For patients who are not candidates for anthracyclines, taxane-based regimens are typically administered. Given the lack of complete cross-resistance between paclitaxel and docetaxel, the alternative agent to the one used in the adjuvant setting is typically administered. For chemotherapy-naive patients, the choice between taxanes is commonly based on the toxicity profiles. Gemcitabine can be administered with paclitaxel (ORR: 41%)55 or at a lower dose when combined with docetaxel (ORR: 43%).56 Although these regimens have not been compared head-to-head, previous single-agent experience suggests that the combination of gemcitabine plus docetaxel produces greater hematologic toxicities. Another commonly used taxane-based combination includes capecitabine and docetaxel every 21 days, which is associated with an ORR of 42%, improves OS when compared with single-agent docetaxel, and demonstrates comparable efficacy with gemcitabine plus docetaxel (PFS: 8.2 vs 8.2 months).57 Meanwhile, ixabepilone in combination with capecitabine has an ORR of 35%. Although rarely administered for mBC due to its inferiority to single-agent capecitabine (ORR: 20% vs 20%; OS: 18 vs 22 months), the previously mentioned CMF combination can be used in patients who cannot tolerate the toxicity or oral administration of capecitabine.58
Most breast cancers that arise in the setting of a germline mutation in the tumor suppressor breast cancer susceptibility gene 1 (BRCA1) are triple negative. Some triple-negative breast cancers are thought to have a degree of BRCA-ness resulting in faulty DNA repair pathways, conferring similar increased sensitivity to regimens containing platinum salts, which cause DNA damage via the production of interstrand DNA cross-links.59–61 Despite the lack of prospective trials demonstrating a survival advantage in mBC, combination platinum regimens are often used in patients with mTNBC.62 This practice pattern is based on the extrapolated data from the neoadjuvant treatment setting, where platinum-based chemotherapy combinations were shown to be associate with a higher rate of pathologic complete response, albeit with more myelosuppression compared with nonplatinum regimens.63,64 High-dose chemotherapy with autologous stem cell transplantation is no longer a treatment option in mBC, following a 2011 systematic review that included six randomized trials, and concluded that the intervention provided minimal benefit with no improvement in OS.65
The epidermal growth factor receptor (EGFR) is commonly overexpressed in mTNBC. However, three Phase II clinical trials evaluating the efficacy of the anti-EGFR monoclonal antibody cetuximab in combination with chemotherapy demonstrated only a modest beneficial treatment effect.66–68 Although angiogenesis inhibitors (ie, bevacizumab) have shown to improve OS in other cancer types and marginally improve PFS in mBC, there have not been prospective data demonstrating an improvement in OS among patients with mTNBC.69–71
Polyadenosine diphosphate-ribose polymerase (PARP) is involved in the molecular events leading to cell recovery from DNA damage. If PARP1 is inhibited under normal conditions, double-strand DNA breaks accumulate and are repaired via the BRCA pathway-dependent homologous recombination mechanism.59–61 PARP inhibitors, currently only FDA approved for advanced ovarian cancer, are a class of agents that are commonly tested within the context of a clinical trial in mTNBC,72 especially among those with a mutation in BRCA. These inhibitors are commonly combined with platinum agents, as the combination is theorized to sensitize BRCA-mutated tumors to the DNA damage effects of chemotherapy. In a recent early-phase study involving women with BRCA-mutated mBC, in which >50% had triple-negative disease, it was found that the PARP inhibitor olaparib administered at 400 mg orally twice daily resulted in an ORR of 41% and a PFS of 5.7 months. It was associated with mild adverse effects, with the most commonly reported grade 3 adverse events being fatigue, nausea, and vomiting.73 Given the similarities between BRCA-mutated mBC and mTNBC, clinical trials are currently underway looking at the efficacy and safety of PARP inhibition in mTNBC (Table 2)74,75 However, a recent study found that iniparib, another PARP inhibitor, had no activity in mBC outside of patients with known germline BRCA mutations.76 The PARP inhibitor veliparib was tested in combination with the oral alkylating agent temozolomide in an early phase study involving 41 women with advanced triple-negative breast cancer (19.5% with a BRCA germline mutation).77 With an ORR of 37.5% vs 7% and a clinical benefit rate (CBR) of 62.5% vs 17%, the majority of the drug activity appeared to be among those patients with BRCA mutations when compared to the study population as a whole.
(To view a larger version of Table 2, click here.)