- In this study, an automated immunofluorescence assay was used to evaluate the DNA repair protein MRE11 as a biomarker of response to trimodality therapy in patients with muscle-invasive bladder cancer
- The 135 patients who had tumor tissue analyzed had been enrolled in one of six prospective NRG/Radiation Therapy Oncology Group clinical trials of trimodality therapy
- Patients with a pretreatment MRE11 nuclear-to-cytoplasmic ratio >1.49 had a significantly lower four-year cumulative incidence of disease-specific mortality than patients whose ratio was at or below that threshold (21% vs. 41%; HR, 0.50; P<0.03)
- The association between a high MRE11 nuclear-to-cytoplasmic ratio and lower disease-specific mortality remained significant in a multivariable regression model after adjustment for clinical covariates, including tumor stage (adjusted HR, 0.42; P=0.009)
- Patients with higher levels of MRE11 may be especially good candidates for trimodality therapy. For patients with lower levels of MRE11, radical cystectomy may be more appropriate than trimodality therapy, or they may benefit from therapy intensification
Trimodality therapy for muscle-invasive bladder cancer (transurethral resection of bladder tumor followed by chemoradiation) is increasingly well accepted because its long-term outcomes are similar to those of radical cystectomy in selected patients with reduced perioperative morbidity and better quality of life.
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T2 disease stage and absence of hydronephrosis or carcinoma in situ correlate with better outcomes, but those factors are imperfect selection criteria. In some studies, high levels of MRE11, a DNA repair protein, have been associated with greater radiosensitivity, but the evidence is mixed.
Rather than rely on standard immunohistochemistry staining and interpretation, Jason A. Efstathiou, MD, DPhil, vice-chair for Faculty & Academic Affairs and director of the Genitourinary Service in the Department of Radiation Oncology and clinical co-director of the Bertucci Center for Genitourinary Cancers at the Mass General Cancer Center, David T. Miyamoto, MD, PhD, investigator in the Center for Cancer Research, and colleagues researched this question by applying a digital immunofluorescence technique to tumor samples from prospective clinical trials. In JAMA Network Open, they report that higher normalized MRE11 expression in muscle-invasive bladder tumors was associated with lower disease-specific mortality after trimodality therapy.
The pretreatment tumor specimens analyzed in this study came from 135 patients who had participated in one of six prospective NRG/Radiation Therapy Oncology Group trials that previously established the value of trimodality therapy. The cohort was 82% male, median age of 65 (range, 34–90), and 81% white. The median follow-up for surviving patients was five years (range, 0.6–11.8).
Unlike immunohistochemistry, immunofluorescence has high sensitivity and a large dynamic range, which allows precise measurement and simultaneous localization of multiple proteins. The researchers used automated quantitative image analysis to calculate a normalized score for MRE11 using an internal standard: nuclear compared with the cytoplasmic signal.
They reasoned that the nuclear-to-cytoplasmic (NC) signal ratio would resist variation across various conditions (batch processing effects, preanalytical variables, and human error).
The median MRE11 NC ratio was 2.41 (first quartile, 1.49; third quartile, 3.34). The four-year cumulative incidence of disease-specific mortality was:
- Patients with MRE11 NC ratio >1.49: 21%
- Patients with MRE11 NC ratio ≤1.49: 41% (HR, 0.50; P<0.03)
There were no significant differences by MRE11 NC ratio for overall survival, bladder-intact overall survival, or complete response.
After adjustment for age, sex, race, ECOG performance status, tumor stage, and complete TURBT (yes/no), disease-specific mortality was associated with the following:
- MRE11 NC ratio >1.49: adjusted HR (aHR), 0.42 (P=0.009)
- Race other than white: aHR, 0.39 (P=0.04)
- Eastern Cooperative Oncology Group performance status of 1 (vs. 0): aHR, 2.69 (P=0.04)
Trimodality therapy for muscle-invasive bladder cancer is a bladder-sparing alternative to radical cystectomy, but biomarkers are needed to select appropriate patients. This study shows that higher levels of MRE11 are associated with improved results after trimodality therapy. Although it may seem counterintuitive that increased expression of a DNA repair protein doesn't produce resistance to radiation-induced DNA damage, a potential explanation is that elevated levels of DNA repair genes reflect a futile attempt of tumor cells to counteract deficiencies in DNA repair that left them more radiosensitive. There is also recent evidence published in Science Advances that ties higher MRE11 levels to increased innate immune response.
Patients with lower levels of MRE11 may thus represent a subgroup with a poorer prognosis. For them, a radical cystectomy may be more appropriate than trimodality therapy, or they may benefit from intensification of therapy such as adding immune checkpoint inhibitors or other targeted therapies.
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