Analysis of MRE11 and Mortality Among Adults With Muscle-Invasive Bladder Cancer Managed With Trimodality Therapy.

Bladder-preserving trimodality therapy can be an effective alternative to radical cystectomy for treatment of muscle-invasive bladder cancer (MIBC), but biomarkers are needed to guide optimal patient selection. The DNA repair protein MRE11 is a candidate response biomarker that has not been validated in prospective cohorts using standardized measurement approaches.

To evaluate MRE11 expression as a prognostic biomarker in MIBC patients receiving trimodality therapy using automated quantitative image analysis.

This prognostic study analyzed patients with MIBC pooled from 6 prospective phase I/II, II, or III trials of trimodality therapy (Radiation Therapy Oncology Group [RTOG] 8802, 8903, 9506, 9706, 9906, and 0233) across 37 participating institutions in North America from 1988 to 2007. Eligible patients had nonmetastatic MIBC and were enrolled in 1 of the 6 trimodality therapy clinical trials. Analyses were completed August 2020.

Trimodality therapy with transurethral bladder tumor resection and cisplatin-based chemoradiation therapy.

MRE11 expression and association with disease-specific (bladder cancer) mortality (DSM), defined as death from bladder cancer. Pretreatment tumor tissues were processed for immunofluorescence with anti-MRE11 antibody and analyzed using automated quantitative image analysis to calculate a normalized score for MRE11 based on nuclear-to-cytoplasmic (NC) signal ratio.

Of 465 patients from 6 trials, 168 patients had available tissue, of which 135 were analyzable for MRE11 expression (median age of 65 years [minimum-maximum, 34-90 years]; 111 [82.2%] men). Median (minimum-maximum) follow-up for alive patients was 5.0 (0.6-11.7) years. Median (Q1-Q3) MRE11 NC signal ratio was 2.41 (1.49-3.34). Patients with an MRE11 NC ratio above 1.49 (ie, above first quartile) had a significantly lower DSM (HR, 0.50; 95% CI, 0.26-0.93; P = .03). The 4-year DSM was 41.0% (95% CI, 23.2%-58.0%) for patients with an MRE11 NC signal ratio of 1.49 or lower vs 21.0% (95% CI, 13.4%-29.8%) for a ratio above 1.49. MRE11 NC signal ratio was not significantly associated with overall survival (HR, 0.84; 95% CI, 0.49-1.44).

Higher MRE11 NC signal ratios were associated with better DSM after trimodality therapy. Lower MRE11 NC signal ratios identified a poor prognosis subgroup that may benefit from intensification of therapy.

JAMA network open. 2022 Nov 01*** epublish ***

Anthony M Magliocco, Jennifer Moughan, David T Miyamoto, Jeff Simko, William U Shipley, Phillip J Gray, Michael P Hagan, Matthew Parliament, William J Tester, Anthony L Zietman, Susan McCarthy, Daryoush Saeed-Vafa, Yin Xiong, Taylor Ayral, Alan C Hartford, Ashish Patel, Seth A Rosenthal, Susan Chafe, Richard Greenberg, Michael A Schwartz, Mark E Augspurger, John A Keech, Kathryn A Winter, Felix Y Feng, Jason A Efstathiou

H. Lee Moffitt Cancer Center, Tampa, Florida., NRG Oncology Statistics and Data Management Center/ACR, Philadelphia, Pennsylvania., Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts., Department of Radiation Oncology, University of California, San Francisco., Hunter Holmes McGuire Veterans Administration Medical Center, Richmond, Virginia., Cross Cancer Institute, Edmonton, Alberta, Canada., Einstein Medical Center Philadelphia, Philadelphia, Pennsylvania., Dartmouth Hitchcock Medical Center, Lebanon, New Hampshire., MD Anderson Cancer Center at Cooper, Camden, New Jersey., Sutter Medical Group, Roseville, California., Fox Chase Cancer Center, Philadelphia, Pennsylvania., Mount Sinai Medical Center, Miami Beach, Florida., Baptist MD Anderson Cancer Center, Jacksonville, Florida., MultiCare Gig Harbor Medical Park, Gig Harbor, Washington.

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