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

Australian Ovarian Cancer Study (AOCS)

doi:10.1038/s41467-018-05564-z

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

Australian Ovarian Cancer Study (AOCS)

Bar-Ilan University - Azrieli Faculty of Medicine

Walter and Eliza Hall Institute of Medical Research
University of Melbourne
Monash University
Royal Women's Hospital
Peter Maccallum Cancer Centre
University of Washington
Olivia Newton-John Cancer Research Institute
La Trobe University
Fox Chase Cancer Center
Mayo Clinic Rochester, MN
Clovis Oncology
Queensland Institute of Medical Research
The University of Sydney
John Hunter Hospital
Royal Hospital for Women, Sydney
Royal North Shore Hospital
Royal Prince Alfred Hospital
Royal Adelaide Hospital
Royal Hobart Hospital
Monash Medical Center
St John of God Health Care
King Edward Memorial Hospital for Women
Canberra Hospital
Bankstown-Lidcombe Hospital
Integrated Cancer Centre
South Eastern Sydney and Illawarra Area Health Service
Nepean Hospital
Hunter Health
Port Macquarie Base Hospital
St. George Hospital
St. Vincent's Hospital Sydney
Wagga Wagga Base Hospital
Westmead Hospital
Mater Group
Royal Brisbane and Women's Hospital
UnitingCare Health
Burnside Hospital
Flinders Medical Centre
Queen Elizabeth Hospital Australia
Epworth HealthCare
Mercy Hospital for Women
Border Medical Oncology, Australia
Andrew Love Cancer Centre
Ballarat Health Services
Bendigo Health
Peninsula Health
Mount Hospital
Westmead Millennium Institute for Medical Research
Imperial College London

Research output: Contribution to journal › Article › peer-review

272 Scopus citations

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.

Original language	English
Article number	3970
Journal	Nature Communications
Volume	9
Issue number	1
DOIs	https://doi.org/10.1038/s41467-018-05564-z
State	Published - 28 Sep 2018

Bibliographical note

Publisher Copyright:
© 2018, The Author(s).

Funding

Competing interests: K.K.L. and T.C.H. are employees of Clovis Oncology, Inc. and hold stock in Clovis Oncology. A.deF. has received research grant support from AstraZeneca. The remaining authors declare no competing interests.

Funders	Funder number
National Cancer Institute	P50CA083636
AstraZeneca

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

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10.1038/s41467-018-05564-z

Cite this

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title = "Methylation of all BRCA1 copies predicts response to the PARP inhibitor rucaparib in ovarian carcinoma",

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.",

author = "\{Australian Ovarian Cancer Study (AOCS)\} and Olga Kondrashova and Monique Topp and Ksenija Nesic and Elizabeth Lieschke and Ho, \{Gwo Yaw\} and Harrell, \{Maria I.\} and Zapparoli, \{Giada V.\} and Alison Hadley and Robert Holian and Emma Boehm and Valerie Heong and Elaine Sanij and Pearson, \{Richard B.\} and Krais, \{John J.\} and Neil Johnson and Orla McNally and Sumitra Ananda and Kathryn Alsop and Hutt, \{Karla J.\} and Kaufmann, \{Scott H.\} and Lin, \{Kevin K.\} and Harding, \{Thomas C.\} and Nadia Traficante and G. Chenevix-Trench and A. Green and P. Webb and D. Gertig and S. Fereday and S. Moore and J. Hung and K. Harrap and T. Sadkowsky and N. Pandeya and M. Malt and A. Mellon and R. Robertson and T. Vanden Bergh and M. Jones and P. Mackenzie and J. Maidens and K. Nattress and Chiew, \{Y. E.\} and A. Stenlake and H. Sullivan and B. Alexander and P. Ashover and S. Brown and T. Corrish and L. Green and I. Haviv",

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AU - Lieschke, Elizabeth

AU - Ho, Gwo Yaw

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AU - Zapparoli, Giada V.

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AU - Kaufmann, Scott H.

AU - Lin, Kevin K.

AU - Harding, Thomas C.

AU - Traficante, Nadia

AU - Chenevix-Trench, G.

AU - Green, A.

AU - Webb, P.

AU - Gertig, D.

AU - Fereday, S.

AU - Moore, S.

AU - Hung, J.

AU - Harrap, K.

AU - Sadkowsky, T.

AU - Pandeya, N.

AU - Malt, M.

AU - Mellon, A.

AU - Robertson, R.

AU - Vanden Bergh, T.

AU - Jones, M.

AU - Mackenzie, P.

AU - Maidens, J.

AU - Nattress, K.

AU - Chiew, Y. E.

AU - Stenlake, A.

AU - Sullivan, H.

AU - Alexander, B.

AU - Ashover, P.

AU - Brown, S.

AU - Corrish, T.

AU - Green, L.

AU - Haviv, I.

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

Abstract

Bibliographical note

Funding

UN SDGs

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