Homologous recombination deficiency in newly diagnosed FIGO stage III/IV high-grade epithelial ovarian cancer: A multi-national observational study

Robert D. Morgan; Andrew R. Clamp; Bethany M. Barnes; Kirsten Timms; Helene Schlecht; Laura Yarram-Smith; Yvonne Wallis; Mikel Valganon-Petrizan; Suzanne Macmahon; Rhian White; Sian Morgan; Sarah McKenna; Emma Hudson; Laura Tookman; Angela George; Ranjit Manchanda; Sudha S. Sundar; Shibani Nicum; James D. Brenton; Rebecca S. Kristeleit; Susana Banerjee; Iain A. McNeish; Jonathan A. Ledermann; Stephen S. Taylor; D. Gareth R. Evans; Gordon C. Jayson

doi:10.1136/ijgc-2022-004211

Homologous recombination deficiency in newly diagnosed FIGO stage III/IV high-grade epithelial ovarian cancer: A multi-national observational study

Robert D. Morgan^*, Andrew R. Clamp, Bethany M. Barnes, Kirsten Timms, Helene Schlecht, Laura Yarram-Smith, Yvonne Wallis, Mikel Valganon-Petrizan, Suzanne Macmahon, Rhian White, Sian Morgan, Sarah McKenna, Emma Hudson, Laura Tookman, Angela George, Ranjit Manchanda, Sudha S. Sundar, Shibani Nicum, James D. Brenton, Rebecca S. KristeleitSusana Banerjee, Iain A. McNeish, Jonathan A. Ledermann, Stephen S. Taylor, D. Gareth R. Evans, Gordon C. Jayson

^*Corresponding author for this work

Cancer and Genomic Sciences

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Abstract

Objective: Olaparib plus bevacizumab maintenance therapy improves survival outcomes in women with newly diagnosed, advanced, high-grade ovarian cancer with a deficiency in homologous recombination. We report data from the first year of routine homologous recombination deficiency testing in the National Health Service (NHS) in England, Wales, and Northern Ireland between April 2021 and April 2022.

Methods: The Myriad myChoice companion diagnostic was used to test DNA extracted from formalin-fixed, paraffin-embedded tumor tissue in women with newly diagnosed International Federation of Gynecology and Obstetrics (FIGO) stage III/IV high-grade epithelial ovarian, fallopian tube, or primary peritoneal cancer. Tumors with homologous recombination deficiency were those with a BRCA1/2 mutation and/or a Genomic Instability Score (GIS) ≥42. Testing was coordinated by the NHS Genomic Laboratory Hub network.

Results: The myChoice assay was performed on 2829 tumors. Of these, 2474 (87%) and 2178 (77%) successfully underwent BRCA1/2 and GIS testing, respectively. All complete and partial assay failures occurred due to low tumor cellularity and/or low tumor DNA yield. 385 tumors (16%) contained a BRCA1/2 mutation and 814 (37%) had a GIS ≥42. Tumors with a GIS ≥42 were more likely to be BRCA1/2 wild-type (n=510) than BRCA1/2 mutant (n=304). The distribution of GIS was bimodal, with BRCA1/2 mutant tumors having a higher mean score than BRCA1/2 wild-type tumors (61 vs 33, respectively, χ² test p<0.0001).

Conclusion: This is the largest real-world evaluation of homologous recombination deficiency testing in newly diagnosed FIGO stage III/IV high-grade epithelial ovarian, fallopian tube, or primary peritoneal cancer. It is important to select tumor tissue with adequate tumor content and quality to reduce the risk of assay failure. The rapid uptake of testing across England, Wales, and Northern Ireland demonstrates the power of centralized NHS funding, center specialization, and the NHS Genomic Laboratory Hub network.

Original language	English
Journal	International Journal of Gynecological Cancer
Early online date	18 Apr 2023
DOIs	https://doi.org/10.1136/ijgc-2022-004211
Publication status	E-pub ahead of print - 18 Apr 2023

Bibliographical note

Funding Information:
The Myriad myChoice® companion diagnostic was funded by AstraZeneca PLC (Address: 1 Francis Crick Avenue, Cambridge Biomedical Campus, Cambridge CB2 0AA, UK; Tel: +44 (0)20 3749 5000).

