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

Olga Kondrashova, Monique Topp, Ksenija Nesic, Elizabeth Lieschke, Gwo Yaw Ho, Maria I. Harrell, Giada V. Zapparoli, Alison Hadley, Robert Holian, Emma Boehm, Valerie Heong, Elaine Sanij, Richard B. Pearson, John J. Krais, Neil Johnson, Orla McNally, Sumitra Ananda, Kathryn Alsop, Karla J. Hutt, Scott H. Kaufmann & 11 others Kevin K. Lin, Thomas C. Harding, Nadia Traficante, Australian Ovarian Cancer Study (AOCS), Anna deFazio, Iain A. McNeish, David D. Bowtell, Elizabeth M. Swisher, Alexander Dobrovic, Matthew J. Wakefield, Clare L. Scott

Research output: Contribution to journalArticleResearchpeer-review

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
Article number3970
Number of pages16
JournalNature Communications
Volume9
Issue number1
DOIs
Publication statusPublished - 1 Dec 2018

Cite this

Kondrashova, Olga ; Topp, Monique ; Nesic, Ksenija ; Lieschke, Elizabeth ; Ho, Gwo Yaw ; Harrell, Maria I. ; Zapparoli, Giada V. ; Hadley, Alison ; Holian, Robert ; Boehm, Emma ; Heong, Valerie ; Sanij, Elaine ; Pearson, Richard B. ; Krais, John J. ; Johnson, Neil ; McNally, Orla ; Ananda, Sumitra ; Alsop, Kathryn ; Hutt, Karla J. ; Kaufmann, Scott H. ; Lin, Kevin K. ; Harding, Thomas C. ; Traficante, Nadia ; Australian Ovarian Cancer Study (AOCS) ; deFazio, Anna ; McNeish, Iain A. ; Bowtell, David D. ; Swisher, Elizabeth M. ; Dobrovic, Alexander ; Wakefield, Matthew J. ; Scott, Clare L. / Methylation of all BRCA1 copies predicts response to the PARP inhibitor rucaparib in ovarian carcinoma. In: Nature Communications. 2018 ; Vol. 9, No. 1.
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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 = "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 {Australian Ovarian Cancer Study (AOCS)} 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 and K. Ferguson and K. Martin and A. Martyn and B. Ranieri and J. White and V. Jayde and P. Mamers and L. Bowes and L. Galletta and D. Giles and J. Hendley and T. Schmidt and H. Shirley and C. Ball and C. Young and S. Viduka and H. Tran and S. Bilic and L. Glavinas and J. Brooks and R. Stuart-Harris and F. Kirsten and J. Rutovitz and P. Clingan and A. Glasgow and A. Proietto and S. Braye and G. Otton and J. Shannon and T. Bonaventura and J. Stewart and S. Begbie and M. Friedlander and D. Bell and S. Baron-Hay and A. Ferrier and G. Gard and D. Nevell and N. Pavlakis and S. Valmadre and B. Young and C. Camaris and R. Crouch and L. Edwards and N. Hacker and D. Marsden and G. Robertson and P. Beale and J. Beith and J. Carter and C. Dalrymple and R. Houghton and P. Russell and M. Links and J. Grygiel and J. Hill and A. Brand and K. Byth and R. Jaworski and P. Harnett and R. Sharma and G. Wain and B. Ward and D. Papadimos and A. Crandon and M. Cummings and K. Horwood and A. Obermair and L. Perrin and D. Wyld and J. Nicklin and M. Davy and Oehler, {M. K.} and C. Hall and T. Dodd and T. Healy and K. Pittman and D. Henderson and J. Miller and J. Pierdes and P. Blomfield and D. Challis and R. McIntosh and A. Parker and B. Brown and R. Rome and D. Allen and P. Grant and S. Hyde and R. Laurie and M. Robbie and D. Healy and T. Jobling and T. Manolitsas and J. McNealage and P. Rogers and B. Susil and E. Sumithran and I. Simpson and K. Phillips and D. Rischin and S. Fox and D. Johnson and S. Lade and M. Loughrey and N. O’Callaghan and W. Murray and P. Waring and V. Billson and J. Pyman and D. Neesham and M. Quinn and C. Underhill and R. Bell and Ng, {L. F.} and R. Blum and V. Ganju and I. Hammond and Y. Leung and A. McCartney and M. Buck and I. Haviv and D. Purdie and D. Whiteman and N. Zeps and Anna deFazio and McNeish, {Iain A.} and Bowtell, {David D.} and Swisher, {Elizabeth M.} and Alexander Dobrovic and Wakefield, {Matthew J.} and Scott, {Clare L.}",
year = "2018",
month = "12",
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doi = "10.1038/s41467-018-05564-z",
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Kondrashova, O, Topp, M, Nesic, K, Lieschke, E, Ho, GY, Harrell, MI, Zapparoli, GV, Hadley, A, Holian, R, Boehm, E, Heong, V, Sanij, E, Pearson, RB, Krais, JJ, Johnson, N, McNally, O, Ananda, S, Alsop, K, Hutt, KJ, Kaufmann, SH, Lin, KK, Harding, TC, Traficante, N, Australian Ovarian Cancer Study (AOCS), deFazio, A, McNeish, IA, Bowtell, DD, Swisher, EM, Dobrovic, A, Wakefield, MJ & Scott, CL 2018, 'Methylation of all BRCA1 copies predicts response to the PARP inhibitor rucaparib in ovarian carcinoma', Nature Communications, vol. 9, no. 1, 3970. https://doi.org/10.1038/s41467-018-05564-z

Methylation of all BRCA1 copies predicts response to the PARP inhibitor rucaparib in ovarian carcinoma. / Kondrashova, Olga; Topp, Monique; Nesic, Ksenija; Lieschke, Elizabeth; Ho, Gwo Yaw; Harrell, Maria I.; Zapparoli, Giada V.; Hadley, Alison; Holian, Robert; Boehm, Emma; Heong, Valerie; Sanij, Elaine; Pearson, Richard B.; Krais, John J.; Johnson, Neil; McNally, Orla; Ananda, Sumitra; Alsop, Kathryn; Hutt, Karla J.; Kaufmann, Scott H.; Lin, Kevin K.; Harding, Thomas C.; Traficante, Nadia; Australian Ovarian Cancer Study (AOCS); deFazio, Anna; McNeish, Iain A.; Bowtell, David D.; Swisher, Elizabeth M.; Dobrovic, Alexander; Wakefield, Matthew J.; Scott, Clare L.

