BRCA1 promoter methylation and clinical outcomes in epithelial ovarian cancer a pooled analysis of individual patient data

Kalachand, Roshni D., Stordal, Britta K. ORCID logoORCID: https://orcid.org/0000-0002-7892-951X, Madden, Stephen, Chandler, Benjamin, Cunningham, Julie, Goode, Ellen L., Ruscito, Ilary, Braicu, Elena I., Sehouli, Jalid, Ignatov, Atanas, Yu, Herbert, Katsaros, Dionyssios, Lu, Lingeng, Mills, Gordon B., Broaddus, Russell, Lu, Karen H., Carey, Mark S., Timms, Kirsten M., Rzepecka, Iwona K., Kupryjanczyk, Jolanta, Swisher, Elizabeth M., Harrell, Maria I, Agnew, Karen, O'Riain, Ciaran, O'Toole, Sharon, O'Leary, John J., Thomas, David M., Chaudhry, Parvesh, Srinivasan, Radhika and Hennessy, Bryan T. (2019) BRCA1 promoter methylation and clinical outcomes in epithelial ovarian cancer a pooled analysis of individual patient data. In: Lorne Cancer Conference, 14-16 Feb 2019, Lorne, Victoria, Australia. . [Conference or Workshop Item]

Abstract

Importance: BRCA1 promoter methylation has been proposed as a mechanism of homologous recombination deficiency in epithelial ovarian cancer (EOC). Studies evaluating BRCA1-methylated EOC (BMEOC) do not consistently support improved survival outcomes following platinum chemotherapy.

Objective: To determine the clinical characteristics and survival outcomes in BMEOC.

Methods: We searched PubMed and conference abstracts combining the terms “BRCA1” and “methylat*” in October 2014 and 2016. We selected studies examining clinical and survival characteristics of BMEOC. The search retrieved 132 publications, of which 15 were eligible. Two further unpublished cohorts were obtained. Data was not available for 6 eligible studies. Data for 2322 patients from 11 retrospective studies was analysed. Associations between BRCA1 methylation and clinico-pathological characteristics were evaluated (Cochran-Mantel-Haenzel test). Overall survival (OS) and progression-free survival (PFS) were determined by Kaplan Meier statistics (Log rank test).

Results: 338 (14.6%) patients’ tumours were BRCA1-methylated. Like BRCA1 mutation, BRCA1 methylation was associated with younger age at diagnosis and advanced-stage high-grade EOC. There was no difference in PFS or OS between BMEOC and non-BMOC median PFS 21 vs 19 months (HR 0.98, 95% CI [0.85 – 1.14], p=0.82); median OS 48 vs 48 months, (HR 1.00 95% CI [0.84 – 1.18], p=0.98). On multivariate analyses, both BRCA1- and BRCA2-mutated EOC were associated with improved PFS (HR 0.71, 95% CI [0.55 -0.93], p=0.01 and HR 0.53 [0.37 – 0.74], p<0.0001, respectively) and OS (HR 0.74, 95% CI [0.59 – 0.98], p=0.03 and HR 0.54 [0.38 -0.79], p=0.001). Interestingly, BMEOC was associated with an improved PFS and OS (multivariate HR for PFS 0.69, 95% CI [0.54 – 0.90], p=0.005; multivariate HR for OS 0.71, 95% CI [0.52 – 0.97], p=0.03) as compared to non-BMEOC in the subset of cohorts utilising methylation-specific PCR.

Conclusion: BMEOC displays similar clinico-pathological features to BRCA1-mutated EOC. Heterogeneity within methylation methodology influences survival outcomes, with BMEOC being associated with improved survival solely in cohorts utilising methylation-specific PCR to detect BRCA1 methylation.

Item Type: Conference or Workshop Item (Speech)
Sustainable Development Goals:
Research Areas: A. > School of Science and Technology > Natural Sciences > Biomarkers for Cancer group
Item ID: 35365
Useful Links:
Depositing User: Britta Stordal
Date Deposited: 07 Jul 2022 12:15
Last Modified: 07 Jul 2022 12:15
URI: https://eprints.mdx.ac.uk/id/eprint/35365

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