Clinicopathologic Significance of Mismatch Repair Defects in Endometrial Cancer: An NRG Oncology/Gynecologic Oncology Group Study.
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.



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.



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.



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.
D. Scott McMeekin and Lisa M. Landrum, University of Oklahoma Health Sciences Center, Oklahoma City, OK; David L. Tritchler, Heather A. Lankes, and Shamshad Ali, NRG Oncology Statistics and Data Management Center; Shashikant B. Lele, Roswell Park Cancer Institute, Buffalo; Michael L. Pearl, Stony Brook University Hospital, Stony Brook, NY; David E. Cohn, Floor J. Backes, and Paul J. Goodfellow, The Ohio State University; Nilsa Ramirez, Research Institute at Nationwide Children's Hospital, Columbus, OH; David G. Mutch, Matthew A. Powell, and Feng Gao, Washington University School of Medicine, St. Louis, MO; Melissa A. Geller, University of Minnesota, Minneapolis, MN; Richard Zaino, Penn State Milton S. Hersey Medical Center, Hershey, PA; Russell D. Broaddus, The University of Texas MD Anderson Cancer Center, Houston, TX; Kathleen M. Darcy, Women's Health Integrated Research Collective, Annandale, VA; and Paul A. DiSilvestro, Women and Infants Hospital of Rhode Island, Providence, RI.
D Scott
DS
McMeekin
D. Scott McMeekin and Lisa M. Landrum, University of Oklahoma Health Sciences Center, Oklahoma City, OK; David L. Tritchler, Heather A. Lankes, and Shamshad Ali, NRG Oncology Statistics and Data Management Center; Shashikant B. Lele, Roswell Park Cancer Institute, Buffalo; Michael L. Pearl, Stony Brook University Hospital, Stony Brook, NY; David E. Cohn, Floor J. Backes, and Paul J. Goodfellow, The Ohio State University; Nilsa Ramirez, Research Institute at Nationwide Children's Hospital, Columbus, OH; David G. Mutch, Matthew A. Powell, and Feng Gao, Washington University School of Medicine, St. Louis, MO; Melissa A. Geller, University of Minnesota, Minneapolis, MN; Richard Zaino, Penn State Milton S. Hersey Medical Center, Hershey, PA; Russell D. Broaddus, The University of Texas MD Anderson Cancer Center, Houston, TX; Kathleen M. Darcy, Women's Health Integrated Research Collective, Annandale, VA; and Paul A. DiSilvestro, Women and Infants Hospital of Rhode Island, Providence, RI.
David L
DL
Tritchler
D. Scott McMeekin and Lisa M. Landrum, University of Oklahoma Health Sciences Center, Oklahoma City, OK; David L. Tritchler, Heather A. Lankes, and Shamshad Ali, NRG Oncology Statistics and Data Management Center; Shashikant B. Lele, Roswell Park Cancer Institute, Buffalo; Michael L. Pearl, Stony Brook University Hospital, Stony Brook, NY; David E. Cohn, Floor J. Backes, and Paul J. Goodfellow, The Ohio State University; Nilsa Ramirez, Research Institute at Nationwide Children's Hospital, Columbus, OH; David G. Mutch, Matthew A. Powell, and Feng Gao, Washington University School of Medicine, St. Louis, MO; Melissa A. Geller, University of Minnesota, Minneapolis, MN; Richard Zaino, Penn State Milton S. Hersey Medical Center, Hershey, PA; Russell D. Broaddus, The University of Texas MD Anderson Cancer Center, Houston, TX; Kathleen M. Darcy, Women's Health Integrated Research Collective, Annandale, VA; and Paul A. DiSilvestro, Women and Infants Hospital of Rhode Island, Providence, RI.
David E
DE
Cohn
D. Scott McMeekin and Lisa M. Landrum, University of Oklahoma Health Sciences Center, Oklahoma City, OK; David L. Tritchler, Heather A. Lankes, and Shamshad Ali, NRG Oncology Statistics and Data Management Center; Shashikant B. Lele, Roswell Park Cancer Institute, Buffalo; Michael L. Pearl, Stony Brook University Hospital, Stony Brook, NY; David E. Cohn, Floor J. Backes, and Paul J. Goodfellow, The Ohio State University; Nilsa Ramirez, Research Institute at Nationwide Children's Hospital, Columbus, OH; David G. Mutch, Matthew A. Powell, and Feng Gao, Washington University School of Medicine, St. Louis, MO; Melissa A. Geller, University of Minnesota, Minneapolis, MN; Richard Zaino, Penn State Milton S. Hersey Medical Center, Hershey, PA; Russell D. Broaddus, The University of Texas MD Anderson Cancer Center, Houston, TX; Kathleen M. Darcy, Women's Health Integrated Research Collective, Annandale, VA; and Paul A. DiSilvestro, Women and Infants Hospital of Rhode Island, Providence, RI.
