensated for silicosis. METHODS: The cohort included 14 929 subjects (14,098 men and 831 women) compensated for silicosis between 1946 and 1979, alive on 1 January 1980, and resident in Tuscany (a region of central Italy with 3,547,000 inhabitants). Mortality follow up ranged from 1980 to 1999. Vital status and the causes of death were determined by linkage with the regional mortality registry and with the national mortality database. The cohort mortality rates were compared to the rates of the local reference population. SMRs and their 95% confidence intervals were computed assuming a Poisson distribution of the observed deaths. Specific SMR analyses were performed according to the level of disability, the year of compensation assignment, and the job type. RESULTS: A significant excess mortality was observed in male silicotics for cancer of the lung, trachea, and bronchus and cancer of the liver, respiratory diseases (silicosis, asbestosis, antracosilicosis, and other pneumoconiosis), and for tubercolosis. Statistically significant mortality excess was observed in female silicotics for respiratory diseases (specifically silicosis and other pneumoconiosis) and tuberculosis. Analyses for period of compensation assignment showed a twofold increased SMR for biliary tract cancer among female workers and for liver cancer among male workers compensated before 1970. CONCLUSIONS: The excess mortality from respiratory tract cancers and respiratory tract diseases detected in Italian compensated silicotics are in agreement with previous epidemiological studies. Although the twofold increased risk for liver cancer among males is suggestive of a possible association with silica dust exposure, the finding needs to be confirmed."
    },
    {
      "ID": "20403",
      "Title": "Mortality of asthma, COPD, and asthma-COPD overlap during an 18-year follow up.",
      "Abstract": "BACKGROUND: We studied asthma, COPD, and asthma-COPD overlap (ACO) to predict mortality in a cohort of Finnish adults with an 18-year follow up. METHODS: A national health examination survey representing Finnish adults aged ≥30 years was performed in 2000-2001. The study cohort included 5922 participants (73.8% of the sample) with all relevant data, including a comprehensive clinical examination and spirometry. These participants were followed continuously from baseline until end of 2018 for total, cardiovascular, cancer, and respiratory mortality through a record linkage. Asthma, COPD, and ACO were defined based on the survey data, including spirometry and register data. There were three separate groups of obstructive subjects (one definition excluding the others). RESULTS: Asthma and COPD were significantly associated with higher total mortality in Cox's model adjusted for sex, age, smoking, education level, BMI, leisure time physical activity, cardiovascular disease, diabetes, and hypertension. Hazard ratios (HR) (95% confidence interval [CI]) for asthma, COPD, and ACO were 1.29 (1.05-1.58), 1.50 (1.20-1.88), and 1.26 (0.97-1.65), respectively. Additionally, asthma (HR 1.47, 95% CI 1.09-1.97) and COPD (HR 1.53, 95% CI 1.08-2.16) were associated with cardiovascular mortality. Although ACO did not predict mortality in the whole cohort, there was a significant association with mortality risk among those with hs-CRP 1-2.99 mg/l. CONCLUSIONS: Asthma or COPD predicts higher total mortality and premature death from cardiovascular diseases."
    },
    {
      "ID": "20404",
      "Title": "Machine Learning and Prediction of All-Cause Mortality in COPD.",
      "Abstract": "BACKGROUND: COPD is a leading cause of mortality. RESEARCH QUESTION: We hypothesized that applying machine learning to clinical and quantitative CT imaging features would improve mortality prediction in COPD. STUDY DESIGN AND METHODS: We selected 30 clinical, spirometric, and imaging features as inputs for a random survival forest. We used top features in a Cox regression to create a machine learning mortality prediction (MLMP) in COPD model and also assessed the performance of other statistical and machine learning models. We trained the models in subjects with moderate to severe COPD from a subset of subjects in Genetic Epidemiology of COPD (COPDGene) and tested prediction performance in the remainder of individuals with moderate to severe COPD in COPDGene and Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE). We compared our model with the BMI, airflow obstruction, dyspnea, exercise capacity (BODE) index; BODE modifications; and the age, dyspnea, and airflow obstruction index. RESULTS: We included 2,632 participants from COPDGene and 1,268 participants from ECLIPSE. The top predictors of mortality were 6-min walk distance, FEV INTERPRETATION: An MLMP-COPD model outperformed four existing models for predicting all-cause mortality across two COPD cohorts. Performance of machine learning was similar to that of traditional statistical methods. The model is available online at: https://cdnm.shinyapps.io/cgmortalityapp/."
