Effect of HIPEC according to HRD/BRCAwt genomic profile in stage III ovarian cancer: Results from the phase III OVHIPEC trial

Simone N. Koole; Philip C. Schouten; Jan Hauke; Roel J. C. Kluin; Petra Nederlof; Lisa K. Richters; Gabriele Krebsbach; Karolina Sikorska; Maartje Alkemade; Mark Opdam; Jules H. Schagen van Leeuwen; Henk W. R. Schreuder; Ralph H. M. Hermans; Ignace H. J. T. de Hingh; Constantijne H. Mom; Henriette J. G. Arts; Maaike van Ham; Peter van Dam; Peter Vuylsteke; Joyce Sanders; Hugo M. Horlings; Koen K. van de Vijver; Eric Hahnen; Willemien J. van Driel; Rita Schmutzler; Gabe S. Sonke; Sabine C. Linn

doi:https://doi.org/10.1002/ijc.34124

Effect of HIPEC according to HRD/BRCAwt genomic profile in stage III ovarian cancer: Results from the phase III OVHIPEC trial

Simone N. Koole, Philip C. Schouten, Jan Hauke, Roel J. C. Kluin, Petra Nederlof, Lisa K. Richters, Gabriele Krebsbach, Karolina Sikorska, Maartje Alkemade, Mark Opdam, Jules H. Schagen van Leeuwen, Henk W. R. Schreuder, Ralph H. M. Hermans, Ignace H. J. T. de Hingh, Constantijne H. Mom, Henriette J. G. Arts, Maaike van Ham, Peter van Dam, Peter Vuylsteke, Joyce SandersHugo M. Horlings, Koen K. van de Vijver, Eric Hahnen, Willemien J. van Driel, Rita Schmutzler, Gabe S. Sonke, Sabine C. Linn

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

18 Citations (Scopus)

Abstract

The addition of hyperthermic intraperitoneal chemotherapy (HIPEC) with cisplatin to interval cytoreductive surgery improves recurrence-free (RFS) and overall survival (OS) in patients with stage III ovarian cancer. Homologous recombination deficient (HRD) ovarian tumors are usually more platinum sensitive. Since hyperthermia impairs BRCA1/2 protein function, we hypothesized that HRD tumors respond best to treatment with HIPEC. We analyzed the effect of HIPEC in patients in the OVHIPEC trial, stratified by HRD status and BRCAm status. Clinical data and tissue samples were collected from patients included in the randomized, phase III OVHIPEC-1 trial. DNA copy number variation (CNV) profiles, HRD-related pathogenic mutations and BRCA1 promotor hypermethylation were determined. CNV-profiles were categorized as HRD or non-HRD, based on a previously validated algorithm-based BRCA1-like classifier. Hazard ratios (HR) and corresponding 99% confidence intervals (CI) for the effect of RFS and OS of HIPEC in the BRCAm, the HRD/BRCAwt and the non-HRD group were estimated using Cox proportional hazard models. Tumor DNA was available from 200/245 (82%) patients. Seventeen (9%) tumors carried a pathogenic mutation in BRCA1 and 14 (7%) in BRCA2. Ninety-one (46%) tumors classified as BRCA1-like. The effect of HIPEC on RFS and OS was absent in BRCAm tumors (HR 1.25; 99%CI 0.48-3.29), and most present in HRD/BRCAwt (HR 0.44; 99%CI 0.21-0.91), and non-HRD/BRCAwt tumors (HR 0.82; 99%CI 0.48-1.42), interaction P value: 0.024. Patients with HRD tumors without pathogenic BRCA1/2 mutation appear to benefit most from treatment with HIPEC, while benefit in patients with BRCA1/2 pathogenic mutations and patients without HRD seems less evident.

