medwireNews: Normalized expression levels of the DNA repair protein MRE11 could help to identify patients with nonmetastatic muscle-invasive bladder cancer (MIBC) likely to benefit from bladder-preserving trimodality therapy, suggests research.
Reporting the findings in JAMA Network Open, David Miyamoto (Massachusetts General Hospital, Boston, USA) and colleagues note that higher levels of MRE11 were associated with better disease-specific mortality (DSM) after trimodality therapy, while lower levels “identified a subgroup for whom trimodality therapy resulted in relatively high DSM.”
They continue: “This poor prognosis subgroup may be more appropriately treated with radical cystectomy, or may benefit from treatment intensification through the addition of immune checkpoint inhibitors or targeted therapies to trimodality therapy.”
The team explains that bladder-preserving trimodality therapy with transurethral bladder tumor resection and cisplatin-based chemoradiotherapy “can be an effective alternative to radical cystectomy” for MIBC, “but biomarkers are needed to guide optimal patient selection.”
For the study, the researchers drew on six clinical trials of trimodality therapy for nonmetastatic MIBC – namely the Radiation Therapy Oncology Group 8802, 8903, 9506, 9706, 9906, and 0233 trials conducted between 1988 and 2007 – to identify 135 patients (82.2% men; median age 65 years) with analyzable pretreatment tumor tissue samples.
The samples were “analyzed using automated quantitative image analysis to calculate a normalized score for MRE11 based on [the] nuclear-to-cytoplasmic (NC) signal ratio,” which helps “to correct for variability and batch effects,” they explain.
The 101 patients with an MRE11 NC ratio above the cutoff of 1.49 (equivalent to the first quartile threshold) had significantly lower DSM than the 34 with a ratio at or below the cutoff, with respective 4-year DSM rates of 21% and 41%, and a hazard ratio (HR) for DSM of 0.50.
These results were confirmed in a multivariable analysis adjusting for variables including age, sex, and tumor stage, which gave a significant HR for DSM of 0.42 in favor of the group with an MRE11 NC ratio above the cutoff.
By contrast, there was no such significant association between MRE11 expression and other clinical outcomes such as overall survival or complete response.
“The finding that higher levels of MRE11 in bladder tumors is associated with better outcomes after chemoradiation is consistent with prior studies,” and is biologically plausible, say the study authors.
“One explanation is that higher levels of DNA repair genes may reflect a futile attempt of tumor cells to counteract intrinsic cellular deficiencies in DNA repair that make them more radiosensitive,” and there is also emerging evidence indicating that “higher MRE11 levels may be associated with increased innate immune response,” they continue.
Miyamoto and team conclude: “Prospective validation in the SWOG/NRG 1806 trial (NCT03775265) and other studies could credential MRE11 and other biomarkers for the precise selection of patients for trimodality therapy, and for the identification of patients with poor prognoses who may benefit from treatment intensification.”
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