Platinum Priority – Bladder CancerEditorial by Cyrill A. Rentsch, Frank Stenner, Christian Ruiz and Lukas Bubendorf on pp. 968–969 of this issueDefects in DNA Repair Genes Predict Response to Neoadjuvant Cisplatin-based Chemotherapy in Muscle-invasive Bladder Cancer
Introduction
Muscle-invasive bladder cancer (MIBC) is characterized by a propensity to metastasize. Currently, neoadjuvant cisplatin-based chemotherapy followed by cystectomy is the standard of care for MIBC on the basis that phase 3 clinical trial data and meta-analyses show better overall survival (OS) with this approach [1], [2]. Pathologic response at the time of cystectomy predicts survival [3]. Unfortunately, only approximately a third of patients achieve such a response [1], [4]. Genomic profiling is an increasingly useful tool for understanding the molecular etiology of bladder cancer; however, while molecular biomarkers are currently used clinically to guide treatment selection in melanoma (BRAF), lung cancer (EGFR) and colorectal cancer (KRAS), validated genomic biomarkers predictive of response to therapy are currently lacking for bladder cancer [5], [6], [7]. We recently reported the results of a clinical trial using three cycles of neoadjuvant accelerated methotrexate, vinblastine, doxorubicin, and cisplatin (AMVAC) in patients with MIBC [4]. Using a discovery set of prospectively collected pretreatment tumor samples from patients treated in this study, we sought to identify potential genomic biomarkers of response, hypothesizing that genomic alterations could be identified that would effectively predict response to DNA-damaging chemotherapy in MIBC. A set of identically collected samples from a follow-up trial of similar design testing three cycles of neoadjuvant dose-dense gemcitabine and cisplatin (DDGC) [8] served as the validation cohort.
Section snippets
Study design and patients
The discovery (AMVAC) and validation (DDGC) sets consisted of pretreatment tumor samples collected from all MIBC patients treated during two previously reported trials (NCT01031420 [4] and NCT01611662 [8], respectively) who received all three cycles of chemotherapy and for whom adequate pretreatment tissue was available. For each cohort, pretreatment formalin-fixed paraffin-embedded (FFPE) sections were obtained and sequenced as described below. Patients provided informed consent for study
Discovery
Of the 44 patients treated on the AMVAC study, 37 received all three cycles of chemotherapy. Three additional patients were excluded because of insufficient pretreatment tissue, yielding a discovery set of 34 for genomic analysis. The baseline characteristics of this cohort are described in Table 1. Within this discovery set, 728 alterations in 212 genes were detected (Fig. 1A) and correlated with pathologic response (defined as no residual MIBC, ≤pT1pN0cM0), PFS, and OS.
Decision tree analysis
Discussion
Failure to repair treatment-induced DNA damage has been widely reported as a key mechanism of sensitivity to cytotoxic chemotherapy [14], [15], [16]. Cisplatin, the key component of the AMVAC and DDGC chemotherapy regimens, acts like an alkylating agent, inducing DNA damage by causing intrastrand and interstrand DNA crosslinks [17]. It has been posited that effective DNA repair is a mechanism of resistance to these regimens in bladder cancer.
ATM, RB1, and FANCC are mutated in approximately 11%,
Conclusions
Genomic alterations in the DNA repair-associated genes ATM, RB1, and FANCC predicted response and clinical benefit after cisplatin-based chemotherapy for MIBC in our two independent prospective data sets. These results suggest that defective DNA repair renders tumors sensitive to cisplatin. Larger independent prospective data sets of homogeneously treated patients are needed to further clarify and validate these findings. We expect that our ability to understand and define the capacity of
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