Methylation of all BRCA1 copies predicts response to the PARP inhibitor rucaparib in ovarian carcinoma
AuthorKondrashova, O; Topp, M; Nesic, K; Lieschke, E; Ho, G-Y; Harrell, M; Zapparoli, G; Hadley, A; Holian, R; Boehm, E; ...
Source TitleNATURE COMMUNICATIONS
PublisherNATURE PUBLISHING GROUP
University of Melbourne Author/sWakefield, Matthew; Kondrashova, Olga; Nesic, Ksenija; Lieschke, Elizabeth; Ho, Gwo Yaw; HOLIAN, ROBERT; BOEHM, EMMA; Heong, Valerie; Sanij, Elaine; Pearson, Richard; ...
AffiliationMedical Biology (W.E.H.I.)
Medicine, Dentistry & Health Sciences
Medicine (St Vincent's)
Medicine, Western Health
Obstetrics and Gynaecology
Melbourne School of Population and Global Health
Sir Peter MacCallum Department of Oncology
Document TypeJournal Article
CitationsKondrashova, O., Topp, M., Nesic, K., Lieschke, E., Ho, G. -Y., Harrell, M., Zapparoli, G., Hadley, A., Holian, R., Boehm, E., Heong, V., Sanij, E., Pearson, R. B., Krais, J. J., Johnson, N., McNally, O., Ananda, S., Alsop, K., Hutt, K. J. ,... Zeps, N. (2018). Methylation of all BRCA1 copies predicts response to the PARP inhibitor rucaparib in ovarian carcinoma. NATURE COMMUNICATIONS, 9 (1), https://doi.org/10.1038/s41467-018-05564-z.
Access StatusOpen Access
Open Access at PMChttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC6162272
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-naive 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 BRCA1 methylation analysis in a pre-treatment biopsy could allow identification of patients most likely to benefit, and facilitate tailoring of PARPi therapy.
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