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Plimack ER , Dunbrack RL , Brennan TA , Andrake MD , Zhou Y , Serebriiskii IG , Slifker M , Alpaugh K , Dulaimi E , Palma N , Hoffman-Censits J , Bilusic M , Wong YN , Kutikov A , Viterbo R , Greenberg RE , Chen DY , Lallas CD , Trabulsi EJ , Yelensky R , McConkey DJ , Miller VA , Golemis EA , Ross EA
Defects in DNA Repair Genes Predict Response to Neoadjuvant Cisplatin-based Chemotherapy in Muscle-invasive Bladder Cancer
Eur Urol. 2015 Dec;68(6) :959-67
PMID: 26238431    PMCID: PMC4764095   
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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.
Plimack, Elizabeth R Dunbrack, Roland L Brennan, Timothy A Andrake, Mark D Zhou, Yan Serebriiskii, Ilya G Slifker, Michael Alpaugh, Katherine Dulaimi, Essel Palma, Norma Hoffman-Censits, Jean Bilusic, Marijo Wong, Yu-Ning Kutikov, Alexander Viterbo, Rosalia Greenberg, Richard E Chen, David Y T Lallas, Costas D Trabulsi, Edouard J Yelensky, Roman McConkey, David J Miller, Vincent A Golemis, Erica A Ross, Eric A P30 CA016672/CA/NCI NIH HHS/United States P30CA00692/CA/NCI NIH HHS/United States R01 GM084453/GM/NIGMS NIH HHS/United States Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Switzerland Eur Urol. 2015 Dec;68(6):959-67. doi: 10.1016/j.eururo.2015.07.009. Epub 2015 Aug 1.