Abstract GS4-07: Results from a randomized placebo-controlled phase 2 trial evaluating exemestane ± enzalutamide in patients with hormone receptor–positive breast cancer

Krop, Ian E.; Abramson, V; Colleoni, Marco; Traina, TA; Holmes, Frankie A.; Estévez, Laura G.; Hart, L.; Awada, Ahmad; Zamagni, Claudio; Morris, PG; Schwartzberg, Lee S.; Chan, Stephanie; Wheatley, Duncan; Gucalp, Ayca; Biganzoli, Laura; Steinberg, Joyce; Gianni, Luca; Trudeau, Maureen; Tudor, IC; Markova, Denka; Barry, Elly; Tarazi, Jamal; Stewart, R. I.; Winer, EP; Yardley, DA

doi:10.1158/1538-7445.sabcs17-gs4-07

Cited by 16 publications

(14 citation statements)

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“…The patients were identified based on a gene based signature biomarker known as Dx, which was used to indicate AR signaling. Interestingly, significant improvement was not noted in the cohort with one prior endocrine therapy ( 54 ). Enzalutamide is also being evaluated for the treatment of triple negative breast cancer.…”

Section: Ar and Androgens In Normal Breast Tissue And Breast Cancermentioning

confidence: 92%

The Divergent Function of Androgen Receptor in Breast Cancer; Analysis of Steroid Mediators and Tumor Intracrinology

Bleach

McIlroy

2018

Front. Endocrinol.

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Androgen receptor (AR) is the most widely expressed steroid receptor protein in normal breast tissue and is detectable in approximately 90% of primary breast cancers and 75% of metastatic lesions. However, the role of AR in breast cancer development and progression is mired in controversy with evidence suggesting it can either inhibit or promote breast tumorigenesis. Studies have shown it to antagonize estrogen receptor alpha (ERα) DNA binding, thereby preventing pro-proliferative gene transcription; whilst others have demonstrated AR to take on the mantle of a pseudo ERα particularly in the setting of triple negative breast cancer. Evidence for a potentiating role of AR in the development of endocrine resistant breast cancer has also been mounting with reports associating high AR expression with poor response to endocrine treatment. The resurgence of interest into the function of AR in breast cancer has resulted in various emergent clinical trials evaluating anti-AR therapy and selective androgen receptor modulators in the treatment of advanced breast cancer. Trials have reported varied response rates dependent upon subtype with overall clinical benefit rates of ~19–29% for anti-androgen monotherapy, suggesting that with enhanced patient stratification AR could prove efficacious as a breast cancer therapy. Androgens and AR have been reported to facilitate tumor stemness in some cancers; a process which may be mediated through genomic or non-genomic actions of the AR, with the latter mechanism being relatively unexplored in breast cancer. Steroidogenic ligands of the AR are produced in females by the gonads and as sex-steroid precursors secreted from the adrenal glands. These androgens provide an abundant reservoir from which all estrogens are subsequently synthesized and their levels are undiminished in the event of standard hormonal therapeutic intervention in breast cancer. Steroid levels are known to be altered by lifestyle factors such as diet and exercise; understanding their potential role in dictating the function of AR in breast cancer development could therefore have wide-ranging effects in prevention and treatment of this disease. This review will outline the endogenous biochemical drivers of both genomic and non-genomic AR activation and how these may be modulated by current hormonal therapies.

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Section: Ar and Androgens In Normal Breast Tissue And Breast Cancermentioning

confidence: 92%

The Divergent Function of Androgen Receptor in Breast Cancer; Analysis of Steroid Mediators and Tumor Intracrinology

Bleach

McIlroy

2018

Front. Endocrinol.

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“…Recently, the androgen receptor (AR) emerged as a possible target for breast cancer therapy. The AR is present in 70-80% of patients with breast cancer, and AR antagonists are under investigation in clinical trials [3][4][5][6].…”

Section: Introductionmentioning

confidence: 99%

Visual and quantitative evaluation of [18F]FES and [18F]FDHT PET in patients with metastatic breast cancer: an interobserver variability study

et al. 2020

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Purpose: Correct identification of tumour receptor status is important for treatment decisions in breast cancer. [ 18 F]FES PET and [ 18 F]FDHT PET allow non-invasive assessment of the oestrogen (ER) and androgen receptor (AR) status of individual lesions within a patient. Despite standardised analysis techniques, interobserver variability can significantly affect the interpretation of PET results and thus clinical applicability. The purpose of this study was to determine visual and quantitative interobserver variability of [ 18 F]FES PET and [ 18 F]FDHT PET interpretation in patients with metastatic breast cancer. Methods: In this prospective, two-centre study, patients with ER-positive metastatic breast cancer underwent both [ 18 F]FES and [ 18 F]FDHT PET/CT. In total, 120 lesions were identified in 10 patients with either conventional imaging (bone scan or lesions > 1 cm on high-resolution CT, n = 69) or only with [ 18 F]FES and [ 18 F]FDHT PET (n = 51). All lesions were scored visually and quantitatively by two independent observers. A visually PET-positive lesion was defined as uptake above background. For quantification, we used standardised uptake values (SUV): SUV max , SUV peak and SUV mean. Results: Visual analysis showed an absolute positive and negative interobserver agreement for [ 18 F]FES PET of 84% and 83%, respectively (kappa = 0.67, 95% CI 0.48-0.87), and 49% and 74% for [ 18 F]FDHT PET, respectively (kappa = 0.23, 95% CI − 0.04-0.49). Intraclass correlation coefficients (ICC) for quantification of SUV max , SUV peak and SUV mean were 0.98 (95% CI 0.96-0.98), 0.97 (95% CI 0.96-0.98) and 0.89 (95% CI 0.83-0.92) for [ 18 F]FES, and 0.78 (95% CI 0.66-0.85), 0.76 (95% CI 0.63-0.84) and 0.75 (95% CI 0.62-0.84) for [ 18 F]FDHT, respectively.

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“…Androgens have variable effects in different BC models [3][4][5]: often antiproliferative [6][7][8][9][10][11][12][13], mainly in ER-positive tumors; sometimes pro-proliferative [14-18], mainly in triple-negative and human epidermal growth factor receptor 2 (HER2)-positive/ER-negative tumors. Both ARagonists [19-22] and AR-antagonists are being studied as antitumor agents in BC [23][24][25][26][27]. Dehydroepiandrosterone (DHEA) is a steroid produced mainly by the adrenal cortex and transformed into sex hormones (androgens and estrogens) within peripheral target tissues [28][29][30][31][32][33].…”

Section: Study Completedmentioning

confidence: 99%

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

et al. 2018

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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.

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Abstract GS4-07: Results from a randomized placebo-controlled phase 2 trial evaluating exemestane ± enzalutamide in patients with hormone receptor–positive breast cancer

Cited by 16 publications

References 0 publications

The Divergent Function of Androgen Receptor in Breast Cancer; Analysis of Steroid Mediators and Tumor Intracrinology

The Divergent Function of Androgen Receptor in Breast Cancer; Analysis of Steroid Mediators and Tumor Intracrinology

Visual and quantitative evaluation of [18F]FES and [18F]FDHT PET in patients with metastatic breast cancer: an interobserver variability study

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

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