Original language	English
Pages (from-to)	1394-1404
Number of pages	11
Journal	International Journal of Cancer
Volume	151
Issue number	8
Early online date	2022
DOIs	https://doi.org/10.1002/ijc.34124
Publication status	Published - 15 Oct 2022

Keywords

HIPEC
homologous recombination deficiency
ovarian cancer

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https://doi.org/10.1002/ijc.34124

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Koole, S. N., Schouten, P. C., Hauke, J., Kluin, R. J. C., Nederlof, P., Richters, L. K., Krebsbach, G., Sikorska, K., Alkemade, M., Opdam, M., Schagen van Leeuwen, J. H., Schreuder, H. W. R., Hermans, R. H. M., de Hingh, I. H. J. T., Mom, C. H., Arts, H. J. G., van Ham, M., van Dam, P., Vuylsteke, P., ... Linn, S. C. (2022). Effect of HIPEC according to HRD/BRCAwt genomic profile in stage III ovarian cancer: Results from the phase III OVHIPEC trial. International Journal of Cancer, 151(8), 1394-1404. https://doi.org/10.1002/ijc.34124

@article{39f72d198d6d43819baa4abf2361f307,

title = "Effect of HIPEC according to HRD/BRCAwt genomic profile in stage III ovarian cancer: Results from the phase III OVHIPEC trial",

abstract = "The addition of hyperthermic intraperitoneal chemotherapy (HIPEC) with cisplatin to interval cytoreductive surgery improves recurrence-free (RFS) and overall survival (OS) in patients with stage III ovarian cancer. Homologous recombination deficient (HRD) ovarian tumors are usually more platinum sensitive. Since hyperthermia impairs BRCA1/2 protein function, we hypothesized that HRD tumors respond best to treatment with HIPEC. We analyzed the effect of HIPEC in patients in the OVHIPEC trial, stratified by HRD status and BRCAm status. Clinical data and tissue samples were collected from patients included in the randomized, phase III OVHIPEC-1 trial. DNA copy number variation (CNV) profiles, HRD-related pathogenic mutations and BRCA1 promotor hypermethylation were determined. CNV-profiles were categorized as HRD or non-HRD, based on a previously validated algorithm-based BRCA1-like classifier. Hazard ratios (HR) and corresponding 99% confidence intervals (CI) for the effect of RFS and OS of HIPEC in the BRCAm, the HRD/BRCAwt and the non-HRD group were estimated using Cox proportional hazard models. Tumor DNA was available from 200/245 (82%) patients. Seventeen (9%) tumors carried a pathogenic mutation in BRCA1 and 14 (7%) in BRCA2. Ninety-one (46%) tumors classified as BRCA1-like. The effect of HIPEC on RFS and OS was absent in BRCAm tumors (HR 1.25; 99%CI 0.48-3.29), and most present in HRD/BRCAwt (HR 0.44; 99%CI 0.21-0.91), and non-HRD/BRCAwt tumors (HR 0.82; 99%CI 0.48-1.42), interaction P value: 0.024. Patients with HRD tumors without pathogenic BRCA1/2 mutation appear to benefit most from treatment with HIPEC, while benefit in patients with BRCA1/2 pathogenic mutations and patients without HRD seems less evident.",

keywords = "HIPEC, homologous recombination deficiency, ovarian cancer",

author = "Koole, {Simone N.} and Schouten, {Philip C.} and Jan Hauke and Kluin, {Roel J. C.} and Petra Nederlof and Richters, {Lisa K.} and Gabriele Krebsbach and Karolina Sikorska and Maartje Alkemade and Mark Opdam and {Schagen van Leeuwen}, {Jules H.} and Schreuder, {Henk W. R.} and Hermans, {Ralph H. M.} and {de Hingh}, {Ignace H. J. T.} and Mom, {Constantijne H.} and Arts, {Henriette J. G.} and {van Ham}, Maaike and {van Dam}, Peter and Peter Vuylsteke and Joyce Sanders and Horlings, {Hugo M.} and {van de Vijver}, {Koen K.} and Eric Hahnen and {van Driel}, {Willemien J.} and Rita Schmutzler and Sonke, {Gabe S.} and Linn, {Sabine C.}",