Publisher Copyright:
© IGCS and ESGO 2023. No commercial re-use. See rights and permissions. Published by BMJ.

Keywords

BRCA1 Protein
BRCA2 Protein
Homologous recombination
Ovarian Cancer

ASJC Scopus subject areas

Oncology
Obstetrics and Gynaecology

UN SDGs

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

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MorganR2023Homologous
This article has been accepted for publication in International Journal of Gynecological Cancer, 2023, following peer review, and the Version of Record can be accessed online at: http://dx.doi.org/10.1136/ijgc-2022-004211. © Authors (or their employer(s))
Accepted author manuscript, 202 KBLicence: Creative Commons: Attribution-NonCommercial (CC BY-NC)

Cite this

Morgan, R. D., Clamp, A. R., Barnes, B. M., Timms, K., Schlecht, H., Yarram-Smith, L., Wallis, Y., Valganon-Petrizan, M., Macmahon, S., White, R., Morgan, S., McKenna, S., Hudson, E., Tookman, L., George, A., Manchanda, R., Sundar, S. S., Nicum, S., Brenton, J. D., ... Jayson, G. C. (2023). Homologous recombination deficiency in newly diagnosed FIGO stage III/IV high-grade epithelial ovarian cancer: A multi-national observational study. International Journal of Gynecological Cancer. Advance online publication. https://doi.org/10.1136/ijgc-2022-004211

@article{e94b7d3ce2b44b35811a53f0d2a9547a,

title = "Homologous recombination deficiency in newly diagnosed FIGO stage III/IV high-grade epithelial ovarian cancer: A multi-national observational study",

abstract = "Objective: Olaparib plus bevacizumab maintenance therapy improves survival outcomes in women with newly diagnosed, advanced, high-grade ovarian cancer with a deficiency in homologous recombination. We report data from the first year of routine homologous recombination deficiency testing in the National Health Service (NHS) in England, Wales, and Northern Ireland between April 2021 and April 2022. Methods: The Myriad myChoice companion diagnostic was used to test DNA extracted from formalin-fixed, paraffin-embedded tumor tissue in women with newly diagnosed International Federation of Gynecology and Obstetrics (FIGO) stage III/IV high-grade epithelial ovarian, fallopian tube, or primary peritoneal cancer. Tumors with homologous recombination deficiency were those with a BRCA1/2 mutation and/or a Genomic Instability Score (GIS) ≥42. Testing was coordinated by the NHS Genomic Laboratory Hub network. Results: The myChoice assay was performed on 2829 tumors. Of these, 2474 (87%) and 2178 (77%) successfully underwent BRCA1/2 and GIS testing, respectively. All complete and partial assay failures occurred due to low tumor cellularity and/or low tumor DNA yield. 385 tumors (16%) contained a BRCA1/2 mutation and 814 (37%) had a GIS ≥42. Tumors with a GIS ≥42 were more likely to be BRCA1/2 wild-type (n=510) than BRCA1/2 mutant (n=304). The distribution of GIS was bimodal, with BRCA1/2 mutant tumors having a higher mean score than BRCA1/2 wild-type tumors (61 vs 33, respectively, χ2 test p<0.0001). Conclusion: This is the largest real-world evaluation of homologous recombination deficiency testing in newly diagnosed FIGO stage III/IV high-grade epithelial ovarian, fallopian tube, or primary peritoneal cancer. It is important to select tumor tissue with adequate tumor content and quality to reduce the risk of assay failure. The rapid uptake of testing across England, Wales, and Northern Ireland demonstrates the power of centralized NHS funding, center specialization, and the NHS Genomic Laboratory Hub network.",

keywords = "BRCA1 Protein, BRCA2 Protein, Homologous recombination, Ovarian Cancer",