    },
    {
      "ID": "20405",
      "Title": "External validation of ADO, DOSE, COTE and CODEX at predicting death in primary care patients with COPD using standard and machine learning approaches.",
      "Abstract": "BACKGROUND: Several models for predicting the risk of death in people with chronic obstructive pulmonary disease (COPD) exist but have not undergone large scale validation in primary care. The objective of this study was to externally validate these models using statistical and machine learning approaches. METHODS: We used a primary care COPD cohort identified using data from the UK Clinical Practice Research Datalink. Age-standardised mortality rates were calculated for the population by gender and discrimination of ADO (age, dyspnoea, airflow obstruction), COTE (COPD-specific comorbidity test), DOSE (dyspnoea, airflow obstruction, smoking, exacerbations) and CODEX (comorbidity, dyspnoea, airflow obstruction, exacerbations) at predicting death over 1-3 years measured using logistic regression and a support vector machine learning (SVM) method of analysis. RESULTS: The age-standardised mortality rate was 32.8 (95%CI 32.5-33.1) and 25.2 (95%CI 25.4-25.7) per 1000 person years for men and women respectively. Complete data were available for 54879 patients to predict 1-year mortality. ADO performed the best (c-statistic of 0.730) compared with DOSE (c-statistic 0.645), COTE (c-statistic 0.655) and CODEX (c-statistic 0.649) at predicting 1-year mortality. Discrimination of ADO and DOSE improved at predicting 1-year mortality when combined with COTE comorbidities (c-statistic 0.780 ADO + COTE; c-statistic 0.727 DOSE + COTE). Discrimination did not change significantly over 1-3 years. Comparable results were observed using SVM. CONCLUSION: In primary care, ADO appears superior at predicting death in COPD. Performance of ADO and DOSE improved when combined with COTE comorbidities suggesting better models may be generated with additional data facilitated using novel approaches."
    },
    {
      "ID": "20406",
      "Title": "Parametric estimation of age-, sex-, and spirometry grade-specific mortality in a cohort of COPD patients from Germany: Results from COSYCONET.",
      "Abstract": "BACKGROUND: Chronic obstructive pulmonary disease (COPD) substantially contributes to morbidity and mortality worldwide. We aimed at estimating Global Initiative for Chronic Obstructive Lung Disease (GOLD) spirometric grade-specific mortality in COPD for Germany, using data from a large-scale cohort of patients with COPD. METHODS: Using COSYCONET data, a cohort of 2741 patients diagnosed with COPD was followed over up to 9 years. We estimated mortality rates for GOLD grades 1 to 4 and stratified into age and sex groups. An exponential survival model was used to estimate mortality after checking model assumptions. Additionally, a Cox proportional hazards model was estimated as plausibility check for the exponential model. RESULTS: A total of 345 deaths were observed during the follow-up period. The data fitted well to an exponential survival model when the first year of follow-up was excluded, suggesting a \"healthy participant effect\". GOLD grade was a strong predictor of mortality, with hazard ratios of 1.6, 3.2, and 8.8 for GOLD 2-4 compared to GOLD 1. Hazard ratios of the Cox model were similar (1.7, 3.4, and 10.0 for grades 2-4 compared to grade 1). At a given grade, mortality strongly increased with age. 1-year mortality ranged from 0.5 % (GOLD 1, <55 years, females) to 54.9 % (GOLD 4, 80+ years, males). Mortality was lower among females by approximately 25 %. CONCLUSION: Based on our findings, mortality in COPD depends on GOLD grade, age, sex and smoking status. Parametric estimation allowed to estimate 1-year mortality for each combination of COPD grade and age group, including uncertainty estimates."
    },
    {
      "ID": "20407",
      "Title": "Impact of chronic obstructive pulmonary disease on mortality: A large national cohort study.",
      "Abstract": "BACKGROUND AND OBJECTIVE: The global burden of chronic obstructive pulmonary disease (COPD) is increasing and COPD patients are at higher risk for all-cause mortality. We aimed to evaluate the impact of COPD on specific-cause mortality using national data. METHODS: This was nationwide retrospective cohort study of 340, 767 adults aged 40-84 years who lacked COPD diagnosis at baseline between 1 January 2003 and 31 December 2013. Incident COPD was defined by reference to COPD claim codes and prescription of COPD medication at least twice annually. Cox proportional hazard ratio (HR) for each cause of death in the COPD group was compared to that of the non-COPD group, with other causes of death accounted as the competing risk. RESULTS: All-cause mortality was higher in the COPD (2,978 per 100, 000 person-years) than the non-COPD group (629 per 100, 000 person-years) and adjusted HR was 1.41 (95% CI = 1.32, 1.50). The association was particularly strong for chronic lower airway disease (adjusted sub-HR = 9.67; 95% CI = 7.21, 12.96) and lung cancer (adjusted sub-HR = 3.16; 95% CI = 2.68, 3.71), and the association was stronger in those aged <60 years. CONCLUSION: In this large national cohort, COPD patients were at a statistically significant higher risk for all-cause mortality than those without COPD. They were more likely to die from chronic lower airway disease, lung cancer and pneumonia than subjects without COPD. The impact of COPD on specific mortalities was stronger in younger subjects."