note = "Funding Information: These analyses were funded by the Starz Foundation and the K{\"o}ln Fortune Program. The OVHIPEC clinical trial was funded by the Dutch Cancer Society. Funding Information: Philip Schouten is partner employed by AstraZeneca, with no direct connection to this work. Ignace de Hingh has an unrestricted research grant from Roche and RanD Biotechnology for unrelated research. The grant is payed to the institute. Rita Schmutzler has a grant from Amgen and AstraZeneca, and received honoraria from presentations from AstraZeneca and Janssen‐Cilag. She reports AdBoards from: AstraZenca, GSK, Clovis Oncology and MSD. Gabe Sonke reports consulting work for Biovica ans Seagen. Research support in paid to the institution from Agendia, AstraZeneca, Merck, Novartis, Roche and Seagen. Sabine Linn has been an advisory board member for AstraZeneca, Cergentis, IBM, Novartis, Pfizer, Roche and Sanofi, and has received unrestricted institutional research support of unrestricted educational funding from Agendia, Amgen, AstraZeneca, Bayer, Daiichi Sankyo, Eurocept Pharmaceuticals, Genentech, Immunomedics, Merck, Roche, Sanofi and TESARO. Sabine Linn has a patent application pending on a BRCA‐like ovarian cancer classifier. All other authors declare no conflicts of interest. Funding Information: We acknowledge the NKI-AVL Core Facility Molecular Pathology & Biobanking (CFMPB) and the Genomic Core Facility database for lab support and collaboration, in particular S. Broersen, L. Braaf, S. Cornelissen, A. Broeks, C. van Steenis, R. Kerkhoven, E. Holman and J. Overwater for support. We thank R. Rahman for technical support. We would like to thank the Hereditary Breast and Ovarian Cancer Research Group Netherlands (HEBON), in particular Mrs. D.J. Jenner and the HEBON study participants for the germline-status data delivery on behalf of HEBON. We thank the nationwide network and registry of histo- and cytopathology in the Netherlands “PALGA: Dutch Pathology Registry,” for national collection and distribution of tissue samples. We thank the Starz Foundation for unrestricted research support for this study. “Peter Vuylsteke's research was supported by the National Center for Advancing Translational Sciences (NCATS), a component of the National Institute of Health (NIH) under award number UL1TR003017. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.” Funding Information: We acknowledge the NKI‐AVL Core Facility Molecular Pathology & Biobanking (CFMPB) and the Genomic Core Facility database for lab support and collaboration, in particular S. Broersen, L. Braaf, S. Cornelissen, A. Broeks, C. van Steenis, R. Kerkhoven, E. Holman and J. Overwater for support. We thank R. Rahman for technical support. We would like to thank the Hereditary Breast and Ovarian Cancer Research Group Netherlands (HEBON), in particular Mrs. D.J. Jenner and the HEBON study participants for the germline‐status data delivery on behalf of HEBON. We thank the nationwide network and registry of histo‐ and cytopathology in the Netherlands “PALGA: Dutch Pathology Registry,” for national collection and distribution of tissue samples. We thank the Starz Foundation for unrestricted research support for this study. “Peter Vuylsteke's research was supported by the National Center for Advancing Translational Sciences (NCATS), a component of the National Institute of Health (NIH) under award number UL1TR003017. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.” Publisher Copyright: {\textcopyright} 2022 UICC.",

year = "2022",

month = oct,

day = "15",

doi = "https://doi.org/10.1002/ijc.34124",

language = "English",

volume = "151",

pages = "1394--1404",

journal = "International Journal of Cancer",

issn = "0020-7136",

publisher = "Wiley-Liss Inc.",

number = "8",

}

Koole, SN, Schouten, PC, Hauke, J, Kluin, RJC, Nederlof, P, Richters, LK, Krebsbach, G, Sikorska, K, Alkemade, M, Opdam, M, Schagen van Leeuwen, JH, Schreuder, HWR, Hermans, RHM, de Hingh, IHJT, Mom, CH, Arts, HJG, van Ham, M, van Dam, P, Vuylsteke, P, Sanders, J, Horlings, HM, van de Vijver, KK, Hahnen, E, van Driel, WJ, Schmutzler, R, Sonke, GS & Linn, SC 2022, 'Effect of HIPEC according to HRD/BRCAwt genomic profile in stage III ovarian cancer: Results from the phase III OVHIPEC trial', International Journal of Cancer, vol. 151, no. 8, pp. 1394-1404. https://doi.org/10.1002/ijc.34124

TY - JOUR

T1 - Effect of HIPEC according to HRD/BRCAwt genomic profile in stage III ovarian cancer

T2 - Results from the phase III OVHIPEC trial

AU - Koole, Simone N.

AU - Schouten, Philip C.

AU - Hauke, Jan

AU - Kluin, Roel J. C.

AU - Nederlof, Petra

AU - Richters, Lisa K.