David G
DG
Mutch
D. Scott McMeekin and Lisa M. Landrum, University of Oklahoma Health Sciences Center, Oklahoma City, OK; David L. Tritchler, Heather A. Lankes, and Shamshad Ali, NRG Oncology Statistics and Data Management Center; Shashikant B. Lele, Roswell Park Cancer Institute, Buffalo; Michael L. Pearl, Stony Brook University Hospital, Stony Brook, NY; David E. Cohn, Floor J. Backes, and Paul J. Goodfellow, The Ohio State University; Nilsa Ramirez, Research Institute at Nationwide Children's Hospital, Columbus, OH; David G. Mutch, Matthew A. Powell, and Feng Gao, Washington University School of Medicine, St. Louis, MO; Melissa A. Geller, University of Minnesota, Minneapolis, MN; Richard Zaino, Penn State Milton S. Hersey Medical Center, Hershey, PA; Russell D. Broaddus, The University of Texas MD Anderson Cancer Center, Houston, TX; Kathleen M. Darcy, Women's Health Integrated Research Collective, Annandale, VA; and Paul A. DiSilvestro, Women and Infants Hospital of Rhode Island, Providence, RI.
Heather A
HA
Lankes
D. Scott McMeekin and Lisa M. Landrum, University of Oklahoma Health Sciences Center, Oklahoma City, OK; David L. Tritchler, Heather A. Lankes, and Shamshad Ali, NRG Oncology Statistics and Data Management Center; Shashikant B. Lele, Roswell Park Cancer Institute, Buffalo; Michael L. Pearl, Stony Brook University Hospital, Stony Brook, NY; David E. Cohn, Floor J. Backes, and Paul J. Goodfellow, The Ohio State University; Nilsa Ramirez, Research Institute at Nationwide Children's Hospital, Columbus, OH; David G. Mutch, Matthew A. Powell, and Feng Gao, Washington University School of Medicine, St. Louis, MO; Melissa A. Geller, University of Minnesota, Minneapolis, MN; Richard Zaino, Penn State Milton S. Hersey Medical Center, Hershey, PA; Russell D. Broaddus, The University of Texas MD Anderson Cancer Center, Houston, TX; Kathleen M. Darcy, Women's Health Integrated Research Collective, Annandale, VA; and Paul A. DiSilvestro, Women and Infants Hospital of Rhode Island, Providence, RI.
Melissa A
MA
Geller
D. Scott McMeekin and Lisa M. Landrum, University of Oklahoma Health Sciences Center, Oklahoma City, OK; David L. Tritchler, Heather A. Lankes, and Shamshad Ali, NRG Oncology Statistics and Data Management Center; Shashikant B. Lele, Roswell Park Cancer Institute, Buffalo; Michael L. Pearl, Stony Brook University Hospital, Stony Brook, NY; David E. Cohn, Floor J. Backes, and Paul J. Goodfellow, The Ohio State University; Nilsa Ramirez, Research Institute at Nationwide Children's Hospital, Columbus, OH; David G. Mutch, Matthew A. Powell, and Feng Gao, Washington University School of Medicine, St. Louis, MO; Melissa A. Geller, University of Minnesota, Minneapolis, MN; Richard Zaino, Penn State Milton S. Hersey Medical Center, Hershey, PA; Russell D. Broaddus, The University of Texas MD Anderson Cancer Center, Houston, TX; Kathleen M. Darcy, Women's Health Integrated Research Collective, Annandale, VA; and Paul A. DiSilvestro, Women and Infants Hospital of Rhode Island, Providence, RI.
Matthew A
MA
Powell
D. Scott McMeekin and Lisa M. Landrum, University of Oklahoma Health Sciences Center, Oklahoma City, OK; David L. Tritchler, Heather A. Lankes, and Shamshad Ali, NRG Oncology Statistics and Data Management Center; Shashikant B. Lele, Roswell Park Cancer Institute, Buffalo; Michael L. Pearl, Stony Brook University Hospital, Stony Brook, NY; David E. Cohn, Floor J. Backes, and Paul J. Goodfellow, The Ohio State University; Nilsa Ramirez, Research Institute at Nationwide Children's Hospital, Columbus, OH; David G. Mutch, Matthew A. Powell, and Feng Gao, Washington University School of Medicine, St. Louis, MO; Melissa A. Geller, University of Minnesota, Minneapolis, MN; Richard Zaino, Penn State Milton S. Hersey Medical Center, Hershey, PA; Russell D. Broaddus, The University of Texas MD Anderson Cancer Center, Houston, TX; Kathleen M. Darcy, Women's Health Integrated Research Collective, Annandale, VA; and Paul A. DiSilvestro, Women and Infants Hospital of Rhode Island, Providence, RI.