    },
    {
      "ID": "20408",
      "Title": "Large-scale international validation of the ADO index in subjects with COPD: an individual subject data analysis of 10 cohorts.",
      "Abstract": "BACKGROUND: Little evidence on the validity of simple and widely applicable tools to predict mortality in patients with chronic obstructive pulmonary disease (COPD) exists. OBJECTIVE: To conduct a large international study to validate the ADO index that uses age, dyspnoea and FEV(1) to predict 3-year mortality and to update it in order to make prediction of mortality in COPD patients as generalisable as possible. DESIGN: Individual subject data analysis of 10 European and American cohorts (n=13 914). SETTING: Population-based, primary, secondary and tertiary care. PATIENTS: COPD GOLD stages I-IV. MEASUREMENTS: We validated the original ADO index. We then obtained an updated ADO index in half of our cohorts to improve its predictive accuracy, which in turn was validated comprehensively in the remaining cohorts using discrimination, calibration and decision curve analysis and a number of sensitivity analyses. RESULTS: 1350 (9.7%) of all subjects with COPD (60% male, mean age 61 years, mean FEV(1) 66% predicted) had died at 3 years. The original ADO index showed high discrimination but poor calibration (p<0.001 for difference between predicted and observed risk). The updated ADO index (scores from 0 to 14) preserved excellent discrimination (area under curve 0.81, 95% CI 0.80 to 0.82) but showed much improved calibration with predicted 3-year risks from 0.7% (95% CI 0.6% to 0.9%, score of 0) to 64.5% (61.2% to 67.7%, score of 14). The ADO index showed higher net benefit in subjects at low-to-moderate risk of 3-year mortality than FEV(1) alone. INTERPRETATION: The updated 15-point ADO index accurately predicts 3-year mortality across the COPD severity spectrum and can be used to inform patients about their prognosis, clinical trial study design or benefit harm assessment of medical interventions."
    },
    {
      "ID": "20409",
      "Title": "Changes in the incidence, prevalence and mortality of bronchiectasis in the UK from 2004 to 2013: a population-based cohort study.",
      "Abstract": "There is a paucity of data on incidence, prevalence and mortality associated with non-cystic fibrosis bronchiectasis.Using the Clinical Practice Research Datalink for participants registered between January 1, 2004 and December 31, 2013, we determined incidence, prevalence and mortality associated with bronchiectasis in the UK and investigated changes over time.The incidence and point prevalence of bronchiectasis increased yearly during the study period. Across all age groups, the incidence in women increased from 21.2 per 100 000 person-years in 2004 to 35.2 per 100 000 person-years in 2013 and in men from 18.2 per 100 000 person-years in 2004 to 26.9 per 100 000 person-years in 2013. The point prevalence in women increased from 350.5 per 100 000 in 2004 to 566.1 per 100 000 in 2013 and in men from 301.2 per 100 000 in 2004 to 485.5 per 100 000 in 2013. Comparing morality rates in women and men with bronchiectasis in England and Wales (n=11 862) with mortality rates in the general population from Office of National Statistics data showed that in women the age-adjusted mortality rate for the bronchiectasis population was 1437.7 per 100 000 and for the general population 635.9 per 100 000 (comparative mortality figure of 2.26). In men, the age-adjusted mortality rate for the bronchiectasis population was 1914.6 per 100 000 and for the general population 895.2 per 100 000 (comparative mortality figure of 2.14).Bronchiectasis is surprisingly common and is increasing in incidence and prevalence in the UK, particularly in older age groups. Bronchiectasis is associated with a markedly increased mortality."
    },
    {
      "ID": "20410",
      "Title": "Age modifies the association between severe sleep apnea and all-cause mortality.",
      "Abstract": "PURPOSE: While sleep apnea (SA) gets more prevalent with advancing age, the impact of age on the association between SA and health outcomes is not well known. We assessed the association between the severity of SA and all-cause mortality in different age groups using large longitudinal data. METHOD: We applied a Natural Language Processing pipeline to extract the apnea-hypopnea index (AHI) from the physicians' interpretation of sleep studies performed at the Veteran Health Administration (FY 1999-2022). We categorized the participants as no SA (n-SA, AHI< 5) and severe SA (s-SA, AHI≥30). We grouped the cohort based on age: Young≤40; Middle-aged:40-65; and Older adults≥65; and calculated the odds ratio (aOR) of mortality adjusted for age, sex, race, ethnicity, BMI, and Charlson-Comorbidity Index (CCI) using n-SA as the reference. RESULTS: We identified 146,148 participants (age 52.23 ± 15.02; BMI 32.11 ± 6.05; male 86.7 %; White 66 %). Prevalence of s-SA increased with age. All-cause mortality was lower in s-SA compared to n-SA in the entire cohort (aOR,0.56; 95%CI: 0.54,0.58). Comparing s-SA to n-SA, the all-cause mortality rates (Young 1.86 % vs 1.49 %; Middle-aged 12.07 % vs 13.34 %; and Older adults 26.35 % vs 40.18 %) and the aOR diminished as the age increased (Young: 1.11, 95%CI: 0.93-1.32; Middle-aged: 0.64, 95%CI: 0.61-0.67; and Older adults: 0.44, 95%CI: 0.41-0.46). CONCLUSION: The prevalence of severe SA increased while the odds of all-cause mortality compared to n-SA diminished with age. SA may exert less harmful effects on the aged population. A causality analysis is warranted to assess the relationship between SA, aging, and all-cause mortality."
