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

Olga Kondrashova ,Jillian Hung ,Debra A Bell ,Kathryn Alsop ,Matthew J Wakefield ,John J Krais ,David G Allen ,J Carter ,Anthony Proietto ,Keir Pittman ,Gwo-Yaw Ho ,Robert M Rome ,Lydia Glavinas ,Tom Jobling ,Catherine A Ball ,John J Grygiel ,Brian M Alexander ,D Papadimos ,Paul Waring ,Akisha Glasgow ,Ian Hammond ,T Vanden Bergh ,Stephen Braye ,Penny Blomfield ,Karla J Hutt ,Richard B Pearson ,Bg Ward ,Sanela Bilic ,Emma Boehm ,Philip Beale ,Alexander J Crandon ,A Green ,Sián Fereday ,Fred Kirsten ,Chris Dalrymple ,Keith Horwood ,V Jayde ,Hang Tran ,Elizabeth Lieschke ,Samantha Moore ,Christian D Young ,B Young ,P Ashover ,Neil Johnson ,K R Harrap ,L M Jackman ,Marcus Davy ,Alexander Dobrovic ,Stephen M Brown ,T Sadkowsky ,Simon Hyde ,Lewis Perrin ,Thomas Schmidt ,P Mackenzie ,Joy Hendley ,Kaltin Ferguson ,Scott H Kaufmann ,Thomas Manolitsas ,Pam Mamers ,L Green ,D.l Healy ,Nick Pavlakis ,Dorota M Gertig ,David D.l Bowtell ,Yee Leung ,Jane Hill ,Craig Underhill ,Catherine Camaris ,G Chenevix-Trench ,Monica B Jones ,P Clingan ,Dc Whiteman ,Peter Grant ,Maurice B Loughrey ,Kathryn Nattress ,Alyssa Parker ,Matthew Links ,Elizabeth M Swisher ,R Stuart-Harris ,Stephen Lade ,L Edwards ,Tom Dodd ,David Nevell ,Daniel Giles ,Donald E Marsden ,Harold C Sullivan ,R Houghton ,Eric Sumithran ,Graeme M Robertson ,Maria I Harrell ,Jenny Shannon ,Ian Simpson ,R Sharma ,B Susil ,Prudence A Russell ,Deborah Neesham ,Rachel Bell ,Sumitra Ananda ,R Paul Robertson ,Alison Brand ,T Corrish ,Gerard Wain ,Anna Defazio ,R Crouch ,J Rutovitz ,Tony Bonaventura ,Vinod Ganju ,D Henderson ,R Laurie ,Penelope M Webb ,David Wyld ,Michael C Quinn ,Robert Blum ,Stephen Begbie ,Jan Pyman ,Karla Martin ,Monique Topp ,Yoke Eng Chiew ,Laura Galletta ,Iain A Mcneish ,Justin White ,Izhak Haviv ,Andreas Obermair ,Cathrine Hall ,Stephen B Fox ,Alison Hadley ,Jessica A Miller ,A Ferrier ,Annie Stenlake ,J Pierdes ,Michael Friedlander ,Neville F Hacker ,Ksenija Nesic ,Peter A W Rogers ,Orla Mcnally ,William K Murray ,Kelly‐Anne Phillips ,Bob D Brown ,Kevin K Lin ,James Stewart ,Rachel Mcintosh ,Jayne Maidens ,Neil O’callaghan ,A Mellon ,M Malt ,D Challis ,Julia Brooks ,Geoffrey Otton ,Melissa Robbie ,S Viduka ,Karen Byth ,Valerie Heong ,H Shirley ,J Mcnealage ,Martin Buck ,Nadia Traficante ,B Ranieri ,Virginia Billson ,Danny Rischin ,Gregory B Gard ,Elaine Sanij ,D M Purdie ,Richard Jaworski ,Michael P Cummings ,Anthony J Mccartney ,Timothy M Healy ,Martin K Oehler ,L.f Ng ,Paul Harnett ,Robert Holian ,Nikolajs Zeps ,Thomas C Harding ,Neha Pandeya ,Susan Valmadre ,D Johnson ,Jane Beith ,Leanne Bowes ,A Martyn ,James L Nicklin ,Giada V Zapparoli ,Sally Baron‐Hay ,Clare L Scott

doi:10.1038/s41467-018-05564-z

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.

Highlights

Identifying patients with high-grade serous ovarian carcinoma (HGSOC) who respond to poly(ADP-ribose) polymerase inhibitor (PARPi) therapy is of great clinical importance
Variable responses to rucaparib were observed in the four chemo-naive HGSOC patient-derived xenografts (PDX) with BRCA1/2 mutations, ranging from complete response (CR) to progressive disease
PARPi response has not been tested in the chemo-naive setting in the clinic, but our results were in keeping with the range of single-agent PARPi responses reported for patients with recurrent BRCA1/2 mutant HGSOC1,32,43

Summary

Introduction

Identifying patients with high-grade serous ovarian carcinoma (HGSOC) who respond to poly(ADP-ribose) polymerase inhibitor (PARPi) therapy is of great clinical importance. In support of BRCA1 methylation conferring an HR defect, it has been associated with the same gene expression signature and copy number alterations observed in BRCA1-mutated HGSOC25 and, more recently, with genomic signatures suggesting HR deficiency in breast cancer[26]. Contrary to these observations, unlike for BRCA1/2 mutations, BRCA1 methylation has not been shown to impact survival in patients with OC, with multiple studies failing to observe a significant improvement in overall survival upon stratification by BRCA1 methylation status[7,11,27,28]. The likelihood of PARPi response in patients with BRCA1-methylated HGSOC requires clarification

Methods

Results

Conclusion