A challenge in treating TNBC is to identify suitable targets for therapy. TNBC is based on the absence of receptors, but comprises a molecularly heterogenous patient population that is only now becoming better understood. With understanding may come better-targeted and effective treatment options. Some promising areas of research are reviewed here.
Results in TNBC to date have been mixed, with modest response rates or no additional benefit in neoadjuvant trials and more substantial benefit in advanced settings. Response may in part depend on BRCA1 status, which is associated with sensitivity to DNA-damaging agents. More prospective studies are needed and several are underway.2,6,14
Ixabepilone is part of the epothilone class of macrolide antibiotics with microtubule stabilizing properties approved as monotherapy, after capecitabine, anthracycline or taxane failure; or in combination with capecitabine following anthracyline/taxane failure, in metastatic or locally advanced BC. Data from a pooled analysis of two phase 3 studies including women with TNBC (n=443) who advanced on AT show a 31% response rate for ixabepilone plus capecitabine versus 15% for capecitabine alone, as well as longer PFS (4.2 months v 1.7 months [HR 0.63; 95% CI 0.52-0.77]) but similar OS (10.3 months v 9 months [HR 0.87; 95% CI 0.71-1.07]).2,4,17
Emerging Targeted Therapies
Aberrant expression of DNA repair molecules and expression of HER1/EGFR in TNBC suggest possible therapeutic targets. Clinical research has been reported on poly (ADP-ribose) polymerase (PARP)1, EGFR, Src, and vascular endothelial growth factor (VEGF) in treating TNBC.
Double-stranded DNA breaks are highly toxic to cells and usually repaired in a process mediated by BRCA. In BRCA-deficient cells (including the majority of TNBC, based on its “BRCAness”), repair shifts toward alternate, PARP1-dependent mechanisms. PARP inhibitors disrupt this second pathway, leading to accumulated double-stranded DNA breaks and apoptosis in a process known as “synthetic lethality.”4,5,18 Due to the relationship between TNBC and BRCA1 associated tumors, PARP inhibitors are being investigated in TNBC.4 A concern is that efficacy in TNBC may be restricted to patients bearing BRCA mutations, a status that has not always been broken out in clinical trials. For example, the efficacy of the oral PARP inhibitor veliparib, which potentiates CT effects in early clinical trials for other cancer types, appears to be limited to BRCA-positive disease.19
The oral PARP inhibitor olaparib has demonstrated acceptable toxicity in a phase 1 safety study (15% of those in the trial had BC), but only in BRCA-positive patients.18 A small phase 2 study enrolled previously treated women with BRCA1/2 mutations and treated them with olaparib, either 100 mg BID (n=27) or 400 mg BID (n=27). Half the women had TNBC. Overall response (OR) was 22% with the lower dose and 41% with the higher dose, but drug-related toxicity led to dose reductions or delays in 30% of participants.3 In another phase 2 study, patients with advanced/metastatic BRCA-positive ovarian or breast cancer, including 21 with TNBC, were treated with olaparib 400 mg BID. There were no complete (CR) or partial (PR) responses in any of the BC patients. Stable disease (SD) rates were higher in BRCA-positive than negative patients. The small sample size or baseline characteristics were hypothesized as reasons for the lack of response in BC.20