Emerging Role of PARP Inhibitors in Metastatic Triple Negative Breast Cancer. Current Scenario and Future Perspectives

Abstract

Triple negative tumors represent 15% of breast cancer and are characterized by the lack of estrogen receptors, progesterone receptor, and HER2 amplification or overexpression. Approximately 25% of patients diagnosed with triple negative breast cancer carry a germline BRCA1 or BRCA2 mutation. They have an aggressive biology, and chemotherapy has been the mainstay of treatment for a long time. Despite intensive therapies, prognosis is still poor, and many patients will eventually relapse or die due to cancer. Therefore, novel targeted agents that can increase the treatment options for this disease are urgently needed. Recently, a new class of molecules has emerged as a standard of care for patients with triple negative breast cancer and germline BRCA1 or BRCA2 mutation: poly (ADP-ribose) (PARP) inhibitors. In the first part of the review, we summarize and discuss evidence supporting the use of PARP inhibitors. Currently, two PARP inhibitors have been approved for triple negative metastatic breast cancer—olaparib and talazoparib—based on two phase III trials, which showed a progression-free survival benefit when compared to chemotherapy. Safety profile was manageable with supportive therapies and dose reductions/interruptions. In addition, other PARP inhibitors are currently under investigation, such as talazoparib, rucaparib, and veliparib. Subsequently, we will discuss the potential role of PARP inhibitors in the future. Clinical research areas are investigating PARP inhibitors in combination with other agents and are including patients without germline BRCA mutations: ongoing phase II/III studies are combining PARP inhibitors with immunotherapy, while phases I and II trials are combining PARP inhibitors with other targeted agents such as ATM and PIK3CA inhibitors. Moreover, several clinical trials are enrolling patients with somatic BRCA mutation or patients carrying mutations in genes, other than BRCA1/2, involved in the homologous recombination repair pathway (e.g., CHECK2, PALB2, RAD51, etc.).

OGG1 Inhibition Triggers Synthetic Lethality and Enhances The Effect of PARP Inhibitor Olaparib in BRCA1-Deficient TNBC Cells

“…TNBC cell lines MDA-MB-231 and Hs 578T were selected for this study, first because this phenotype is frequently associated to the lack of BRCA1 , and we thought that they could best represent a BRCA1 -deficiency context, and secondly because TNBC is the most aggressive subtype and presents limited choices of therapy ( 29 , 30 ). We used CRISPR/Cas9 to silence the BRCA1 gene in these cell lines and BRCA1 knockout (KO) single colony clones were generated.…”

The Present and Future of Clinical Management in Metastatic Breast Cancer

“…One of the most translationally investigated families of inhibitors are the ones against Poly (ADP-ribose) polymerases (PARP), enzymes involved in DNA repair, with specific importance in TNBC with BRCA1/2 inactivation. Thus, in ongoing clinical trials, several novel combinations of PARPi with CDK4/6i, immunotherapy and/or targeted therapies, are currently being investigated for their clinical efficacy and their ability to induce synthetic lethality [ 126 , 127 ].…”

Personalised Therapies for Metastatic Triple-Negative Breast Cancer: When Target Is Not Everything

“…Furthermore, recent studies have demonstrated that PARP inhibitors could play an important role as a maintenance treatment of advanced ovarian cancer, with improved PFS in patients with CR or PR, compared to platinum-based chemotherapy. Relying on this data, PARP inhibitors seem to deserve further investigation, in order to understand their role as a form of maintenance therapy in TNBC [ 45 ].…”