The presence of a mutation in any one of three genes known to be involved in DNA damage repair may be associated with complete pathologic response to cisplatin-based neoadjuvant chemotherapy, as measured by pathologic downstaging at the time of cystectomy in patients with muscle-invasive urothelial carcinoma, according to a recent study published by Elizabeth R. Plimack, MD, MS, FASCO, and colleagues in European Urology.
Elizabeth R. Plimack, MD, MS, FASCO
Background
“The SWOG S8710 randomized trial provided level 1 evidence supporting the use of neoadjuvant chemotherapy in eligible patients with muscle-invasive [urothelial carcinoma], but uptake was disappointing because the magnitude of the effect was considered modest,” explained senior study author David James McConkey, PhD, of the Johns Hopkins Greenberg Bladder Cancer Institute. “[W]e designed the S1314 COXEN trial to test whether a tumor biomarker known as the COXEN score could predict which patients had tumors that were likely to respond to neoadjuvant chemotherapy,” he continued.
Study Methods and Results
In the recent S1314 COXEN trial, investigators analyzed pretreatment tumor specimens from 105 patients with localized muscle-invasive urothelial carcinoma. They used banked tissue samples to test the complementary hypothesis that mutations in specific DNA damage repair genes may be enriched in tumors that were sensitive to cisplatin-based neoadjuvant chemotherapy, and therefore, tumors with these mutations may be more likely to be eradicated by the treatment.
The investigators found that patients whose tumors had a mutation in the ERCC2, ATM, or RB1 genes were more than five times as likely to achieve a complete pathologic response to the chemotherapy compared with those whose tumors lacked the mutations.
Conclusions
The findings indicated that pretreatment tests to identify mutations in these three genes in combination with careful clinical assessment may help physicians determine which patients are eligible for continued surveillance instead of bladder surgery. The RETAIN trial and other similar studies are currently exploring data to test this hypothesis.
“The evolution of more effective systemic neoadjuvant therapies in conjunction with innovative tools such as urine-based tests for detection and monitoring patients on bladder surveillance will build on this work toward a goal of avoiding cystectomy in cases where radical surgery is not required to achieve cure,” concluded lead study author Dr. Plimack, of Fox Chase Cancer Center.
Disclosure: The research in this trial was funded in part by a donation from the Family of George Zazanis, MD, to Fox Chase Cancer Center and by the National Cancer Institute/National Institutes of Health. For full disclosures of the study authors, visit sciencedirect.com.
