Anti-androgen therapy in triple-negative breast cancer

Inhibition of the androgen receptor (AR) represents the most important therapeutic target in prostate cancer. Although AR is expressed in 77% of all breast cancers (BCs), even more than estrogen receptors (ERs), its role in BC growth and progression remains indefinite [Guedj et al. 2012]. AR expression is associated with somewhat more indolent BC [Lehmann et al. 2011; Liedtke et al. 2008; Cochrane et al. 2014]. The drug development pipeline of AR-targeted therapeutics in prostate cancer is facilitating the evaluation of AR signaling inhibition in triple-negative breast cancer (TNBC): including bicalutamide, a nonsteroidal partial agonist; enzalutamide, an inhibitor of nuclear localization of AR; and VT-464, a dual inhibitor of CYP17 and AR. Given the controversy in the role of AR, other ongoing or completed trials are testing dehydroepiandrosterone (DHEA) or 4-OH testosterone (see Table 1). Table 1. Clinical trials of AR therapies in breast cancer. Figure 1. AR signaling integration in TNBC. Preclinical justification for anti-androgen therapies in breast cancer Gene expression profiling of BC suggests a significant functional role for AR in multiple subtypes of BC [Guedj et al. 2012; Lehmann et al. 2011]. While AR is expressed to varying degrees across all BC subtypes, preclinical modeling suggests that its functional role in disease progression is subtype-specific. Gene expression profiling of TNBC has revealed a number of potential subtypes within TNBC, including basal-like 1, basal-like 2, immunomodulatory, mesenchymal-like, mesenchymal stem-like, and luminal AR (LAR) [Lehmann et al. 2011], although these subtypes do not yet dictate individualized treatment with specific targeted agents to date. Although ER expression is absent, the LAR subtype is characterized by AR signaling with a gene expression pattern similar to luminal BC. Patients with LAR tumors are more slowly growing when metastatic, however they have decreased relapse-free survival in the adjuvant setting relative to other TNBC subtypes [Cochrane et al. 2014], perhaps due to lower chemotherapy sensitivity. LAR cell line models are sensitive to the AR partial antagonist bicalutamide [Lehmann et al. 2011], and are even more sensitive to the next-generation AR inhibitor enzalutamide [Cochrane et al. 2014]. AR is expressed in 12–55% of cases of TNBC [Barton et al. 2015; Collins et al. 2011; Gucalp et al. 2013; Thike et al. 2014; Traina et al. 2015]. Some of the variability in frequency of expression between studies is due to different anti-AR antibodies used and to different assay cutoffs (1% versus 10%). Preclinically, BC expressing as little as 1% AR may respond to enzalutamide, although higher levels may be associated with greater response [Barton et al. 2015]. Optimal assay for response to AR inhibitors in clinic is as yet unknown. Although the LAR subtype of TNBC is AR enriched, other TNBC subtypes also express AR, and have responded to AR inhibition using preclinical models [Barton et al. 2015]. In TNBC models, AR appears to regulate amphiregulin (AREG), an epidermal growth factor receptor (EGFR) ligand, which when secreted could potentially support even AR negative tumor cells [Barton et al. 2015]. Phosphoinositide 3-kinase (PI3K3) activation through loss of phosphatase and tensin homolog (PTEN) or mutation of PIK3CA is common in TNBC [Shah et al. 2012; Kriegsmann et al. 2014], and is associated with increased AR levels in BC [Gonzalez-Angulo et al. 2009]. The combination of bicalutamide and the PI3K inhibitors pictilisib and apitolisib showed additive efficacy in PI3K-mutant TNBC cells in vitro and in vivo [Lehmann et al. 2014]. Enzalutamide plus everolimus appeared to be synergistic in multiple in vitro preclinical models of BC, including TNBC [Gordon et al. 2014].