Competing Interests Statement RMS, TAC and LGTM are inventors on a provisional patent application (62/569,053) filed by MSK, relating to the use of TMB in cancer immunotherapy.MDH, NAR and TAC are inventors on a PCT patent application (PCT/US2015/062208) filed by MSK, relating to the use of TMB in lung cancer immunotherapy.MSK and the inventors may receive a share of commercialization revenue from license agreements relating to these patent applications. CHL received research funding from Eisai, BMS, Exelixis, Pfizer, Calithera and consulting fees from Exelixis and Eisai. ANS has received research support from Bristol Myers Squibb, Immunocore, Astra-Zeneca, Xcovery and serves on the advisory board for Bristol Myers Squibb, Immunocore, Castle Biosciences; he also receives royalties from UpToDate. MDH receives research funding from Bristol-Myers Squibb; is paid consultant to Merck

Tumor molecular profiling is a fundamental component of precision oncology, enabling the identification of genomic alterations in genes and pathways that can be targeted therapeutically. The existence of recurrent targetable alterations across distinct histologically-defined tumor types, coupled with an expanding portfolio of molecularly-targeted therapies, demands flexible and comprehensive approaches to profile clinically significant genes across the full spectrum of cancers. We established a large-scale, prospective clinical sequencing initiative utilizing a comprehensive assay, MSK-IMPACT, through which we have compiled matched tumor and normal sequence data from a unique cohort of more than 10,000 patients with advanced cancer and available pathological and clinical annotations. Using these data, we identified clinically relevant somatic mutations, novel non-coding alterations, and mutational signatures that were shared among common and rare tumor types. Patients were enrolled on genomically matched clinical trials at a rate of 11%. To enable discovery of novel biomarkers and deeper investigation into rare alterations and tumor types, all results are publicly accessible.

Executive Summary PURPOSE With prospective clinical sequencing of tumors emerging as a mainstay in cancer care, there is an urgent need for a clinical support tool that distills the clinical implications associated with specific mutation events into a standardized and easily interpretable format. To this end, we developed OncoKB, an expert-guided precision oncology knowledge base. METHODS OncoKB annotates the biological and oncogenic effect and the prognostic and predictive significance of somatic molecular alterations. Potential treatment implications are stratified by the level of evidence that a specific molecular alteration is predictive of drug response based on US Food and Drug Administration (FDA) labeling, National Comprehensive Cancer Network (NCCN) guidelines, disease-focused expert group recommendations and the scientific literature. RESULTS To date, over 3000 unique mutations, fusions, and copy number alterations in 418 cancer-associated genes have been annotated. To test the utility of OncoKB, we annotated all genomic events in 5983 primary tumor samples in 19 cancer types. Forty-one percent of samples harbored at least one potentially actionable alteration, of which 7.5% were predictive of clinical benefit from a standard treatment. OncoKB annotations are available through a public web resource (http://oncokb.org/) and are also incorporated into the cBioPortal for Cancer Genomics to facilitate the interpretation of genomic alterations by physicians and researchers. CONCLUSION OncoKB, a comprehensive and curated precision oncology knowledge base, offers oncologists detailed, evidence-based information about individual somatic mutations and structural alterations present in patient tumors with the goal of supporting optimal treatment decisions.

We sought to define whether there are intrinsic molecular subtypes of high-grade bladder cancer. Consensus clustering performed on gene expression data from a meta-dataset of highgrade, muscle-invasive bladder tumors identified two intrinsic, molecular subsets of high-grade bladder cancer, termed "luminal" and "basal-like," which have characteristics of different stages of urothelial differentiation, reflect the luminal and basal-like molecular subtypes of breast cancer, and have clinically meaningful differences in outcome. A gene set predictor, bladder cancer analysis of subtypes by gene expression (BASE47) was defined by prediction analysis of microarrays (PAM) and accurately classifies the subtypes. Our data demonstrate that there are at least two molecularly and clinically distinct subtypes of high-grade bladder cancer and validate the BASE47 as a subtype predictor. Future studies exploring the predictive value of the BASE47 subtypes for standard of care bladder cancer therapies, as well as novel subtypespecific therapies, will be of interest.I n the United States, urothelial carcinoma (UC) of the bladder is the fourth most common malignancy in men and the ninth most common in women, with 72,570 new cases and 15,210 deaths expected in 2013 (1). Bladder cancer is heterogeneous and can be histologically divided into low-grade and high-grade disease. Whereas low-grade tumors are almost invariably noninvasive (Ta), high-grade tumors can be classified based on invasion into the muscularis propria of the bladder, as non-muscle invasive bladder cancer (NMIBC; Tis, Ta, T1) or muscle invasive bladder cancer (MIBC; ≥T2). Low-grade tumors are associated with a high rate of recurrence but an excellent overall prognosis, with a 5-y survival in the range of 90%. In contrast, high-grade MIBC has a relatively poor 5-y overall survival, 68% for T2 and decreasing to 15% for non-organ-confined disease (i.e., pT3 and pT4) (1, 2).Along with divergent pathologies and prognosis, low-grade and high-grade UCs are associated with distinct genetic alterations. For example, low-grade UCs are enriched for activating mutations in fibroblast growth factor 3 (FGFR3), phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA), and inactivating lysine (K)-specific demethylase 6A (KDM6A) mutations, whereas high-grade, muscle-invasive tumors are enriched for tumor protein p53 (TP53) and retinoblastoma 1 (RB1) pathway alterations (3-10).Several reports have examined the gene expression profiles of primary bladder tumors. From these studies, it is apparent that low-grade noninvasive and high-grade muscle-invasive tumors harbor distinct gene expression patterns, and that further molecular subsets can be identified within low-grade and high-grade tumors (5,(11)(12)(13)(14). Moreover, a number of gene signatures have been developed that can predict tumor stage, lymph node metastases, and bladder cancer progression (11-13, 15-18). There are established gene expression patterns that differentiate lowgrade and high-grade tumors;...