Methylation of all BRCA1 copies predicts response to the PARP inhibitor rucaparib in ovarian carcinoma
Olga Kondrashova(The University of Melbourne), Monique Topp(Walter and Eliza Hall Institute of Medical Research), Ksenija Nesic(The University of Melbourne), Elizabeth Lieschke(Walter and Eliza Hall Institute of Medical Research), Gwo‐Yaw Ho(Royal Women's Hospital), Maria I. Harrell(University of Washington), Giada V. Zapparoli(La Trobe University), Alison Hadley(The University of Melbourne), Robert Holian(The University of Melbourne), Emma Boehm(The University of Melbourne), Valerie Heong(Royal Women's Hospital), Elaine Sanij(The University of Melbourne), Richard B. Pearson(The University of Melbourne), John J. Krais(Fox Chase Cancer Center), Neil Johnson(Fox Chase Cancer Center), 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 in Arizona), Kevin Lin(Clovis Oncology (United States)), Thomas C. Harding(Clovis Oncology (United States)), Nadia Traficante(The University of Melbourne), Australian Ovarian Cancer Study (AOCS)(QIMR Berghofer Medical Research Institute), Georgia Chenevix‐Trench(QIMR Berghofer Medical Research Institute), A. Green(QIMR Berghofer Medical Research Institute), Penelope M. Webb(The University of Melbourne), Dorota M. Gertig(The University of Melbourne), Sián Fereday(QIMR Berghofer Medical Research Institute), Suzanne Moore(The University of Sydney), Jillian A. Hung(The University of Sydney), K.R. Harrap(QIMR Berghofer Medical Research Institute), T. Sadkowsky(QIMR Berghofer Medical Research Institute), Nirmala Pandeya(QIMR Berghofer Medical Research Institute), M. Malt(QIMR Berghofer Medical Research Institute), A. Mellon(John Hunter Hospital), R. Paul Robertson(Royal Hospital for Women), T. Vanden Bergh(Royal Hospital for Women), Milissa U. Jones(Royal Hospital for Women), P. Mackenzie(Royal Hospital for Women), J. Maidens(Royal Prince Alfred Hospital), K. Nattress(The University of Sydney), Yoke-Eng Chiew(The University of Sydney), Annie Stenlake(The University of Sydney), Harold C. Sullivan(The University of Sydney), Brian M. Alexander(QIMR Berghofer Medical Research Institute), P. Ashover(QIMR Berghofer Medical Research Institute), Stephen M. Brown(QIMR Berghofer Medical Research Institute), T. Corrish(QIMR Berghofer Medical Research Institute), L. Green(QIMR Berghofer Medical Research Institute), L. M. Jackman(QIMR Berghofer Medical Research Institute), Kaltin Ferguson(QIMR Berghofer Medical Research Institute), Karla Martin(QIMR Berghofer Medical Research Institute), A. Martyn(QIMR Berghofer Medical Research Institute), B. Ranieri(Royal Adelaide Hospital), J. White(Royal Adelaide Hospital), V. Jayde(Monash Medical Centre), Pam Mamers(Peter MacCallum Cancer Centre), Leanne Bowes(Peter MacCallum Cancer Centre), Laura Galletta(Peter MacCallum Cancer Centre), Daniel A. Giles(Peter MacCallum Cancer Centre), Joy Hendley(Peter MacCallum Cancer Centre), Thomas Schmidt, H. Shirley(King Edward Memorial Hospital), C. Ball(King Edward Memorial Hospital), Christian D. Young(King Edward Memorial Hospital), S. Viduka, Hang Tran, Sanela Bilic, Lydia Glavinas(St John of God Subiaco Hospital), Julia Brooks(St John of God Subiaco Hospital), R. Stuart‐Harris(Bankstown Lidcombe Hospital), Fred Kirsten(Bankstown Lidcombe Hospital), J Rutovitz(Wollongong Hospital), P. Clingan(Wollongong Hospital), Akisha Glasgow(John Hunter Hospital), Anthony Proietto(John Hunter Hospital), Stephen Braye(John Hunter Hospital), Geoffrey Otton(John Hunter Hospital), Jenny Shannon(Mater Misericordiae Hospital), Tony Bonaventura(Mater Misericordiae Hospital), James Stewart(Mater Misericordiae Hospital), Stephen Begbie(The University of Sydney), Michael Friedländer(The University of Sydney), Debra Bell(Royal North Shore Hospital), Sally Baron‐Hay(Royal North Shore Hospital), A. Ferrier(Royal North Shore Hospital), G. Gard(Royal North Shore Hospital), David Nevell(Royal North Shore Hospital), Nick Pavlakis(Royal North Shore Hospital), Susan Valmadre(Royal North Shore Hospital), B. Young(Royal