PARP inhibitors are targeted agents that inhibit the activity of the PARP polymerase family of enzymes. These enzymes are essential in repairing DNA damage, particularly single-strand breaks through the base excision repair pathway [34]. In cells that are deficient in alternate DNA repair pathways, inhibiting the activity of PARP enzymes leads to cell death through synthetic lethality [34]. An example of synthetic lethality is illustrated by the use of PARP inhibitors in BRCA-mutated cancers. BRCA-mutated cells are deficient in the homologous recombination (HR) pathway for repair of DNA double-strand breaks. By inhibiting the activity of the PARP enzymes, the base excision repair pathway is also eliminated as a potential mechanism for DNA repair. Single-strand breaks can then accumulate, due to inefficient base excision repair, and lead to double-strand breaks at replication forks. In this way, cell death can occur through synthetic lethality [35]. This concept has been tested clinically in populations of BRCA-mutated carriers and shown to be active in BRCA-mutated cancers [35]. A phase II trial of the PARP inhibitor, olaparib, in BRCA-mutated metastatic breast cancer patients showed objective response rates ranging from 21 to 44%. Over 50% of these patients had TNBC. Objective response rates ranged from 21 to 44% [35]. Since BRCA-mutated breast cancers and TNBC share clinical and pathologic characteristics, such as sensitivity to DNA-damaging agents, high pathologic grade, and high rate of p53 mutations, it is proposed that TNBC, which is most like BRCA-mutated breast cancer, is also deficient in the HR pathway [34]. This characteristic would render TNBC vulnerable to PARP inhibition in the same way as BRCA-mutated breast cancer. The use of PARP inhibitors in TNBC is an area of active research. A phase II trial of the intravenous PARP inhibitor, iniparib (BSI-201), in combination with gemcitabine and carboplatin was performed in a population of 120 women with metastatic, pretreated TNBC [36]. Clinical benefit rates were 62% in patients who had received BSI-208 versus 21% with chemotherapy alone. Progression-free and overall survival were also improved with the addition of BSI-201 [36]. A phase III follow-up study compared iniparib in combination with gemcitabine and carboplatin to gemcitabine and carboplatin alone in 519 women with metastatic, pretreated TNBC. The primary endpoints of overall survival and progression-free survival were not met. Subgroup analysis showed that there was a survival benefit in the group of women who had received two or more prior lines of treatment [37]. In vitro data has shown, however, that iniparib demonstrates little or no ability to inhibit formation of PARP polymers or induce apoptosis in cell lines which are deficit in homologous repair pathway, such as BRCA-mutated cells [38, 39]. Further studies of agents with true PARP inhibition have shown promising results. A neoadjuvant study of the PARP inhibitor, veliparib, in combination with paclitaxel and carboplatin showed pCR rates that improved from 26 to 51% with the addition of veliparib in TNBC. Potential biomarker candidates to predict pCR were also evaluated [40, 41]. This combination will be evaluated in a phase III trial.

The PI3K/AKT/mTOR pathway is frequently activated in breast cancer and is another area of active research. This pathway leads to cell survival through activation of a series of proteins, including AKT kinase and mTOR (mammalian target of rapamycin inhibitors) [42]. The pathway is activated by binding of a ligand to various tyrosine kinase receptors, including HER proteins, EGFR, and IGF-1 (insulin growth factor) receptors [42]. This rich pathway presents a number of options for drug targets. A neoadjuvant study of an AKT inhibitor, MK-2206, in combination with standard chemotherapy showed a pCR rate of 40% [43]. The PI3K/AKT/mTOR pathway provides stability of the homologous recombination repair pathway, which is deficient among BRCA-mutated cells. Inhibition of AKT has been shown to render TNBC more sensitive to PARP inhibitors by inducing deficiencies in the HR pathway [42]. In an in vitro study of TNBC, the AKT inhibitor, buparlisib, was shown to sensitize TNBC cells to the PARP inhibitor, olaparib [44]. The tyrosine kinase inhibitor, neratinib , which inhibits binding of the ligand for ErbB and Her family of receptors, was evaluated in the neoadjuvant setting in all subtypes of breast cancer. While neratinib was found to be most efficacious in ER-, Her-2 + breast cancers, there was a subset of TNBC which showed pCR rates of up to 66% with neratinib in combination with anthracycline and taxane. Molecular signatures of these responders show that these tumors showed phosphorylation of EGFR or Her-2/neu [45].

Antibody-drug conjugates are being tested in the treatment of TNBC. Sacituzumab govitecan is a humanized anti-Trop-2 antibody linked to a high concentration of SN-38, which is the active metabolite of irinotecan. Trophoblast cell-surface antigen, Trop-2, is a target that is expressed in multiple solid tumors. The Trop-2 gene encodes a transmembrane calcium signal transducer, which is linked to cell migration. The gene is also referred to as tumor-associated calcium signal transducer 2 (TACSTD2) [46]. Among breast cancer patients, increased expression of Trop-2 is linked to shorter survival [47]. Expression of TACSTD2 is active among TNBC cell lines [48]. A phase II trial of sacituzumab govitecan conducted in 58 TNBC patients, with a median of 4 prior therapies, demonstrated an overall response rate (CR + PR) of 31% and clinical benefit rate (CR+PR+SD) of 49%. Given that this study was conducted among a heavily pretreated population, these outcomes are very promising in patients with refractory TNBC [49]. Glembatumumab vedotin is an antibody-drug conjugate of the cytotoxin, monomethyl auristatin E, that targets glycoprotein NMB (gpNMB). gpNMB is overexpressed in a multiple tumor types and is a poor prognostic factor among breast cancer patients. A phase I trial glembatumumab vedotin among metastatic breast cancer showed response rates of up to 40% among TNBC patients with gpNMB overexpression [50].