A phase I trial has recently evaluated

A phase I trial has recently evaluated enzalutamide, an anti-androgen agent, in patients with ER- and AR-positive advanced BC to estimate safety and tolerability of enzalutamide therapy alone or in association to anastrozole, exemestane or fulvestrant [65]. The results of major clinical trials with androgen inhibitors are summarized in Table 1. In conclusion, results of ongoing and future prospective clinical trials are awaited to establish which AR-targeted agents (or combination) are the best treatment options in AR/ER-positive BC (Table 2).
Potential biomarkers New knowledge on the biology of AR has elicited the search for its possible implication in the mechanisms of resistance to endocrine therapy in the treatment of BC with ER expression. It is also crucial to identify biomarkers for prediction treatment response in treatment with anti-androgen agents. Li et al. recently conducted a biomarker analysis of BCA2001 as part of a phase 2 study [64]. In this trial, postmenopausal ER-positive HER2-negative metastatic BC patients were administered either abiraterone acetate plus prednisone (AA) versus abiraterone acetate plus prednisone plus exemestane (AAE) versus exemestane alone (E). Weimin et al. analyzed a series of tumor biomarkers from serum, circulating tumor nelfinavir receptor (CTCs), and formalin-fixed paraffin-embedded tissues (FFPETs). They found a significant decrease in serum testosterone and estrogens levels in AA and AAE-treated patients, with a concomitant increase in progesterone levels. However, this increase was not associated with better outcome. On the contrary, the baseline AR and ER dual expression in CTCs were found to be positively associated with PFS in the AAE arm compared to the E arm (HR 0.41, p = 0.07). Moreover, when considering patients with recent FFPETs (<1 year prior to the last dose) the expression of AR was associated with better PFS in AAE-treated patients compared to E-treated patients (HR 0.56, p = 0.19), might be due to a sample more representative of the tumor biology [11]. A progressive enrichment of AR expression in metastatic BC previously treated with NSAIs was also suggested to predict improved PFS with antiandrogen therapy [33]. Furthermore, the AR signaling pathway seems to be involved in the development of tamoxifen resistance. Indeed, it has been reported that AR mRNA decreases in ERα-positive tumors responsive to neoadjuvant endocrine therapy, while it does not decrease in resistant tumors. Additionally, high levels of AR were found in tamoxifen-resistant BC cells, and it was suggested that AR overexpression could enhance the agonistic activity of this drug [33], [66]. As already mentioned, ERα-positive BC patients with AR to ER ratio >2 seem to have a four-time higher risk of disease progression and tamoxifen failure, leading to the hypothesize that the AR:ER ratio might be a new predictive biomarker of resistance to endocrine therapies [34], [66]. Cochrane et al. also provided the first preclinical evidence that enzalutamide might be an effective therapeutic strategy for AR positive BCs (both ERα positive and negative BCs). Thus, high AR to ER ratio would represent a marker of response to enzalutamide alone or enzalutamide plus tamoxifen. Another emerging biomarker is represented by AR splice variants (AR-V), especially the AR-V7 variant, which is often associated with the resistance of PC cells to androgen deprivation therapy [67]. Likewise, AR-V7 is commonly expressed in BC tissue and could promote the growth of cancer cells and mediate resistance to antiandrogen strategies due to constitutively activation. This transcript was usually expressed at low levels in about 50% of BCs, but a high expression was found in a subset of ERα-negative BC patients, particularly HER2-enriched cases. Furthermore, treatment with enzalutamide can induce transcription of AR and expression of AR-V7 [12]. Amyloid precursor protein (APP) is a transcription factor highly expressed in brain tissue and involved in the pathogenesis of Alzheimer’s disease. In recent years, this protein has been increasingly implicated in a series of malignancies, including PC and BC. Particularly, the overexpression of APP and amyloid precursor-like protein 2 (AMPLP2) in BC tissue causes increased proliferation and invasion leading to metastatization [68]. Takayama et al. showed that APP is an androgen-regulated gene that mediates androgens signaling in PC. Moreover, authors have reported that high intensity of APP immunostaining enhances the androgen-dependent growth of cancer cells; on the other hand, the knockdown of APP in cultured cells and mice seems to repress proliferation [69]. Given these data, Tagaki et al. analyzed APP in human BC and demonstrated the immunolocalization of this protein in the tissue of about 50% of BCs. Furthermore, they reported an association between APP status and AR expression; notably, APP status seems to be associated with proliferation and Ki-67 index in ER-positive tumors, representing an independent prognostic factor of DFS in this subset of patients [70].