We previously reported that tumors harboring any one of four gene mutations (ATM, RB1, FANCC, or ERCC2) were likely to respond to neoadjuvant cisplatin-based chemotherapy (NAC), resulting in cancer-free surgical specimens at the time of cystectomy (pT0). Here, we report our validation of this finding. Using the CARIS 592 Gene Panel (Caris Life Sciences, Phoenix, AZ, USA), we analyzed 105 pre-NAC tumor specimens from a large multicenter trial (S1314) of either neoadjuvant gemcitabine and cisplatin (GC), or dose-dense methotrexate, vinblastine, Adriamycin, and cisplatin (DDMVAC). We found that a mutation in any one of these four genes predicted for pT0 at surgery (odds ratio = 5.36; 95% confidence interval [CI] 2.05, 14.02; two-sided p = 0.0006). The biomarker was better at predicting the presence of disease (negative predictive value for pT0 86%; 95% CI 73%, 94%) than the absence of disease (positive predictive value for pT0 48%; 95% CI 35%, 62%). There was no evidence of an interaction between the treatment arm (DDMVAC vs GC) and the genetic variant in terms of pT0. When combined with clinical assessment, these findings help inform patient selection for bladder preservation after cisplatin-based chemotherapy. PATIENT SUMMARY: A common standard of care for patients with muscle-invasive bladder cancer is neoadjuvant chemotherapy (NAC) followed by cystectomy to achieve cure. We previously discovered that specific DNA mutations in tumor samples collected at initial biopsy (transurethral resection of a bladder tumor) were predictive of a complete response to NAC. In other words, patients with these mutations were more likely to have a bladder found to be cancer free after surgery. In this study, we analyzed a larger set of tumor samples from a national clinical trial of chemotherapy followed by cystectomy to validate these earlier findings. We conclude that this biomarker test, when combined with careful clinical assessment, can be used to allocate patients to careful bladder surveillance instead of surgery. This hypothesis has been tested in the RETAIN trial presented previously (NCT02710734).
European urology. 2024 Jul 12 [Epub ahead of print]
Elizabeth R Plimack, Catherine Tangen, Melissa Plets, Rutika Kokate, Joanne Xiu, Chadi Nabhan, Eric A Ross, Erin Grundy, Woonyoung Choi, Colin P N Dinney, I-Ling C Lee, Megan Fong, M Scott Lucia, Siamak Daneshmand, Dan Theodorescu, Amir Goldkorn, Seth P Lerner, Thomas W Flaig, David J McConkey
Fox Chase Cancer Center, Temple Health, Philadelphia, PA, USA. Electronic address: ., Fred Hutchinson Cancer Research Center, Seattle, WA, USA; SWOG Statistics and Data Management Center, Seattle, WA, USA., Fred Hutchinson Cancer Research Center, Seattle, WA, USA., Fox Chase Cancer Center, Temple Health, Philadelphia, PA, USA., Caris Life Sciences, Phoenix, AZ, USA., Nationwide Children's Hospital, Columbus, OH, USA., Johns Hopkins Greenberg Bladder Cancer Institute, Baltimore, MD, USA., University of Texas MD Anderson Cancer Center, Houston, TX, USA., University of Colorado School of Medicine, Aurora, CO, USA., Department of Urology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA., Samuel Oschin Comprehensive Cancer Institute, Los Angeles, CA, USA., Division of Medical Oncology, Department of Medicine, Keck School of Medicine and Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, USA., Baylor College of Medicine, Houston, TX, USA.