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Mismatch repair deficiency linked to increased risk for endometrial cancer recurrence

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February 25, 2019

Women with high-intermediate-risk endometrioid endometrial cancer and defective DNA mismatch repair had higher recurrence rates and poorer RFS than women with intact mismatch repair, according to research published in Cancer.

“The objective of the current study was to assess the correlation between mismatch repair status, recurrence patterns and RFS in patients with high-intermediate-risk endometrial cancer,” Floor J. Backes, MD, associate professor in the division of gynecologic oncology at The Ohio State University Comprehensive Cancer Center, and colleagues wrote. “We also sought to explore differences in response to adjuvant treatment according to mismatch repair status.”

Loss of DNA mismatch repair is common in endometrial cancer and has been associated with more aggressive tumor characteristics in endometrioid endometrial cancer, according to study background.

In the single-institution chart review, Backes and colleagues evaluated consecutive patients diagnosed with endometrial cancer at The Ohio State University Comprehensive Cancer Center between 2007 and 2016. Researchers established tumor mismatch repair status using reported findings for the proteins mutL homolog 1 (MLH1), postmeiotic segregation (PMS2), mutS homolog 2 (MSH2) and MSH6 histochemistry. They defined defective mismatch repair as the absence of expression of at least one of these proteins.

The study included 197 women who met the Gynecologic Oncology Group 249 criteria for high-intermediate-risk endometrioid endometrial cancer. Among them, 64 had defective mismatch repair and 133 had intact mismatch repair.

Most of the women (55%) received no adjuvant therapy, whereas 27% received vaginal brachytherapy, 10.7% received chemotherapy and 7.6% underwent external-beam radiation therapy.

Median follow-up was 54 months.

Thirty-two women (16.2%) experienced disease recurrence, which included 19 local and 13 distant recurrences.

Women with defective mismatch repair status had a higher recurrence rate than those with intact status (28% vs. 10.5%, P = .002), including a substantially higher rate of distant recurrences (14.1% vs. 3%, P = .003).

The survival analysis showed shorter estimated 5-year RFS among those with defective vs. intact mismatch repair (66% vs. 89%, P = .001), with a similar difference observed in an analysis that excluded isolated vaginal recurrences (73.5% vs. 95%, P = .0004).

Multivariable logistic regression models that included mismatch repair status and one other variable showed no association between recurrence and age, presence of lymphovascular space invasion, tumor grade or adjuvant therapy.

An analysis controlling for BMI, stage and receipt of radiation therapy found that the presence of defective mismatch repair (OR = 5.16; 95% CI, 2.1-12.69) was significantly associated with recurrence. A univariable regression model revealed that defective mismatch repair was significantly linked to distant recurrence (OR = 5.28; 95% CI, 1.56-17.86), but not to local recurrence.

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In a related editorial, Ramez N. Eskander, MD, assistant professor of obstetrics, gynecology and reproductive sciences in the division of gynecologic oncology at UC San Diego Moores Cancer Center, noted the importance of these findings but emphasized the need for further research.
defective mismatch repair in patients with endometrial cancer and an improved understanding of the prognostic and therapeutic implications, it is anticipated that more effective treatments will be developed,” Eskander wrote. “However, most patients with advanced-stage or recurrent disease are mismatch repair proficient, emphasizing the need for dynamic drug development, which will rely on improved molecular understanding of the disease as well as innovative trial designs with combinatorial approaches.” – by Jennifer Byrne

Disclosures: Backes reports research grants from Eisai Inc. and ImmunoGen Clovis Oncology; advisory board roles with Agenus, Clovis, Merck and Tesaro; a speaker role with CEC Oncology; and honorarium from UpToDate. Please see the study for all other authors’ relevant financial disclosures. Eskander reports personal fees from AstraZeneca, Clovis, Genentech, Pfizer and Tesaro outside the submitted work.

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