Poster Presentation 31st Lorne Cancer Conference 2019

Methylation of all BRCA1 copies predicts response to the PARP inhibitor rucaparib in ovarian carcinoma (#341)

Ksenija Nesic 1 2 , Olga Kondrashova 1 2 3 , Monique Topp 1 4 , Elizabeth Lieschke 1 2 , Gwo-Yaw Ho 1 2 5 6 , Maria I Harrell 7 , Giada V Zapparoli 8 9 , Alison Hadley 1 2 , Robert Holian 1 2 , Emma Boehm 1 2 , Valerie Heong 1 2 5 , Elaine Sanij 2 6 , Richard B Pearson 2 4 6 , John J Krais 10 , Neil Johnson 10 , Orla McNally 5 , Sumitra Ananda 5 , Kathryn Alsop 6 , Karla J Hutt 4 , Scott H Kaufmann 11 , Kevin K Lin 12 , Thomas Harding 12 , Nadia Traficante 2 6 , Anna deFazio 13 14 , Iain A McNeish 15 , David D Bowtell 2 6 , Elizabeth M Swisher 7 , Alexander Dobrovic 2 8 9 , Matthew J Wakefield 1 2 , Clare L Scott 1 2 5
  1. Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia
  2. University of Melbourne, Parkville, VIC, Australia
  3. QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia
  4. Monash University, Clayton, VIC, Australia
  5. Royal Women’s Hospital, Melbourne, VIC, Australia
  6. Peter MacCallum Cancer Center, Melbourne, VIC, Australia
  7. University of Washington, Seattle, WA, United States of America
  8. Olivia Newton-John Cancer Research Institute, Heidelberg, VIC, Australia
  9. La Trobe University, Bundoora, VIC, Australia
  10. Fox Chase Cancer Center, Philadelphia, Pennsylvania, United States of America
  11. Mayo Clinic, Rochester, MN, United States of America
  12. Clovis Oncology, Boulder, CO, United States of America
  13. Westmead Institute for Medical Research, Sydney, NSW, Australia
  14. Westmead Hospital, Sydney, NSW, Australia
  15. Imperial College London, London, United Kingdom

High-grade serous ovarian carcinoma (HGSOC) is the most common subtype of ovarian cancer, and is characterized by frequent loss of homologous recombination (HR) DNA double-strand break (DSB) repair pathway proteins, such as BRCA1 and BRCA2. Despite the promising efficacy of PARP inhibitors (PARPi) in treating HR Deficient (HRD) cancers, less than 50% of BRCA1/2-defective relapsed HGSOC demonstrate an objective response. Thus, accurate identification of HGSOC patients predicted to respond to PARPi is of great clinical importance.

 

HR genes can be inactivated by deleterious mutations, but BRCA1 can also be silenced by promoter DNA methylation. Previously, however, methylation of BRCA1 was shown not to correlate with PARPi response as well as cases with BRCA1 or BRCA2 gene mutation. Using a well-characterized cohort of HGSOC cell lines and PDX with various BRCA1 methylation states, we demonstrated that methylation of all copies of BRCA1 was required to predict PARPi response, while a single unmethylated copy of BRCA1 was enough to restore HR and cause PARPi resistance. This was confirmed in an analysis of 21 BRCA1-methylated platinum-sensitive recurrent HGSOC (from the ARIEL2 Part 1 trial), accounting for the effects of neoplastic cellularity, where homozygous or hemizygous BRCA1 methylation predicted clinical response to the PARPi rucaparib, and methylation loss could occur after exposure to chemotherapy. Furthermore, constitutional BRCA1 methylation, which has been shown to strongly predispose towards the development of BRCA1 methylated breast cancer, was detected in one of the four BRCA1 methylated HGSOC PDX in our cohort.

 

This analysis has now been extended to Australian Ovarian Cancer Study samples with publicly available methylation array data, where more potential BRCA1 heterozygously methylated tumors have been identified, including some that have lost methylation following exposure to chemotherapy.

 

This work has uncovered a new approach for identifying BRCA1-methylated HGSOC patients who are most likely to derive benefit from PARPi therapy and may, in future, support changes in the way PARPi treatment regimens are tailored in the clinic.