Methylation of all BRCA1 copies predicts response to the PARP inhibitor rucaparib in ovarian carcinoma

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Title: Methylation of all BRCA1 copies predicts response to the PARP inhibitor rucaparib in ovarian carcinoma
Author(s): McNeish, IA
Kondrashova, O
Topp, M
Nesic, K
Lieschke, E
Ho, G-Y
Harrell, MI
Zapparoli, GV
Hadley, A
Holian, R
Boehm, E
Heong, V
Sanij, E
Pearson, RB
Krais, JJ
Johnson, N
McNally, O
Ananda, S
Alsop, K
Hutt, KJ
Kaufmann, SH
Lin, KK
Harding, TC
Traficante, N
DeFazio, A
Bowtell, DD
Swisher, EM
Dobrovic, A
Wakefield, MJ
Scott, CL
Item Type: Journal Article
Abstract: Accurately identifying patients with high-grade serous ovarian carcinoma (HGSOC) who respond to poly(ADP-ribose) polymerase inhibitor (PARPi) therapy is of great clinical importance. Here we show that quantitative BRCA1 methylation analysis provides new insight into PARPi response in preclinical models and ovarian cancer patients. The response of 12 HGSOC patient-derived xenografts (PDX) to the PARPi rucaparib was assessed, with variable dose-dependent responses observed in chemo-naïve BRCA1/2-mutated PDX, and no responses in PDX lacking DNA repair pathway defects. Among BRCA1-methylated PDX, silencing of all BRCA1 copies predicts rucaparib response, whilst heterozygous methylation is associated with resistance. Analysis of 21 BRCA1-methylated platinum-sensitive recurrent HGSOC (ARIEL2 Part 1 trial) confirmed that homozygous or hemizygous BRCA1 methylation predicts rucaparib clinical response, and that methylation loss can occur after exposure to chemotherapy. Accordingly, quantitative BRCA1methylation analysis in a pre-treatment biopsy could allow identification of patients most likely to benefit and facilitate tailoring of PARPi therapy.
Publication Date: 28-Sep-2018
Date of Acceptance: 25-Jun-2018
ISSN: 2041-1723
Publisher: Nature Publishing Group
Journal / Book Title: Nature Communications
Copyright Statement: This paper is embargoed until publication. Once published it will be available fully open access.
Sponsor/Funder: Imperial College Healthcare NHS Trust- BRC Funding
Cancer Research UK
Funder's Grant Number: RDB01
Keywords: MD Multidisciplinary
Publication Status: Accepted
Embargo Date: publication subject to indefinite embargo
Appears in Collections:Division of Surgery
Division of Cancer
Faculty of Medicine

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