PARP Inhibitors in the Treatment of Triple-Negative Breast Cancer

Abstract

Breast cancer is a heterogeneous disease, manifesting in a broad differentiation in phenotypes and morphologic profiles, resulting in variable clinical behavior. Between 10 and 20% of all breast cancers are triple negative. Triple-negative breast cancer (TNBC) lacks the expression of human epidermal growth factor receptor 2 (HER2) and hormone receptors; therefore, to date, chemotherapy remains the backbone of treatment. TNBC tends to be aggressive and has a high histological grade, resulting in a poor 5-year prognosis. It has a high prevalence of BRCA1 mutations and an increased Ki-67 expression. This subtype usually responds well to taxanes and/or platinum compounds and poly (ADP-ribose) polymerase (PARP) inhibitors. Studies with PARP inhibitors have demonstrated promising results in the treatment of BRCA-mutated breast and ovarian cancer, and PARP inhibitors have been studied as monotherapy and in combination with cytotoxic therapy or radiotherapy. PARP inhibitor efficacy on poly (ADP-ribose) polymer (PAR) formation in vivo can be quantified by pharmacodynamic assays that measure PAR activity in peripheral blood mononuclear cells (PBMC). Biomarkers such as TP53, ATM, PALB2 and RAD51C might be prognostic or predictive indicators for treatment response, and could also provide targets for novel treatment strategies. In summary, this review provides an overview of the treatment options for basal-like TNBC, including PARP inhibitors, and focuses on the pharmacotherapeutic options in these patients.

Chromosome 12p Amplification in Triple-Negative/BRCA1-Mutated Breast Cancer Associates with Emergence of Docetaxel Resistance and Carboplatin Sensitivity

“…Some genomic alterations identified in TNBC tumors are associated with various responses to chemotherapy and targeted therapies (11,12). However, no mutations or chromosomal rearrangements in TNBC tumors have been found that confer resistance to specific chemotherapeutic agents.…”

Nitroxyl as a Potential Theranostic in the Cancer Arena

“…As a key component in the DNA repair machinery, the poly (ADP-Ribose) polymerase (PARP) is a main target during chemotherapies and radiation therapies in cancer cells (31,118). The PARP family plays a pivotal role in diverse cellular processes, and their inhibitors are therapeutic agents in the treatment of breast cancer (53,75). An interesting study has shown that HNO donors elicit strong…”

Immunotherapeutic interventions of Triple Negative Breast Cancer

“…PARP inhibitors are promising agents for the treatment of BL-1 (basal-like 1) TNBC, which features an enriched cell cycle, elevated DNA damage response (ATR/BRCA), proliferation pathway, and cell-cycle checkpoint loss pathways [ 97 ]. PARP inhibitors serve as a group of novel oral anticancer drugs that are highly active in TNBC with selected mutations or epigenetic silencing of genes involved in the DNA damage response (DDR), including BRCA1 and BRCA2 [ 98 ]. However, PARP inhibitors can upregulate PD-L1 expression and enhance cancer-associated immunosuppression.…”