Floor J
FJ
Backes
D. Scott McMeekin and Lisa M. Landrum, University of Oklahoma Health Sciences Center, Oklahoma City, OK; David L. Tritchler, Heather A. Lankes, and Shamshad Ali, NRG Oncology Statistics and Data Management Center; Shashikant B. Lele, Roswell Park Cancer Institute, Buffalo; Michael L. Pearl, Stony Brook University Hospital, Stony Brook, NY; David E. Cohn, Floor J. Backes, and Paul J. Goodfellow, The Ohio State University; Nilsa Ramirez, Research Institute at Nationwide Children's Hospital, Columbus, OH; David G. Mutch, Matthew A. Powell, and Feng Gao, Washington University School of Medicine, St. Louis, MO; Melissa A. Geller, University of Minnesota, Minneapolis, MN; Richard Zaino, Penn State Milton S. Hersey Medical Center, Hershey, PA; Russell D. Broaddus, The University of Texas MD Anderson Cancer Center, Houston, TX; Kathleen M. Darcy, Women's Health Integrated Research Collective, Annandale, VA; and Paul A. DiSilvestro, Women and Infants Hospital of Rhode Island, Providence, RI.
Lisa M
LM
Landrum
D. Scott McMeekin and Lisa M. Landrum, University of Oklahoma Health Sciences Center, Oklahoma City, OK; David L. Tritchler, Heather A. Lankes, and Shamshad Ali, NRG Oncology Statistics and Data Management Center; Shashikant B. Lele, Roswell Park Cancer Institute, Buffalo; Michael L. Pearl, Stony Brook University Hospital, Stony Brook, NY; David E. Cohn, Floor J. Backes, and Paul J. Goodfellow, The Ohio State University; Nilsa Ramirez, Research Institute at Nationwide Children's Hospital, Columbus, OH; David G. Mutch, Matthew A. Powell, and Feng Gao, Washington University School of Medicine, St. Louis, MO; Melissa A. Geller, University of Minnesota, Minneapolis, MN; Richard Zaino, Penn State Milton S. Hersey Medical Center, Hershey, PA; Russell D. Broaddus, The University of Texas MD Anderson Cancer Center, Houston, TX; Kathleen M. Darcy, Women's Health Integrated Research Collective, Annandale, VA; and Paul A. DiSilvestro, Women and Infants Hospital of Rhode Island, Providence, RI.
Richard
R
Zaino
D. Scott McMeekin and Lisa M. Landrum, University of Oklahoma Health Sciences Center, Oklahoma City, OK; David L. Tritchler, Heather A. Lankes, and Shamshad Ali, NRG Oncology Statistics and Data Management Center; Shashikant B. Lele, Roswell Park Cancer Institute, Buffalo; Michael L. Pearl, Stony Brook University Hospital, Stony Brook, NY; David E. Cohn, Floor J. Backes, and Paul J. Goodfellow, The Ohio State University; Nilsa Ramirez, Research Institute at Nationwide Children's Hospital, Columbus, OH; David G. Mutch, Matthew A. Powell, and Feng Gao, Washington University School of Medicine, St. Louis, MO; Melissa A. Geller, University of Minnesota, Minneapolis, MN; Richard Zaino, Penn State Milton S. Hersey Medical Center, Hershey, PA; Russell D. Broaddus, The University of Texas MD Anderson Cancer Center, Houston, TX; Kathleen M. Darcy, Women's Health Integrated Research Collective, Annandale, VA; and Paul A. DiSilvestro, Women and Infants Hospital of Rhode Island, Providence, RI.
Russell D
RD
Broaddus
D. Scott McMeekin and Lisa M. Landrum, University of Oklahoma Health Sciences Center, Oklahoma City, OK; David L. Tritchler, Heather A. Lankes, and Shamshad Ali, NRG Oncology Statistics and Data Management Center; Shashikant B. Lele, Roswell Park Cancer Institute, Buffalo; Michael L. Pearl, Stony Brook University Hospital, Stony Brook, NY; David E. Cohn, Floor J. Backes, and Paul J. Goodfellow, The Ohio State University; Nilsa Ramirez, Research Institute at Nationwide Children's Hospital, Columbus, OH; David G. Mutch, Matthew A. Powell, and Feng Gao, Washington University School of Medicine, St. Louis, MO; Melissa A. Geller, University of Minnesota, Minneapolis, MN; Richard Zaino, Penn State Milton S. Hersey Medical Center, Hershey, PA; Russell D. Broaddus, The University of Texas MD Anderson Cancer Center, Houston, TX; Kathleen M. Darcy, Women's Health Integrated Research Collective, Annandale, VA; and Paul A. DiSilvestro, Women and Infants Hospital of Rhode Island, Providence, RI.
