TY - JOUR
T1 - Defects in DNA Repair Genes Predict Response to Neoadjuvant Cisplatin-based Chemotherapy in Muscle-invasive Bladder Cancer
AU - Plimack, Elizabeth R.
AU - Dunbrack, Roland L.
AU - Brennan, Timothy A.
AU - Andrake, Mark D.
AU - Zhou, Yan
AU - Serebriiskii, Ilya G.
AU - Slifker, Michael
AU - Alpaugh, Katherine
AU - Dulaimi, Essel
AU - Palma, Norma
AU - Hoffman-Censits, Jean
AU - Bilusic, Marijo
AU - Wong, Yu Ning
AU - Kutikov, Alexander
AU - Viterbo, Rosalia
AU - Greenberg, Richard E.
AU - Chen, David Y.T.
AU - Lallas, Costas D.
AU - Trabulsi, Edouard J.
AU - Yelensky, Roman
AU - McConkey, David J.
AU - Miller, Vincent A.
AU - Golemis, Erica A.
AU - Ross, Eric A.
N1 - Funding Information:
Elizabeth R. Plimack certifies that all conflicts ofinterest, including specific financial interests and relationships andaffiliations relevant to the subject matter or materials discussed in themanuscript (eg, employment/affiliation, grants or funding, consultancies,honoraria, stock ownership or options, expert testimony, royalties,or patents filed, received, or pending), are the following: ER Plimack andEA Ross have a patent filing related to these findings.Funding/Support and role of the sponsor: This work was supported inpart by the Fox Chase Cancer Center Institutional Research Pilot Program, Fox Chase Cancer Center NCI Core Grant #P30CA00692, and Grant IRG-92-027-17 from the American Cancer Society.Acknowledgments: The authors would like to thank the patients enrolledin our two clinical trials for consenting to donate tissue samples for thisstudy, as well as research staff at the Fox Chase Cancer Center ExtramuralResearch Program (B. Adaire-Halenda, G. Duncan, and C. Jerome), the FoxChase Cancer Center Protocol Management Office (C. Cione, C. O’Sullivan,K.C. Wright, and A. Eigenbrode), and Thomas Jefferson University Hospital(D. Kilpatrick). Ilya G. Serebriiskii received partial salary support for thisproject from the Russian Government Program of Competitive Growth ofKazan Federal University. We dedicate this manuscript to the memory ofNancy Finnegan, supporter of bladder cancer research.
Funding Information:
Acknowledgments: The authors would like to thank the patients enrolled in our two clinical trials for consenting to donate tissue samples for this study, as well as research staff at the Fox Chase Cancer Center Extramural Research Program (B. Adaire-Halenda, G. Duncan, and C. Jerome), the Fox Chase Cancer Center Protocol Management Office (C. Cione, C. O'Sullivan, K.C. Wright, and A. Eigenbrode), and Thomas Jefferson University Hospital (D. Kilpatrick). Ilya G. Serebriiskii received partial salary support for this project from the Russian Government Program of Competitive Growth of Kazan Federal University. We dedicate this manuscript to the memory of Nancy Finnegan, supporter of bladder cancer research.
Funding Information:
Funding/Support and role of the sponsor: This work was supported in part by the Fox Chase Cancer Center Institutional Research Pilot Program, Fox Chase Cancer Center NCI Core Grant #P30CA00692, and Grant IRG-92-027-17 from the American Cancer Society.
Publisher Copyright:
© 2015 European Association of Urology.
PY - 2015
Y1 - 2015
N2 - 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.
AB - 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.
KW - ATM
KW - Biomarkers
KW - Bladder cancer
KW - Cisplatin resistance
KW - Cisplatin sensitivity
KW - DNA repair
KW - FANCC
KW - Neoadjuvant chemotherapy
KW - RB1
KW - Urothelial carcinoma
UR - http://www.scopus.com/inward/record.url?scp=84983161309&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84983161309&partnerID=8YFLogxK
U2 - 10.1016/j.eururo.2015.07.009
DO - 10.1016/j.eururo.2015.07.009
M3 - Article
C2 - 26238431
AN - SCOPUS:84983161309
SN - 0302-2838
VL - 68
SP - 959
EP - 967
JO - European Urology
JF - European Urology
IS - 6
ER -