Journal
JOURNAL OF CLINICAL ONCOLOGY
Volume 34, Issue 25, Pages 3062-+Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1200/JCO.2016.67.8722
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Funding
- SPORE in Endometrial Cancer [P50 CA134254]
- Barnes-Jewish Hospital and Siteman Cancer Center
- The Ohio State University James Comprehensive Cancer Center
- National Cancer Institute (Gynecologic Oncology Group [GOG] Administrative Office) [CA 27469]
- National Cancer Institute (GOG Statistical Office) [CA 37517]
- National Cancer Institute (NRG Oncology Group) [1 U10 CA180822]
- National Cancer Institute (GOG Tissue Bank) [U10 CA180868]
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Purpose The clinicopathologic significance of mismatch repair (MMR) defects in endometrioid endometrial cancer (EEC) has not been definitively established. We undertook tumor typing to classify MMR defects to determine if MMR status is prognostic or predictive. Methods Primary EECs from NRG/GOG0210 patients were assessed for microsatellite instability (MSI), MLH1 methylation, and MMR protein expression. Each tumor was assigned to one of four MMR classes: normal, epigenetic defect, probable mutation (MMR defect not attributable to MLH1 methylation), or MSI-low. The relationships between MMR classes and clinicopathologic variables were assessed using contingency table tests and Cox proportional hazard models. Results A total of 1,024 tumors were assigned to MMR classes. Epigenetic and probable mutations in MMR were significantly associated with higher grade and more frequent lymphovascular space invasion. Epigenetic defects were more common in patients with higher International Federation of Gynecology and Obstetrics stage. Overall, there were no differences in outcomes. Progression-free survival was, however, worse for women whose tumors had epigenetic MMR defects compared with the MMR normal group (hazard ratio, 1.37; P < .05; 95% CI, 1.00 to 1.86). An exploratory analysis of interaction between MMR status and adjuvant therapy showed a trend toward improved progression-free survival for probable MMR mutation cases. Conclusion MMR defects in EECs are associated with a number of well-established poor prognostic indicators. Women with tumors that had MMR defects were likely to have higher-grade cancers and more frequent lymphovascular space invasion. Surprisingly, outcomes in these patients were similar to patients with MMR normal tumors, suggesting that MMR defects may counteract the effects of negative prognostic factors. Altered immune surveillance of MMR-deficient tumors, and other host/tumor interactions, is likely to determine outcomes for patients with MMR-deficient tumors. (C) 2016 by American Society of Clinical Oncology
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