Nilsa
N
Ramirez
D. Scott McMeekin and Lisa M. Landrum, University of Oklahoma Health Sciences Center, Oklahoma City, OK; David L. Tritchler, Heather A. Lankes, and Shamshad Ali, NRG Oncology Statistics and Data Management Center; Shashikant B. Lele, Roswell Park Cancer Institute, Buffalo; Michael L. Pearl, Stony Brook University Hospital, Stony Brook, NY; David E. Cohn, Floor J. Backes, and Paul J. Goodfellow, The Ohio State University; Nilsa Ramirez, Research Institute at Nationwide Children's Hospital, Columbus, OH; David G. Mutch, Matthew A. Powell, and Feng Gao, Washington University School of Medicine, St. Louis, MO; Melissa A. Geller, University of Minnesota, Minneapolis, MN; Richard Zaino, Penn State Milton S. Hersey Medical Center, Hershey, PA; Russell D. Broaddus, The University of Texas MD Anderson Cancer Center, Houston, TX; Kathleen M. Darcy, Women's Health Integrated Research Collective, Annandale, VA; and Paul A. DiSilvestro, Women and Infants Hospital of Rhode Island, Providence, RI.
Feng
F
Gao
D. Scott McMeekin and Lisa M. Landrum, University of Oklahoma Health Sciences Center, Oklahoma City, OK; David L. Tritchler, Heather A. Lankes, and Shamshad Ali, NRG Oncology Statistics and Data Management Center; Shashikant B. Lele, Roswell Park Cancer Institute, Buffalo; Michael L. Pearl, Stony Brook University Hospital, Stony Brook, NY; David E. Cohn, Floor J. Backes, and Paul J. Goodfellow, The Ohio State University; Nilsa Ramirez, Research Institute at Nationwide Children's Hospital, Columbus, OH; David G. Mutch, Matthew A. Powell, and Feng Gao, Washington University School of Medicine, St. Louis, MO; Melissa A. Geller, University of Minnesota, Minneapolis, MN; Richard Zaino, Penn State Milton S. Hersey Medical Center, Hershey, PA; Russell D. Broaddus, The University of Texas MD Anderson Cancer Center, Houston, TX; Kathleen M. Darcy, Women's Health Integrated Research Collective, Annandale, VA; and Paul A. DiSilvestro, Women and Infants Hospital of Rhode Island, Providence, RI.
Shamshad
S
Ali
D. Scott McMeekin and Lisa M. Landrum, University of Oklahoma Health Sciences Center, Oklahoma City, OK; David L. Tritchler, Heather A. Lankes, and Shamshad Ali, NRG Oncology Statistics and Data Management Center; Shashikant B. Lele, Roswell Park Cancer Institute, Buffalo; Michael L. Pearl, Stony Brook University Hospital, Stony Brook, NY; David E. Cohn, Floor J. Backes, and Paul J. Goodfellow, The Ohio State University; Nilsa Ramirez, Research Institute at Nationwide Children's Hospital, Columbus, OH; David G. Mutch, Matthew A. Powell, and Feng Gao, Washington University School of Medicine, St. Louis, MO; Melissa A. Geller, University of Minnesota, Minneapolis, MN; Richard Zaino, Penn State Milton S. Hersey Medical Center, Hershey, PA; Russell D. Broaddus, The University of Texas MD Anderson Cancer Center, Houston, TX; Kathleen M. Darcy, Women's Health Integrated Research Collective, Annandale, VA; and Paul A. DiSilvestro, Women and Infants Hospital of Rhode Island, Providence, RI.
Kathleen M
KM
Darcy
D. Scott McMeekin and Lisa M. Landrum, University of Oklahoma Health Sciences Center, Oklahoma City, OK; David L. Tritchler, Heather A. Lankes, and Shamshad Ali, NRG Oncology Statistics and Data Management Center; Shashikant B. Lele, Roswell Park Cancer Institute, Buffalo; Michael L. Pearl, Stony Brook University Hospital, Stony Brook, NY; David E. Cohn, Floor J. Backes, and Paul J. Goodfellow, The Ohio State University; Nilsa Ramirez, Research Institute at Nationwide Children's Hospital, Columbus, OH; David G. Mutch, Matthew A. Powell, and Feng Gao, Washington University School of Medicine, St. Louis, MO; Melissa A. Geller, University of Minnesota, Minneapolis, MN; Richard Zaino, Penn State Milton S. Hersey Medical Center, Hershey, PA; Russell D. Broaddus, The University of Texas MD Anderson Cancer Center, Houston, TX; Kathleen M. Darcy, Women's Health Integrated Research Collective, Annandale, VA; and Paul A. DiSilvestro, Women and Infants Hospital of Rhode Island, Providence, RI.
