DNA Repair Protein MRE11 Expression and Disease-Specific Mortality Among Patients With Muscle-Invasive Bladder Cancer Receiving Trimodality Therapy

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In a retrospective analysis reported in JAMA Network Open, Magliocco et al found that among patients with muscle-invasive bladder cancer receiving bladder-preserving trimodality therapy, those with a lower expression of the DNA repair protein MRE11 had significantly poorer disease-specific mortality.

Study Details

The study involved analysis of patients with nonmetastatic muscle-invasive bladder cancer pooled from six prospective phase I/II, II, or III trials of transurethral bladder tumor resection and cisplatin-based chemoradiation therapy (RTOG 8802, 8903, 9506, 9706, 9906, and 0233 trials.) 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 signal ratio. The association of MRE11 expression and disease-specific mortality was analyzed.

Key Points

Among the 465 patients from six trials, 168 had available tissue and 135 could be evaluated for MRE11 expression. The 135 patients had a median age of 65 years (range = 34–90 years). Median follow-up for surviving patients was 5.0 years (range = 0.6–11.7 years).

The median MRE11 nuclear-to-cytoplasmic signal ratio among all patients was 2.41, with median ratios of 1.49 in the first quartile and 3.34 in the third quartile. Patients with MRE11 nuclear-to-cytoplasmic ratio of > 1.49 (3 highest quartiles, n = 101) had a 4-year disease-specific mortality of 21.0% (95% CI = 13.4%–29.8%) vs 41.0% (95% confidence interval [CI] = 23.2%–58.0%) among patients (n = 34) with ratios ≤ 1.49 (HR = 0.50, 95% CI = 0.26–0.93, P = .03).

Overall survival at 4 years was 64.5% (95% CI = 53.9%–73.2%) among patients with ratios > 1.49 vs 51.4% (95% CI = 31.9%–67.9%) among those with ratios ≤ 1.49 (HR = 0.84, 95% CI = 0.49–1.44, P = .52).

In multivariate analysis for disease-specific mortality, the hazard ratio was 0.42 (95% CI = 0.22–0.81, P = .009) for MRE11 nuclear-to-cytoplasmic ratio > 1.49 vs ≤ 1.49. Other factors significantly associated with disease-specific mortality were Eastern Cooperative Group performance status (1 vs 0: HR = 2.69, 95% CI = 1.05–6.88, P = .04) and race (other vs White; HR = 0.39, 95% CI = 0.16–0.94, P = .04).

The investigators concluded, “Higher MRE11 nuclear-to-cytoplasmic signal ratios were associated with better disease-specific mortality after trimodality therapy. Lower MRE11 nuclear-to-cytoplasmic signal ratios identified a poor-prognosis subgroup that may benefit from intensification of therapy.”

David T. Miyamoto, MD, PhD, of the Department of Radiation Oncology, Massachusetts General Hospital, is the corresponding author for the JAMA Network Open article.

Disclosure: The study was supported by grants from the National Cancer Institute and others. For full disclosures of the study authors, visit

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