Hospital for Women), C. Camaris(Royal Hospital for Women), R. Crouch(Royal Hospital for Women), L. Edwards(Royal Hospital for Women), Neville F. Hacker(Royal Hospital for Women), Donald E. Marsden(Royal Hospital for Women), G.M. Robertson(Royal Prince Alfred Hospital), Philip Beale(Royal Prince Alfred Hospital), Jane Beith(Royal Prince Alfred Hospital), Jonathan Carter(Royal Prince Alfred Hospital), C. Dalrymple(Royal Prince Alfred Hospital), R. Houghton(Royal Prince Alfred Hospital), Prudence A. Russell(Royal Prince Alfred Hospital), Matthew Links(St Vincent's Hospital Sydney), John J. Grygiel(St Vincent's Hospital Sydney), Jane Hill(Westmead Hospital), Alison H. Brand(Westmead Hospital), Karen Byth(Westmead Hospital), Richard Jaworski(Westmead Hospital), Paul R. Harnett(The University of Sydney), R. Sharma(The University of Sydney), Gerard Wain(Mater Misericordiae Hospital), B. Ward(Mater Misericordiae Hospital), D. Papadimos(Royal Brisbane and Women's Hospital), A. Crandon(Royal Brisbane and Women's Hospital), Michael P. Cummings(Royal Brisbane and Women's Hospital), K. Horwood(Royal Brisbane and Women's Hospital), Andreas Obermair(Royal Brisbane and Women's Hospital), Lewis Perrin(Royal Brisbane and Women's Hospital), David Wyld(Royal Brisbane and Women's Hospital), James Nicklin(Royal Adelaide Hospital), Marcus Davy(Royal Adelaide Hospital), Martin K. Oehler(Royal Adelaide Hospital), Cathrine Hall(Royal Adelaide Hospital), Tom Dodd(Royal Adelaide Hospital), Timothy M. Healy, Keir Pittman(Flinders Medical Centre), Deborah J. Henderson(Flinders Medical Centre), Jessica A. Miller(St John of God Subiaco Hospital), J. Pierdes(St John of God Subiaco Hospital), Penny Blomfield(Royal Hobart Hospital), D. Challis(Royal Hobart Hospital), Rachel McIntosh(Royal Hobart Hospital), Alyssa Parker(Royal Hobart Hospital), Robert Brown(Freemasons Foundation Centre for Men's Health), Robert Rome(Mercy Hospital for Women), David G. Allen(Mercy Hospital for Women), Peter Grant(Mercy Hospital for Women), Simon Hyde(Mercy Hospital for Women), R. Laurie(Mercy Hospital for Women), Melissa Robbie(Mercy Hospital for Women), David Healy(Monash Medical Centre), Tom Jobling(Monash Medical Centre), T. Manolitsas(Monash Medical Centre), J. McNealage(Monash Medical Centre), Peter A. W. Rogers(Monash Medical Centre), B. Susil(Monash Medical Centre), E. Sumithran(Monash Medical Centre), Ian Simpson(Peter MacCallum Cancer Centre), Kelly‐Anne Phillips(Peter MacCallum Cancer Centre), Danny Rischin(Peter MacCallum Cancer Centre), Stephen B. Fox(Peter MacCallum Cancer Centre), Debi Johnson(Peter MacCallum Cancer Centre), Stephen Lade(Peter MacCallum Cancer Centre), Maurice B. Loughrey(Peter MacCallum Cancer Centre), N. O’Callaghan(Peter MacCallum Cancer Centre), William K. Murray(The University of Melbourne), Paul Waring(Royal Women's Hospital), Virginia Billson(Royal Women's Hospital), Jan Pyman(Royal Women's Hospital), Deborah Neesham(Royal Women's Hospital), Michael Quinn(Royal Women's Hospital), Craig Underhill, Rachel Bell(Ballarat Health Services), L. F. Ng(Ballarat Health Services), Robert Blum(Peninsula Health), Vinod Ganju(King Edward Memorial Hospital), Ian Hammond(King Edward Memorial Hospital), Yee Leung(King Edward Memorial Hospital), Anthony J. McCartney(King Edward Memorial Hospital), Martin Buck(Bar-Ilan University), I. Haviv(Bar-Ilan University), D. Purdie(QIMR Berghofer Medical Research Institute), David C. Whiteman(QIMR Berghofer Medical Research Institute), Nikolajs Zeps(The University of Sydney), Anna DeFazio(The University of Sydney), Iain A. McNeish(The University of Melbourne), David D.L. Bowtell(The University of Melbourne), Elizabeth M. Swisher(The University of Melbourne), Alexander Dobrovic(The University of Melbourne), Matthew J. Wakefield(The University of Melbourne), Clare L. Scott(Walter and Eliza Hall Institute of Medical Research)
Cited by 288Open Access
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.
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