TY - JOUR
T1 - BRCA1 Promoter Methylation and Clinical Outcomes in Ovarian Cancer
T2 - An Individual Patient Data Meta-Analysis
AU - Kalachand, Roshni D.
AU - Stordal, Britta
AU - Madden, Stephen
AU - Chandler, Benjamin
AU - Cunningham, Julie
AU - Goode, Ellen L.
AU - Ruscito, Ilary
AU - Braicu, Elena I.
AU - Sehouli, Jalid
AU - Ignatov, Atanas
AU - Yu, Herbert
AU - Katsaros, DIonyssios
AU - Mills, Gordon B.
AU - Lu, Karen H.
AU - Carey, Mark S.
AU - Timms, Kirsten M.
AU - Kupryjanczyk, Jolanta
AU - Rzepecka, Iwona K.
AU - Podgorska, Agnieszka
AU - McAlpine, Jessica N.
AU - Swisher, Elizabeth M.
AU - Bernards, Sarah S.
AU - O'Riain, Ciaran
AU - O'Toole, Sharon
AU - O'Leary, John J.
AU - Bowtell, David D.
AU - Thomas, David M.
AU - Prieske, Katharina
AU - Joosse, Simon A.
AU - Woelber, Linn
AU - Chaudhry, Parvesh
AU - Häfner, Norman
AU - Runnebaum, Ingo B.
AU - Hennessy, Bryan T.
N1 - Publisher Copyright:
© 2020 The Author(s) 2020. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.
PY - 2020/12/1
Y1 - 2020/12/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85089864435&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85089864435&partnerID=8YFLogxK
U2 - 10.1093/jnci/djaa070
DO - 10.1093/jnci/djaa070
M3 - Review article
C2 - 32413141
AN - SCOPUS:85089864435
SN - 0027-8874
VL - 112
SP - 1190
EP - 1203
JO - Journal of the National Cancer Institute
JF - Journal of the National Cancer Institute
IS - 12
ER -