Genomic Tumor Correlates of Clinical Outcomes Following Organ-Sparing Chemoradiation Therapy for Bladder Cancer.

There is an urgent need for biomarkers of radiation response in organ-sparing therapies. Bladder preservation with trimodality therapy (TMT), consisting of transurethral tumor resection followed by chemoradiation, is an alternative to radical cystectomy for muscle-invasive bladder cancer (MIBC), but molecular determinants of response are poorly understood.

We characterized genomic and transcriptomic features correlated with long-term response in a single institution cohort of MIBC patients homogeneously treated with TMT. Pre-treatment tumors from 76 MIBC patients underwent whole exome sequencing, 67 with matched transcriptomic profiling. Molecular features were correlated with clinical outcomes including modified bladder-intact event-free survival (mBI-EFS), a composite endpoint that reflects long-term cancer control with bladder preservation.

With a median follow-up of 74.6 months in alive patients, 37 patients had favorable long-term response to TMT while 39 had unfavorable long-term response. Tumor mutational burden was not associated with outcomes after TMT. DNA damage response gene alterations were associated with improved locoregional control and mBI-EFS. Of these alterations, somatic ERCC2 mutations stood out as significantly associated with favorable long-term outcomes; patients with ERCC2 mutations had significantly improved mBI-EFS (HR 0.15, 95%CI: 0.06-0.37, p=0.030) and improved BI-EFS, an endpoint that includes all-cause mortality (HR: 0.33, 95%CI: 0.15-0.68, p=0.044). ERCC2 mutant bladder cancer cell lines were significantly more sensitive to concurrent cisplatin and radiation treatment in vitro than isogenic ERCC2 wildtype cells.

Our data identify ERCC2 mutation as a candidate biomarker associated with sensitivity and long-term response to chemoradiation in MIBC. These findings warrant validation in independent cohorts.

Clinical cancer research : an official journal of the American Association for Cancer Research. 2023 Oct 19 [Epub ahead of print]

Sophia C Kamran, Yuzhen Zhou, Keisuke Otani, Michael Drumm, Yukako Otani, Shulin Wu, Chin-Lee Wu, Adam S Feldman, Matthew Wszolek, Richard J Lee, Philip J Saylor, Jochen Lennerz, Eliezer Van Allen, Henning Willers, Theodore S Hong, Yang Liu, Elai Davicioni, Ewan A Gibb, William U Shipley, Kent W Mouw, Jason A Efstathiou, David T Miyamoto

Massachusetts General Hospital, Boston, MA, United States., Dana-Farber Cancer Institute, Boston, MA, United States., Northwestern University, Feinberg School of Medicine, Chicago, IL, United States., Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States., Harvard Medical School, Boston, United States., Harvard Medical School, Boston, MA, United States., Massachusetts General Hospital, Boston, Massachusetts, United States., Massachusetts General Hospital, Boston, United States., Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States., Veracyte inc., Vancouver, Canada., Decipher Biosciences Inc, La Jolla, CA, United States., Veracyte, Inc., Vancouver, British Columbia, Canada.

Read an Expert Commentary by Bishoy Faltas, MD