Defects in DNA Repair Genes Predict Response to Neoadjuvant Cisplatin-based chemotherapy in Muscle-invasive Bladder Cancer

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Plimack E.R., Dunbrack R.L., Brennan T.A., Andrake M.D., Zhou Y., Serebriiskii I.G., Slifker M., Alpaugh K., Dulaimi E., Palma N., Hoffman-Censits J., Bilusic M., Wong Y.-N., Kutikov A., Viterbo R., Greenberg R.E., Chen D.Y.T., Lallas C.D., Trabulsi E.J., Yelensky R., McConkey D.J., Miller V.A., Golemis E.A., Ross E.A.

European Urology 2015 

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. Genomic alterations in the DNA repair-associated genes ATM, RB1, and FANCC predicted response and clinical benefit after neoadjuvant cisplatin-based chemotherapy for muscle-invasive bladder cancer in discovery and validation sets of pretreatment tumor samples. These results suggest that defective DNA repair renders tumors sensitive to cisplatin.

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