BRCA1 Promoter Methylation and Clinical Outcomes in Ovarian Cancer: An Individual Patient Data Meta-Analysis

Roshni D. Kalachand, Britta Stordal, Stephen Madden, Benjamin Chandler, Julie Cunningham, Ellen L. Goode, Ilary Ruscito, Elena I. Braicu, Jalid Sehouli, Atanas Ignatov, Herbert Yu, DIonyssios Katsaros, Gordon B. Mills, Karen H. Lu, Mark S. Carey, Kirsten M. Timms, Jolanta Kupryjanczyk, Iwona K. Rzepecka, Agnieszka Podgorska, Jessica N. McAlpineElizabeth M. Swisher, Sarah S. Bernards, Ciaran O'Riain, Sharon O'Toole, John J. O'Leary, David D. Bowtell, David M. Thomas, Katharina Prieske, Simon A. Joosse, Linn Woelber, Parvesh Chaudhry, Norman Häfner, Ingo B. Runnebaum, Bryan T. Hennessy

    Research output: Contribution to journalReview articlepeer-review

    5 Scopus citations

    Abstract

    Background: BRCA1 methylation has been associated with homologous recombination deficiency, a biomarker of platinum sensitivity. Studies evaluating BRCA1-methylated tubal and ovarian cancer (OC) do not consistently support improved survival following platinum chemotherapy. We examine the characteristics of BRCA1-methylated OC in a meta-analysis of individual participant data. Methods: Data of 2636 participants across 15 studies were analyzed. BRCA1-methylated tumors were defined according to their original study. Associations between BRCA1 methylation and clinicopathological characteristics were evaluated. The effects of methylation on overall survival (OS) and progression-free survival (PFS) were examined using mixed-effects models. All statistical tests were 2-sided. Results: 430 (16.3%) tumors were BRCA1-methylated. BRCA1 methylation was associated with younger age and advanced-stage, high-grade serous OC. There were no survival differences between BRCA1-methylated and non-BRCA1-methylated OC (median PFS = 20.0 vs 18.5 months, hazard ratio [HR] = 1.01, 95% CI = 0.87 to 1.16; P =. 98; median OS = 46.6 vs 48.0 months, HR = 1.02, 95% CI = 0.87 to 1.18; P =. 96). Where BRCA1/2 mutations were evaluated (n = 1248), BRCA1 methylation displayed no survival advantage over BRCA1/2-intact (BRCA1/2 wild-type non-BRCA1-methylated) OC. Studies used different methods to define BRCA1 methylation. Where BRCA1 methylation was determined using methylation-specific polymerase chain reaction and gel electrophoresis (n = 834), it was associated with improved survival (PFS: HR = 0.80, 95% CI = 0.66 to 0.97; P =. 02; OS: HR = 0.80, 95% CI = 0.63 to 1.00; P =. 05) on mixed-effects modeling. Conclusion: BRCA1-methylated OC displays similar clinicopathological features to BRCA1-mutated OC but is not associated with survival. Heterogeneity within BRCA1 methylation assays influences associations. Refining these assays may better identify cases with silenced BRCA1 function and improved patient outcomes.

    Original languageEnglish (US)
    Pages (from-to)1190-1203
    Number of pages14
    JournalJournal of the National Cancer Institute
    Volume112
    Issue number12
    DOIs
    StatePublished - Dec 1 2020

    ASJC Scopus subject areas

    • Oncology
    • Cancer Research

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