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

Article

Kalachand, R., Stordal, B., Madden, S., Chandler, B., Cunningham, J., Goode, E., Ruscito, I., Braicu, E., Sehouli, J., Ignatov, A., Yu, H., Katsaros, D., Mills, G., Lu, K., Carey, M., Timms, K., Kupryjanczyk, J., Rzepecka, I., Podgorska, A., McAlpine, J., Swisher, E., Bernards, S., O'Riain, C., O'Toole, S., O'Leary, J., Bowtell, D., Thomas, D., Prieske, K., Joosse, S., Woelber, L., Chaudhry, P., Häfner, N., Runnebaum, I. and Hennessy, B. 2020. BRCA1 promoter methylation and clinical outcomes in ovarian cancer: an individual patient data meta-analysis. Journal of the National Cancer Institute. 112 (12), pp. 1190-1203. https://doi.org/10.1093/jnci/djaa070
TypeArticle
TitleBRCA1 promoter methylation and clinical outcomes in ovarian cancer: an individual patient data meta-analysis
AuthorsKalachand, R., Stordal, B., Madden, S., Chandler, B., Cunningham, J., Goode, E., Ruscito, I., Braicu, E., Sehouli, J., Ignatov, A., Yu, H., Katsaros, D., Mills, G., Lu, K., Carey, M., Timms, K., Kupryjanczyk, J., Rzepecka, I., Podgorska, A., McAlpine, J., Swisher, E., Bernards, S., O'Riain, C., O'Toole, S., O'Leary, J., Bowtell, D., Thomas, D., Prieske, K., Joosse, S., Woelber, L., Chaudhry, P., Häfner, N., Runnebaum, I. and Hennessy, B.
Abstract

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.

Research GroupBiomarkers for Cancer group
PublisherOxford University Press (OUP)
JournalJournal of the National Cancer Institute
ISSN0027-8874
Electronic1460-2105
Publication dates
Online15 May 2020
Print14 Dec 2020
Publication process dates
Deposited02 Aug 2020
Accepted11 May 2020
Submitted02 Feb 2020
Output statusPublished
Accepted author manuscript
Copyright Statement

This is a pre-copyedited, author-produced version of an article accepted for publication in Journal of the National Cancer Institute following peer review. The version of record Roshni D Kalachand, Britta Stordal, Stephen Madden, Benjamin Chandler, Julie Cunningham, Ellen L Goode, Ilary Ruscito, Elena I Braicu, Jalid Sehouli, Atanas Ignatov, Herbert Yu, Dionyssios Katsaros, Gordon B Mills, Karen H Lu, Mark S Carey, Kirsten M Timms, Jolanta Kupryjanczyk, Iwona K Rzepecka, Agnieszka Podgorska, Jessica N McAlpine, Elizabeth M Swisher, Sarah S Bernards, Ciaran O’Riain, Sharon O’Toole, John J O’Leary, David D Bowtell, David M Thomas, Katharina Prieske, Simon A Joosse, Linn Woelber, Parvesh Chaudhry, Norman Häfner, Ingo B Runnebaum, Bryan T Hennessy, BRCA1 Promoter Methylation and Clinical Outcomes in Ovarian Cancer: An Individual Patient Data Meta-Analysis, JNCI: Journal of the National Cancer Institute, Volume 112, Issue 12, December 2020, Pages 1190–1203, is available online at: https://academic.oup.com/jnci/article/112/12/1190/5837681 and https://doi.org/10.1093/jnci/djaa070 on the OUP website

Digital Object Identifier (DOI)https://doi.org/10.1093/jnci/djaa070
PubMed ID32413141
PubMed Central ID7735770
Web of Science identifierWOS:000606177900005
LanguageEnglish
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