AU - Krebsbach, Gabriele

AU - Sikorska, Karolina

AU - Alkemade, Maartje

AU - Opdam, Mark

AU - Schagen van Leeuwen, Jules H.

AU - Schreuder, Henk W. R.

AU - Hermans, Ralph H. M.

AU - de Hingh, Ignace H. J. T.

AU - Mom, Constantijne H.

AU - Arts, Henriette J. G.

AU - van Ham, Maaike

AU - van Dam, Peter

AU - Vuylsteke, Peter

AU - Sanders, Joyce

AU - Horlings, Hugo M.

AU - van de Vijver, Koen K.

AU - Hahnen, Eric

AU - van Driel, Willemien J.

AU - Schmutzler, Rita

AU - Sonke, Gabe S.

AU - Linn, Sabine C.

N1 - Funding Information: These analyses were funded by the Starz Foundation and the Köln Fortune Program. The OVHIPEC clinical trial was funded by the Dutch Cancer Society. Funding Information: Philip Schouten is partner employed by AstraZeneca, with no direct connection to this work. Ignace de Hingh has an unrestricted research grant from Roche and RanD Biotechnology for unrelated research. The grant is payed to the institute. Rita Schmutzler has a grant from Amgen and AstraZeneca, and received honoraria from presentations from AstraZeneca and Janssen‐Cilag. She reports AdBoards from: AstraZenca, GSK, Clovis Oncology and MSD. Gabe Sonke reports consulting work for Biovica ans Seagen. Research support in paid to the institution from Agendia, AstraZeneca, Merck, Novartis, Roche and Seagen. Sabine Linn has been an advisory board member for AstraZeneca, Cergentis, IBM, Novartis, Pfizer, Roche and Sanofi, and has received unrestricted institutional research support of unrestricted educational funding from Agendia, Amgen, AstraZeneca, Bayer, Daiichi Sankyo, Eurocept Pharmaceuticals, Genentech, Immunomedics, Merck, Roche, Sanofi and TESARO. Sabine Linn has a patent application pending on a BRCA‐like ovarian cancer classifier. All other authors declare no conflicts of interest. Funding Information: We acknowledge the NKI-AVL Core Facility Molecular Pathology & Biobanking (CFMPB) and the Genomic Core Facility database for lab support and collaboration, in particular S. Broersen, L. Braaf, S. Cornelissen, A. Broeks, C. van Steenis, R. Kerkhoven, E. Holman and J. Overwater for support. We thank R. Rahman for technical support. We would like to thank the Hereditary Breast and Ovarian Cancer Research Group Netherlands (HEBON), in particular Mrs. D.J. Jenner and the HEBON study participants for the germline-status data delivery on behalf of HEBON. We thank the nationwide network and registry of histo- and cytopathology in the Netherlands “PALGA: Dutch Pathology Registry,” for national collection and distribution of tissue samples. We thank the Starz Foundation for unrestricted research support for this study. “Peter Vuylsteke's research was supported by the National Center for Advancing Translational Sciences (NCATS), a component of the National Institute of Health (NIH) under award number UL1TR003017. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.” Funding Information: We acknowledge the NKI‐AVL Core Facility Molecular Pathology & Biobanking (CFMPB) and the Genomic Core Facility database for lab support and collaboration, in particular S. Broersen, L. Braaf, S. Cornelissen, A. Broeks, C. van Steenis, R. Kerkhoven, E. Holman and J. Overwater for support. We thank R. Rahman for technical support. We would like to thank the Hereditary Breast and Ovarian Cancer Research Group Netherlands (HEBON), in particular Mrs. D.J. Jenner and the HEBON study participants for the germline‐status data delivery on behalf of HEBON. We thank the nationwide network and registry of histo‐ and cytopathology in the Netherlands “PALGA: Dutch Pathology Registry,” for national collection and distribution of tissue samples. We thank the Starz Foundation for unrestricted research support for this study. “Peter Vuylsteke's research was supported by the National Center for Advancing Translational Sciences (NCATS), a component of the National Institute of Health (NIH) under award number UL1TR003017. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.” Publisher Copyright: © 2022 UICC.

