@article{244d6d1b92ae45ebbc2235c36c5ea4ba,
title = "Novel algorithmic approach predicts tumor mutation load and correlates with immunotherapy clinical outcomes using a defined gene mutation set",
abstract = "Background: While clinical outcomes following immunotherapy have shown an association with tumor mutation load using whole exome sequencing (WES), its clinical applicability is currently limited by cost and bioinformatics requirements. Methods: We developed a method to accurately derive the predicted total mutation load (PTML) within individual tumors from a small set of genes that can be used in clinical next generation sequencing (NGS) panels. PTML was derived from the actual total mutation load (ATML) of 575 distinct melanoma and lung cancer samples and validated using independent melanoma (n = 312) and lung cancer (n = 217) cohorts. The correlation of PTML status with clinical outcome, following distinct immunotherapies, was assessed using the Kaplan-Meier method. Results: PTML (derived from 170 genes) was highly correlated with ATML in cutaneous melanoma and lung adenocarcinoma validation cohorts (R2 = 0.73 and R2 = 0.82, respectively). PTML was strongly associated with clinical outcome to ipilimumab (anti-CTLA-4, three cohorts) and adoptive T-cell therapy (1 cohort) clinical outcome in melanoma. Clinical benefit from pembrolizumab (anti-PD-1) in lung cancer was also shown to significantly correlate with PTML status (log rank P value < 0.05 in all cohorts). Conclusions: The approach of using small NGS gene panels, already applied to guide employment of targeted therapies, may have utility in the personalized use of immunotherapy in cancer.",
keywords = "CTLA-4, Immunotherapy, Lung cancer, Melanoma, PD-1, Total mutation load",
author = "Jason Roszik and Haydu, {Lauren E.} and Hess, {Kenneth R.} and Junna Oba and Joon, {Aron Y.} and Siroy, {Alan E.} and Karpinets, {Tatiana V.} and Stingo, {Francesco C.} and Veera Baladandayuthapani and Tetzlaff, {Michael T.} and Wargo, {Jennifer A.} and Ken Chen and Forget, {Marie Andr{\'e}e} and Haymaker, {Cara L.} and Chen, {Jie Qing} and Funda Meric-Bernstam and Eterovic, {Agda K.} and Shaw, {Kenna R.} and Mills, {Gordon B.} and Gershenwald, {Jeffrey E.} and Radvanyi, {Laszlo G.} and Patrick Hwu and Futreal, {P. Andrew} and Gibbons, {Don L.} and Lazar, {Alexander J.} and Chantale Bernatchez and Davies, {Michael A.} and Woodman, {Scott E.}",
note = "Funding Information: Dr. Roszik is a consultant in Merck KGaA. Dr. Hess is an unpaid consultant in Angiochem, Inc. Dr. Tetzlaff serves on the advisory board for Advisory boards of Myriad Genetics and Seattle Genetics. Dr. Wargo is a speaker or advisory board for Dava Oncology, Roche Genentech, Novartis, GSK, and Illumina. Dr. Chen is an employee of Lion Biotechnologies. Dr. Meric-Bernstam has a consulting/advisory role in Genentech, Novartis, Roche, Inflection Biosciences, Celgene, and receives Honoraria from Genentech, Roche Diagnostics and research support from Novartis, AstraZeneca, Taiho Pharmaceutical, Genentech, Calithera Biosciences, Debiopharm Group, Bayer, Aileron Therapeutics, PUMA Biotechnology, Verastem, and CytomX Therapeutics. Dr. Mills is a consultant in Adventist Health, Allostery, AstraZeneca, Catena Pharmaceuticals, Critical Outcome Technologies, ImmunoMET, Isis Pharmaceuticals, Lilly, Medimmune, Novartis, Precision Medicine, Provista Diagnostics, Signalchem, Lifesciences, Symphogen, Takeda/Millenium Pharmaceuticals, Tau Therapeutics Tarveda, and receives sponsored research from the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation, AstraZeneca, Breast Cancer Research Foundation, Critical Outcome Technologies, Illumina, Karus, Komen Research Foundation, Nanostring, and Takeda/Millenium Pharmaceuticals. Dr. Gershenwald has a consulting or advisory role in Navidea, Castle Biosciences, and Merck, and intellectual property in Mercator therapeutics. Dr. Radvanyi is an employee of EMD Serono. Dr. Hwu has a stock or other ownership and consulting or advisory role in Lion Biotechnologies Immatics US, Inc., and receives research funding from Genentech and Bristol-Myers Squibb. Dr. Bernatchez has a consulting or advisory role in Lion Biotechnologies, and receives research funding from Nektar, Idera. Dr. Davies has a consulting or advisory role in GlaxoSmithKline, Genentech/Roche, Novartis, Sanofi, and Vaccinex, and receives research funding from the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation, GlaxoSmithKline, Genentech/Roche, AstraZeneca, Merck, Oncothyreon, Myriad Genetics, and Sanofi. No other disclosures are reported. Funding Information: This study was supported through a Rising Stars Award, University of Texas System (SEW), UT MD Anderson Cancer Center NCI SPORE in Melanoma (SEW, P50 CA093459), NIH National Cancer Institute (NCI) grant T32 CA163185 (AES), NCI Grant No. U01 CA180964 (FMB), Khalifa Bin Zayed Al Nahyan Foundation, NCATS grant UL1 TR000371 (Center for Clinical and Translational Sciences), The University of Texas MD Anderson Cancer Center Support grant (NIH/NCI P30 CA016672), CPRIT RP150405 and Lung Cancer Moon Shot (DLG), Dr. Miriam and Sheldon G. Adelson Medical Research Foundation, Aim at Melanoma Foundation, Miriam & Jim Mulva Research Funds, and philanthropic contributions to The MD Anderson Cancer Center Melanoma Moon Shots Program. Publisher Copyright: {\textcopyright} 2016 The Author(s).",
year = "2016",
month = oct,
day = "25",
doi = "10.1186/s12916-016-0705-4",
language = "English",
volume = "14",
journal = "BMC Medicine",
issn = "1741-7015",
publisher = "BioMed Central",
number = "1",
}