    },
    {
      "ID": "20411",
      "Title": "Breathlessness and incidence of COPD, cardiac events and all-cause mortality: A 44-year follow-up from middle age throughout life.",
      "Abstract": "BACKGROUND: Breathlessness is prevalent in the general population and may be associated with adverse health outcomes. This study aimed to evaluate the association of breathlessness with Chronic Obstructive Pulmonary Disease (COPD) events, cardiac events and all-cause mortality from middle-age throughout life. METHODS: Breathlessness was measured in 699, 55-year old men residing in Malmö, Sweden using modified Medical Research Council (mMRC). COPD events (hospitalisation, death or diagnosis) cardiac events and all-cause mortality was assessed using The Swedish Causes of Death Register and Hospital Discharge Register. Data was analyzed using Cox- and competing risks (Fine-Gray) regression analysis. RESULTS: 695 (99%) of 699 participants died and four emigrated during follow up. Eighty-seven (12%) had mMRC = 1 and 19 (3%) had mMRC≥2. Breathlessness was associated with COPD events; adjusted Sub-Hazard Ratio 2.1 (95% CI, 1.2-3.6) for mMRC = 1 and 7.5 (2.6-21.7) for mMRC ≥ 2 but not associated with cardiac events when adjusting for competing events and confounding. Breathlessness was associated increased all- cause mortality (Hazard Ratios of 1.4 (1.1-1.7) (mMRC = 1) and 3.4 (2.1-5.6) (mMRC ≥ 2)). CONCLUSION: Breathlessness is associated with increased risk of COPD events and increase in all-cause mortality from age 55 until death."
    },
    {
      "ID": "20412",
      "Title": "Development and validation of a multivariable mortality risk prediction model for COPD in primary care.",
      "Abstract": "Risk stratification of chronic obstructive pulmonary disease (COPD) patients is important to enable targeted management. Existing disease severity classification systems, such as GOLD staging, do not take co-morbidities into account despite their high prevalence in COPD patients. We sought to develop and validate a prognostic model to predict 10-year mortality in patients with diagnosed COPD. We constructed a longitudinal cohort of 37,485 COPD patients (149,196 person-years) from a UK-wide primary care database. The risk factors included in the model pertained to demographic and behavioural characteristics, co-morbidities, and COPD severity. The outcome of interest was all-cause mortality. We fitted an extended Cox-regression model to estimate hazard ratios (HR) with 95% confidence intervals (CI), used machine learning-based data modelling approaches including k-fold cross-validation to validate the prognostic model, and assessed model fitting and discrimination. The inter-quartile ranges of the three metrics on the validation set suggested good performance: 0.90-1.06 for model fit, 0.80-0.83 for Harrel's c-index, and 0.40-0.46 for Royston and Saurebrei's [Formula: see text] with a strong overlap of these metrics on the training dataset. According to the validated prognostic model, the two most important risk factors of mortality were heart failure (HR 1.92; 95% CI 1.87-1.96) and current smoking (HR 1.68; 95% CI 1.66-1.71). We have developed and validated a national, population-based prognostic model to predict 10-year mortality of patients diagnosed with COPD. This model could be used to detect high-risk patients and modify risk factors such as optimising heart failure management and offering effective smoking cessation interventions."
    },
    {
      "ID": "20413",
      "Title": "Are Predictors for Overall Mortality in COPD Patients Robust over Time?",
      "Abstract": "(1) Background: Mortality is a major outcome in research on chronic obstructive pulmonary disease (COPD) with various predictors described. However, the dynamic courses of important predictors over time are disregarded. This study evaluates if longitudinal assessment of predictors provides additional information on the mortality risk in COPD when compared with a cross-sectional analysis.; (2) In a longitudinal, prospective, non-interventional cohort study including mild to very severe COPD patients, mortality and its various possible predictors were annually assessed up to seven years.; (3) Results: 297 patients were analysed. Mean (SD) age was 62.5 (7.6) years and 66% males. Mean (SD) FEV1 was 48.8 (21.4)%. A total of 105 events (35.4%) happened with a median (95% CI) survival time of 8.2 (7.2/NA) years. No evidence for a difference between the raw variable and the variable history on the predictive value for all tested variables over each visit was found. There was no evidence for changing effect estimates (coefficients) across the study visits due to the longitudinal assessment; (4) Conclusions: We found no evidence that predictors of mortality in COPD are time dependent. This implies that cross-sectional measured predictors show robust effect estimates over time and multiple assessments seem not to change the predictive value of the measure."