author = "Morgan, {Robert D.} and Clamp, {Andrew R.} and Barnes, {Bethany M.} and Kirsten Timms and Helene Schlecht and Laura Yarram-Smith and Yvonne Wallis and Mikel Valganon-Petrizan and Suzanne Macmahon and Rhian White and Sian Morgan and Sarah McKenna and Emma Hudson and Laura Tookman and Angela George and Ranjit Manchanda and Sundar, {Sudha S.} and Shibani Nicum and Brenton, {James D.} and Kristeleit, {Rebecca S.} and Susana Banerjee and McNeish, {Iain A.} and Ledermann, {Jonathan A.} and Taylor, {Stephen S.} and Evans, {D. Gareth R.} and Jayson, {Gordon C.}",

note = "Funding Information: The Myriad myChoice{\textregistered} companion diagnostic was funded by AstraZeneca PLC (Address: 1 Francis Crick Avenue, Cambridge Biomedical Campus, Cambridge CB2 0AA, UK; Tel: +44 (0)20 3749 5000). Publisher Copyright: {\textcopyright} IGCS and ESGO 2023. No commercial re-use. See rights and permissions. Published by BMJ.",

year = "2023",

month = apr,

day = "18",

doi = "10.1136/ijgc-2022-004211",

language = "English",

journal = "International Journal of Gynecological Cancer",

issn = "1048-891X",

publisher = "Lippincott Williams and Wilkins",

}

Morgan, RD, Clamp, AR, Barnes, BM, Timms, K, Schlecht, H, Yarram-Smith, L, Wallis, Y, Valganon-Petrizan, M, Macmahon, S, White, R, Morgan, S, McKenna, S, Hudson, E, Tookman, L, George, A, Manchanda, R, Sundar, SS, Nicum, S, Brenton, JD, Kristeleit, RS, Banerjee, S, McNeish, IA, Ledermann, JA, Taylor, SS, Evans, DGR & Jayson, GC 2023, 'Homologous recombination deficiency in newly diagnosed FIGO stage III/IV high-grade epithelial ovarian cancer: A multi-national observational study', International Journal of Gynecological Cancer. https://doi.org/10.1136/ijgc-2022-004211

TY - JOUR

T1 - Homologous recombination deficiency in newly diagnosed FIGO stage III/IV high-grade epithelial ovarian cancer

T2 - A multi-national observational study

AU - Morgan, Robert D.

AU - Clamp, Andrew R.

AU - Barnes, Bethany M.

AU - Timms, Kirsten

AU - Schlecht, Helene

AU - Yarram-Smith, Laura

AU - Wallis, Yvonne

AU - Valganon-Petrizan, Mikel

AU - Macmahon, Suzanne

AU - White, Rhian

AU - Morgan, Sian

AU - McKenna, Sarah

AU - Hudson, Emma

AU - Tookman, Laura

AU - George, Angela

AU - Manchanda, Ranjit

AU - Sundar, Sudha S.

AU - Nicum, Shibani

AU - Brenton, James D.

AU - Kristeleit, Rebecca S.

AU - Banerjee, Susana

AU - McNeish, Iain A.

AU - Ledermann, Jonathan A.

AU - Taylor, Stephen S.

AU - Evans, D. Gareth R.

AU - Jayson, Gordon C.

N1 - Funding Information: The Myriad myChoice® companion diagnostic was funded by AstraZeneca PLC (Address: 1 Francis Crick Avenue, Cambridge Biomedical Campus, Cambridge CB2 0AA, UK; Tel: +44 (0)20 3749 5000). Publisher Copyright: © IGCS and ESGO 2023. No commercial re-use. See rights and permissions. Published by BMJ.

