Emerging Therapeutic Approaches in Triple-Negative Breast Cancer

Of the estimated 226,870 new breast cancer (BC) cases in 2012,¹ from 15% to 20% will be of the triple-negative phenotype, a subtype of breast cancer responsible for a  high proportion of breast cancer mortality and associated with poor prognosis.^2,3 Unlike the more prevalent luminal-type breast cancers, which express estrogen (ER) and progesterone (PR) receptors, triple-negative breast cancer (TNBC) is clinically negative for hormone receptors as well as HER2 expression.^2,4 Most (75%-85%) TNBC falls into the basal-like (BL) subtype of breast cancer.^2,3 Although the terms have been used interchangeably, “triple-negative” is a clinical term based on assays for ER/PR/HER2 while BL is a molecular phenotype based on cDNA microarrays.^5,6 The remaining proportion of TNBC is non-basal-like and includes luminal subtype B with minimal ER expression and the recently identified claudin-low subtypes.^2,3,5

TNBC generally carries classic basal epithelial cell markers, including higher expression (than luminal cells) of cytokeratin (CK) 5, CK14, and CK17; epidermal growth factor receptor (HER1/EGFR), and a variety of others.⁵ While >50% of BRCA1-mutation-driven tumors are TNBC, only about 10% of TNBC carries the mutation, and no association with BRCA2 has emerged. Both BL BC and TNBC have a relatively high degree of “BRCAness,” a term used to connote qualities shared between BRCA-associated and “sporadic” breast cancers (eg, expression of CK5 and EFGR).^3,5-7 Most TNBC are invasive ductal carcinomas, pathologically grade III, and associated with high proliferation rates, nuclear pleomorphism, “pushing” borders of invasion, geographic necrosis, and p53 mutations.^6,9

TNBC exhibits unique patterns of recurrence temporally and by location. Recurrence and mortality are higher in the first 3 years after diagnosis, after which risk is similar to other BC types.^5,8,9 After 5 years, risk for relapse is lower than with hormone-receptor positive cancer.³ In women with recurrence, distal relapse is the pattern, skipping over local relapse.¹⁰ Recurrence occurs less often in bone than in other BC types, and more often in the viscera and soft tissue.

Consistent with its unique molecular and recurrence patterns, TNBC has distinct epidemiologic and risk factor profiles. Women diagnosed with TNBC tend to be of younger age, premenopausal, and black more than white.^8,13 The highest prevalence of TNBC in the Carolina Breast Cancer Study was found among premenopausal black women, whereas the highest prevalence of luminal A was among postmenopausal white women.¹³ Risk factors are shown in Table 1.^8,13 In the Carolina study, the two strongest risk factors were no breastfeeding and high abdominal obesity; researchers hypothesized that one-third (in the younger African American population) to half (in the general population) of BL/TN BC could be averted by modifying these two risk factors.¹³

Treatment Considerations

Overall, women with TNBC have a poor prognosis, but those who achieve a pathological complete response (pCR) on chemotherapy (CT) have a similar outlook as women with other types of BC. For those who do not achieve pCR, prognosis is diminished due to the lack of therapeutic response.^2,3

Cytotoxic CT is beneficial in neoadjuvant, adjuvant, and metastatic settings to treat TNBC.¹⁴ Women with TNBC have a more potent early response to anthracycline-based neoadjuvant CT than women with luminal or HER2+ BC, but a paradox is that despite this, they have shorter progression-free (PFS) and overall (OS) survival times than other women.^3,14-16 In a seminal study, a retrospective analysis found 22% complete response to neoadjuvant CT in TNBC versus 11% in non-TNBC.^6,12 Taxanes are also of benefit, independent of receptor status, and, although some of the data is conflicting, have been shown to be as effective in metastatic TNBC as in other metastatic BC types.¹⁴ Ongoing clinical trials evaluating CT in TNBC include the addition of bevacizumab or capecitabine to adjuvant CT and the addition of ixabepilone to AC (anthracycline, cyclophosphamide) or FEC (fluorouracil, epirubicin, cyclophosphamide) regimens.⁶