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ASTRO 2022: Can Genetic Mutations Determine Response to Trimodality Therapy in Bladder Cancer?

By: Emily Rhode
Posted: Friday, November 4, 2022

Molecular determinants of response are poorly understood in trimodality therapy—transurethral resection of bladder tumor followed by chemoradiotherapy—an alternative to radical cystectomy for certain patients with muscle-invasive bladder cancer. New research by Sophia C. Kamran, MD, of Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, and colleagues suggests that alterations in the key DNA damage response gene ERCC2 may improve response to trimodality therapy. The findings were presented at the 2022 American Society for Radiation Oncology (ASTRO) Annual Meeting (Abstract 137).

The study focused on the characterization of the genomic and transcriptomic landscape in patients with muscle-invasive bladder cancer treated with trimodality therapy. Pretreatment transurethral resections of bladder tumor samples were sampled for DNA and RNA, and whole-exome sequencing and transcriptome-wide expression profiling were executed. Researchers then identified somatic mutations, insertions and deletions, and copy number variants while also using expression profiles to obtain DNA damage response pathway scores. Patients were identified as either responders (having a complete response at posttreatment cystoscopy with no recurrence) or nonresponders (having an incomplete response at posttreatment cystoscopy, having salvage cystectomy, or having regional or distant disease progression).

A total of 77 samples were sequenced from patients. After a median follow-up of 42 months, 39 patients were designated as nonresponders and 38 were responders. More of the responsive patients had mutations in the ERCC2 gene (n = 7) compared with the nonresponsive cohort (n = 1). Of the patients with ERCC2 mutations, six had undergone cisplatin-based chemotherapy. Higher hallmark DNA repair scores were observed in samples with ERCC2 mutations, and tumors with ERCC2 mutations had higher levels of genomic subtype classifier luminal subtype compared with wild-type ERCC2. Improved disease-specific survival was observed in patients with ERCC2 mutations (95% confidence interval = 0.064–0.41; hazard ratio = 0.17; P = .04). Finally, the researchers conducted in vitro studies that showed increased sensitivity to cisplatin and radiation therapy in ERCC2-mutant bladder cancer cell lines compared with ERCC2 wild-type cell lines.

Disclosure: To view full disclosures for Dr. Kamran, visit

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