Treating Triple-Negative Breast Cancer: Where Are We?

Abstract

Unlike estrogen receptor (ER)-positive and HER2-positive breast cancer, triple-negative breast cancer (TNBC) lacks a repertoire of targeted therapies. Hence, chemotherapy is the only available systemic option in current clinical practice. In general, survival of patients with TNBC is worse than that for those with ER-positive and HER2-positive breast cancer, especially for advanced-stage disease. Thus, a great unmet need exists. Conventional chemotherapeutic agents such as platinumsalts have been examined for specific benefit in TNBC; however, no one agent has yet been shown to offer a differential incremental benefit in metastatic TNBC. The hope is that ongoing research in targetable molecular pathways will lead to new therapeutic options for TNBC. Because these patients are likely to be increasingly subcategorized using potentially targetable molecular alterations, investigators will need to be mindful of the challenges in designing and conducting clinical trials in smaller subpopulations. The successful incorporation of targeted therapies in routine clinical practice for TNBC, which mirrors the success achieved by anti-HER2 and endocrine therapies, is awaited. (J Natl Compr Canc Netw 2015;13:(e8-e18) and rare types, such as adenoid cystic, metaplastic, apocrine, and neuroendocrine carcinoma.3 Nevertheless, the clinical utility of this categorization has been robust as a prognostic and predictive biomarker.Patients with TNBC are more likely to have a poor prognosis than those with estrogen receptor (ER)/ progesterone receptor (PR)-positive and/or HER2-positive breast cancer.4 This is likely partially attributable to a dearth of novel therapeutic options for TNBC, in contrast to the recent expansion of endocrine and anti-HER2 therapies (eg, ado-trastuzumab-emtansine, pertuzumab, everolimus with exemestane).5-7 Therefore, great interest has been shown in exploring potential biomarkers (prognostic and predictive) and developing new therapeutic options. This article reviews current treatment options ("where are we now?") and ongoing therapeutic research ("where are we going?") for TNBC. Heterogeneity of TNBCBecause the utilitarian definition of TNBC is simply based on the exclusion of ER/PR/HER2 expression, it is not unexpected that this clinical subtype remains biologically heterogeneous. Studies examining tumor characteristics have found correlations between TNBC and certain molecular genomic features, such as basal cytokeratin (eg, CK5/6) and epidermal growth factor receptor (EGFR) expression, checkpoint kinase (Chk1), p53 alterations, and BRCA1 germline mutations.8-13 TNBC has also been shown to have overlapping features with the basal-like subtype (intrinsic breast cancer classification), 14,15 including a high frequency of poorly differentiated tumors, expression of cytokeratins and EGFR, and p53 mutations. Although the basal-like-subtypes are most often triple-negative, they are not equivalent groups.16

Advances in Small-Molecule Drug Discovery for Triple-Negative Breast Cancer

“…However, in a Phase III clinical trial with the same treatment combination among 516 patients with TNBC, the results suggest that iniparib did not meet the criteria for significance for co-primary endpoints of OS and PFS [21]. Disappointingly, iniparib was discontinued due to loss of efficacy and associated toxicity in Phase III clinical trials [22,23]. Furthermore, recent studies suggest that iniparib may not actually inhibit the PARP enzyme [24,25].…”