FROM THE JOURNAL OF CLINICAL ONCOLOGY
Endometrioid endometrial tumors with DNA mismatch repair (MMR) defects were associated with lower progression-free survival than were tumors that lacked these epigenetic defects, according to a large prospective study published online June 20 in the Journal of Clinical Oncology.
“The overall effect was less than would be expected given the strong association [between MMR defects and] higher grade (66% grade 2 or 3), higher stage (22% stage III or IV), and frequent lymphovascular space invasion (33%),” Dr. Scott McMeekin of the University of Oklahoma Health Sciences Center, Oklahoma City, and his associates wrote. Perhaps MMR-deficient tumors “are eliciting an antitumor immune response, as has been described for POLE ultramutated tumors,” they suggested.
Endometrioid endometrial tumors comprise about 80% of uterine cancers, and about 20%-40% of endometrioid endometrial cancer (EEC) tumors show loss of MMR, but “the relationship between MMR defects and outcomes in patients with endometrial cancer has not been fully established,” the researchers wrote.
Their study looked for links between MMR classes, clinicopathologic features, and outcomes, including response to adjuvant therapy. Understanding these links “will be critical to the design and implementation of trials for treating advanced-stage and recurrent EEC, including biologic therapies such as immune checkpoint blockade,” they wrote (J Clin Oncol. 2016. doi: 10.1200/JCO.2016.67.8722 ).
The study included 1,043 women with primary EEC prospectively recruited between 2003 and 2007 by the NRG/Gynecologic Oncology Group.
Tumor slides and clinical reports for a total of 1,024 EECs were centrally reviewed, and the tumors were tested for microsatellite instability (MSI), MLH1 methylation, and MMR protein expression. Each tumor was classified as being either MMR normal, having an epigenetic defect, having a probable mutation (that is, an MMR defect not attributable to MLH1 methylation), or as being MSI-low.
Progression-free survival was significantly lower among women whose tumors had epigenetic defects, compared with women whose tumors were MMR normal (hazard ratio, 1.37; 95% confidence interval, 1.00-1.86; P less than .05).
However, trends in disease-specific survival were similar, regardless of MMR type, the researchers wrote. Importantly, an exploratory analysis revealed a possible link between MMR status and response to adjuvant therapy. Specifically, women classified as having probable MMR mutations who received adjuvant therapy had substantially better progression-free survival, with a P-value that trended toward significant (HR, 0.24; 95% CI, 0.05-1.16; P = .07).
“No such effect was seen in the epigenetic defect group, and the differences in outcomes for patients with the two different classes of MMR defect are highly suggestive,” the researchers wrote. “Despite the large size of our study, our power to detect differences in survival is limited by the modest number of cases whose tumors were classified as probable mutation (99, 10% of cohort) and further by the fact that only 26 subjects received adjuvant therapy.”
Since many cancer centers regularly test tumor specimens for MMR defects and MLH1 methylation, “it should be possible to rapidly undertake retrospective studies to validate the findings we report here,” the researchers noted.
Dr. McMeekin reported having no financial disclosures. His coauthors reported ties to several companies, including Repros Therapeutics, Ethicon, Vitatex, Genentech, Janssen Oncology, Tesaro, AstraZeneca, and OvaGene Oncology.
