There remains a critical need to identify markers to predict response to cisplatin-based neoadjuvant chemotherapy (NAC) for muscle invasive bladder cancer (MIBC) so that we can avoid NAC and proceed to timely surgery in likely non-responders. Recent small series have suggested that mutations in DNA damage repair genes (DDR) are highly predictive of outcome after NAC. Similar findings have been made with respect to molecular subtyping of bladder cancer. Here we aimed to combine these markers in a multicenter cohort of patients to determine the interaction and complementary value of both biomarkers.
Whole exome sequencing and whole transcriptome microarray analysis were performed on pre-NAC MIBC samples. Any mutation in one of 10 DDR genes (ATM, ATR, BRCA1, BRCA2, ERCC2, GANCC, RECQL4, ERCC5, RAD51C and RB1) that was predicted to be deleterious was considered a DDR mutation. Molecular subtypes were determined using a genomic single patient classifier (GSC). Response to NAC was defined as the absence of MIBC in the cystectomy sample. Overall survival (OS) was analyzed by Kaplan Meier estimate and the log-rank test was used to compare survival curves.
Our cohort of 97 patients with a median follow-up of 2.3 years included 63 (64.9%) non-responders and 34 (35.1%) responders (60% with DDR mutation). Patients with one or more DDR mutations had an improved OS with a HR of 2.7 (p=0.01) but this was not associated with pathological response. A mutation in ERCC2, ATM or RB1 predicted pathological response with an OR of 4.6 (p=0.002). These alterations were not prognostic in a cohort treated without NAC. With the caveats of small sample size in each subtype, OS could be further sub-stratified by DDR mutation status in basal tumors but not in the other subtypes.
Both DDRG mutations and molecular subtypes predict survival after NAC for MIBC. This is the largest NAC cohort to date with DDR mutation results, and the first to incorporate also subtyping. Both markers appear to provide complementary predictive information.