PY - 2022/10/15

Y1 - 2022/10/15

N2 - The addition of hyperthermic intraperitoneal chemotherapy (HIPEC) with cisplatin to interval cytoreductive surgery improves recurrence-free (RFS) and overall survival (OS) in patients with stage III ovarian cancer. Homologous recombination deficient (HRD) ovarian tumors are usually more platinum sensitive. Since hyperthermia impairs BRCA1/2 protein function, we hypothesized that HRD tumors respond best to treatment with HIPEC. We analyzed the effect of HIPEC in patients in the OVHIPEC trial, stratified by HRD status and BRCAm status. Clinical data and tissue samples were collected from patients included in the randomized, phase III OVHIPEC-1 trial. DNA copy number variation (CNV) profiles, HRD-related pathogenic mutations and BRCA1 promotor hypermethylation were determined. CNV-profiles were categorized as HRD or non-HRD, based on a previously validated algorithm-based BRCA1-like classifier. Hazard ratios (HR) and corresponding 99% confidence intervals (CI) for the effect of RFS and OS of HIPEC in the BRCAm, the HRD/BRCAwt and the non-HRD group were estimated using Cox proportional hazard models. Tumor DNA was available from 200/245 (82%) patients. Seventeen (9%) tumors carried a pathogenic mutation in BRCA1 and 14 (7%) in BRCA2. Ninety-one (46%) tumors classified as BRCA1-like. The effect of HIPEC on RFS and OS was absent in BRCAm tumors (HR 1.25; 99%CI 0.48-3.29), and most present in HRD/BRCAwt (HR 0.44; 99%CI 0.21-0.91), and non-HRD/BRCAwt tumors (HR 0.82; 99%CI 0.48-1.42), interaction P value: 0.024. Patients with HRD tumors without pathogenic BRCA1/2 mutation appear to benefit most from treatment with HIPEC, while benefit in patients with BRCA1/2 pathogenic mutations and patients without HRD seems less evident.

AB - The addition of hyperthermic intraperitoneal chemotherapy (HIPEC) with cisplatin to interval cytoreductive surgery improves recurrence-free (RFS) and overall survival (OS) in patients with stage III ovarian cancer. Homologous recombination deficient (HRD) ovarian tumors are usually more platinum sensitive. Since hyperthermia impairs BRCA1/2 protein function, we hypothesized that HRD tumors respond best to treatment with HIPEC. We analyzed the effect of HIPEC in patients in the OVHIPEC trial, stratified by HRD status and BRCAm status. Clinical data and tissue samples were collected from patients included in the randomized, phase III OVHIPEC-1 trial. DNA copy number variation (CNV) profiles, HRD-related pathogenic mutations and BRCA1 promotor hypermethylation were determined. CNV-profiles were categorized as HRD or non-HRD, based on a previously validated algorithm-based BRCA1-like classifier. Hazard ratios (HR) and corresponding 99% confidence intervals (CI) for the effect of RFS and OS of HIPEC in the BRCAm, the HRD/BRCAwt and the non-HRD group were estimated using Cox proportional hazard models. Tumor DNA was available from 200/245 (82%) patients. Seventeen (9%) tumors carried a pathogenic mutation in BRCA1 and 14 (7%) in BRCA2. Ninety-one (46%) tumors classified as BRCA1-like. The effect of HIPEC on RFS and OS was absent in BRCAm tumors (HR 1.25; 99%CI 0.48-3.29), and most present in HRD/BRCAwt (HR 0.44; 99%CI 0.21-0.91), and non-HRD/BRCAwt tumors (HR 0.82; 99%CI 0.48-1.42), interaction P value: 0.024. Patients with HRD tumors without pathogenic BRCA1/2 mutation appear to benefit most from treatment with HIPEC, while benefit in patients with BRCA1/2 pathogenic mutations and patients without HRD seems less evident.

KW - HIPEC

KW - homologous recombination deficiency

KW - ovarian cancer

UR - http://www.scopus.com/inward/record.url?scp=85131596442&partnerID=8YFLogxK

U2 - https://doi.org/10.1002/ijc.34124

DO - https://doi.org/10.1002/ijc.34124

M3 - Article

C2 - 35583992

SN - 0020-7136

VL - 151

SP - 1394

EP - 1404

JO - International Journal of Cancer

JF - International Journal of Cancer

IS - 8

ER -

Effect of HIPEC according to HRD/BRCAwt genomic profile in stage III ovarian cancer: Results from the phase III OVHIPEC trial

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