    },
    {
      "ID": "20414",
      "Title": "Mortality risk and causes of death in patients with non-cystic fibrosis bronchiectasis.",
      "Abstract": "BACKGROUND: All-cause mortality risk and causes of death in bronchiectasis patients have not been fully investigated. The aim of this study was to compare the mortality risk and causes of death between individuals with bronchiectasis and those without bronchiectasis. METHODS: Patients with or without bronchiectasis determined based on chest computed tomography (CT) at one centre between 2005 and 2016 were enrolled. Among the patients without bronchiectasis, a control group was selected after applying additional exclusion criteria. We compared the mortality risk and causes of death between the bronchiectasis and control groups without lung disease. Subgroup analyses were also performed according to identification of Pseudomonas or non-tuberculous mycobacteria, airflow limitation, and smoking status. RESULTS: Of the total 217,702 patients who underwent chest CT, 18,134 bronchiectasis patients and 90,313 non-bronchiectasis patients were included. The all-cause mortality rate in the bronchiectasis group was 1608.8 per 100,000 person-years (95% confidence interval (CI), 1531.5-1690.0), which was higher than that in the control group (133.5 per 100,000 person-years; 95% CI, 124.1-143.8; P < 0.001). The bronchiectasis group had higher all-cause (adjusted hazard ratio (aHR), 1.26; 95% CI, 1.09-1.47), respiratory (aHR, 3.49; 95% CI, 2.21-5.51), and lung cancer-related (aHR, 3.48; 95% CI, 2.33-5.22) mortality risks than the control group. In subgroup analysis, patients with airflow limitation and ever smokers showed higher all-cause mortality risk among bronchiectasis patients. Therefore, we observed significant interrelation between bronchiectasis and smoking, concerning the risks of all-cause mortality (P for multiplicative interaction, 0.030, RERI, 0.432; 95% CI, 0.097-0.769) and lung cancer-related mortality (RERI, 8.68; 95% CI, 1.631-15.736). CONCLUSION: Individuals with bronchiectasis had a higher risk of all-cause, respiratory, and lung cancer-related mortality compared to control group. The risk of all-cause mortality was more prominent in those with airflow limitation and in ever smokers."
    },
    {
      "ID": "20415",
      "Title": "Prognostic variables and scores identifying the end of life in COPD: a systematic review.",
      "Abstract": "INTRODUCTION: COPD is a major cause of mortality, and the unpredictable trajectory of the disease can bring challenges to end-of-life care. We aimed to investigate known prognostic variables and scores that predict prognosis in COPD in a systematic literature review, specifically including variables that contribute to risk assessment of patients for death within 12 months. METHODS: We conducted a systematic review on prognostic variables, multivariate score or models for COPD. Ovid MEDLINE, EMBASE, the Cochrane database, Cochrane CENTRAL, DARE and CINAHL were searched up to May 1, 2016. RESULTS: A total of 5,276 abstracts were screened, leading to 516 full-text reviews, and 10 met the inclusion criteria. No multivariable indices were developed with the specific aim of predicting all-cause mortality in stable COPD within 12 months. Only nine indices were identified from four studies, which had been validated for this time period. Tools developed using expert knowledge were also identified, including the Gold Standards Framework Prognostic Indicator Guidance, the RADboud Indicators of Palliative Care Needs, the Supportive and Palliative Care Indicators Tool and the Necesidades Paliativas program tool. CONCLUSION: A number of variables contributing to the prediction of all-cause mortality in COPD were identified. However, there are very few studies that are designed to assess, or report, the prediction of mortality at or less than 12 months. The quality of evidence remains low, such that no single variable or multivariable score can currently be recommended."
    },
    {
      "ID": "20416",
      "Title": "Risk for Cardiovascular Disease and One-Year Mortality in Patients With Chronic Obstructive Pulmonary Disease and Obstructive Sleep Apnea Syndrome Overlap Syndrome.",
      "Abstract": "nan"
    },
    {
      "ID": "20417",
      "Title": "Self-reported symptoms of sleep-disordered breathing and risk of cardiovascular diseases: Observational and Mendelian randomization findings.",
      "Abstract": "Sleep-disordered breathing may increase the risk of cardiovascular diseases, but observational findings are inconclusive. We investigated whether sleep-disordered breathing-related symptoms are associated with risk of several cardiovascular diseases using data from a cohort study and by performing Mendelian randomization analyses. The cohort study included 43,624 adults (56-94 years old) who completed questionnaires regarding symptoms of snoring and cessation of breathing, lifestyle habits and health characteristics. Participants were followed up for incident cardiovascular diseases and death over 8 years through linkage to the Swedish National Patient and Death Registers. The Mendelian randomization analyses were conducted using single-nucleotide polymorphisms robustly associated with sleep apnea in a recent genome-wide association study and summary-level data for major cardiovascular diseases from large-scale consortia. In the cohort study, an increased risk of atrial fibrillation was observed in participants who reported both snoring and cessation of breathing (hazard ratio [95% confidence interval] = 1.16 [1.03-1.30]) compared with those without sleep-disordered breathing symptoms. There was no association between sleep-disordered breathing symptoms and risk of myocardial infarction, heart failure, aortic valve stenosis or abdominal aortic aneurysm in multivariable analyses. Mendelian randomization analyses showed no association of genetic liability to sleep apnea with myocardial infarction, heart failure or atrial fibrillation, but revealed a suggestive association with coronary artery disease (odds ratio [95% confidence interval] = 1.24 [1.02-1.52])."
