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

Kalachand, Roshni D. ; Stordal, Britta ; Madden, Stephen ; Chandler, Benjamin

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

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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 wildtype 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 mixedeffects 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.

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