Michael L
ML
Pearl
D. Scott McMeekin and Lisa M. Landrum, University of Oklahoma Health Sciences Center, Oklahoma City, OK; David L. Tritchler, Heather A. Lankes, and Shamshad Ali, NRG Oncology Statistics and Data Management Center; Shashikant B. Lele, Roswell Park Cancer Institute, Buffalo; Michael L. Pearl, Stony Brook University Hospital, Stony Brook, NY; David E. Cohn, Floor J. Backes, and Paul J. Goodfellow, The Ohio State University; Nilsa Ramirez, Research Institute at Nationwide Children's Hospital, Columbus, OH; David G. Mutch, Matthew A. Powell, and Feng Gao, Washington University School of Medicine, St. Louis, MO; Melissa A. Geller, University of Minnesota, Minneapolis, MN; Richard Zaino, Penn State Milton S. Hersey Medical Center, Hershey, PA; Russell D. Broaddus, The University of Texas MD Anderson Cancer Center, Houston, TX; Kathleen M. Darcy, Women's Health Integrated Research Collective, Annandale, VA; and Paul A. DiSilvestro, Women and Infants Hospital of Rhode Island, Providence, RI.
Paul A
PA
DiSilvestro
D. Scott McMeekin and Lisa M. Landrum, University of Oklahoma Health Sciences Center, Oklahoma City, OK; David L. Tritchler, Heather A. Lankes, and Shamshad Ali, NRG Oncology Statistics and Data Management Center; Shashikant B. Lele, Roswell Park Cancer Institute, Buffalo; Michael L. Pearl, Stony Brook University Hospital, Stony Brook, NY; David E. Cohn, Floor J. Backes, and Paul J. Goodfellow, The Ohio State University; Nilsa Ramirez, Research Institute at Nationwide Children's Hospital, Columbus, OH; David G. Mutch, Matthew A. Powell, and Feng Gao, Washington University School of Medicine, St. Louis, MO; Melissa A. Geller, University of Minnesota, Minneapolis, MN; Richard Zaino, Penn State Milton S. Hersey Medical Center, Hershey, PA; Russell D. Broaddus, The University of Texas MD Anderson Cancer Center, Houston, TX; Kathleen M. Darcy, Women's Health Integrated Research Collective, Annandale, VA; and Paul A. DiSilvestro, Women and Infants Hospital of Rhode Island, Providence, RI.
Shashikant B
SB
Lele
D. Scott McMeekin and Lisa M. Landrum, University of Oklahoma Health Sciences Center, Oklahoma City, OK; David L. Tritchler, Heather A. Lankes, and Shamshad Ali, NRG Oncology Statistics and Data Management Center; Shashikant B. Lele, Roswell Park Cancer Institute, Buffalo; Michael L. Pearl, Stony Brook University Hospital, Stony Brook, NY; David E. Cohn, Floor J. Backes, and Paul J. Goodfellow, The Ohio State University; Nilsa Ramirez, Research Institute at Nationwide Children's Hospital, Columbus, OH; David G. Mutch, Matthew A. Powell, and Feng Gao, Washington University School of Medicine, St. Louis, MO; Melissa A. Geller, University of Minnesota, Minneapolis, MN; Richard Zaino, Penn State Milton S. Hersey Medical Center, Hershey, PA; Russell D. Broaddus, The University of Texas MD Anderson Cancer Center, Houston, TX; Kathleen M. Darcy, Women's Health Integrated Research Collective, Annandale, VA; and Paul A. DiSilvestro, Women and Infants Hospital of Rhode Island, Providence, RI. paul.goodfellow@osumc.edu.
Paul J
PJ
Goodfellow
D018269:Carcinoma, Endometrioid / Q000235:genetics* / Q000473:pathology; D015331:Cohort Studies; D053843:DNA Mismatch Repair; D018572:Disease-Free Survival; D016889:Endometrial Neoplasms / Q000235:genetics* / Q000473:pathology; D005260:Female; D006801:Humans; D053842:Microsatellite Instability; D008875:Middle Aged; D016016:Proportional Hazards Models