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

Olga Kondrashova, Monique Topp, Ksenija Nesic, Elizabeth Lieschke, Gwo-Yaw Ho, Maria I. Harrell, Giada V. Zapparoli, Alison Hadley, Robert Holian, Emma Boehm, Valerie Heong, Elaine Sanij, Richard B. Pearson, John J. Krais, Neil Johnson, Orla McNally, Sumitra Ananda, Kathryn Alsop, Karla J. Hutt, Scott H. Kaufmann, Kevin K. Lin, Thomas C. Harding, Nadia Traficante, Anna deFazio, Iain A. McNeish, David D. Bowtell, Elizabeth M. Swisher, Alexander Dobrovic, Matthew J. Wakefield and Clare L. Scott ()
Additional contact information
Olga Kondrashova: The Walter and Eliza Hall Institute of Medical Research
Monique Topp: The Walter and Eliza Hall Institute of Medical Research
Ksenija Nesic: The Walter and Eliza Hall Institute of Medical Research
Elizabeth Lieschke: The Walter and Eliza Hall Institute of Medical Research
Gwo-Yaw Ho: The Walter and Eliza Hall Institute of Medical Research
Maria I. Harrell: University of Washington
Giada V. Zapparoli: Olivia Newton-John Cancer Research Institute
Alison Hadley: The Walter and Eliza Hall Institute of Medical Research
Robert Holian: The Walter and Eliza Hall Institute of Medical Research
Emma Boehm: The Walter and Eliza Hall Institute of Medical Research
Valerie Heong: The Walter and Eliza Hall Institute of Medical Research
Elaine Sanij: Peter MacCallum Cancer Centre
Richard B. Pearson: Peter MacCallum Cancer Centre
John J. Krais: Fox Chase Cancer Centre
Neil Johnson: Fox Chase Cancer Centre
Orla McNally: Royal Women’s Hospital
Sumitra Ananda: Royal Women’s Hospital
Kathryn Alsop: Peter MacCallum Cancer Centre
Karla J. Hutt: Monash University
Scott H. Kaufmann: Mayo Clinic
Kevin K. Lin: Clovis Oncology
Thomas C. Harding: Clovis Oncology
Nadia Traficante: Peter MacCallum Cancer Centre
Anna deFazio: Westmead Hospital
Iain A. McNeish: Imperial College London, Kensington
David D. Bowtell: Peter MacCallum Cancer Centre
Elizabeth M. Swisher: University of Washington
Alexander Dobrovic: Olivia Newton-John Cancer Research Institute
Matthew J. Wakefield: The Walter and Eliza Hall Institute of Medical Research
Clare L. Scott: The Walter and Eliza Hall Institute of Medical Research

Nature Communications, 2018, vol. 9, issue 1, 1-16

Abstract: 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-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.

Date: 2018
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DOI: 10.1038/s41467-018-05564-z

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