    },
    {
      "ID": "20418",
      "Title": "Mortality in Miners with Coal-Workers' Pneumoconiosis in the Czech Republic in the Period 1992-2013.",
      "Abstract": "While working underground, miners are exposed to a number of risk factors that have a negative impact on their health and may be a cause of an increased mortality in miners. The aim of the study was to compare total and specific mortality in black coal miners with acknowledged coal-workers' pneumoconiosis (CWP) and without CWP, and the mortality of the general male population in the Czech Republic in the period 1992-2013. The sample consisted of 3476 coal miners with CWP and 6687 ex-coal miners without CWP, who were removed after achieving the maximum permissible exposure (MPE). The mortality risk differences were analyzed with the use of the standardized mortality ratio (SMR) and 95% confidence interval. Significantly higher total mortality (SMR = 1.10; 95% CI: 1.02-1.17), and mortality from malignant neoplasm (SMR = 1.16; 95% CI: 1.03-1.30), lung cancers (SMR = 1.70; 95% CI: 1.41-2.04), and non-malignant respiratory diseases (SMR = 2.78; 95% CI: 2.32-3.31) were found in the sample of coal miners with CWP. In this sample, the severity of CWP was assessed, and the SMR increased with the severity of CWP. The total (SMR = 0.86; 95% CI: 0.82-0.91) and specific mortality of miners without CWP were not higher compared with the general population. In the case where the miners were removed from underground work after achieving the MPE (without CWP), their mortality was not higher than that of the general population, but the mortality of miners with CWP was higher compared to the general population. This mortality was affected by malignant and non-malignant respiratory diseases."
    },
    {
      "ID": "20419",
      "Title": " Mortality from cancer and other causes in a cohort of workers with asbestosis in Hong Kong. ",
      "Abstract": "nan"
    },
    {
      "ID": "20420",
      "Title": "Impact of COPD on mortality: An 8-year observational retrospective healthcare claims database cohort study.",
      "Abstract": "BACKGROUND: Chronic obstructive pulmonary disease (COPD) is one of the leading causes of morbidity and mortality. Here we present a large observational study on the association of COPD and exacerbations with mortality (AvoidEx Mortality). METHODS: A real-world, observational cohort study with longitudinal analyses of German healthcare claims data in patients ≥40 years of age with a COPD diagnosis from 2011 to 2018 (n = 250,723) was conducted. Patients entered the cohort (index date) upon the first COPD diagnosis. To assess the impact of COPD on all-cause death, a propensity score-matched control group of non-COPD patients was constructed. The number and severity of exacerbations during a 12-month pre-index period were used to form subgroups. For each exacerbation subgroup the exacerbations during 12 months prior to death were analysed. RESULTS: COPD increases the all-cause mortality risk by almost 60% (HR 1.57 (95% CI 1.55-1.59)) in comparison to matched non-COPD controls, when controlling for other baseline covariates. The cumulative risk of death after 8 years was highest in patients with a history of more than one moderate or severe exacerbation. Among all deceased COPD patients, 17.2% had experienced a severe, and 34.8% a moderate exacerbation, within 3 months preceding death. Despite increasing exacerbation rates towards death, more than the half of patients were not receiving any recommended pharmacological COPD therapy in the year before death. CONCLUSION: Our study illustrates the impact of COPD on mortality risk and highlights the need for consequent COPD management comprising exacerbation assessment and treatment."
    },
    {
      "ID": "20421",
      "Title": "Sleep disordered breathing and mortality: eighteen-year follow-up of the Wisconsin sleep cohort.",
      "Abstract": "BACKGROUND: Sleep-disordered breathing (SDB) is a treatable but markedly under-diagnosed condition of frequent breathing pauses during sleep. SDB is linked to incident cardiovascular disease, stroke, and other morbidity. However, the risk of mortality with untreated SDB, determined by polysomnography screening, in the general population has not been established. METHODS: An 18-year mortality follow-up was conducted on the population-based Wisconsin Sleep Cohort sample (n = 1522), assessed at baseline for SDB with polysomnography, the clinical diagnostic standard. SDB was described by the number of apnea and hypopnea episodes/hour of sleep; cutpoints at 5, 15 and 30 identified mild, moderate, and severe SDB, respectively. Cox proportional hazards regression was used to estimate all-cause and cardiovascular mortality risks, adjusted for potential confounding factors, associated with SDB severity levels. RESULTS: All-cause mortality risk, adjusted for age, sex, BMI, and other factors was significantly increased with SDB severity. The adjusted hazard ratio (HR, 95% CI) for all-cause mortality with severe versus no SDB was 3.0 (1.4,6.3). After excluding persons who had used CPAP treatment (n = 126), the adjusted HR (95% CI) for all-cause mortality with severe versus no SDB was 3.8 (1.6,9.0); the adjusted HR (95% CI) for cardiovascular mortality was 5.2 (1.4,19.2). Results were unchanged after accounting for daytime sleepiness. CONCLUSIONS: Our findings of a significant, high mortality risk with untreated SDB, independent of age, sex, and BMI underscore the need for heightened clinical recognition and treatment of SDB, indicated by frequent episodes of apnea and hypopnea, irrespective of symptoms of sleepiness."
