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

Research output: Contribution to journalArticle

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.

Original languageEnglish
JournalOncologist
DOIs
Publication statusAccepted/In press - Jan 1 2018

Fingerprint

Dehydroepiandrosterone
Androgen Receptors
Breast Neoplasms
Estrogen Receptors
Aromatase Inhibitors
Androgens
Estrogens
Triple Negative Breast Neoplasms
Safety
Musculoskeletal Pain
Gene Amplification
Sleep Stages
Erythema
Serum
Patient Selection
Fatigue
Neoplasms

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Phase II Study of Dehydroepiandrosterone in Androgen Receptor-Positive Metastatic Breast Cancer. / Pietri, Elisabetta; Massa, Ilaria; Bravaccini, Sara; Ravaioli, Sara; Tumedei, Maria Maddalena; Petracci, Elisabetta; Donati, Caterina; Schirone, Alessio; Piacentini, Federico; Gianni, Lorenzo; Nicolini, Mario; Campadelli, Enrico; Gennari, Alessandra; Saba, Alessandro; Campi, Beatrice; Valmorri, Linda; Andreis, Daniele; Fabbri, Francesco; Amadori, Dino; Rocca, Andrea.

In: Oncologist, 01.01.2018.

Research output: Contribution to journalArticle

@article{4a0e4cafc267469ebccb480f268c65a2,
title = "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.",
author = "Elisabetta Pietri and Ilaria Massa and Sara Bravaccini and Sara Ravaioli and Tumedei, {Maria Maddalena} and Elisabetta Petracci and Caterina Donati and Alessio Schirone and Federico Piacentini and Lorenzo Gianni and Mario Nicolini and Enrico Campadelli and Alessandra Gennari and Alessandro Saba and Beatrice Campi and Linda Valmorri and Daniele Andreis and Francesco Fabbri and Dino Amadori and Andrea Rocca",
year = "2018",
month = "1",
day = "1",
doi = "10.1634/theoncologist.2018-0243",
language = "English",
journal = "Oncologist",
issn = "1083-7159",
publisher = "Wiley Blackwell",

}

TY - JOUR

T1 - Phase II Study of Dehydroepiandrosterone in Androgen Receptor-Positive Metastatic Breast Cancer

AU - Pietri, Elisabetta

AU - Massa, Ilaria

AU - Bravaccini, Sara

AU - Ravaioli, Sara

AU - Tumedei, Maria Maddalena

AU - Petracci, Elisabetta

AU - Donati, Caterina

AU - Schirone, Alessio

AU - Piacentini, Federico

AU - Gianni, Lorenzo

AU - Nicolini, Mario

AU - Campadelli, Enrico

AU - Gennari, Alessandra

AU - Saba, Alessandro

AU - Campi, Beatrice

AU - Valmorri, Linda

AU - Andreis, Daniele

AU - Fabbri, Francesco

AU - Amadori, Dino

AU - Rocca, Andrea

PY - 2018/1/1

Y1 - 2018/1/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85059118003&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85059118003&partnerID=8YFLogxK

U2 - 10.1634/theoncologist.2018-0243

DO - 10.1634/theoncologist.2018-0243

M3 - Article

AN - SCOPUS:85059118003

JO - Oncologist

JF - Oncologist

SN - 1083-7159

ER -