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Background: To date, economic analyses of tissue-based next generation sequencing genomic profiling (NGS) for advanced solid tumors have typically required models with assumptions, with little real-world evidence on overall survival (OS), clinical trial enrollment or end-of-life quality of care. Methods: Cost consequence analysis of NGS testing (555 or 161-gene panels) for advanced solid tumors through the OCTANE clinical trial (NCT02906943). This is a longitudinal, propensity score-matched retrospective cohort study in Ontario, Canada using linked administrative data. Patients enrolled in OCTANE at Princess Margaret Cancer Centre from August 2016 until March 2019 were matched with contemporary patients without large gene panel testing from across Ontario not enrolled in OCTANE. Patients were matched according to 19 patient, disease and treatment variables. Full 2-year follow-up data was available. Sensitivity analyses considered alternative matched cohorts. Main Outcomes were mean per capita costs (2019 Canadian dollars) from a public payer's perspective, OS, clinical trial enrollment and end-of-life quality metrics. Findings: There were 782 OCTANE patients with 782 matched controls. Variables were balanced after matching (standardized difference <0.10). There were higher mean health-care costs with OCTANE ($79,702 vs. $59,550), mainly due to outpatient and specialist visits. Publicly funded drug costs were less with OCTANE ($20,015 vs. $24,465). OCTANE enrollment was not associated with improved OS (restricted mean survival time [standard error]: 1.50 (±0.03) vs. 1.44 (±0.03) years, log-rank p = 0.153), varying by tumor type. In five tumor types with ≥35 OCTANE patients, OS was similar in three (breast, colon, uterus, all p > 0.40), and greater in two (ovary, biliary, both p < 0.05). OCTANE was associated with greater clinical trial enrollment (25.4% vs. 9.5%, p < 0.001) and better end-of-life quality due to less death in hospital (10.2% vs. 16.4%, p = 0.003). Results were robust in sensitivity analysis. Interpretation: We found an increase in healthcare costs associated with multi-gene panel testing for advanced cancer treatment. The impact on OS was not significant, but varied across tumor types. OCTANE was associated with greater trial enrollment, lower publicly funded drug costs and fewer in-hospital deaths suggesting important considerations in determining the value of NGS panel testing for advanced cancers. Funding: T.P H holds a research grant provided by the Ontario Institute for Cancer Research through funding provided by the Government of Ontario (#IA-035 and P.HSR.158) and through funding of the Canadian Network for Learning Healthcare Systems and Cost-Effective 'Omics Innovation (CLEO) via Genome Canada (G05CHS).
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OBJECTIVES: Abnormalities in mismatch repair have been described in ovarian cancer, but few studies have examined the causes of mismatch repair deficiency (MMRd). To address this, we completed targeted mutational and methylation sequencing on MMRd ovarian cancer cases. The objective of this study was to explore the molecular mechanism of MMRd using our targeted next generation sequencing panel. METHODS: Newly diagnosed non-serous/mucinous ovarian cancers (n=215) were prospectively recruited from three cancer centers in Ontario, Canada, between 2015 and 2018. Tumors were reflexively assessed for mismatch repair protein by immunohistochemistry. Matched tumor-normal MMRd cases were analyzed on a custom next generation sequencing panel to identify germline and somatic mutations, copy number variants, rearrangements, and promoter methylation in mismatch repair and associated genes. RESULTS: Of 215 cases, 28 (13%) were MMRd. The MMRd cohort had a median age of 52.3 years (range 33.6-62.2), with mostly stage I (50%) and grade 1 or 2 endometrioid histotype (57%). Of the 28 cases, 22 were available for molecular analysis, and Lynch syndrome was detected in 50% of MMRd cases (11/22; seven ovarian cancer and four synchronous ovarian and endometrial cancer: seven MSH6, two MLH1, one PMS2, and one MSH2). An explanation for the observed mismatch repair phenotype was available for 22/22 deficient cases, including 12 MLH1/PMS2 deficient (nine somatic methylation, one bi-allelic somatic deletion, and two pathogenic germline variant), one PMS2 deficient (one pathogenic germline variant), seven MSH6 deficient (seven pathogenic germline variant), and two MSH2/MSH6 deficient (one pathogenic germline variant and one bi-allelic somatic mutation). Concordance between clinical germline testing and panel sequencing results was 100%. CONCLUSIONS: Use of our custom next generation sequencing panel allowed for the streamlined assessment of hereditary and somatic causes of MMRd in ovarian cancers.
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Genomic instability affects the reproducibility of experiments that rely on cancer cell lines. However, measuring the genomic integrity of these cells throughout a study is a costly endeavor that is commonly forgone. Here, we validate the identity of cancer cell lines in three pharmacogenomic studies and screen for genetic drift within and between datasets. Using SNP data from these datasets encompassing 1,497 unique cell lines and 63 unique pharmacological compounds, we show that genetic drift is widely prevalent in almost all cell lines with a median of 4.5%-6.1% of the total genome size drifted between any two isogenic cell lines. This study highlights the need for molecular profiling of cell lines to minimize the effects of passaging or misidentification in biomedical studies. We developed the CCLid web application, available at www.cclid.ca, to allow users to screen the genomic profiles of their cell lines against these datasets. A record of this paper's transparent peer review process is included in the Supplemental Information.