Poly(ADP-Ribose) polymerase inhibition: "targeted" therapy for triple-negative breast cancer

Abstract

In contrast to endocrine-sensitive and human epidermal growth factor receptor 2 (HER2)-positive breast cancer, novel agents capable of treating advanced triple-negative breast cancer (TNBC) are lacking. Poly(ADP-ribose) polymerase (PARP) inhibitors are emerging as one of the most promising "targeted" therapeutics to treat TNBC, with the intended "target" being DNA repair. PARPs are a family of enzymes involved in multiple cellular processes, including DNA repair. TNBC shares multiple clinico-pathologic features with BRCA-mutated breast cancers, which harbor dysfunctional DNA repair mechanisms. Investigators hypothesized that PARP inhibition, in conjunction with the loss of DNA repair via BRCA-dependent mechanisms, would result in synthetic lethality and augmented cell death. This hypothesis has borne out in both preclinical models and in clinical trials testing PARP inhibitors in both BRCA-deficient and triple-negative breast cancer. The focus of this review includes an overview of the preclinical rationale for evaluating PARP inhibitors in TNBC, the presumed mechanism of action of this novel therapeutic class, promising results from several influential clinical trials of PARP inhibition in advanced breast cancer (both TNBC and BRCA deficient), proposed mechanisms of acquired resistance to PARP inhibitors, and, finally, concludes with current challenges and future directions for the development of PARP inhibitors in the treatment of breast cancer.

Figure 1

Figure 1a: Two main pathways which contribute to repair of DNA double strand breaks: non-homologous end joining (NHEJ) and homologous recombination (HR). This figure was published in Abeloff's Clinical Oncology, 4th Edition. JM Ford and MB Kastan, Chapter 10: DNA damage response pathways and cancer. p. 149. (Reprinted with permission, Copyright 2008, Churchill Livingstone, an Imprint of Elsevier) (5). Figure 1b: ‘Synthetic lethality’ and subsequent cell death due to loss of parallel DNA repair pathways. In the presence of one (or both) functional BRCA- or PARP-dependent DNA repair pathways, cells survive. In the absence of both, cell death ensues (Reprinted with permission, from EA Comen and M Robson: ONCOLOGY 24(1):55-68, 2010) (52).

Figure 1

Figure 1a: Two main pathways which contribute to repair of DNA double strand breaks: non-homologous end joining (NHEJ) and homologous recombination (HR). This figure was published in Abeloff's Clinical Oncology, 4th Edition. JM Ford and MB Kastan, Chapter 10: DNA damage response pathways and cancer. p. 149. (Reprinted with permission, Copyright 2008, Churchill Livingstone, an Imprint of Elsevier) (5). Figure 1b: ‘Synthetic lethality’ and subsequent cell death due to loss of parallel DNA repair pathways. In the presence of one (or both) functional BRCA- or PARP-dependent DNA repair pathways, cells survive. In the absence of both, cell death ensues (Reprinted with permission, from EA Comen and M Robson: ONCOLOGY 24(1):55-68, 2010) (52).

Figure 2

Kaplan Meier curves illustrating an overall survival advantage for patients with triple negative metastastic breast cancer treated with the PARP inhibitor, BSI-201 (BiPAR Sciences/Sanofi Aventis) plus carboplatin/gemcitabine chemotherapy compared to chemotherapy alone (12.2 versus 7.2 months, p = 0.005)(36).