Abstract
BackgroundMismatch repair (MMR) system has been implicated in the response of mammalian cells to ionizing radiation and DNA damaging agents. We investigated the value of the MMR system in predicting response to adjuvant therapy in endometrial cancer.MethodsThis was a single institution retrospective study. MMR protein status of endometrial carcinomas was assessed by immunohistochemistry. MMR deficient (MMR‐D) tumors were identified as MLH1 methylated or nonmethylated by methylation‐specific multiplex ligation‐dependent probe amplification. Tumors with abnormal p53 staining or polymerase ϵ exonuclease domain mutation were excluded from the MMR proficient subgroup, which was termed as “no specific molecular profile” (NSMP). Disease‐specific survival analyses were adjusted for age, stage, histology and grade, depth of myometrial invasion, and lymphovascular space invasion.ResultsA total of 505 patients were included in the study. Median follow‐up time was 81 months (range 1–136). Whole pelvic radiotherapy (adjusted hazard ratio [HR] 0.092 vs. no adjuvant therapy) and chemotherapy combined with radiotherapy (adjusted HR 0.18) were associated with improved disease‐specific survival in the NSMP subgroup (n = 218). In contrast, adjuvant therapies showed no effect on disease‐specific survival in the full MMR‐D cohort (n = 287) or in MLH1 methylated tumors (n = 154). Whole pelvic radiotherapy (adjusted HR 25 vs. no adjuvant therapy/vaginal brachytherapy) and chemotherapy combined with whole pelvic radiotherapy (adjusted HR 32) were associated with poor disease‐specific survival in MMR‐D nonmethylated tumors (n = 70).ConclusionMMR protein and MLH1 methylation status predict the response to adjuvant therapy in endometrial cancer. The MMR system could be utilized for selection of patients who most likely benefit from adjuvant therapy.
Highlights
The mismatch repair (MMR) system is a highly conserved DNA repair mechanism that corrects mismatched base pairs generated during DNA replication
Conforming to the Proactive Molecular Risk Classifier for Endometrial Cancer (ProMisE),[5] we excluded from MMR proficient cases those that showed aberrant p53 (p53 abn) staining or polymerase ε (POLE) exonuclease domain mutation (EDM), and termed this subgroup as “no specific molecular profile” (NSMP)
Whole pelvic radiotherapy and chemotherapy combined with radiotherapy were associated with improved outcome
Summary
The mismatch repair (MMR) system is a highly conserved DNA repair mechanism that corrects mismatched base pairs generated during DNA replication. Several in vitro studies have implicated MMR system in the response of mammalian cells to ionizing radiation and DNA damaging agents.[7,8] The role of MMR in response to ionizing radiation is yet controversial, but available preclinical data suggest that tumors containing a significant fraction of cells deficient in MMR will demonstrate reduced responsiveness to specific drugs. It has not been unequivocally defined whether MMR protein status influences the efficacy of adjuvant therapy in endometrial cancer. We studied MLH1 methylation status as a predictor of treatment response in MMR deficient (MMR-D) endometrial cancers
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