PY - 2023/4/18

Y1 - 2023/4/18

N2 - Objective: Olaparib plus bevacizumab maintenance therapy improves survival outcomes in women with newly diagnosed, advanced, high-grade ovarian cancer with a deficiency in homologous recombination. We report data from the first year of routine homologous recombination deficiency testing in the National Health Service (NHS) in England, Wales, and Northern Ireland between April 2021 and April 2022. Methods: The Myriad myChoice companion diagnostic was used to test DNA extracted from formalin-fixed, paraffin-embedded tumor tissue in women with newly diagnosed International Federation of Gynecology and Obstetrics (FIGO) stage III/IV high-grade epithelial ovarian, fallopian tube, or primary peritoneal cancer. Tumors with homologous recombination deficiency were those with a BRCA1/2 mutation and/or a Genomic Instability Score (GIS) ≥42. Testing was coordinated by the NHS Genomic Laboratory Hub network. Results: The myChoice assay was performed on 2829 tumors. Of these, 2474 (87%) and 2178 (77%) successfully underwent BRCA1/2 and GIS testing, respectively. All complete and partial assay failures occurred due to low tumor cellularity and/or low tumor DNA yield. 385 tumors (16%) contained a BRCA1/2 mutation and 814 (37%) had a GIS ≥42. Tumors with a GIS ≥42 were more likely to be BRCA1/2 wild-type (n=510) than BRCA1/2 mutant (n=304). The distribution of GIS was bimodal, with BRCA1/2 mutant tumors having a higher mean score than BRCA1/2 wild-type tumors (61 vs 33, respectively, χ2 test p<0.0001). Conclusion: This is the largest real-world evaluation of homologous recombination deficiency testing in newly diagnosed FIGO stage III/IV high-grade epithelial ovarian, fallopian tube, or primary peritoneal cancer. It is important to select tumor tissue with adequate tumor content and quality to reduce the risk of assay failure. The rapid uptake of testing across England, Wales, and Northern Ireland demonstrates the power of centralized NHS funding, center specialization, and the NHS Genomic Laboratory Hub network.

AB - Objective: Olaparib plus bevacizumab maintenance therapy improves survival outcomes in women with newly diagnosed, advanced, high-grade ovarian cancer with a deficiency in homologous recombination. We report data from the first year of routine homologous recombination deficiency testing in the National Health Service (NHS) in England, Wales, and Northern Ireland between April 2021 and April 2022. Methods: The Myriad myChoice companion diagnostic was used to test DNA extracted from formalin-fixed, paraffin-embedded tumor tissue in women with newly diagnosed International Federation of Gynecology and Obstetrics (FIGO) stage III/IV high-grade epithelial ovarian, fallopian tube, or primary peritoneal cancer. Tumors with homologous recombination deficiency were those with a BRCA1/2 mutation and/or a Genomic Instability Score (GIS) ≥42. Testing was coordinated by the NHS Genomic Laboratory Hub network. Results: The myChoice assay was performed on 2829 tumors. Of these, 2474 (87%) and 2178 (77%) successfully underwent BRCA1/2 and GIS testing, respectively. All complete and partial assay failures occurred due to low tumor cellularity and/or low tumor DNA yield. 385 tumors (16%) contained a BRCA1/2 mutation and 814 (37%) had a GIS ≥42. Tumors with a GIS ≥42 were more likely to be BRCA1/2 wild-type (n=510) than BRCA1/2 mutant (n=304). The distribution of GIS was bimodal, with BRCA1/2 mutant tumors having a higher mean score than BRCA1/2 wild-type tumors (61 vs 33, respectively, χ2 test p<0.0001). Conclusion: This is the largest real-world evaluation of homologous recombination deficiency testing in newly diagnosed FIGO stage III/IV high-grade epithelial ovarian, fallopian tube, or primary peritoneal cancer. It is important to select tumor tissue with adequate tumor content and quality to reduce the risk of assay failure. The rapid uptake of testing across England, Wales, and Northern Ireland demonstrates the power of centralized NHS funding, center specialization, and the NHS Genomic Laboratory Hub network.

KW - BRCA1 Protein

KW - BRCA2 Protein

KW - Homologous recombination

KW - Ovarian Cancer

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U2 - 10.1136/ijgc-2022-004211

DO - 10.1136/ijgc-2022-004211

M3 - Article

C2 - 37072323

AN - SCOPUS:85159169854

SN - 1048-891X

JO - International Journal of Gynecological Cancer

JF - International Journal of Gynecological Cancer

ER -

Homologous recombination deficiency in newly diagnosed FIGO stage III/IV high-grade epithelial ovarian cancer: A multi-national observational study

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

UN SDGs

Access to Document

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Cite this