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

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Methylation of all BRCA1 copies predicts response to the PARP inhibitor rucaparib in ovarian carcinoma

AU - Kondrashova, Olga

AU - Topp, Monique

AU - Nesic, Ksenija

AU - Lieschke, Elizabeth

AU - Ho, Gwo Yaw

AU - Harrell, Maria I.

AU - Zapparoli, Giada V.

AU - Hadley, Alison

AU - Holian, Robert

AU - Boehm, Emma

AU - Heong, Valerie

AU - Sanij, Elaine

AU - Pearson, Richard B.

AU - Krais, John J.

AU - Johnson, Neil

AU - McNally, Orla

AU - Ananda, Sumitra

AU - Alsop, Kathryn

AU - Hutt, Karla J.

AU - Kaufmann, Scott H.

AU - Lin, Kevin K.

AU - Harding, Thomas C.

AU - Traficante, Nadia

AU - Australian Ovarian Cancer Study (AOCS)

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 - Jackman, L.

AU - Ferguson, K.

AU - Martin, K.

AU - Martyn, A.

AU - Ranieri, B.

AU - White, J.

AU - Jayde, V.

AU - Mamers, P.

AU - Bowes, L.

AU - Galletta, L.

AU - Giles, D.

AU - Hendley, J.

AU - Schmidt, T.

AU - Shirley, H.

AU - Ball, C.

AU - Young, C.

AU - Viduka, S.

AU - Tran, H.

AU - Bilic, S.

AU - Glavinas, L.

AU - Brooks, J.

AU - Stuart-Harris, R.

AU - Kirsten, F.

AU - Rutovitz, J.

AU - Clingan, P.

AU - Glasgow, A.

AU - Proietto, A.

AU - Braye, S.

AU - Otton, G.

AU - Shannon, J.

AU - Bonaventura, T.

AU - Stewart, J.

AU - Begbie, S.

AU - Friedlander, M.

AU - Bell, D.

AU - Baron-Hay, S.

AU - Ferrier, A.

AU - Gard, G.

AU - Nevell, D.

AU - Pavlakis, N.

AU - Valmadre, S.

AU - Young, B.

AU - Camaris, C.

AU - Crouch, R.

AU - Edwards, L.

AU - Hacker, N.

AU - Marsden, D.

AU - Robertson, G.

AU - Beale, P.

AU - Beith, J.

AU - Carter, J.

AU - Dalrymple, C.

AU - Houghton, R.

AU - Russell, P.

AU - Links, M.

AU - Grygiel, J.

AU - Hill, J.

AU - Brand, A.

AU - Byth, K.

AU - Jaworski, R.

AU - Harnett, P.

AU - Sharma, R.

AU - Wain, G.

AU - Ward, B.

AU - Papadimos, D.

AU - Crandon, A.

AU - Cummings, M.

AU - Horwood, K.

AU - Obermair, A.

AU - Perrin, L.

AU - Wyld, D.

AU - Nicklin, J.

AU - Davy, M.

AU - Oehler, M. K.

AU - Hall, C.

AU - Dodd, T.

AU - Healy, T.

AU - Pittman, K.

AU - Henderson, D.

AU - Miller, J.

AU - Pierdes, J.

AU - Blomfield, P.

AU - Challis, D.

AU - McIntosh, R.

AU - Parker, A.

AU - Brown, B.

AU - Rome, R.

AU - Allen, D.

AU - Grant, P.

AU - Hyde, S.

AU - Laurie, R.

AU - Robbie, M.

AU - Healy, D.

AU - Jobling, T.

AU - Manolitsas, T.

AU - McNealage, J.

AU - Rogers, P.

AU - Susil, B.

AU - Sumithran, E.

AU - Simpson, I.

AU - Phillips, K.

AU - Rischin, D.

AU - Fox, S.

AU - Johnson, D.

AU - Lade, S.

AU - Loughrey, M.

AU - O’Callaghan, N.

AU - Murray, W.

AU - Waring, P.

AU - Billson, V.

AU - Pyman, J.

AU - Neesham, D.

AU - Quinn, M.

AU - Underhill, C.

AU - Bell, R.

AU - Ng, L. F.

AU - Blum, R.

AU - Ganju, V.

AU - Hammond, I.

AU - Leung, Y.

AU - McCartney, A.

AU - Buck, M.

AU - Haviv, I.

AU - Purdie, D.

AU - Whiteman, D.

AU - Zeps, N.

AU - deFazio, Anna

AU - McNeish, Iain A.

AU - Bowtell, David D.

AU - Swisher, Elizabeth M.

AU - Dobrovic, Alexander

AU - Wakefield, Matthew J.

AU - Scott, Clare L.

PY - 2018/12/1

Y1 - 2018/12/1

N2 - 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.

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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DO - 10.1038/s41467-018-05564-z

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JO - Nature Communications

JF - Nature Communications

SN - 2041-1723

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