Elsevier

European Urology

Volume 68, Issue 6, December 2015, Pages 959-967
European Urology

Platinum Priority – Bladder Cancer
Editorial by Cyrill A. Rentsch, Frank Stenner, Christian Ruiz and Lukas Bubendorf on pp. 968–969 of this issue
Defects in DNA Repair Genes Predict Response to Neoadjuvant Cisplatin-based Chemotherapy in Muscle-invasive Bladder Cancer

https://doi.org/10.1016/j.eururo.2015.07.009Get rights and content

Abstract

Background

Cisplatin-based neoadjuvant chemotherapy (NAC) before cystectomy is the standard of care for muscle-invasive bladder cancer (MIBC), with 25–50% of patients expected to achieve a pathologic response. Validated biomarkers predictive of response are currently lacking.

Objective

To discover and validate biomarkers predictive of response to NAC for MIBC.

Design, setting, and participants

Pretreatment MIBC samples prospectively collected from patients treated in two separate clinical trials of cisplatin-based NAC provided the discovery and validation sets. DNA from pretreatment tumor tissue was sequenced for all coding exons of 287 cancer-related genes and was analyzed for base substitutions, indels, copy number alterations, and selected rearrangements in a Clinical Laboratory Improvements Amendments–certified laboratory.

Outcome measurements and statistical analysis

The mean number of variants and variant status for each gene were correlated with response. Variant data from the discovery cohort were used to create a classification tree to discriminate responders from nonresponders. The resulting decision rule was then tested in the independent validation set.

Results and limitations

Patients with a pathologic complete response had more alterations than those with residual tumor in both the discovery (p = 0.024) and validation (p = 0.018) sets. In the discovery set, alteration in one or more of the three DNA repair genes ATM, RB1, and FANCC predicted pathologic response (p < 0.001; 87% sensitivity, 100% specificity) and better overall survival (p = 0.007). This test remained predictive for pathologic response in the validation set (p = 0.033), with a trend towards better overall survival (p = 0.055). These results require further validation in additional sample sets.

Conclusions

Genomic alterations in the DNA repair-associated genes ATM, RB1, and FANCC predict response and clinical benefit after cisplatin-based chemotherapy for MIBC. The results suggest that defective DNA repair renders tumors sensitive to cisplatin.

Patient summary

Chemotherapy given before bladder removal (cystectomy) improves the chance of cure for some but not all patients with muscle-invasive bladder cancer. We found a set of genetic mutations that when present in tumor tissue predict benefit from neoadjuvant chemotherapy, suggesting that testing before chemotherapy may help in selecting patients for whom this approach is recommended.

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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