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Modulating Androgen Receptor Activity in Breast Cancer Treatment: Comparison
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Please note this is a comparison between Version 2 by Jessie Wu and Version 3 by Jessie Wu.

The androgen receptor (AR) is a steroid hormone receptor widely detected in breast cancer. Evidence suggests that the AR might be a tumor suppressor in estrogen receptor alpha-positive (ERα+ve) breast cancer but a tumor promoter in estrogen receptor alpha-negative (ERα-ve) breast cancer. Modulating AR activity could be a potential strategy for treating breast cancer.

  • breast cancer
  • AR
  • ERα

1. Activation of Androgen Receptor Can Suppress Estrogen Receptor Alpha-Positiα+ve Breast Cancer

The possibility of modulating androgen receptor (AR) activity for breast cancer treatment can be traced back to 1939, when the first record of breast cancer patients who might benefit from receiving testosterone propionate to activate the AR was published [1]. Subsequently, similar observations were reported to support the potential application of androgens in treating breast cancer [2][3][4][5]. Although the expression status of estrogen receptor alpha (ERα) in the tumors was not indicated in these studies, they indicated the therapeutic value of utilizing androgens in breast cancer patients. Nevertheless, this innovative therapeutic strategy for breast cancer has not been widely studied for decades, since people found that androgens could be converted to estrogen via steroid aromatase. Such an effect may enhance the activity of the oncoprotein ERα. As more and more evidence revealed the anti-ERα properties of AR in breast cancers, investigators started to revisit the potential of androgens in treating ERα breast patients.
In a retrospective study, 508 postmenopausal and ovariectomized women who had received testosterone implants in addition to conventional hormone therapy were followed up for a mean duration of 5.8 years. The incidence of breast cancer was recorded, and the results showed that using testosterone might reduce the occurrence of conventional-hormone-therapy-induced breast cancer [6]. A prospective study recruiting 1268 pre-/postmenopausal women who were subcutaneously implanted with testosterone alone or combined with an aromatase inhibitor anastrozole to treat symptoms of hormone deficiency aimed to study the influence of the treatments on the occurrence of breast cancer: the 5-year interim report indicated that the annual incidence rate in the intent to treat patients was estimated to be 142 cases per 100,000 individuals (0.142%) and it could be further reduced to 73 cases per 100,000 people (0.073%) if the subjects received testosterone therapy, which was significantly lower than the control groups (0.293–0.39%) [7]; the 10-year analysis results showed the incidence rate of breast cancer in the testosterone-treated population was also significantly less than the age-specific Surveillance, Epidemiology, and End Results (SEER) expected result (0.165% vs. 0.271%). This study supported the role of testosterone in lowering the risk of hormone-therapy-related breast cancer [8].
The combination of testosterone and anastrozole was also applied to treat menopausal symptoms in 72 breast cancer survivors. The treatment was effective in relieving the symptoms without elevating estradiol; no tumor relapse was found for up to 8 years [9]. Combining testosterone and anastrozole for treating a hormone-receptor-positive breast cancer patient presented a promising result with a 12-fold decrease in the tumor volume and without elevation of estradiol [10]. Similarly, the treatment of testosterone and another aromatase inhibitor, letrozole, in hormone-receptor-positive invasive breast cancer patients led to 43% diminished tumor size with complete pathologic response when given in combination with chemotherapy [11].
Another study provided more direct evidence to support that androgens as a single drug could be an effective anti-cancer agent for treating ERα+ve breast cancer patients. The study recruited 53 ERα+ve/PR+ve metastatic breast cancer patients whose tumors no longer responded to anti-hormonal therapies. These patients were treated with testosterone propionate. Approximately 60% of the subjects showed disease regression or stabilization, representing a positive result [12]. An independent group performed a similar study. Hormone-receptor-positive metastatic breast cancer patients were subjected to receiving another androgen, fluoxymesterone. The results showed that around 43% of the participants achieved clinical benefit (3% complete response, 10% partial response and 30% stable disease) for at least 6 months [13].
As proof of principle, a phase II trial (NCT01616758) on evaluating the efficacy and safety of enobosarm, a synthetic and selective AR activating agent, in ERα+ve metastatic breast cancer demonstrated that around 50% (8/16) of the patients reached the best response with a median duration of 4.5 months. The drug was well tolerated [14]. Due to the promising result, a larger-scale trial (NCT02463032) was subsequently conducted. In the enobosarm-treated ERα+ve metastatic breast cancer patients whose nuclei AR staining is more than 40%, the clinical benefit rate (CBR), the best objective tumor response (BOR) and the median radiographic progression-free survival (rPFS) were 80%, 48% and 5.47 months (mean = 7.15 months), respectively. In comparison, in the patients whose nuclei AR staining is less than 40%, the CBR, BOR and rPFS were 18%, 0% and 2.72 months (mean = 2.7 months), respectively, suggesting the anti-cancer potential of enobosarm in ERα+ve breast cancer [15]. To further confirm these results in a larger cohort, a phase III study (NCT04869943) to evaluate the efficacy of enobosarm in AR+ve/ERα+ve metastatic breast cancer patients has been recently launched and is ongoing.
More recently, a pre-clinical study also demonstrated that activation of the AR by either DHT or enobosarm in ERα+ve endocrine-resistant breast cancer patient-derived xenografts (PDXs) significantly suppressed the estrogen-induced tumor growth. By contrast, inhibition of the AR activity via the AR antagonist enzalutamide enhanced the ability of estrogen to stimulate tumor growth [16]. These studies reflected the safety and efficacy of androgens in decreasing the risk of hormone-induced breast cancer, suppressing the tumor progression and inhibiting tumor growth, indicating the feasibility of utilizing androgens for treating ERα+ve breast cancer patients.

