Work

“Primary” and “secondary” muscle-invasive bladder cancer is more than just a surrogate for molecular subtypes

Year: 2019

Type: article

Abstract: We would like to thank Drs. Szarvas, Olah, and Reis for their thoughtful and insightful comments regarding our recent publication on patients who initially present with muscle-invasive bladder cancer ("primary" MIBC) compared to patients with non-muscle-invasive bladder cancer (NMIBC) who unfortunately experience progression to MIBC ("secondary" MIBC).As this latter group account for only 15-20% of MIBC patients, such patients were underrepresented in the clinical trials from which guidelines for neoadjuvant chemotherapy were based.To address the possibility that patients with secondary MIBC might respond to neoadjuvant chemotherapy differently than patients with primary" MIBC, we performed a retrospective analysis that integrated tumor genomic profiling data generated at MSKCC and by the Tumor Cancer Genome Network with patient demographic and treatment response data.We observed that the pathologic response rate to neoadjuvant chemotherapy was lower among patients with secondary MIBC than patients with primary MIBC on both univariable (26% vs. 45%, P=0.02) and multivariable analyses adjusted for age, sex, and tumor stage (odds ratio =0.4; 95% confidence interval: 0.18-0.84,P=0.02) (1).Further, we found that secondary MIBC was associated with significantly worse recurrence-free survival (RFS), cancer-specific survival (CSS), and overall survival (OS) compared to primary MIBC.Unexpectedly, we found that patients with secondary MIBC who had received neoadjuvant chemotherapy had worse oncologic outcomes than patients with secondary MIBC treated with immediate cystectomy.We next analyzed the mutational profiles of the two groups to determine whether differences in the pattern of oncogenic drivers could explain the lack of sensitivity of secondary MIBC to platinum-based neoadjuvant chemotherapy.Among mutations previously implicated in chemotherapy response, only ERCC2 missense mutations were significantly enriched in the primary versus secondary MIBC tumors (11% vs. 1.8%,P=0.044).We then sought to validate these findings in an independent cohort of prospectively sequenced MIBC tumors from chemotherapynaïve patients treated at MSK.Again, we found that ERCC2 missense mutations were significantly enriched in primary versus secondary MIBC specimens (17.1% vs. 0%, P=0.033) in this prospectively enrolled cohort.In the combined analysis of all patients, ERCC2 missense mutations were significantly more common in primary versus secondary MIBC tumors [12% (48/400) vs. 1.3% (1/79), P=0.004].There are limitations to all retrospective studies, and we strongly believe that prospective validation in intentionto-treat cohorts is required before a change in clinical guidelines, but our observation of disparate treatment outcomes between primary and secondary MIBC raises several testable hypotheses while we await prospective validation.NMIBC is a heterogenous disease.While Szarvas et al. note that tumor mutational burden is lower in noninvasive versus MIBC, this applies mainly to low-grade tumors.Our group has reported on the genomic profile of over 100 NMIBC tumors using MSK-IMPACT, a targeted exon-capture next-generation sequencing platform (2).This analysis found a high rate of DNA damage repair gene mutations and high overall tumor mutational burden in high-grade NIMBC.The results suggest that low and high grade NMIBC have distinct genomic profiles with

Source: Translational Cancer Research

DOI: 10.21037/tcr.2019.12.21