Theranostic biomarkers and PARP-inhibitors effectiveness in patients with non-BRCA associated homologous recombination deficient tumors: Still looking through a dirty glass window?

DSBs, double-strand breaks; HR, Homologous Recombination; HRD, Homologous Recombination Deficiency; PARPi, poly(ADP)ribose polymerase (PARP)-inhibitor; PVs, Pathogenic Variants. [Display omitted] • The best characterized HRR genes are BRCA1 and BRCA2. • Recently, an increased number of individuals have been referred for multigene panel testing. • Deleterious variants in HR-related genes other than BRCA1/2 also confer HRD. • Several approved PARPis are not restricted to BRCA1/2 -mutated patients. • The magnitude of PARPi benefit and the optimal HRD biomarkers in this population are debated. Breast cancer susceptibility gene 1 (BRCA1) and breast cancer susceptibility gene 2 (BRCA2) deleterious variants were the first and, still today, the main biomarkers of poly(ADP)ribose polymerase (PARP)-inhibitors (PARPis) benefit. The recent, increased, numbers of individuals referred for counseling and multigene panel testing, and the remarkable expansion of approved PARPis, not restricted to BRCA1/BRCA2 -Pathogenic Variants (PVs), produced a strong clinical need for non- BRCA biomarkers. Significant limitations of the current testing and assays exist. The different approaches that identify the causes of Homologous Recombination Deficiency (HRD), such as the germline and somatic Homologous Recombination Repair (HRR) gene PVs, the testing showing its consequences, such as the genomic scars, or the novel functional assays such as the RAD51 foci testing, are not interchangeable, and should not be considered as substitutes for each other in clinical practice for guiding use of PARPi in non- BRCA , HRD-associated tumors. Today, the deeper knowledge on the significant relationship among all proteins involved in the HRR, not limited to BRCA , expands the possibility of a successful non- BRCA , HRD-PARPi synthetic lethality and, at the same time, reinforces the need for enhanced definition of HRD biomarkers predicting the magnitude of PARPi benefit. [ABSTRACT FROM AUTHOR]