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)., Competing Interests: A.H reports research support from Gilead (to institution outside the submitted work). Honoraria for lectures from TTCC. Support for attending oncology meetings from Kyowa Kirin, MSD and Bristol Myers Squibb. P.B reports support for the present manuscript from Ontario Institute for Cancer Research and Princess Margaret Cancer Foundation. Grants or contracts from BMS, Sanofi, AstraZeneca, Genentech/Roche, GSK, Novartis, Merck, SeaGen, Lilly, Amgen, Bicara Therapeutics, Zymeworks, Medicenna, Bayer and Takeda (all to institution). Participation on a Data Safety Monitoring Board or Advisory Board from the Myeloma Cancer Research Foundation, Lilly and Roche. Leadership or fiduciary role in other board, society, committee or advocacy group in the Breast International Group. D.W reports funding to institution from Genome British Columbia/Genome Canada (G05CHS). Consulting fees from Roche Canada and AstraZeneca Canada outside the submitted work. Support for attending meetings from Illumina and leadership role co-directing IMPRINT Research Consulting outside the submitted work. E.A reports consulting fees from AstraZeneca, Novartis and Seagen. D.R reports grants funding from Roche to Institution outside the submitted work and support for attending meetings from Illumina. B.G reports consulting fees from Vivio Health. B.W reports grants from BMS unrelated to the present work and payment or honoraria from AstraZeneca. N.M reports grants or contracts from Genome Canada with funding for Breast Cancer Screening costing algorithm made to Sunnybrook Health Sciences Centre and the University of Toronto. Leadership or fiduciary role as full-time employee of the Canadian Agency for Drugs and Technologies in Health outside the submitted work. A.R.A.R reports institutional support for the present manuscript from AstraZeneca, Deciphera, Karyopharm Therapeutics, Pfizer, Roche/Genentech, Bristol Myers Squibb, MedImmune, Amgen, GlaxoSmithKline, Blueprint Medicines, Merck, AbbVie, Adaptimmune, Iterion Therapeutics, 23&Me, Rain Therapeutics, Neoleukin Therapeutics, Daiichi Sankyo, Symphogen, and Frontier Therapeutics. Consulting fees from Adaptimmune, Bayer, GlaxoSmithkline, Medison, Inhibrx. A.S reports grants or contract from Novartis, Bristol-Myers Squibb, Symphogen, AstraZeneca/MedImmune, Merck, Bayer, Surface Oncology, Northern Biologics, Jansen Oncology/Johnson & Johnson, Roche, Regeneron, Alkermes, Array Biompharma/Pfizer, GSK, Nubiyota, Oncorus, Treadwell, Amgen, ALX Oncology, Genentech, Seagen and Servier. Consulting fees from Bristol-Myers Squibb and Merck (both compensated). T.S reports payment or honoraria from Illumina for presentation on molecular profiling. Participation on an Advisory Board with honoraria from AstraZeneca, Jansen, Pfizer, Merck and Bayer. L.L.S reports institutional support for clinical trials from Novartis, Bristol-Myers Squibb, Pfizer, Boerhinger-Ingelheim, GlaxoSmithKline, Roche/Genentech, Karyopharm, AstraZeneca, Merck, Celgene, Astellas, Bayer, Abbvie, Amgen, Symphogen, Intensity Therapeutics, Mirati Therapeutics, Shattucks. Consulting/Advisory role from Merck, Pfizer, AstraZeneca, Roche, Symphogen, Seattle Genetics, GlaxoSmithKline, Voronoi, Arvinas, Tessa, Navire, Relay, Rubius, Janpix, Daiichi Sanyko, Coherus, Marengo, InteRNA. Leadership or fiduciary role Treadwell Therapeutics (spouse) and stock or stock options at Agios (spouse). T.P.H reports leadership or fiduciary role Radiation Oncology Clinical Quality Lead for Ontario Health Cancer Care Ontario. The rest of the authors report no conflicts of interest., (© 2024 The Author(s).)