ABSTRACT
Homologous Recombination Deficiency (HRD) was initially described in cancers with germline mutations of BRCA1 and BRCA2 and thereafter in both sporadic and hereditary cancers carrying mutations or epigenetic inactivation of other genes involved in HR. Since cancers harbouring HRD are particularly susceptible to PARP inhibitors (PARPi), identifying methods to detect HRD that can accurately predict clinical sensitivity to PARPi beyond BRCA1/2 mutations has been challenging. In this review, we describe the HRD biomarkers identified up to now, pointing out strengths and weaknesses of each associated assay. Multigene panel testing, genomic scar assays and the most recent functional assays developed in the last ten years are associated with several drawbacks, mainly due to the possible restoration of HR proficiency and tumor heterogeneity. The use of functional assays on samples obtained from liquid biopsy could overcome these issues, providing a dynamic readout of HRD status and helping in clinical decision-making especially in the recurrent setting. Composite HRD scores involving two or more biomarkers would be probably required to define “HRDness” and to predict response to PARPi alone or in combination regimens.

IMPACT STATEMENT
The current available biomarkers to infer the presence of HRD, including multigene panel testing, genomic scar and functional assays, are inadequate predictors of response to PARPi.