Lynch syndrome (LS) was present among 2.8% of patients in an endometrial cancer (EC) cohort, and was associated with longer recurrence-free survival (RFS) and higher rates of second cancers, according to the results of a study published in the Journal of the National Cancer Institute. The authors stated that “This is the first study investigating the prognostic value of LS within the [MMR-deficient (MMRd)]-EC subgroup.”

Women with LS frequently develop EC as their first LS-associated cancer. Mutations in several different DNA mismatch repair (MMR) genes can result in LS, although not all MMRd disease is characterized as LS.

The study ( Identifier: NCT00411138) included 1336 patients from the PORTEC-1, -2, and -3 clinical trials who had stage I low-intermediate and high-intermediate–risk endometrioid EC. Patients were eligible if their tumor samples harbored loss of expression of at least 1 of 4 MMR proteins or had high microsatellite instability. Tumor samples were assessed for MLH1 methylation and next-generation sequencing for MLH1, MSH2, MSH6, PMS2, POLE, and POLD1 variants. LS was defined as a germline mutation in MLH1, MSH2, MSH6, or PMS2.

Continue Reading

MMRd disease was present in 30.7% of patients of the entire cohort, with 2.8% identified as having LS. Of the evaluable patients with MMRd disease (380 patients), 9.5% had LS. The remaining 72.4% of patients had tumors with MLH1-hypermethylation, and 18.2% had MMRd due to other causes.

“Limiting screening of EC patients to ≤60 or ≤70 years would have resulted in missing 18 (50.0%) and 6 (16.7%) LS diagnoses,” the authors reported.

There was a trend of different 5-year RFS among the 3 groups, with the shortest among patients with MLH1-hypermethylated disease at 78.6% compared with 95.5% among patients with other causes of MMRd (hazard ratio [HR], 0.17; 95% CI, 0.05-0.55; P =.003) and 91.7% among patients with LS (HR, 0.45; 95% CI, 0.16-1.24; P =.12).

The risk of developing a secondary cancer also differed among the groups, with the greatest risk in patients with LS at 11.6%, compared with 7.0% among patients with MLH1-hypermethylated disease and 1.5% among patients with other causes of MMRd.

The authors concluded that “Besides a prognostic impact, screening all incident ECs without upper age limit to identify LS using tumor-based triage may benefit counselling, impact treatment decisions, and facilitate prevention strategies for current and future patients and their families.”


Post CCB, Stelloo E, Smit VTHBM, et al. Prevalence and prognosis of lynch syndrome and sporadic mismatch repair deficiency in endometrial cancer. J Natl Cancer Inst. Published online March 6, 2021. doi:10.1093/jnci/djab029