Genomic Differences Between "Primary" and "Secondary" Muscle-invasive Bladder Cancer as a Basis for Disparate Outcomes to Cisplatin-based Neoadjuvant Chemotherapy - Beyond the Abstract

Most guidelines recommend that cisplatin-based neoadjuvant chemotherapy be given before radical cystectomy to all eligible patients with muscle-invasive bladder cancer (MIBC). These guidelines are based on two large randomized trials and subsequent meta-analyses demonstrating a survival benefit for chemotherapy responders. However, since patients initially presenting with non-muscle-invasive bladder cancer (NMIBC) that eventually progresses to “secondary” MIBC after failure of intravesical bacille Calmette-Guérin (BCG) treatment account for only 15%–20% of all MIBC patients, they are usually underrepresented in studies, including the clinical trials used to derive guidelines for neoadjuvant chemotherapy.
To address the possibility that patients with secondary MIBC might respond to neoadjuvant chemotherapy differently than patients initially presenting with MIBC (“primary” MIBC), we performed a retrospective analysis of the Memorial Sloan Kettering Cancer Center (MSK) radical cystectomy experience. We looked at patients with clinical stage T2-4aN0M0 MIBC (classified as either primary or secondary) who received 3-4 cycles of cisplatin-based neoadjuvant chemotherapy before radical cystectomy. We found that the pathologic response rate to neoadjuvant chemotherapy was lower among patients with secondary MIBC than among patients with primary MIBC on both univariable (26% vs 45%, p = 0.02) and multivariable analyses adjusted for age, sex, and T classification (odds ratio = 0.4 [95% confidence interval = 0.18–0.84], p = 0.02). 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.

As a secondary analysis, we then compared patients with primary MIBC treated with neoadjuvant chemotherapy before cystectomy to patients with primary MIBC treated with cystectomy only. We saw the expected benefits of cisplatin-based chemotherapy with higher pathologic downstaging (45% v. 16%, p = 0.001) and improved RFS (p <0.04). However, when we looked at patients with secondary MIBC treated with cisplatin-based neoadjuvant chemotherapy before cystectomy compared to patients with secondary MIBC treated with cystectomy alone, we found no statistical difference in pathologic downstaging (26% v. 20%, p = 0.4). Treatment with neoadjuvant chemotherapy was associated with worse RFS (p = 0.007), CSS (p = 0.002), and OS (p = 0.013) compared with radical cystectomy alone. The worse oncologic outcomes observed in patients with secondary MIBC who received neoadjuvant chemotherapy may in part stem from a significant delay in time to cystectomy (5.8 vs 1.7 months, p <0.001) while these patients were receiving but not responding to chemotherapy.

Around the same time as we were doing this clinical analysis, our group was performing molecular profiling on tumors from patients with NMIBC using our targeted exon capture next-generation sequencing assay, MSK-IMPACT.1 We had found a high rate of DNA damage repair gene mutations and high tumor mutational burden in high-grade NIMBC. The most common alterations seen were missense mutations in the DNA damage repair gene ERCC2, occuring in 17% of high-grade NMIBC. Since ERCC2 mutations were previously shown to be sensitizing to neoadjuvant chemotherapy in MIBC, it led us to ask whether differences in the genomic profiles of primary and secondary MIBC tumors could explain the disparate clinical outcomes we had observed.

To answer this question, we assembled a retrospective cohort of chemotherapy-naïve MIBC tumors that were previously sequenced as part of research projects conducted at MSK or through the urothelial TCGA (the Cancer Genome Atlas). We compared primary and secondary MIBC tumors for differences in ERCC2 and other genes previously implicated in chemotherapy response (ATM, FANCC, RB1). Among these genes, 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 chemotherapy-naïve MIBC specimens from patients treated at MSK. We again found that ERCC2 missense mutations were significantly enriched in primary MIBC specimens (17.1% vs 0% in secondary MIBC specimens, p = 0.033). Thus, in the combined genomic analysis, ERCC2 missense mutations were significantly more common in primary versus secondary MIBC tumors (12% [48/400] vs 1.3% [1/79], p = 0.004).

To determine if differences in molecular subtypes might also account for the observed differences in primary and secondary MIBC, we also analyzed the RNA expression data available from the TCGA patients. We found no difference in basal/luminal subtypes using either TCGA k=5 or BASE47 classifers, suggesting our observations were independent of molecular subtype.

Although our study is not without limitations, our data strongly suggest that secondary MIBC is a distinct clinical and genetic entity and that these patients are less likely to benefit from cisplatin-based neoadjuvant chemotherapy. Of course, our findings need to be prospectively validated in an intention-to-treat cohort—which might be possible in the context of the Southwest Oncology Group (SWOG) COXEN study (NCT02177695) investigating multiple biomarkers association with neoadjuvant chemotherapy response, or the Alliance for Clinical Trials in Oncology bladder-sparing trial (NCT03609216), which seeks to avoid cystectomy in patients with select DNA damage repair gene alterations (eg, ERCC2) if they achieve clinical downstaging following cisplatin-based neoadjuvant chemotherapy.

Written by: Eugene J. Pietzak, MD, Urologic Oncology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York

1. Pietzak EJ, Bagrodia A, Cha EK, Drill EN, Iyer G, Isharwal S, Ostrovnaya I, Baez P, Li Q, Berger MF, Zehir A, Schultz N, Rosenberg JE, Bajorin DF, Dalbagni G, Al-Ahmadie H, Solit DB, Bochner BH. Next-generation Sequencing of Nonmuscle Invasive Bladder Cancer Reveals Potential Biomarkers and Rational Therapeutic Targets. Eur Urol 2017; 72:952-959.
2. Van Allen EM, Mouw KW, Kim P, Iyer G, Wagle N, Al-Ahmadie H, Zhu C, Ostrovnaya I, Kryukov GV, O'Connor KW, Sfakianos J, Garcia-Grossman I, Kim J, Guancial EA, Bambury R, Bahl S, Gupta N, Farlow D, Qu A, Signoretti S, Barletta JA, Reuter V, Boehm J, Lawrence M, Getz G, Kantoff P, Bochner BH, Choueiri TK, Bajorin DF, Solit DB, Gabriel S, D'Andrea A, Garraway LA, Rosenberg JE. Somatic ERCC2 mutations correlate with cisplatin sensitivity in muscle-invasive urothelial carcinoma. Cancer Discov 2014; 4:1140-1153. PMC4238969

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