Methylation of all BRCA1 copies predicts response to the PARP inhibitor rucaparib in ovarian carcinoma
Authors: Kondrashova Olga , Topp Monique , Nesic Ksenija , Lieschke Elizabeth , Ho Gwo-Yaw , Harrell Maria I. , Zapparoli Giada V. , Hadley Alison , Holian Robert , Boehm Emma , Heong Valerie , Sanij Elaine , Pearson Richard B. , Krais John J. , Johnson Neil , McNally Orla , Ananda Sumitra , Alsop Kathryn , Hutt Karla J. , Kaufmann Scott H. , Lin Kevin K. , Harding Thomas C. , Traficante Nadia ,   Australian Ovarian Cancer Study (AOCS), Chenevix-Trench G. , Green A. , Webb P. , Gertig D. , Fereday S. , Moore S. , Hung J. , Harrap K. , Sadkowsky T. , Pandeya N. , Malt M. , Mellon A. , Robertson R. , Vanden Bergh T. , Jones M. , Mackenzie P. , Maidens J. , Nattress K. , Chiew Y. E. , Stenlake A. , Sullivan H. , Alexander B. , Ashover P. , Brown S. , Corrish T. , Green L. , Jackman L. , Ferguson K. , Martin K. , Martyn A. , Ranieri B. , White J. , Jayde V. , Mamers P. , Bowes L. , Galletta L. , Giles D. , Hendley J. , Schmidt T. , Shirley H. , Ball C. , Young C. , Viduka S. , Tran H. , Bilic S. , Glavinas L. , Brooks J. , Stuart-Harris R. , Kirsten F. , Rutovitz J. , Clingan P. , Glasgow A. , Proietto A. , Braye S. , Otton G. , Shannon J. , Bonaventura T. , Stewart J. , Begbie S. , Friedlander M. , Bell D. , Baron-Hay S. , Ferrier A. , Gard G. , Nevell D. , Pavlakis N. , Valmadre S. , Young B. , Camaris C. , Crouch R. , Edwards L. , Hacker N. , Marsden D. , Robertson G. , Beale P. , Beith J. , Carter J. , Dalrymple C. , Houghton R. , Russell P. , Links M. , Grygiel J. , Hill J. , Brand A. , Byth K. , Jaworski R. , Harnett P. , Sharma R. , Wain G. , Ward B. , Papadimos D. , Crandon A. , Cummings M. , Horwood K. , Obermair A. , Perrin L. , Wyld D. , Nicklin J. , Davy M. , Oehler M. K. , Hall C. , Dodd T. , Healy T. , Pittman K. , Henderson D. , Miller J. , Pierdes J. , Blomfield P. , Challis D. , McIntosh R. , Parker A. , Brown B. , Rome R. , Allen D. , Grant P. , Hyde S. , Laurie R. , Robbie M. , Healy D. , Jobling T. , Manolitsas T. , McNealage J. , Rogers P. , Susil B. , Sumithran E. , Simpson I. , Phillips K. , Rischin D. , Fox S. , Johnson D. , Lade S. , Loughrey M. , O’Callaghan N. , Murray W. , Waring P. , Billson V. , Pyman J. , Neesham D. , Quinn M. , Underhill C. , Bell R. , Ng L. F. , Blum R. , Ganju V. , Hammond I. , Leung Y. , McCartney A. , Buck M. , Haviv I. , Purdie D. , Whiteman D. , Zeps N. , deFazio Anna , McNeish Iain A. , Bowtell David D. , Swisher Elizabeth M. , Dobrovic Alexander , Wakefield Matthew J. , Scott Clare L. 
Published: September 2018

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.