    },
    {
      "ID": "20422",
      "Title": "Mortality of workers compensated for silicosis during the period 1959-1963 in the Veneto region of Italy.",
      "Abstract": "After reports appeared from other countries indicating an excess risk of lung cancer among silicotics, a cohort of workers compensated for silicosis during the period 1959-1963 in the Veneto region of Italy was constructed and followed for mortality through 1984. The results of the study showed a large mortality excess for infectious diseases (180 observed versus 9.5 expected), due to silicotuberculosis, and for diseases of the respiratory system (270 observed versus 33.5 expected) due to silicosis. An elevated standardized mortality ratio of 239 (70 observed versus 29.3 expected) from lung cancer was also detected. An increasing pattern was observed with time since first exposure, while the relationship with employment category and duration of exposure was less clear-cut. The lung cancer excess was also strongly associated with cigarette smoking, there being a dose-response relationship with daily cigarette consumption. The study confirms the results from other epidemiologic studies on silicotics which show this pathological condition to be associated with increased lung cancer mortality."
    },
    {
      "ID": "20423",
      "Title": "Association Between Asthma and All-Cause Mortality and Cardiovascular Disease Morbidity and Mortality: A Meta-Analysis of Cohort Studies.",
      "Abstract": "BACKGROUND: Asthma and cardiovascular disease (CVD) share many risk factors. Previous meta-analyses indicated that asthma is associated with an increased risk of CVD and all-cause mortality, but these studies were limited by unstandardized search strategies and the number of articles included. OBJECTIVE: We sought to systematically synthesize evidence investigating the impact of asthma on all-cause mortality and CVD morbidity and mortality. METHODS: We searched in PubMed and EMBASE for observational cohort studies (inception dates to November 10, 2021) that had both asthma groups and control groups. We also manually searched the reference lists of correlative articles to include other eligible studies. Data for associations between asthma and all-cause mortality and CVD morbidity and mortality were needed. RESULTS: We summarized the findings from 30 cohort studies comprising 4,157,823 participants. Asthma patients had increased CVD morbidity [relative risk (RR) = 1.28, 95% confidence interval (CI) = 1.16-1.40] and increased CVD mortality (RR = 1.25, 95% CI = 1.14-1.38). Asthma patients also had increased risk of all-cause mortality (RR = 1.38, 95% CI = 1.07-1.77). In subgroup analyses, female asthma patients had a higher risk of CVD morbidity and all-cause mortality than male asthma patients, and late-onset asthma patients had a higher risk of CVD morbidity than early-onset asthma patients. CONCLUSION: Asthma patients have increased risk of all-cause mortality and CVD morbidity and mortality. This information reminds clinicians to be aware of the risk of CVD and all-cause mortality in asthma patients. SYSTEMATIC REVIEW REGISTRATION: http://www.crd.york.ac.uk/PROSPERO/, PROSPERO, identifier: CRD 42021290082."
    },
    {
      "ID": "20424",
      "Title": "Epidemiological characteristics of asthma-COPD overlap, its association with all-cause mortality, and the mediating role of depressive symptoms: evidence from NHANES 2005-2018.",
      "Abstract": "BACKGROUND: Asthma-COPD overlap (ACO) is a distinct and intricate respiratory condition that requires specific attention and management. The objective of this cohort study was to examine the epidemiological characteristics of ACO, explore the association between ACO and all-cause mortality, and investigate the potential mediating role of depressive symptoms in this association. METHODS: This retrospective cohort study used data from the National Health and Nutrition Examination Survey (NHANES) 2005-2018 and National Death Index (NDI) 2019. A total of 22,745 participants were included: 705 with ACO, 2352 with asthma-only, 853 with COPD-only, and 18,835 without asthma or COPD. The non-ACO group (N = 22,040) referred to the individuals without ACO. Statistical tests were employed to assess differences in some characteristics between the ACO group and the other groups. Cox proportional hazards models were applied to evaluate the relationship between ACO and all-cause mortality, estimating hazard ratios (HR) with 95% confidence intervals. Mediation analysis was conducted to investigate the potential mediating effects of depressive symptoms on the association of ACO with all-cause mortality. RESULTS: The prevalence of ACO was 3.10% in our study population. Compared to the non-ACO participants, the ACO participants exhibited significantly different characteristics, including higher age, a lower family income-to-poverty ratio, a higher body mass index, higher rates of comorbidities i.e., hypertension, diabetes, hyperlipidemia, cardiovascular disease, and cancer, poorer dietary habits, and a higher rate of depressive disorders. Compared to the participants without ACO, the participants with ACO exhibited a significant increase in all-cause mortality (HR = 1.908, 95%CI 1.578-1.307, p < 0.001). The proportions mediated by depressive symptoms for ACO -associated all-cause mortality were 8.13% (CI: 4.22%-14.00%, p < 0.001). CONCLUSIONS: This study revealed a strong relationship between ACO and all-cause mortality and uncovered a potential psychological mechanism underlying this relationship. Our study indicates the possible necessity of offering comprehensive care to ACO patients, encompassing early detection, lifestyle guidance, and mental health support. Nevertheless, due to the limitations in the study design and the dataset, the results should be interpreted with caution."
