Abstract and Introduction
During the last 2 decades, extensive research has focused on the molecular functions of BRCA1 and BRCA2 genes. This has led to the development of Poly(ADP-ribose) polymerase inhibitors (PARPi), as effective target therapies, based on their preferential cytotoxicity in tumor cells harboring germline BRCA1 and BRCA2 mutations. At the present time, 2 PARPi (Olaparib and Talazoparib) are approved as single agent for the treatment of patients with metastatic HER2–ve breast cancer, who have BRCA germline mutations. The clinical benefit of these agents might be also anticipated in patients harboring germline mutations in some additional genes involved in the process of homologous recombination repair (HRR) other than BRCA1/BRCA2. In this review, we summarize the molecular rational for the therapeutic development of PARPi and the clinical evidence supporting their use as anticancer drugs in breast cancer patients with BRCA1/BRCA2 germline mutations. We also discuss the role of platinum-based chemotherapy and how it compares with PARPi in the management of these patients. We will go through some relevant clinical trials of various combinations of PARPi with cytotoxic or immunotherapeutic agents, which may potentially provide better treatment results, compared to what is already achieved with their use as monotherapy.
Approximately 5–10% of breast cancers are secondary to inherited mutations. Within this group, the vast majority is caused by mutations in the tumour suppressor genes BRCA1 and BRCA2. BRCA1-mutation carriers have a lifetime risk of up to 85% to develop breast cancer and about 45% for ovarian cancer, while those harboring BRCA2 germline mutations have a lifetime risk of around 66% and 12% to develop breast cancer and ovarian cancer, respectively.[2,3] BRCA2 mutations also predispose to cancers of the male breast, pancreas, prostate and other organs.
BRCA1-mutated breast cancers are frequently triple negative (only ~10% are HER2-positive) and show a higher mitotic index and increased lymphocytic infiltration compared to sporadic cancers. Moreover, they generally exhibit basal-like characteristics, defined by the expression of genes specific to the basal mammary myoepithelial cells.[4–6] Conversely, 77% of breast tumors arising in BRCA2 mutation carriers are ER-positive and only 15% are triple negative, largely mimicking the general population in terms of breast cancer phenotypes.[4,6,7]
In spite of these epidemiologic and phenotypic dissimilarities related to tumors associated with BRCA1 and BRCA2 mutations, still the loss of function of any of these 2 genes can lead to one common genetic outcome, known as defective DNA homologous recombination repair (HRR). This in turn results in frequent accumulation of genetic mutations, which would ultimately increase susceptibly to develop breast cancer and ovarian cancer and hence the term hereditary breast and ovarian cancer (HBOC) syndrome.[2,8,9]
Chin Clin Oncol. 2021;10(5):50 © 2021 AME Publishing Company