Mutations in DNA damage-repair (DDR) genes – the best-known of these genes are BRCA1/2, linked to breast, ovarian, colon and prostate cancer – make it more likely that someone will get cancer, and get a more aggressive form of it. But there is a silver lining: certain drugs and forms of chemotherapy can target these mutations.

Two collaborative studies, both presented at the 2022 meeting of the American Society of Clinical Oncology, have shown that people with muscle-invasive bladder cancer (MIBC) who have certain DDR mutations respond well to neoadjuvant cisplatin-based combination chemotherapy. In this study, the DDR mutations were somatic: they happened because of the cancer. They were not germline, or inherited, mutations.

With investigators from Memorial Sloan Kettering Cancer Center, Fox-Chase Cancer Center, and other institutions, Greenberg Bladder Cancer Institute (GBCI) scientists Woonyoung Choi, Ph.D, M.S., and David McConkey, Ph.D., Director of the GBCI and the Erwin and Stephanie Greenberg Professor of Urology, performed the first prospective evaluation of the relationship between DDR mutations and response to cisplatin-based chemotherapy (https://ascopubs.org/doi/abs/10.1200/JCO.2022.40.16_suppl.4522) . This was done in conjunction with the Southwest Oncology Group’s Phase 2 clinical trial comparing dose-dense MVAC chemotherapy (a combination of methotrexate, vinblastine sulfate, adriamycin, and cisplatin) to gemcitabine plus cisplatin. “In both arms of the trial, we confirmed that the presence of these mutations was associated with response,” says McConkey, “particularly in patients with mutations in ERCC2 or ATM.” Choi is working with Fox-Chase scientists “to determine whether the inclusion of liquid biopsy measurements of tumor DNA in blood and urine can further enhance predictive accuracy.”

In related research, McConkey, Choi, and colleagues looked at the link between mutations of ATM, RB1, ERCC2, and FANCC and pathologic complete response at cystectomy after neoadjuvant chemotherapy in patients with MIBC. “We believe this research can help guide the decision for bladder preservation in selected patients.”

• Eliezer M. Van Allen, Kent W. Mouw, Philip Kim, Gopa Iyer, Nikhil Wagle, Hikmat Al-Ahmadie, Cong Zhu, Irina Ostrovnaya, Gregory V. Kryukov, Kevin W. O'Connor, John Sfakianos, Ilana Garcia-Grossman, Jaegil Kim, Elizabeth A. Guancial, Richard Bambury, Samira Bahl, Namrata Gupta, Deborah Farlow, Angela Qu, Sabina Signoretti, Justine A. Barletta, Victor Reuter, Jesse Boehm, Michael Lawrence, Gad Getz, Philip Kantoff, Bernard H. Bochner, Toni K. Choueiri, Dean F. Bajorin, David B. Solit, Stacey Gabriel, Alan D'Andrea, Levi A. Garraway, Jonathan E. Rosenberg; Somatic ERCC2 Mutations Correlate with Cisplatin Sensitivity in Muscle-Invasive Urothelial Carcinoma. Cancer Discov 1 October 2014; 4 (10): 1140–1153. https://doi.org/10.1158/2159-8290.CD-14-0623
• Qiang Li, Alexis W. Damish, Zoë Frazier, David Liu, Elizaveta Reznichenko, Atanas Kamburov, Andrew Bell, Huiyong Zhao, Emmet J. Jordan, S. Paul Gao, Jennifer Ma, Philip H. Abbosh, Joaquim Bellmunt, Elizabeth R. Plimack, Jean-Bernard Lazaro, David B. Solit, Dean Bajorin, Jonathan E. Rosenberg, Alan D. D'Andrea, Nadeem Riaz, Eliezer M. Van Allen, Gopa Iyer, Kent W. Mouw; ERCC2 Helicase Domain Mutations Confer Nucleotide Excision Repair Deficiency and Drive Cisplatin Sensitivity in Muscle-Invasive Bladder Cancer. Clin Cancer Res 1 February 2019; 25 (3): 977–988. https://doi.org/10.1158/1078-0432.CCR-18-1001
• Liu D, Plimack ER, Hoffman-Censits J, et al. Clinical Validation of Chemotherapy Response Biomarker ERCC2 in Muscle-Invasive Urothelial Bladder Carcinoma. JAMA Oncol. 2016;2(8):1094–1096. doi:10.1001/jamaoncol.2016.1056
• Elizabeth R. Plimack, Roland L. Dunbrack, Timothy A. Brennan, Mark D. Andrake, Yan Zhou, Ilya G. Serebriiskii, Michael Slifker, Katherine Alpaugh, Essel Dulaimi, Norma Palma, Jean Hoffman-Censits, Marijo Bilusic, Yu-Ning Wong, Alexander Kutikov, Rosalia Viterbo, Richard E. Greenberg, David Y.T. Chen, Costas D. Lallas, Edouard J. Trabulsi, Roman Yelensky, David J. McConkey, Vincent A. Miller, Erica A. Golemis, Eric A. Ross. Defects in DNA Repair Genes Predict Response to Neoadjuvant Cisplatin-based Chemotherapy in Muscle-invasive Bladder Cancer. European Urology. 2015; 68 (6): 959-967. https://doi.org/10.1016/j.eururo.2015.07.009.
• Russell E.N. Becker, Alexa R. Meyer, Aaron Brant, Adam C. Reese, Michael J. Biles, Kelly T. Harris, George Netto, Andres Matoso, Jean Hoffman-Censits, Noah M. Hahn, Woonyoung Choi, David McConkey, Phillip M. Pierorazio, Michael H. Johnson, Mark P. Schoenberg, Max R. Kates, Alex Baras, Trinity J. Bivalacqua.
• Clinical Restaging and Tumor Sequencing are Inaccurate Indicators of Response to Neoadjuvant Chemotherapy for Muscle-invasive Bladder Cancer. European Urology. 2021; 79 (3): 364-371. https://doi.org/10.1016/j.eururo.2020.07.016.