Abstract and Introduction
The discovery of cancer-causing BRCA1/2 mutations and the emergence of genetic testing have brought precision in patient selection for poly-(ADP)-ribose polymerase inhibitor (PARPi) treatment. Interestingly, patients who are carriers of BRCA1/2 mutations have a higher risk for developing cancer, but respond better to DNA-damaging cytotoxic therapy, such as platinum-based chemotherapy. The distinctive biology of ovarian cancer involves high genomic instability consisting of gene amplification, gene deletion, oncogene hypomethylation, loss of heterozygosity, and tumor suppressor gene promoter hypermethylation in many of the DNA damage response (DDR) genes, including BRCA1/2. Several of these genetic abnormalities can impair high fidelity DNA damage repair increasing the therapeutic audience for PARPi's. This is especially important given the clinical development over the last decade of this group of agents and the dramatic increase in progression free survival among ovarian cancer patients who received PARPi, both in treatment or maintenance setting. In this review, we summarize our current understanding of the role of BRCA1/2 mutations in ovarian cancer and present relevant clinical trials in which BRCA1/2 was investigated as biomarker for therapy. We also outline the role of homologous recombination (HR) deficiency as biomarker by presenting the recent clinical development and recent approvals PARPi for first-line maintenance in ovarian cancer.
Ovarian cancer is the most lethal gynecological cancer of women with a 5-year survival rate of only 47%. This is mainly due to the fact that up to 59% of ovarian cancers are detected at advanced stages, for which survival is 29%. Cytoreductive surgery in combination with platinum- and taxane-based chemotherapy represents the gold standard for first-line therapy in ovarian cancer, and several studies have shown that gross residual disease correlates with survival. Two randomized phase III trials have been carried out adding bevacizumab to first-line chemotherapy and maintenance.[3,4] Both studies suggested that the use of bevacizumab prolongs the median progression free survival in patients with advanced epithelial cancer. The consistency in the data across these trials, along with a prolific safety database, led to approval of bevacizumab for first-line maintenance in Europe and US.[3,4] However, the recurrence rate in ovarian cancer is approximately 80%, even for patients who respond to initial treatment. Furthermore, it has been observed that recurring tumors have substantial heterogeneity due to multiple spontaneous genetic and epigenetic abnormalities. Represented clinically, this dynamic phenotype results in most patients undergoing multiple rounds of different chemotherapy, some with temporal benefit, but with nearly all patients succumbing to the emergence of drug resistance.
Both BRCA1 and BRCA2 are proteins involved in DNA double strand break repair by homologous recombination (HR). Loss of the functional fidelity of these proteins can lead to HR deficiency (HRD) and when present in the tumor, interventions inducing DNA double strand breaks can be differentially more lethal to the cancer cell. PARP, or poly-(ADP)-ribose polymerase, among other cellular processes, is instrumental in single strand DNA repair. When PARP is pharmacologically inhibited or trapped on DNA, single strand DNA breaks can become double strand breaks necessitating HR for repair. As is demonstrated below, conditions of HRD have provided clinical proof-of-concept for PARP inhibitor (PARPi) treatment. The rapidly expanding evidence-based for PARPi therapy in patients with ovarian and breast cancer has place a premium on identifying tumor-based HRD.
Chin Clin Oncol. 2020;9(5):63 © 2020 AME Publishing Company