乳腺癌中的AR治疗策略

乳腺癌中ER、PR、HER2是其主驱动因素，表达与否极其重要。
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AR表达与否，对乳腺癌也极其重要，涉及到不同的治疗策略。
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4 f8 C! ^" r  {) k! l3 d3 }  ^简单来说就是如果ER阴性AR阳性，就要抑制AR；如果ER阳性，就要激活AR。
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一、AR阳性的三阴乳腺癌（ER阴性），抑制AR有疗效

6 _, K- J0 O. ]/ b下面两个临床试验的结果证实了这点：
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1、《Enzalutamide for the Treatment of Androgen Receptor-Expressing Triple-Negative Breast Cancer》
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Results Of 118 patients enrolled, 78 were evaluable. CBR at 16 weeks was 25% (95% CI, 17% to 33%) in the ITT population and 33% (95% CI, 23% to 45%) in the evaluable subgroup. Median progression-free survival was 2.9 months (95% CI, 1.9 to 3.7 months) in the ITT population and 3.3 months (95% CI, 1.9 to 4.1 months) in the evaluable subgroup. Median overall survival was 12.7 months (95% CI, 8.5 months to not yet reached) in the ITT population and 17.6 months (95% CI, 11.6 months to not yet reached) in the evaluable subgroup. Fatigue was the only treatment-related grade 3 or higher adverse event with an incidence of > 2%. Conclusion Enzalutamide demonstrated clinical activity and was well tolerated in patients with advanced AR-positive TNBC. Adverse events related to enzalutamide were consistent with its known safety profile.
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. F/ s/ c( ^/ u- _! i5 F2、《Efficacy of antiandrogens in androgen receptor-positive triple-negative metastatic breast cancer: Real-life data》
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Antiandrogens (AA) have been tested in clinical trials in androgen receptor (AR) + triple-negative breast cancer (TNBC). We aim to assess the clinical benefit rate (CBR) of AA in real life. The primary end-point was CBR at 6 months. Twenty-four patients were assessable and received: abiraterone acetate (62 %), enzalutamide (8 %) and bicalutamide (30 %). CBR at 6 months was 29 % (7/24) with 2 CR, 3 PR and 2 SD. Four patients had a clinical benefit >12 months. Real-life efficacy of AA use in metastatic AR + TNBC are in line with data from published trials.
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三阴乳腺癌的很后线治疗，单药AR抑制剂就能有25%以上的CBR，是很不错的疗效了，要知道K药单药治疗三阴乳腺癌CBR还不到10%。

0 `+ W) a- O" O$ l当然这并不意味着只用AR抑制剂单药治疗三阴乳腺癌。肿瘤是多因素驱动的，治疗方案要根据基因检测等精准检测结果来定，可以把AR抑制剂加到联合方案中去。



二、AR阳性、ER阳性、HER2阴性的乳腺癌

1、AR阳性、ER阳性、HER2阴性的乳腺癌，激活AR有治疗 作用。一种新型口服选择性雄激素受体调节剂enobosarm 24年3月发布的二期临床试验结果证实了这点。
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" D  o# R8 ^& I" `+ T《Activity and safety of enobosarm, a novel, oral, selective androgen receptor modulator, in androgen receptor-positive, oestrogen receptor-positive, and HER2-negative advanced breast cancer (Study G200802): a randomised, open-label, multicentre, multinational, parallel design, phase 2 trial》
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Background: The androgen receptor is a tumour suppressor in oestrogen receptor-positive breast cancer. The activity and safety of enobosarm, an oral selective androgen receptor modulator, was evaluated in women with oestrogen receptor (ER)-positive, HER2-negative, and androgen receptor (AR)-positive disease.

Methods: Women who were postmenopausal (aged ≥18 years) with previously treated ER-positive, HER2-negative, locally advanced or metastatic breast cancer with an Eastern Cooperative Oncology Group performance status of 0-2 were enrolled in a randomised, open-label, multicentre, multinational, parallel design, phase 2 trial done at 35 cancer treatment centres in nine countries. Participants were stratified on the setting of immediately preceding endocrine therapy and the presence of bone-only metastasis and randomly assigned (1:1) to 9 mg or 18 mg oral enobosarm daily using an interactive web response system. The primary endpoint was clinical benefit rate at 24 weeks in those with centrally confirmed AR-positive disease (ie, the evaluable population). This trial is registered with ClinicalTrials.gov (NCT02463032).

Findings: Between Sept 10, 2015, and Nov 28, 2017, 136 (79%) of 172 patients deemed eligible were randomly assigned to 9 mg (n=72) or 18 mg (n=64) oral enobosarm daily. Of these 136 patients, 102 (75%) patients formed the evaluable population (9 mg, n=50; 18 mg, n=52). The median age was 60·5 years (IQR 52·3-69·3) in the 9 mg group and 62·5 years (54·0-69·3) in the 18 mg group. The median follow-up was 7·5 months (IQR 2·9-14·1). At 24 weeks, 16 (32%, 95% CI 20-47) of 50 in the 9 mg group and 15 (29%, 17-43) of 52 in the 18 mg group had clinical benefit. Six (8%) of 75 patients who received 9 mg and ten (16%) of 61 patients who received 18 mg had grade 3 or grade 4 drug-related adverse events, most frequently increased hepatic transaminases (three [4%] of 75 in the 9 mg group and two [3%] of 61 in the 18 mg group), hypercalcaemia (two [3%] and two [3%]), and fatigue (one [1%] and two [3%]). Four deaths (one in the 9 mg group and three in the 18 mg group) were deemed unrelated to the study drug.

5 t- K7 {: v  L" X( Q+ hInterpretation: Enobosarm has anti-tumour activity in patients with ER-positive, HER2-negative advanced breast cancer, showing that AR activation can result in clinical benefit, supporting further clinical investigation of selective AR activation strategies for the treatment of AR-positive, ER-positive, HER2-negative advanced breast cancer.

enobosarm目前买得到原料药，自救群有ER阳性的乳腺癌病友在用，确有疗效。

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2、我过去曾提出过一个治疗策略，就是对于ER阳性乳腺癌患者，什么时机用AR激活剂比较合适？举例来说，比如ESR1突变的患者，ERα是阳性的所以ER一直是阳性的。如果巴多昔芬、拉索昔芬这样的能抑制降解ERα从而治疗ESR1突变的SERM都用过了耐药了，这个时候可以用AR激活剂。因为AR激活剂作用机制是激活AR去压制ER，并不是直接作用于ER，从而可以避免SERM的交叉耐药。
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下面这个AR激活剂 RAD140 治疗ER阳性乳腺癌的一期临床试验结果证实了我这个治疗策略是完全可行的：
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《A First-in-Human Phase 1 Study of a Novel Selective Androgen Receptor Modulator (SARM), RAD140, in ER+/HER2- Metastatic Breast Cancer》
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At the MTD of 100 mg/day, 1 patient with an ESR1 mutation at baseline had a partial response.
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