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DNA Damage-Repair Gene Mutations and Neoadjuvant Chemotherapy in MIBC

11/11/2022
Published in Discovery - Winter 2023

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. 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.”