BRCA1 promoter methylation and clinical outcomes in ovarian cancer: an individual patient data meta-analysis
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.
|ISBN||1460-2105 (Electronic) 0027-8874 (Linking)|
|Authors||Kalachand, R. D.; Stordal, B.; Madden, S.; Chandler, B.; Cunningham, J.; Goode, E. L.; Ruscito, I.; Braicu, E. I.; Sehouli, J.; Ignatov, A.; Yu, H.; Katsaros, D.; Mills, G. B.; Lu, K. H.; Carey, M. S.; Timms, K. M.; Kupryjanczyk, J.; Rzepecka, I. K.; Podgorska, A.; McAlpine, J. N.; Swisher, E. M.; Bernards, S. S.; O'Riain, C.; O'Toole, S.; O'Leary, J. J.; Bowtell, D. D.; Thomas, D. M.; Prieske, K.; Joosse, S. A.; Woelber, L.; Chaudhry, P.; Hafner, N.; Runnebaum, I. B.; Hennessy, B. T.|
|Responsible Garvan Author|
|Publisher Name||JNCI-Journal of the National Cancer Institute|
|URL link to publisher's version||https://www.ncbi.nlm.nih.gov/pubmed/32413141|