PARP inhibitors in the management of breast cancer: current data and future prospects

Abstract

Poly(ADP-ribose) polymerases (PARP) are enzymes involved in DNA-damage repair. Inhibition of PARPs is a promising strategy for targeting cancers with defective DNA-damage repair, including BRCA1 and BRCA2 mutation-associated breast and ovarian cancers. Several PARP inhibitors are currently in trials in the adjuvant, neoadjuvant, and metastatic settings for the treatment of ovarian, BRCA-mutated breast, and other cancers. We herein review the development of PARP inhibitors and the basis for the excitement surrounding these agents, their use as single agents and in combinations, as well as their toxicities, mechanisms of acquired resistance, and companion diagnostics.

General Overview and Treatment Recommendations for Young Women with Breast Cancer

“…An important characteristic of BRCA-mutated cancers is defective function of one of the major DNA damage repair pathways, the homologous recombination pathway 142 . The discovery of the family of nuclear enzymes poly(ADP-ribose) polymerases (PARP), and their role in DNA damage repair pathways led to development of a new class of drugs, so-called PARP inhibitors, which have the ability to interfere with the DNA damage repair systems of cancer cells.…”

“…There are several phase III trials currently ongoing in both the metastatic and neo/adjuvant and are limited to patients with BRCA1/2-associated tumors 142 .…”

Base Excision Repair Manipulation in Breast Carcinoma: A Prospective Avenue to Potentiate Genome Insulting Approach

“…Recently, combinatorial drugs/inhibitors treatment regiments are described involving PARP and PI3K pathway inhibitors. The human breast cancer cell lines demonstrated heightened cell death and apoptosis in case of combined use of PARP and PI3K inhibitors [5,20,95]. Recently, olaparib (Lynparza), PARP inhibitor are directed towards cancer types with debilitating DNA repair pathways as BRCA1 and BRCA2 mutation [10].…”

Triple Negative Breast Cancer: A review of common therapeutic Targets and Current Treatment options.

“…Furthermore, the PARP inhibitor iniparib, when combined with chemotherapy and carboplatin for the treatment of TNBC, demonstrated a 41% reduction in risk progression and a 43% reduction in mortality with a minimal increase in toxicity [24,27]. As with other targeted therapies, cancers can develop resistance to PARP inhibitors, which can limit their clinical effectives and utility [28]. Another concern with regards to PARP inhibitors is their ability to increase the risk of developing new primary malignancies due to their DNA-damaging mechanism of action [27].…”