Clinicopathologic characteristics and outcomes of endometrial Cancer patients with mismatch repair deficiency in the era of universal Lynch syndrome screening

Gynecol Oncol. 2020 Dec;159(3):712-720. doi: 10.1016/j.ygyno.2020.09.039. Epub 2020 Oct 10.

Abstract

Objective: To evaluate clinicopathologic characteristics and survival impact associated with mismatch repair (MMR) deficient subgroups of endometrial cancer (EC) in patients undergoing universal screening for Lynch Syndrome.

Methods: A retrospective cohort study using a prospectively maintained gynecologic oncology registry of patients who underwent surgery for EC was conducted. All pathology specimens underwent tumor testing using immunohistochemistry for MMR deficiency with reflex MLH1 promotor methylation testing. Tumors were classified as MMR-I (intact MMR expression), MMR-DM (MMR deficient due to MLH1 methylation), and MMR-DU (MMR deficient without MLH1 methylation). Univariate and multivariate analysis performed to determine factors associated with MMR-DM. Progression-free survival (PFS) and overall survival (OS) analyzed by stage and endometrioid subgroup.

Results: From 2012 to 2016, 1018 EC patients were identified and screened. Overall, 71.6% were classified as MMR-I, 23.8% MMR-DM, and 4.6% MMR-DU. In comparison to MMR-DU, MMR-DM tumors were associated with older age, postmenopausal status, lymphovascular space invasion, and pure endometrioid histology. Compared to MMR-I, MMR-DM tumors were associated with older age, endometrioid histology, lymphovascular space invasion, and higher grade on multivariable analysis. There was no difference in PFS and OS between the three groups overall. In patients with endometrioid EC, MMR-DM tumors were associated with lower PFS vs. MMR-I (HR:2.51, CI:1.54, 4.10, P < 0.001). This effect persisted for stage I/II endometrioid EC (HR 2.66, CI:1.34, 5.26 p = 0.005). No difference in PFS or OS was noted among stage III/IV endometrioid tumors.

Conclusion: MMR deficiency is associated with adverse prognostic factors and worse PFS among endometrioid tumors, particularly in early stage EC. MMR testing outside of LS screening has prognostic value, warranting consideration for inclusion as a biomarker in prospective clinical trials.

Keywords: Endometrial cancer; Endometrioid endometrial cancer; Mismatch repair deficiency.

MeSH terms

  • Age Factors
  • Aged
  • Carcinoma, Endometrioid / diagnosis
  • Carcinoma, Endometrioid / genetics
  • Carcinoma, Endometrioid / mortality*
  • Carcinoma, Endometrioid / surgery
  • Colorectal Neoplasms, Hereditary Nonpolyposis / diagnosis*
  • Colorectal Neoplasms, Hereditary Nonpolyposis / genetics
  • DNA Methylation
  • DNA Mismatch Repair*
  • Early Detection of Cancer / methods
  • Early Detection of Cancer / statistics & numerical data*
  • Endometrial Neoplasms / diagnosis
  • Endometrial Neoplasms / genetics
  • Endometrial Neoplasms / mortality*
  • Endometrial Neoplasms / surgery
  • Endometrium / pathology
  • Endometrium / surgery
  • Female
  • Humans
  • Hysterectomy
  • Middle Aged
  • MutL Protein Homolog 1 / deficiency
  • MutL Protein Homolog 1 / genetics
  • Mutation
  • Neoplasm Grading
  • Neoplasm Invasiveness / genetics
  • Neoplasm Staging
  • Prognosis
  • Progression-Free Survival
  • Promoter Regions, Genetic / genetics
  • Prospective Studies
  • Registries / statistics & numerical data
  • Retrospective Studies
  • Risk Factors

Substances

  • MLH1 protein, human
  • MutL Protein Homolog 1