    },
    {
      "ID": "20425",
      "Title": "Risk of All-Cause Mortality in Mild Chronic Obstructive Pulmonary Disease: Evidence From the NHANES III and 2007-2012.",
      "Abstract": "BACKGROUND: It is unclear whether patients with Global Initiative for Chronic Obstructive Lung Disease stage 1 (mild) chronic obstructive pulmonary disease (COPD) have a higher risk of all-cause mortality than participants with normal spirometry results. METHODS: We used the data from the National Health and Nutrition Examination Survey (NHANES) III and 2007-2012, which included participants aged 20-79 years, to investigate whether patients with mild COPD (whole population and subgroups) have a higher risk of all-cause mortality than participants with normal spirometry. Mild COPD was defined as prebronchodilator forced expiratory volume in 1 second /forced vital capacity"
    }
  ],
  "indexer_fields": [
    {
      "name": "country",
      "description": "Country or countries where the study population was recruited or data originates. Use standard country names.",
      "data_type_primary": "array-string",
      "examples": [
        "United Kingdom",
        "United States",
        "Denmark",
        "International"
      ],
      "examples_mode": "guide",
      "depth": "minimal"
    },
    {
      "name": "study_size",
      "description": "Total number of participants in the analysed cohort as a numeric value if explicitly stated; null if absent.",
      "data_type_primary": "number",
      "examples": [
        "32091",
        "1263"
      ],
      "examples_mode": "guide",
      "depth": "minimal"
    },
    {
      "name": "year_coverage",
      "description": "Decade bins covering the study data collection period. Select all applicable ranges.",
      "data_type_primary": "array-string",
      "examples": [
        "1980-1989",
        "1990-1999",
        "2000-2009",
        "2010-2019",
        "2020-2029"
      ],
      "examples_mode": "enum",
      "depth": "minimal"
    },
    {
      "name": "gender",
      "description": "Sex distribution of the study population.",
      "data_type_primary": "string",
      "examples": [
        "Both",
        "Male",
        "Female",
        "Not Applicable"
      ],
      "examples_mode": "enum",
      "depth": "minimal"
    },
    {
      "name": "age",
      "description": "Age categories of the study population. Select all applicable bins based on stated age range or mean/median age.",
      "data_type_primary": "array-string",
      "examples": [
        "<45",
        "45-65",
        "65+"
      ],
      "examples_mode": "enum",
      "depth": "minimal"
    },
    {
      "name": "publication_type",
      "description": "Study design or publication type explicitly stated.",
      "data_type_primary": "string",
      "examples": [
        "Prospective cohort study",
        "Retrospective cohort study",
        "Meta-analysis",
        "Randomized controlled trial",
        "Cross-sectional study",
        "Systematic review"
      ],
      "examples_mode": "enum",
      "depth": "minimal"
    },
    {
      "name": "model_type",
      "description": "Statistical or analytical modelling approaches used.",
      "data_type_primary": "array-string",
      "examples": [
        "Cox proportional hazards model",
        "Logistic regression",
        "Random-effect meta-analysis",
        "Poisson regression"
      ],
      "examples_mode": "guide",
      "depth": "minimal"
    },
    {
      "name": "data_source",
      "description": "Dataset, registry, cohort, or database from which study data were obtained.",
      "data_type_primary": "array-string",
      "examples": [
        "UK Biobank",
        "NHANES",
        "Clinical Practice Research Datalink"
      ],
      "examples_mode": "guide",
      "depth": "minimal"
    },
    {
      "name": "subpopulation",
      "description": "Specific subgroups or eligibility criteria analysed within the study.",
      "data_type_primary": "array-string",
      "examples": [
        "General population",
        "Smokers",
        "COPD",
        "Lung Cancer",
        "Hypertensive subjects"
      ],
      "examples_mode": "guide",
      "depth": "minimal"
    },
    {
      "name": "age_exact",
      "description": "Exact reported age summary statistic when available (e.g. mean, median with SD/IQR); null if absent.",
      "data_type_primary": "string",
      "examples": [
        "59.7 (11.9)",
        "~55",
        "68.9 (12.8)"
      ],
      "examples_mode": "guide",
      "depth": "minimal"
    },
    {
      "name": "follow_up_years",
      "description": "Duration of participant follow-up in predefined year ranges. Select all applicable bins.",
      "data_type_primary": "array-string",
      "examples": [
        "<5",
        "5-9",
        "10-19",
        "20+"
      ],
      "examples_mode": "enum",
      "depth": "minimal"
    }
  ],
  "country_values": [
    "England, Wales",
    "United Kingdom",
    "Sardinia",
    "United Kingdom, Belgium, Italy",
    "Australia",
    "Taiwan",
    "Sweden",
    "Canada",
    "Italy",
    "Finland",
    "Germany",
    "International",
    "United Kingdom, England, Wales",
    "Czech Republic",
    "Hong Kong"
  ]
}