Citations 1
BRCA1Promoter Methylation and Clinical Outcomes in Ovarian Cancer: An Individual Patient Data Meta-Analysis
Kalachand, Roshni , Stordal, Britta , Madden, Stephen F. , Chandler, Benjamin C. , Cunningham, Julie M. , Goode, Ellen L. , Ruscito, Ilary , Braicu, Elena Ioana , Ignatov, Atanas , Katsaros, Dionyssios , Lu, Karen H. , Carey, Mark , Timms, Kirsten M. , Podgórska, Agnieszka , Swisher, Elizabeth M. , Bernards, Sarah S., Ó’Riain, Ciarán, O’Toole, Sharon , O’Leary, John , Bowtell, David D.L. , Thomas, David M. , Prieske, Katharina , Joosse, Simon A. , Woelber, Linn, Chaudhry, Parvesh, Runnebaum, Ingo B. , Hennessy, Bryan T. , Cunningham, Julie, Swisher, Elizabeth M , Bowtell, David D , Joosse, Simon A , Sehouli, Jalid , Yu, Kai , Mills, Gordon B. , Kupryjańczyk, Jolanta , Rzepecka, Iwona K. , McAlpine, Jessica N. , Woelber, Linn Lena , Häfner, Norman
JNCI: Journal of the National Cancer Institute | May 11, 2020 | Volume: 112 | Issue: 12 | Pages: 1190-1203
AbstractBackgroundBRCA1 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.MethodsData 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.Results430 (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.ConclusionBRCA1-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.