2. Blocking of Androgen Receptor Can Suppress Estrogen Receptor Alpha-Positiα-ve Breast Cancer

2.1. Evidence from Clinical Studies

Many AR suppressive agents are available for treating prostate cancer. These agents significantly contributed to improving patients’ treatment outcomes. Due to the importance of the AR in ERα-ve breast cancer, studies on evaluating the efficacy of anti-androgens, alone or combined with other anti-breast cancer drugs, have been documented. A phase II clinical trial (NCT02091960) was conducted to evaluate the therapeutic value of the AR antagonist enzalutamide. In the trial, enzalutamide was used on advanced ERα-ve/AR+ve/HER2+ve breast cancer patients. In all, 24% of the patients exhibited a clinical benefit at 24 weeks [17]. A case report described a 55-year-old patient with metastatic TNBC with 100% of nuclei showing a positive signal for AR staining revealed by IHC. The patient received seven lines of cytotoxic chemotherapy and radiotherapy for which only a partial response could be reached, and the disease progressed. The anti-androgen drug bicalutamide was then introduced, to which the patient achieved a complete clinical response at four months and sustained for eight more months [18].
Another phase II study (NCT00468715) demonstrated bicalutamide in AR+ve/ERα-ve/PgR-ve metastatic breast cancer. The results showed a clinical benefit rate of 19% at 6 months and a median progression-free survival of 12 weeks, comparable to other chemotherapies studies in TNBC patients [19]. Similarly, a study (NCT01889238) evaluated the effect of enzalutamide on locally advanced or metastatic AR+ve/TNBC. A clinical benefit rate of 33% was achieved with improved progression-free survival (3.3 months) and overall survival (17.6 months) [20].
An ongoing phase II trial (NCT03383679) combined an androgen-receptor antagonist darolutamide with a chemo-drug capecitabine in advanced AR+ve/TNBC patients recently reported the first-stage result of the study that darolutamide is well tolerated and 26.3% of the patients present a clinical benefit at 16 weeks. The project is now moving to its second stage [21]. Another ongoing phase IIB trial project (NCT02689427) applying enzalutamide in combination with the chemo-drug paclitaxel to treat AR+ve/TNBC patients reported that 33.3% of the patients who were resistant to the doxorubicin-based drugs showed complete response or minimal residual disease to the treatment. This value was lowered to 23% in patients with luminal androgen receptor (LAR). The results suggested a unique pathological feature in this sub-population; noteworthy, around 85% of the LAR TNBC patients were detected to have aberrant PI3K pathway activation in the study. Hence, additional PI3K-targeted drugs for patients who belong to this specific subtype may significantly enhance the treatment outcomes [22].
Other than AR inhibitory drugs, agents targeting androgen synthesis also showed promising potential in clinical application for TNBC patient management. Abiraterone acetate is a CYP17A1-specific inhibitor that suppresses the production of androgens [23]. Combined abiraterone acetate and prednisone for treating locally advanced or metastatic AR+ve/TNBC patients in a phase II trial (NCT01842321) have been tested. The results demonstrated that the clinical benefit rate at 6 months was 20.0%, with one subject having a complete response and five subjects with stable disease for more than 6 months. The median progression-free survival was 2.8 months [24].
A novel antiandrogenic drug seviteronel which functions by a unique dual mechanism of action that lowers the biosynthesis of androgen via inhibiting CYP17 lyase, as well as blocking AR activation via antagonizing AR, has attracted great attention since the drug is more effective than abiraterone acetate in suppressing AR activity [25]. An open-label phase I study proved that seviteronel was well-tolerated at the dose of 450 mg once daily. Of the enrolled TNBC patients, 28.6% (2/7) under this dose reached clinical benefit at 4 months, indicating the drug’s safety and efficacy in treating the patients [26]. In stage I of the phase II study (NCT02580448), the preliminary result showed that 33% of the TNBC subjects could achieve a clinical benefit at 4 months, which was similar to the study mentioned above; moreover, 70% of the subjects presented with decreased circulating tumor cells after the treatment. The results confirmed the clinical activity of seviteronel in breast cancer therapy [27]. Furthermore, multiple clinical trials (NCT03004534, NCT02457910, NCT03207529, NCT03090165, NCT05095207, NCT01990209, NCT04947189) are underway investigating the feasibility of AR-targeting therapy, alone or combined with other therapeutic agents, in AR+ve/ERα-ve breast cancer patients. These results highlight the feasibility of using anti-androgen agents for treating ER-ve breast cancer.

