Prevalence and Prognosis of Lynch Syndrome and Sporadic Mismatch Repair Deficiency in Endometrial Cancer

Abstract

Background: Standard screening of endometrial cancer (EC) for Lynch syndrome (LS) is gaining traction; however, the prognostic impact of an underlying hereditary etiology is unknown. We established the prevalence, prognosis, and subsequent primary cancer incidence of patients with LS-associated EC in relation to sporadic mismatch repair deficient (MMRd)-EC in the large combined Post Operative Radiation Therapy in Endometrial Carcinoma-1, -2, and -3 trial cohort.

Methods: After MMR-immunohistochemistry, MLH1-promoter methylation testing, and next-generation sequencing, tumors were classified into 3 groups according to the molecular cause of their MMRd-EC. Kaplan-Meier method, log-rank test, and Cox model were used for survival analysis. Competing risk analysis was used to estimate the subsequent cancer probability. All statistical tests were 2-sided.

Results: Among the 1336 ECs, 410 (30.7%) were MMRd. A total of 380 (92.7%) were fully triaged: 275 (72.4%) were MLH1-hypermethylated MMRd-ECs; 36 (9.5%) LS MMRd-ECs, and 69 (18.2%) MMRd-ECs due to other causes. Limiting screening of EC patients to 60 years or younger or to 70 years or younger would have resulted in missing 18 (50.0%) and 6 (16.7%) LS diagnoses, respectively. Five-year recurrence-free survival was 91.7% (95% confidence interval [CI] = 83.1% to 100%; hazard ratio = 0.45, 95% CI = 0.16 to 1.24, P = .12) for LS, 95.5% (95% CI = 90.7% to 100%; hazard ratio = 0.17, 95% CI = 0.05 to 0.55, P = .003) for "other" vs 78.6% (95% CI = 73.8% to 83.7%) for MLH1-hypermethylated MMRd-EC. The probability of subsequent LS-associated cancer at 10 years was 11.6% (95% CI = 0.0% to 24.7%), 1.5% (95% CI = 0.0% to 4.3%), and 7.0% (95% CI = 3.0% to 10.9%) within the LS, "other," and MLH1-hypermethylated MMRd-EC groups, respectively.

Conclusions: The LS prevalence in the Post Operative Radiation Therapy in Endometrial Carcinoma trial population was 2.8% and among MMRd-ECs was 9.5%. Patients with LS-associated ECs showed a trend towards better recurrence-free survival and higher risk for second cancers compared with patients with MLH1-hypermethylated MMRd-EC.

Figure 1.

Flowchart. ^aOne case with MLH1 promoter hypermethylation in the tumor carried a germline MLH1 variant. ^bInsufficient material for assay. EC = endometrial cancer; LS = Lynch syndrome; Methylation (+) = MLH1 promoter hypermethylation; Methylation (−) = no MLH1 promoter hypermethylation; MMR = mismatch repair; MMRd = mismatch repair deficient; MMRp = mismatch repair proficient; MSI = microsatellite instability; NGS = next-generation sequencing.

Figure 2.

Details on the mismatch repair (MMR) protein expression according to the molecular cause of their MMR-deficient endometrial cancer (MMRd-EC). MMR protein expression was scored as following: complete loss (CL), retained (R), subclonal loss (SL), unknown/failed (UK). ^aThe concordance of these 2 columns shows that a 2-antibody (MSH6 and PMS2) panel is as sensitive as the full panel to detect Lynch syndrome (LS). ^bAll MMRd-ECs including those with insufficient material for MLH1 methylation assay (n = 27) and next-generation sequencing (n = 3).

Figure 3.

Kaplan-Meier survival curves for recurrence-free survival (A) and overall survival (B) for patients with methylated mismatch repair deficient (MMRd), other MMRd and Lynch syndrome (LS) associated MMRd endometrial cancer (EC). All cases with MMRd phenotype are included in this analysis, including cases with a concurrent POLE variant affecting function (POLEmut-MMRd-EC). P values reflect 2-sided log-rank test.