Lessons learned: The androgen receptor (AR) is present in most breast cancers (BC), but its exploitation as a therapeutic target has been limited.This study explored the activity of dehydroepiandrosterone (DHEA), a precursor being transformed into androgens within BC cells, in combination with an aromatase inhibitor (to block DHEA conversion into estrogens), in a two-stage phase II study in patients with AR-positive/estrogen receptor-positive/human epidermal growth receptor 2-negative metastatic BC.Although well tolerated, only 1 of 12 patients obtained a prolonged clinical benefit, and the study was closed after its first stage for poor activity.
Background: Androgen receptors (AR) are expressed in most breast cancers, and AR-agonists have some activity in these neoplasms. We investigated the safety and activity of the androgen precursor dehydroepiandrosterone (DHEA) in combination with an aromatase inhibitor (AI) in patients with AR-positive metastatic breast cancer (MBC).
Methods: A two-stage phase II study was conducted in two patient cohorts, one with estrogen receptor (ER)-positive (resistant to AIs) and the other with triple-negative MBC. DHEA 100 mg/day was administered orally. The combination with an AI aimed to prevent the conversion of DHEA into estrogens. The main endpoint was the clinical benefit rate. The triple-negative cohort was closed early.
Results: Twelve patients with ER-positive MBC were enrolled. DHEA-related adverse events, reported in four patients, included grade 2 fatigue, erythema, and transaminitis, and grade 1 drowsiness and musculoskeletal pain. Clinical benefit was observed in one patient with ER-positive disease whose tumor had AR gene amplification. There was wide inter- and intra-patient variation in serum levels of DHEA and its metabolites.
Conclusion: DHEA showed excellent safety but poor activity in MBC. Although dose and patient selection could be improved, high serum level variability may hamper further DHEA development in this setting.
经验获取
• 虽然雄激素受体 (AR) 存在于大多数乳腺癌 (BC) 中，但是，人们将其作为治疗靶点进行的开发利用十分有限。
• 本研究探索了脱氢表雄酮(DHEA，一种可在 BC 细胞中转化为雄激素的前体)与芳香化酶抑制剂(可阻止 DHEA 转化为雌激素)在两阶段 II 期研究中联合治疗 AR‐阳性/雌激素受体‐阳性/人类表皮生长受体 2‐阴性的转移性 BC 患者的活性。
• 虽然耐受性良好，但是，在 12 名患者中仅有 1 名患者维持了长时间的临床获益，而且，研究在第一阶段之后因活性较差而关闭。
摘要
背景。雄激素受体 (AR) 存在于大多数乳腺癌中，AR‐激动剂在此类肿瘤中具有一些活性。我们研究了雄激素前体脱氢表雄酮 (DHEA) 和芳香化酶抑制剂 (AI) 联合治疗 AR‐阳性转移性乳腺癌 (MBC) 患者的安全性和活性。
方法。我们在两个患者队列中执行了一项两阶段 II 期研究，一个队列中的患者为雌激素受体 (ER)‐阳性(对 AI 耐药)，另一个队列中的患者为三阴性 MBC。按照 100 mg/天的剂量口服 DHEA。AI 联合治疗旨在防止 DHEA 转化为雌激素。主要终点为临床获益率。三阴性队列提前关闭。
结果。12 名 ER‐阳性 MBC 患者加入研究。4 名患者报告与 DHEA 相关的不良反应，包括 2 级疲劳、红斑和转氨酶升高以及 1 级困倦和肌肉骨骼痛。在 1 名 ER‐阳性疾病患者中观察到临床获益，该患者的肿瘤出现 AR 基因扩增。DHEA 及其代谢物的血清水平在患者之间和患者内部的变化较大。
结论。虽然 DHEA 显示出良好的安全性，但是，它在 MBC 中的活性较差。尽管可以改进剂量和患者的选择，但是，血清水平变化性高可能会妨碍 DHEA 在这种设定中的进一步开发。
Trial registration: ClinicalTrials.gov NCT02000375.
© AlphaMed Press; the data published online to support this summary are the property of the authors.