Real-world data in patients with BRCA mutated breast cancer treated with poly (ADP-ribose) polymerase inhibitors

Abstract

Breast cancer is the most common type of cancer globally. Hereditary breast cancer accounts for 10% of new cases and 4%-5% of cases are associated to pathogenic variants in BRCA1 or BRCA2 genes. In recent years, poly-adenosine-diphosphate-ribose polymerase inhibitors (PARPi) olaparib and talazoparib have been approved for patients with BRCA-associated, HER2 -negative breast cancer. These drugs have shown positive results in the early and advanced setting with a favourable toxicity profile based on the OlympiAD, OlympiA and EMBRACA phase 3 trials. However, patients included in these randomised trials are highly selected, making toxicity and efficacy in patients encountered in routine clinical care a concern. Since the approval of olaparib and talazoparib for advanced human epidermal growth factor receptor 2-negative (HER2-negative) breast cancer, several phase IIIb-IV trials, expanded access cohorts, and retrospective cohorts have provided information on the efficacy and tolerability of these treatments in patient subgroups underrepresented in the registration trials, such as older adults, patients with poor performance status, and heavily pretreated patients. The aim of this review is to present a critical review of the information regarding the use of PARPi in real-world breast cancer patients.

Keywords: BRCA1 gene; BRCA2 gene; breast cancer; poly(ADP-ribose) polymerase inhibitors.

Figure 1.. PARPi mechanism of action. (a): In healthy cells, the PARP enzymes play a key role in the repair of single-strand breaks because they recognise the damaged DNA site, bind to it and recruit other repair enzymes to the site of break. (b): By administering PARPi, the cell is unable to repair single-strand breaks due to a collapse of the replication fork which leads to double-strand breaks. In cells with wild-type germline BRCA (and other HRR -related genes), double-strand breaks are repaired via the HRR pathway. (c). In BRCA mutated cells, the HRR pathway is compromised and these double-strand breaks are not susceptible to repair which leads to eventual cell death. Adapted from ‘PARPi: Treatment for BRCA Mutant Breast Cancer’, by BioRender.com (2023). Retrieved from https://app.biorender.com/biorender-templates.