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

Elisabetta Pietri, Ilaria Massa, Sara Bravaccini, Sara Ravaioli, Maria Maddalena Tumedei, Elisabetta Petracci, Caterina Donati, Alessio Schirone, Federico Piacentini, Lorenzo Gianni, Mario Nicolini, Enrico Campadelli, Alessandra Gennari, Alessandro Saba, Beatrice Campi, Linda Valmorri, Daniele Andreis, Francesco Fabbri, Dino Amadori, Andrea Rocca, Elisabetta Pietri, Ilaria Massa, Sara Bravaccini, Sara Ravaioli, Maria Maddalena Tumedei, Elisabetta Petracci, Caterina Donati, Alessio Schirone, Federico Piacentini, Lorenzo Gianni, Mario Nicolini, Enrico Campadelli, Alessandra Gennari, Alessandro Saba, Beatrice Campi, Linda Valmorri, Daniele Andreis, Francesco Fabbri, Dino Amadori, Andrea Rocca

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.

Trial registration: ClinicalTrials.gov NCT02000375.

© AlphaMed Press; the data published online to support this summary are the property of the authors.

Figures

Figure 1.
Figure 1.
(A) Time to progression and (B) overall survival of the estrogen receptor‐positive cohort. Abbreviations: OS, overall survival; TTP, time to progression.
Figure 2.
Figure 2.
Individual serum concentrations of dehydroepiandrosterone (DHEA) and metabolites in 10 patients from the estrogen receptor‐positive cohort. The following are reported for each patient: Left panels: serum concentrations of DHEA, androstane‐3alpha,17beta‐diol‐3‐glucuronide (3α‐diol‐3G), and androstane‐3alpha,17beta‐diol‐17glucuronide (3α‐diol‐17G) at different time points during treatment. Right panels: serum concentrations of androsterone glucuronide (ADT‐G) at different time points during treatment. Solid line: DHEA levels; dotted line: 3α‐diol‐3G levels; dashed line: 3α‐diol‐17G levels; dash‐dotted line: ADT‐G levels. Abbreviations: Baseline, before starting treatment; C1D14, cycle 1 day 14; C2D1, cycle 2 day 1; EOT, end of treatment.
Figure 3.
Figure 3.
Boxplots of serum concentrations of DHEA and metabolites. Box and whisker plots, showing the median, interquartile range, and the highest and lowest values for each analyte at three time points (baseline, cycle 2 day 1, and end of treatment). Abbreviations: C2, cycle 2 day 1; DHEA, dehydroepiandrosterone; EOT, end of treatment.

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Source: PubMed

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