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

Int J Gynecol Cancer. 2023 Aug 7;33(8):1253-1259. doi: 10.1136/ijgc-2022-004211.

Authors

Robert D Morgan^{1

2}, Andrew R Clamp^{3

2}, Bethany M Barnes², Kirsten Timms⁴, Helene Schlecht⁵, Laura Yarram-Smith⁶, Yvonne Wallis⁷, Mikel Valganon-Petrizan⁸, Suzanne MacMahon⁸, Rhian White⁹, Sian Morgan⁹, Sarah McKenna¹⁰, Emma Hudson¹¹, Laura Tookman¹², Angela George^{13

14}, Ranjit Manchanda^{15

16

17}, Sudha S Sundar^{18

19}, Shibani Nicum^{20

21}, James D Brenton^{22

23}, Rebecca S Kristeleit²⁴, Susana Banerjee^{13

14}, Iain A McNeish^{12

25}, Jonathan A Ledermann^{20

21}, Stephen S Taylor², D Gareth R Evans^{26

27}, Gordon C Jayson^{3

2}

Affiliations

¹ The Christie NHS Foundation Trust, Manchester, UK [email protected].
² Division of Cancer Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK.
³ The Christie NHS Foundation Trust, Manchester, UK.
⁴ Myriad Genetics, Inc, Salt Lake City, Utah, USA.
⁵ North West Genomic Laboratory Hub, Manchester University NHS Foundation Trust, Manchester, UK.
⁶ South West Genomic Laboratory Hub, North Bristol NHS Trust, Bristol, UK.
⁷ Central and South Genomic Laboratory Hub, Birmingham Women's and Children's NHS Foundation Trust, Birmingham, UK.
⁸ North Thames Genomic Laboratory Hub, The Royal Marsden Hospital NHS Foundation Trust, Surrey, UK.
⁹ All Wales Genomics Laboratory, Institute of Medical Genetics, University Hospital Wales, Cardiff, UK.
¹⁰ Belfast Health and Social Care Trust, Belfast, UK.
¹¹ Velindre University NHS Trust, Cardiff, UK.
¹² Imperial College Healthcare NHS Trust, London, UK.
¹³ The Royal Marsden NHS Foundation Trust, London, UK.
¹⁴ The Institute of Cancer Research, London, UK.
¹⁵ Barts Health NHS Trust, London, UK.
¹⁶ Department of Health Services Research, The Faculty of Public Health and Policy, London School of Hygiene & Tropical Medicine, London, UK.
¹⁷ Wolfson Institute of Population Health, Queen Mary's University of London, London, UK.
¹⁸ Sandwell and West Birmingham Hospitals NHS Trust, Birmingham, UK.
¹⁹ Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK.
²⁰ University College London Hospitals NHS Foundation Trust, London, UK.
²¹ UCL Cancer Institute, London, UK.
²² Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.
²³ CRUK Cambridge Institute, University of Cambridge, Cambridge, UK.
²⁴ Guy's and St Thomas' NHS Foundation Trust, London, UK.
²⁵ Ovarian Cancer Action Research Centre, Department of Surgery and Cancer, Imperial College London, London, UK.
²⁶ Manchester University NHS Foundation Trust, Manchester, UK.
²⁷ Division of Evolution, Infection and Genomics, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK.

PMID: 37072323
DOI: 10.1136/ijgc-2022-004211

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.

Publication types

Observational Study
Research Support, Non-U.S. Gov't

MeSH terms

BRCA1 Protein* / genetics
BRCA2 Protein / genetics
Carcinoma, Ovarian Epithelial / genetics
Female
Genomic Instability
Homologous Recombination
Humans
Mutation
Ovarian Neoplasms* / pathology
State Medicine

Substances

BRCA1 protein, human
BRCA1 Protein
BRCA2 protein, human
BRCA2 Protein

Abstract

Publication types

MeSH terms

Substances

Grants and funding