Iniparib differs from others in the PARP inhibitor class in that it interacts with the DNA binding domain of PARP-1 instead of the catalytic site of PARP. Its antitumor mechanism of action is unclear.6,19 Although a phase 2 trial in TNBC had promising results, a phase 3 trial failed to meet its primary endpoint of combined OS/PFS. Patients were treatment naïve or could have had ≤2 prior treatments for metastatic TNBC. Those who progressed on GC (gemcitabine, carboplatin) were allowed to cross over to GCI (GC plus iniparib); 59% did so.21 In the phase 2 study, also open-label, women with TNBC received GC or GCI. Significant improvements on the primary endpoint, clinical benefit for 6 months (34% with GC vs 56% with GCI; P=0.01),  and survival measures (P=0.01 for OS and PFS) were noted in the trial. No additional toxicities were noted.22

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EGFR inhibitors are of interest because TNBC overexpresses EGFR, but to date results have been disappointing.2,23 Cetuximab was evaluated in a phase 2, randomized trial with 102 TNBC patients. Although the combination was well tolerated, the response rate was low (<20% of patients).24 In preclinical research using breast cancer cell lines, a combination of mammalian target of rapamycin (mTOR) inhibition and the EGFR inhibitor, lapatinib, was synergistic in vitro and in vivo, opening another avenue of exploration.23

The oral tyrosine kinase inhibitor dasatinib, approved for treatment of Ph+CML, inhibits the protein product of Src, a proto-oncogene involved in cell signaling, including proliferation, differentiation, and survival; Src is overexpressed in TNBC and represents a potential target for research.25 Women with advanced TNBC were treated with dasatinib 100 mg BID (later reduced to 70 mg BID) in a phase 2, single-agent trial. Response on the primary endpoint was <5%, but the disease control rate was 9.3% and 27.9% of patients had stable disease.25

Anti-angiogenesis agents appear to be effective for TNBC to the same extent as in other BC subtypes.3 A randomized trial assigned women with TNBC (n=663) to receive neoadjuvant EC (epirubicin, cyclophosphamide) followed by docetaxel, or EC followed by docetaxol with  bevacizumab (ECB). The primary endpoint, pCR, was achieved in 39.3% (ECB) and 27.9% (EC) the patients in their respective study group (HR 1.67 (1.21-2.31)].27 The ATHENA trial enrolled untreated patients cared for in clinical practice; most received a combination of bevacizumab and a taxane. In a subgroup analysis of those with TNBC (n=585), the median time to progression was 7.2 months and the overall RR was 49% (10% CR). Illustrating again the difficulty of treating these patients, the median OS was 18.3 months (95% CI: 16.4-19.7) versus 27.3 months in those without TNBC (n=1616).28 In a subgroup of the RIBBON-2 study, which evaluated bevacizumab in the second-line setting, patients with metastatic BC who had progressed on CT were randomly assigned to CT plus bevacizumab or CT plus placebo. The primary endpoint, PFS, was significantly longer in the group that received bevacizumab (6 months vs 2.7 months [HR 0.494, 95% CI 0.33-0.74; P=0.0006]). Adverse events and tolerability were similar to other bevacizumab studies.7 Sunitinib is a dual inhibitor of VEGF and platelet-derived growth factor studied in a phase 2, single-agent trial. In pretreated, metastatic BC patients (including 20 with TNBC), the objective response rate was 15% (3/20) in TNBC patients.2 In an exploratory study of sunitinib plus paclitaxel, the objective response rate in women with metastatic TNBC was 33% (3/9).29

Current Treatment Recommendations

At present, national guidelines recommend anthracycline-based regimens in dose-dense or metronomic schedules for treatment of TNBC; taxanes can serve as adjunct therapy.6,30,31 Platinum agents currently are not recommended outside of clinical trials.30