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  • On the contrary Birrel and colleagues observed divergent

    2023-01-10

    On the contrary, Birrel and colleagues observed divergent proliferative responses to androgens in different BC cell lines: DHT and mibolerone were found to inhibit the T47-D and ZR-75-1 SB 242084 australia growth, while the proliferation of MCF-7 cells was increased by both the androgens [53]. It is worth noying that a growth-stimulatory effect of androgens on modified MCF-7 cells was reported by conversion of androstenedione into estrogens [8], but when combining an AI therapy with testosterone administration, an increase in apoptosis was confirmed [9]. Regarding the role of AR-inhibitors, enzalutamide was shown to abrogate both the androgen-mediated and the estrogen-induced proliferation of MCF-7 and BCK-4 ER-positive BC cell lines, in vitro, and in MCF-7 xenograft models, in vivo, by inhibiting receptors translocation [34]. Focusing on the cross-talk between AR and ER, De Amicis and colleagues induced resistance to tamoxifen in MCF-7 BC cells by exogenous overexpression of AR, both in vivo and in vitro, with stable sensitivity to growth with DHT and inhibition with bicalutamide, thus reconsidering the role of AR in tamoxifen resistance [33].
    Clinical evidence Many pieces of clinical evidence supported the use of steroidal androgens for patients with advanced BC. Natural androgens such as testosterone propionate, DHT [54], [55] and synthetic steroidal androgens (e.g.,fluoxymesterone and medroxyprogesterone acetate) [56], [57], [58] have demonstrated anti-cancer activity and this was pronounced in BC with AR expression. As previously mentioned, SARMs activate AR in BC without side effects with steroidal androgens. In a small phase II study, enobosarm, a non-steroidal SARM, specifically an androgen agonist without estrogenic properties, has been evaluated in 22 patients with ER and AR positive metastatic BC. Among the evaluated patients, 42% had a favorable response with a disease stabilization and a good treatment tolerability [59]. Currently, enobosarm is still being examined in a phase II clinical trial in patients with ER-positive BC [60]. Abiraterone acetate is a steroidal CYP17A1 inhibitor which has been shown to improve outcome in patients with metastatic castration-resistant PC by blocking testicular, adrenal and intratumoral androgen synthesis [61], [62]. In phase I/II trials in postmenopausal ER and AR-positive metastatic BC patients with two or more prior endocrine treatments, an antitumor effect of abiraterone acetate was observed. After one month of treatment, abiraterone acetate reduced androgen and estradiol hormone concentrations below the analytical detection limit. A clinical benefit was observed in a total of 32 ER and AR-positive BC patients. Specifically, 22% of patients obtained a stable disease for more than 24 weeks of treatment [63]. Moreover, a randomized open label phase II trial was conducted to analyze the hypothesis that a complete inhibition of both androgen and estrogen signaling is associated with a better response in AR and ER-positive metastatic BC patients. The primary endpoint was PFS. In this trial, nearly 300 pre-treated patients received a daily therapy of 1000 mg abiraterone acetate plus 5 mg prednisone or abiraterone acetate plus 25 mg exemestane or exemestane alone. No significant differences were recorded in term of PFS when the association of abiraterone acetate plus exemestane was compared to exemestane alone. Intriguingly, an increased serum progesterone was observed in the two treatment arms with abiraterone acetate but not in the exemestane alone arm, suggesting an abiraterone-induced progesterone elevation, even though it demonstrated the inhibition of androgen synthesis in postmenopausal with ER/AR-positive and NSAI-resistant metastatic BC. The investigators suggested that this event could have contributed to the lack of clinical activity expected from abiraterone acetate in combination with the NSAI therapy. More grade 3–4 adverse events emerged in the combination arm, in particular, hypokalemia, and hypertension [64].