Prevalence and Prognosis of Lynch Syndrome and Sporadic Mismatch Repair Deficiency in Endometrial Cancer
Menée à partir de l'analyse immunohistochimique et génétique d'échantillons tumoraux prélevés sur 1 336 patientes atteintes d'un cancer de l'endomètre, cette étude analyse la prévalence d'un syndrome de Lynch et d'une déficience sporadique du processus de réparation des mésappariement de l'ADN, puis estime l'effet d'un syndrome de Lynch et d'une hyperméthylation du promoteur du gène MLH1 sur la survie sans récidive et le risque de second cancer
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 PORTEC-1,-2 and -3 trial cohort.
Methods : After MMR-immunohistochemistry, MLH1-promoter methylation testing, and next-generation sequencing, tumors were classified into three 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 two-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 or
≤
70 years would have resulted in missing 18 (50.0%) and 6 (16.7%) LS diagnoses. Five-year recurrence-free survival (RFS) was 91.7% (95% confidence interval [CI] = 83.1–100%; hazard ratio [HR] = 0.45, 95%CI =0.16–1.24, p = .12) for LS, 95.5% (95% CI = 90.7–100%; HR = 0.17, 95% CI = 0.05–0.55, p = .003) for ‘other’ versus 78.6% (95% CI = 73.8–83.7%) for MLH1-hypermethylated MMRd-EC. The probability of subsequent LS-associated cancer at 10 years was 11.6% (95%CI = 0.0–24.7%), 1.5% (95%CI = 0.0–4.3%) and 7.0% (95%CI = 3.0–10.9%) within the LS, ‘other’ and MLH1-hypermethylated MMRd-EC groups.
Conclusion : The LS prevalence in the PORTEC-trial population was 2.8%, and among MMRd-ECs 9.5%. Patients with LS-associated ECs showed a trend towards better RFS and higher risk for second cancers compared to patients with MLH1-hypermethylated MMRd-EC.
Journal of the National Cancer Institute , article en libre accès, 2020