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

Australian Ovarian Cancer Study (AOCS)

Research output: Contribution to journalArticle

17 Citations (Scopus)

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 languageEnglish (US)
Article number3970
JournalNature Communications
Volume9
Issue number1
DOIs
StatePublished - Dec 1 2018

Fingerprint

methylation
Methylation
inhibitors
Heterografts
cancer
ribose
adenosine diphosphate
Carcinoma
grade
therapy
Chemotherapy
Biopsy
Platinum
Repair
chemotherapy
rucaparib
Poly(ADP-ribose) Polymerase Inhibitors
DNA Repair
pretreatment
Ovarian Neoplasms

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

Cite this

Methylation of all BRCA1 copies predicts response to the PARP inhibitor rucaparib in ovarian carcinoma. / Australian Ovarian Cancer Study (AOCS).

In: Nature Communications, Vol. 9, No. 1, 3970, 01.12.2018.

Research output: Contribution to journalArticle

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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 L. Jackman",
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AU - Topp, Monique

AU - Nesic, Ksenija

AU - Lieschke, Elizabeth

AU - Ho, Gwo Yaw

AU - Harrell, Maria I.

AU - Zapparoli, Giada V.

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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 - Jackman, L.

PY - 2018/12/1

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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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