R E Miller1, A Leary2, C L Scott3, V Serra4, C J Lord5, D Bowtell3, D K Chang6, D W Garsed3, J Jonkers7, J A Ledermann8, S Nik-Zainal9, I Ray-Coquard10, S P Shah11, X Matias-Guiu12, E M Swisher13, L R Yates14. 1. Department of Medical Oncology, University College London, London, UK; Department of Medical Oncology, St Bartholomew's Hospital, London, UK. 2. Department of Medicine and INSERM U981, Gustave Roussy Cancer Center, Université Paris-Saclay, Paris, France. 3. Peter MacCallum Cancer Centre, Melbourne, Australia; The University of Melbourne, Melbourne, Australia. 4. Experimental Therapeutics Group Vall d'Hebron Institute of Oncology, Barcelona, Spain. 5. The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London, UK; CRUK Gene Function Laboratory, The Institute of Cancer Research, London, UK. 6. Glasgow Precision Oncology Laboratory, Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, UK; West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow, UK. 7. Division of Molecular Pathology, Oncode Institute, Netherlands Cancer Institute, Amsterdam, The Netherlands. 8. UCL Cancer Institute, University College London, London, UK. 9. Department of Medical Genetics, School of Clinical Medicine, University of Cambridge, Cambridge, UK; MRC Cancer Unit, School of Clinical Medicine, University of Cambridge, Cambridge, UK. 10. Centre Leon Berard, Lyon, France; University Claude Bernard Groupe University of Lyon, France. 11. Computational Oncology, Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, USA. 12. Departments of Pathology, Hospital U Arnau de Vilanova and Hospital U de Bellvitge, Universities of Lleida and Barcelona, Irblleida, Idibell, Ciberonc, Barcelona, Spain. 13. Department of Obstetrics and Gynecology, University of Washington, Seattle, USA. 14. Wellcome Sanger Institute, Wellcome Genome Campus, Cambridge; Guy's Cancer Centre, Guys and St Thomas' NHS Foundation Trust, London, UK. Electronic address: education@esmo.org.
Abstract
BACKGROUND: Homologous recombination repair deficiency (HRD) is a frequent feature of high-grade serous ovarian, fallopian tube and peritoneal carcinoma (HGSC) and is associated with sensitivity to PARP inhibitor (PARPi) therapy. HRD testing provides an opportunity to optimise PARPi use in HGSC but methodologies are diverse and clinical application remains controversial. MATERIALS AND METHODS: To define best practice for HRD testing in HGSC the ESMO Translational Research and Precision Medicine Working Group launched a collaborative project that incorporated a systematic review approach. The main aims were to (i) define the term 'HRD test'; (ii) provide an overview of the biological rationale and the level of evidence supporting currently available HRD tests; (iii) provide recommendations on the clinical utility of HRD tests in clinical management of HGSC. RESULTS: A broad range of repair genes, genomic scars, mutational signatures and functional assays are associated with a history of HRD. Currently, the clinical validity of HRD tests in ovarian cancer is best assessed, not in terms of biological HRD status per se, but in terms of PARPi benefit. Clinical trials evidence supports the use of BRCA mutation testing and two commercially available assays that also incorporate genomic instability for identifying subgroups of HGSCs that derive different magnitudes of benefit from PARPi therapy, albeit with some variation by clinical scenario. These tests can be used to inform treatment selection and scheduling but their use is limited by a failure to consistently identify a subgroup of patients who derive no benefit from PARPis in most studies. Existing tests lack negative predictive value and inadequately address the complex and dynamic nature of the HRD phenotype. CONCLUSIONS: Currently available HRD tests are useful for predicting likely magnitude of benefit from PARPis but better biomarkers are urgently needed to better identify current homologous recombination proficiency status and stratify HGSC management.
BACKGROUND: Homologous recombination repair deficiency (HRD) is a frequent feature of high-grade serous ovarian, fallopian tube and peritoneal carcinoma (HGSC) and is associated with sensitivity to PARP inhibitor (PARPi) therapy. HRD testing provides an opportunity to optimise PARPi use in HGSC but methodologies are diverse and clinical application remains controversial. MATERIALS AND METHODS: To define best practice for HRD testing in HGSC the ESMO Translational Research and Precision Medicine Working Group launched a collaborative project that incorporated a systematic review approach. The main aims were to (i) define the term 'HRD test'; (ii) provide an overview of the biological rationale and the level of evidence supporting currently available HRD tests; (iii) provide recommendations on the clinical utility of HRD tests in clinical management of HGSC. RESULTS: A broad range of repair genes, genomic scars, mutational signatures and functional assays are associated with a history of HRD. Currently, the clinical validity of HRD tests in ovarian cancer is best assessed, not in terms of biological HRD status per se, but in terms of PARPi benefit. Clinical trials evidence supports the use of BRCA mutation testing and two commercially available assays that also incorporate genomic instability for identifying subgroups of HGSCs that derive different magnitudes of benefit from PARPi therapy, albeit with some variation by clinical scenario. These tests can be used to inform treatment selection and scheduling but their use is limited by a failure to consistently identify a subgroup of patients who derive no benefit from PARPis in most studies. Existing tests lack negative predictive value and inadequately address the complex and dynamic nature of the HRD phenotype. CONCLUSIONS: Currently available HRD tests are useful for predicting likely magnitude of benefit from PARPis but better biomarkers are urgently needed to better identify current homologous recombination proficiency status and stratify HGSC management.
Authors: F Guffanti; M F Alvisi; A Anastasia; F Ricci; M Chiappa; A Llop-Guevara; V Serra; R Fruscio; A Degasperi; S Nik-Zainal; M R Bani; M Lupia; R Giavazzi; E Rulli; G Damia Journal: Br J Cancer Date: 2021-11-03 Impact factor: 7.640
Authors: Terri Patricia McVeigh; Karl J Sweeney; Donal J Brennan; Una M McVeigh; Simon Ward; Ann Strydom; Sheila Seal; Katherine Astbury; Paul Donnellan; Joanne Higgins; Maccon Keane; Michael J Kerin; Carmel Malone; Pauline McGough; Ray McLaughlin; Michael O'Leary; Margaret Rushe; Michael Kevin Barry; Geraldine MacGregor; Michael Sugrue; Ala Yousif; Dhafir Al-Azawi; Eileen Berkeley; Terence J Boyle; Elizabeth M Connolly; Carmel Nolan; Elaine Richardson; Claire Giffney; Samantha B Doyle; Sheila Broderick; William Boyd; Ruaidhri McVey; Thomas Walsh; Michael Farrell; David J Gallagher; Nazneen Rahman; Angela J George Journal: Fam Cancer Date: 2022-08-27 Impact factor: 2.446