@article{91dcccfe60b34843807fabe414c5fdab,
title = "The Cancer Genome Atlas Expression Subtypes Stratify Response to Checkpoint Inhibition in Advanced Urothelial Cancer and Identify a Subset of Patients with High Survival Probability",
abstract = "Analysis of the IMvigor 210 trials involving patients with platinum-refractory or cisplatin-ineligible urothelial carcinoma who were treated with the PD-L1 inhibitor atezolizumab identified a resistance signature as an immune biomarker. Transcriptome profiling of 368 tumor samples from this trial revealed that the “genomically unstable” Lund subtype classification was associated with the best response. We developed and applied a novel single-patient subtype classifier based on The Cancer Genome Atlas 2017 expression-based molecular subtypes. We identified 11 patients with a neuronal subtype, with a 100% response rate in eight confirmed cases (2 complete response, 6 partial response), and 72% overall, including 3/11 patients with an unconfirmed response. The survival probability was extraordinarily high for the neuronal subtype, which represents a high-risk cohort with advanced disease, and may be secondary to low levels of TGFβ expression and high mutation/neoantigen burden. Patient summary: We describe a methodology for genomic classification of an individual patient's bladder cancer tumor and have identified a subtype that is associated with a high response rate to immunotherapy. This is an important step forward in identifying the right treatment for the right patient, which is the goal of personalized precision medicine. We describe a novel single-patient classifier based on The Cancer Genome Atlas 2017 scheme that identified the neuronal subtype of urothelial carcinoma as an extreme responder to anti-PD-L1 therapy. In the future, trials targeting subtype-based therapy may improve precision delivery of care for urothelial carcinoma.",
keywords = "Anti-PD-L1 antibody, Bladder cancer, Immunotherapy, Neuronal, RB1, Subtypes, TP53, The Cancer Genome Atlas, Urothelial cancer",
author = "Jaegil Kim and David Kwiatkowski and McConkey, {David J.} and Meeks, {Joshua J.} and Freeman, {Samuel S.} and Joaquim Bellmunt and Gad Getz and Lerner, {Seth P.}",
note = "Funding Information: Financial disclosures: Seth P. Lerner certifies that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: The Broad Institute has filed disclosure to US patent office for the TCGA single patient classifier on behalf of the authors. David J. McConkey has stock options in Apocell and has received research funding from AstraZeneca, Janssen, and Bioclin. Joshua J. Meeks is a consultant for Merck and Ferring and a consultant and principal investigator for a trial for AstraZeneca. Joaquim Bellmunt is an advisor for Genentech, Merck, AstraZeneca, BMS, Pfizer, Pierre Fabre, and Janssen; has received lecturer fees from Pfizer, Merck, GSK, Novartis, and Pfizer; and has received research funding from Takeda, Pfizer, and MSD. Seth P. Lerner has played a role in clinical trials for Endo, FKD, JBL (SWOG), Roche/Genentech (SWOG), and Viventia; is a consultant for Anchiano Therapeutics, UroGen, and Vaxiion; is an advisory board member for Anchiano Therapeutics, miR Scientific, QED Therapeutics, and UroGen; and is a speaker for MSD Korea. The remaining authors have nothing to disclose. Publisher Copyright: {\textcopyright} 2019 European Association of Urology Copyright: Copyright 2019 Elsevier B.V., All rights reserved.",
year = "2019",
month = jun,
doi = "10.1016/j.eururo.2019.02.017",
language = "English (US)",
volume = "75",
pages = "961--964",
journal = "European Urology",
issn = "0302-2838",
publisher = "Elsevier",
number = "6",
}