BRCA1 promoter methylation and clinical outcomes in ovarian cancer: an individual patient data meta-analysis

Kalachand, Rd; Stordal, B; Madden, S; Chandler, B; Cunningham, J; Goode, El; Ruscito, I; Braicu, Ei; Sehouli, J; Ignatov, A; H, Yu; Katsaros, D; Mills, Gb; Kh, Lu; Carey, Ms; Timms, Km; Kupryjanczyk, J; Rzepecka, Ik; Podgorska, A; Mcalpine, Jn; Swisher, Em; Bernards, Ss; O'Riain, C; O'Toole, S; O'Leary, Jj; Bowtell, Dd; Thomas, Dm; Prieske, K; Joosse, Sa; Woelber, L; Chaudhry, P; Häfner, N; Runnebaum, Ib; Hennessy, Bt.

doi:10.1093/jnci/djaa070

Background: BRCA1 methylation has been associated with homologous recombination deficiency, a biomarker of platinum sensitivity. Studies evaluating BRCA1-methylated tubal/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: 2636 participants' data across 15 studies were analyzed. BRCA1-methylated tumors were defined according to their original study. Associations between BRCA1 methylation and clinico-pathological 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 two-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, HR = 1.01, 95% CI = 0.87-1.16, P=0.98; median OS = 46.6 vs 48.0 months, HR = 1.02, 95% CI = 0.87-1.18, P=0.96). 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 PCR and gel electrophoresis (n = 834), it was associated with improved survival (PFS: HR = 0.80, 95% CI = 0.66-0.97, P=0.02; OS: HR = 0.80, 95% CI = 0.63-1.00, P=0.05) on mixed-effects modelling. Conclusion: BRCA1-methylated OC displays similar clinico-pathological 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

BRCA1 promoter methylation and clinical outcomes in ovarian cancer: an individual patient data meta-analysis / Kalachand, Rd; Stordal, B; Madden, S; Chandler, B; Cunningham, J; Goode, El; Ruscito, I; Braicu, Ei; Sehouli, J; Ignatov, A; Yu, H; Katsaros, D; Mills, Gb; Lu, Kh; Carey, Ms; Timms, Km; Kupryjanczyk, J; Rzepecka, Ik; Podgorska, A; McAlpine, Jn; Swisher, Em; Bernards, Ss; O'Riain, C; O'Toole, S; O'Leary, Jj; Bowtell, Dd; Thomas, Dm; Prieske, K; Joosse, Sa; Woelber, L; Chaudhry, P; Häfner, N; Runnebaum, Ib; Hennessy, Bt.. - In: JOURNAL OF THE NATIONAL CANCER INSTITUTE. - ISSN 0027-8874. - (2020), pp. 1-14. [10.1093/jnci/djaa070]