Small-scale mutations are infrequent as mechanisms of resistance in post-PARP inhibitor tumour samples in high grade serous ovarian cancer
Authors: Burdett Nikki L. , Willis Madelynne O. , Pandey Ahwan , Fereday Sian ,   AOCS Study Group,   Management Group, Bowtell D. , Chenevix-Trench G. , Green A. , Webb P. , DeFazio A. , Gertig D. ,   Project and Data Managers, Traficante N. , Fereday S. , Moore S. , Hung J. , Harrap K. , Sadkowsky T. , Pandeya N. ,   Research Nurses and Assistants, 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. , Alsop K. , Schmidt T. , Shirley H. , Ball C. , Young C. , Viduka S. , Tran Hoa , Bilic Sanela , Glavinas Lydia , Brooks Julia ,   Clinical and Scientific Collaborators, 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. , Mileshkin L. , Au-Yeung G. , 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 , Bowtell David D. L. , Christie Elizabeth L. 
Published: December 2023

AbstractWhile the introduction of poly-(ADP)-ribose polymerase (PARP) inhibitors in homologous recombination DNA repair (HR) deficient high grade serous ovarian, fallopian tube and primary peritoneal cancers (HGSC) has improved patient survival, resistance to PARP inhibitors frequently occurs. Preclinical and translational studies have identified multiple mechanisms of resistance; here we examined tumour samples collected from 26 women following treatment with PARP inhibitors as part of standard of care or their enrolment in clinical trials. Twenty-one had a germline or somatic BRCA1/2 mutation. We performed targeted sequencing of 63 genes involved in DNA repair processes or implicated in ovarian cancer resistance. We found that just three individuals had a small-scale mutation as a definitive resistance mechanism detected, having reversion mutations, while six had potential mechanisms of resistance detected, with alterations related to BRCA1 function and mutations in SHLD2. This study indicates that mutations in genes related to DNA repair are detected in a minority of HGSC patients as genetic mechanisms of resistance. Future research into resistance in HGSC should focus on copy number, transcriptional and epigenetic aberrations, and the contribution of the tumour microenvironment.