Clinicopathologic significance of mismatch repair defects in endometrial cancer: An NRG oncology/gynecologic oncology group study

D. Scott McMeekin, David L. Tritchler, David E. Cohn, David G. Mutch, Heather A. Lankes, Melissa A. Geller, Matthew A. Powell, Floor J. Backes, Lisa M. Landrum, Richard Zaino, Russell D. Broaddus, Nilsa Ramirez, Feng Gao, Shamshad Ali, Kathleen M. Darcy, Michael L. Pearl, Paul A. DiSilvestro, Shashikant B. Lele, Paul J. Goodfellow

Research output: Contribution to journalArticlepeer-review

69 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)3062-3068
Number of pages7
JournalJournal of Clinical Oncology
Volume34
Issue number25
DOIs
StatePublished - Sep 1 2016

Bibliographical note

Funding Information:
Support Supported by SPORE in Endometrial Cancer Grant No. P50 CA134254 to Washington University School of Medicine, Barnes-Jewish Hospital and Siteman Cancer Center, The Ohio State University James Comprehensive Cancer Center, and National Cancer Institute Grants No. CA 27469 (Gynecologic Oncology Group [GOG] Administrative Office), CA 37517 (GOG Statistical Office), 1 U10 CA180822 (NRG Oncology Group), and U10 CA27469, U24 CA114793, and U10 CA180868 (GOG Tissue Bank).

Publisher Copyright:
© 2016 by American Society of Clinical Oncology.

Copyright:
Copyright 2017 Elsevier B.V., All rights reserved.

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