As discussed, AR can trigger or suppress the oncogenic features of breast tumors depending on the bioavailability of estrogens [36
]. In this vain, both AR agonists and antagonists have been tested as potential therapies (Figure 2
). Moreover, the interaction of AR with other molecular pathways has led to the investigation of therapies with AR-targeted agents in combination with signal transduction inhibitors.
So far, although, natural and synthetic steroidal androgens have been used as therapeutic approach for ERα-positive BC, they have induced serious side effects [37
]. Selective AR modulators (SARMs) such as enobosarm have been preclinically tested giving favorable results concerning migration and invasion. In vivo studies revealed that SARMs were able to reduce the tumor weight by 90%, as well as the tumor-induced cachexia, in 5 weeks [38
]. Moreover, postmenopausal women exhibit minor side effects, and the treatment is currently being investigated in a phase II clinical trial for patients with metastatic or locally-advanced ER+ and AR+ breast cancer (NCT02463032) (Table 1
AR antagonists are also being investigated in preclinical and clinical studies. Presently-available AR inhibitors are being widely used to treat prostate cancer and are showing encouraging results in several clinical trials in breast cancer. A phase II clinical trial evaluating bicalutamide, a first-generation AR antagonist, in AR-positive/ERα-negative/PgR-negative advanced breast cancers, showed a clinical benefit rate of 19% at 6 months and a median progression-free survival duration of 12 weeks [25
]. This was the first proof for efficacy of AR-targeted treatment in AR-positive TNBC. To date, a phase II clinical study testing bicalutamide in metastatic TNBC is ongoing; its outcomes have reported a modest clinical benefit rate of 20% (NCT00468715) (Table 1
Enzalutamide is a second-generation AR antagonist approved for castration-resistant prostate cancer patients [39
]. A phase II clinical trial evaluating enzalutamide in AR-positive TNBC showed a clinical benefit rate of 33% at 16 weeks, 28% at 24 weeks, median overall survival of 16.5 months, and a median progression free survival duration of 3.3 months in the evaluable subgroup of patients [32
]. Another phase II clinical study evaluating enzalutamide in combination with transtuzumab in patients with HER2+ AR+ metastatic or locally-advanced breast cancer (NCT02091960) is ongoing (Table 1
). The primary objective was clinical benefit rate at 24 weeks (CBR24), defined as complete or partial response (CR or PR) or stable disease (SD) for ≥24 weeks in evaluable patients. Another ongoing phase IIb trial is investigating whether a combination of enzalutamide and paclitaxel would exhibit benefits in early-stage, AR-positive TNBC patients (NCT02689427) (Table 1
). Abiraterone acetate and seviteronel, both CYP17A1 inhibitors, target androgen biosynthesis and production respectively [40
], and are currently being clinically evaluated. A phase I/II clinical trial of abiraterone acetate in postmenopausal women with advanced or metastatic breast cancer has been completed, presenting a clinical benefit rate of 20% in 24 weeks with a median progression-free survival duration of 2.8 months (NCT00755885) (Table 1
). Another study combining abiraterone acetate with prednisone presented promising results for patients with molecular apocrine-like tumors (NCT01842321) (Table 1
]. Seviteronel, which lowers the production of both androgens and estrogens [40
], has been evaluated in a phase I/II trial (NCT02580448) (Table 1
). Phase I revealed that seviteronel was generally well tolerated in women with TNBC and ER+ breast cancer. Interestingly, the 26.3% and 11% of the subjects reached at least a clinical benefit rate at four (CBR16) and six (CBR24) months, respectively.
At present, the standard treatment for advanced TNBC is exclusively nonspecific, cytotoxic chemotherapy [5
]. Although treatments that target AR allow patients with advanced or metastatic TNBC to be treated with less toxic endocrine agents, the need remains for the development of novel predictive biomarkers that will identify the patients that will benefit the most.