2.2. Evidence from Pre-Clinical Studies

In pre-clinical studies, blocking AR signaling in ERα-ve breast cancer models has been shown to suppress cell growth. Inhibition of AR activity by shRNA or enzalutamide could interfere with cell proliferation in AR+ve/ERα-ve/HER2+ve breast cancer cell lines and xenograft models; when combined with trastuzumab, it could further enhance the suppressive capacity. Enzalutamide could reduce the expression of the proliferation marker Ki-67 and induce the expression of active caspase-3 in the xenograft model, demonstrating an anti-proliferative property after AR suppression in HER2+ve breast cancer [28].
A combination of enzalutamide and trastuzumab or mTOR inhibitor everolimus in AR+ve/ERα-ve/HER2+ve and AR+ve/TNBC could synergistically inhibit cell proliferation [29]. Additionally, inhibition of AR in a trastuzumab-resistant HER2+ve breast cancer cell line has been shown to suppress cell proliferation effectively and re-sensitize cells to trastuzumab [29]. It has been shown that concurrent treatment of TNBC cells with bicalutamide and EGFR, PDGFRβ and Erk1/2 inhibitors or PI3K inhibitor could additively inhibit cell proliferation; suppression of the PI3K/mTOR pathway in the cells was demonstrated to decrease the expression of the AR, which indicates a potential direction for anti-androgen drug development for treatment of TNBC patients [30][31].
Blocking the AR could significantly suppress proliferation and increase apoptosis in both in vitro and in vivo AR+ve/ERα-ve models, which might result from the inhibition of Wnt/β-catenin and EGFR signaling pathways [32][33]. ERα-ve cases tend to have more aggressive clinical features, such as higher tumor grade and metastatic nature. Unfortunately, the option for available targeted therapies for this population is limited. Patients who initially responded to treatment quickly relapse later. Therefore, the patients usually have a poor prognosis [34]. The introduction of anti-androgen drugs in these subtypes of patients may help to relieve this predicament.

References

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