ESMO recommendations on predictive biomarker testing for homologous recombination deficiency and PARP inhibitor benefit in ovarian cancer

• Published in: Annals of oncology Vol. 31; no. 12; pp. 1606 - 1622
• Main Authors: Miller, R.E., Leary, A., Scott, C.L., Serra, V., Lord, C.J., Bowtell, D., Chang, D.K., Garsed, D.W., Jonkers, J., Ledermann, J.A., Nik-Zainal, S., Ray-Coquard, I., Shah, S.P., Matias-Guiu, X., Swisher, E.M., Yates, L.R.
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01-12-2020
• Subjects: Biomarkers; BRCA; Carcinoma, Ovarian Epithelial; Female; genomic scar assays; Homologous Recombination; homologous recombination deficiency (HRD); Humans; Ovarian Neoplasms - drug therapy; Ovarian Neoplasms - genetics; Poly(ADP-ribose) Polymerase Inhibitors - therapeutic use; poly-ADP ribose inhibitors (PARPi); BRCA; genomic scar assays; poly-ADP ribose inhibitors (PARPi); homologous recombination deficiency (HRD)
• ISSN: 0923-7534; 1569-8041
• DOI: 10.1016/j.annonc.2020.08.2102

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.
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.
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.
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.
•Homologous recombination repair deficiency (HRD) is a common feature of high-grade serous gynaecological cancers (HGSC).•Currently, the clinical validity of HRD tests in ovarian cancer is best assessed in terms of PARPi benefit.•Germline and somatic BRCA mutation and genomic instability tests help to predict likely magnitude of benefit from a PARPi.•Existing HRD tests fail to consistently identify a subgroup of patients who derive no benefit from PARPis in most studies.•HRD is a dynamic entity and better biomarkers that capture current homologous recombination proficiency status are needed.