Prevalence and Prognosis of Lynch Syndrome and Sporadic Mismatch Repair Deficiency in Endometrial Cancer
Post, Cathalijne C.B.; Stelloo, Ellen; Smit, Vincent T.H.B.M.; Ruano, Dina; Tops, Carli M.; Vermij, Lisa; Rutten, Tessa A.; Jürgenliemk-Schulz, Ina M.; Lutgens, Ludy C.H.W.; Jobsen, Jan J.; Nout, Remi A.; Crosbie, Emma J.; Powell, Melanie E.; Mileshkin, Linda; Leary, Alexandra; Bessette, Paul; Putter, Hein; de Boer, Stephanie M.; Horeweg, Nanda; Nielsen, Maartje; Wezel, Tom van; Bosse, Tjalling; Creutzberg, Carien L.
(2021) Journal of the National Cancer Institute, volume 113, issue 9, pp. 1212 - 1220
(Article)
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
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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.
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Keywords: Brain Neoplasms, Colorectal Neoplasms, Colorectal Neoplasms, Hereditary Nonpolyposis/diagnosis, DNA Methylation, DNA Mismatch Repair/genetics, Endometrial Neoplasms/epidemiology, Female, Humans, MutL Protein Homolog 1/genetics, Neoplastic Syndromes, Hereditary, Prevalence, Prognosis, Oncology, Cancer Research, Research Support, Non-U.S. Gov't, Journal Article
ISSN: 0027-8874
Publisher: Oxford University Press
Note: Publisher Copyright: © 2021 The Author(s). Published by Oxford University Press.
(Peer reviewed)