Phase II Study of Dehydroepiandrosterone in Androgen Receptor-Positive Metastatic Breast Cancer

Abstract

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.

Components of the human-specific, p53-mediated “kill switch” tumor suppression mechanism are usurped by human tumors, creating the possibility of therapeutic exploitation

“…A recent clinical study of DHEA (100 mg/day) in advanced metastatic breast cancer showed virtually no activity. This is what we would predict, based upon the lack of specificity of administered DHEA for tumor tissue [ 29 ] . To the extent that some of the tumors in those patients expressed significant levels of OATP transport proteins and STS, fluasterone sulfate could be predicted to have shown a much greater degree of tumor-specific toxicity.…”

Cortisol and Testosterone Induce Bax and Bcl-2 Gene Expression and Caspases-8 and -9 Activity in Colon Cancer Cells (ht29) and Reduced the Cell Viability

“…Adrenocortical steroids, dehydroepiandrosterone (DHEA), are increasingly shown to be critical mammalian hormones, as the use of DHEA by mice and rats inhibits skin, colon, lungs, breast and lymphatic tissues from developing induced tumors. (41,42).…”

Androgen receptor in breast cancer: The “5W” questions

“…DHEA is transformed into sex hormones within peripheral target tissues ( 96 , 105 – 107 ), as well as in BC cells where preclinical evidences of DHEA antitumor activity are reported ( 108 – 110 ). In this context, a phase II prospective clinical study was conducted, evaluating the safety and the activity of DHEA combined with AI in two AR positive metastatic BC patient cohorts: one ER-positive and one TN ( 111 ). The administration of an aromatase inhibitor (AI) prevents DHEA conversion into estrogens and favors its conversion into androgens.…”

“…The AR gene amplification present in the only patient who showed a prolonged clinical benefit was intriguing, prompting to hypothesize the potential value of AR gene amplification as a predictive biomarker of response to AR agonists in BC ( Figure 3 ). Similarly, the role of phosphorylated AR remains to be ascertained ( Figure 3 ) ( 111 ). However, this study was limited by the small number of patients considered and the low rate of clinical benefit and no definitive conclusions could be drawn.…”