Enobosarm: A targeted therapy for metastatic, androgen receptor positive, breast cancer.

Overmoyer, Beth; Sanz-Altamira, Pedro; Taylor, R. A. J.; Hancock, Michael L.; Dalton, James T.; Johnston, Mary Ann; Steiner, Mitchell S.

doi:10.1200/jco.2014.32.15_suppl.568

Cited by 21 publications

(15 citation statements)

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“…18 F-FDHT PET may therefore be an interesting tool to select patients eligible for clinical trials with AR antagonists and to analyze the receptor occupancy of these drugs. AR-targeted therapy is not yet standard in breast cancer patients, but preliminary results of phase II trials are promising, with stable disease in 35% of metastatic breast cancer patients (20,21). More clinical studies exploring the efficacy of AR-targeted therapy in AR-positive metastatic breast cancer are currently ongoing (e.g., NCT00468715, NCT00755885).…”

Section: Discussionmentioning

confidence: 99%

Androgen and Estrogen Receptor Imaging in Metastatic Breast Cancer Patients as a Surrogate for Tissue Biopsies

et al. 2017

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In addition to the well-known estrogen receptor (ER) and human epidermal growth factor receptor 2, the androgen receptor (AR) is also a potential drug target in breast cancer treatment. Whole-body imaging can provide information across lesions within a patient. ER expression in tumor lesions can be visualized by F-fluoroestradiol (F-FES) PET, and AR expression has been visualized in prostate cancer patients with F-fluorodihydrotestosterone (F-FDHT) PET. Our aim was to assess the concordance between F-FDHT andF-FES PET and tumor AR and ER expression measured immunohistochemically in patients with metastatic breast cancer. Patients with ER-positive metastatic breast cancer were eligible for the study, irrespective of tumor AR status. The concordance ofF-FDHT and F-FES uptake on PET with immunohistochemical expression of AR and ER in biopsies of corresponding metastases was analyzed. Patients underwentF-FDHT PET and F-FES PET. A metastasis was biopsied within 8 wk of the PET procedures. Tumor samples with more than 10% and 1% nuclear tumor cell staining were considered, respectively, AR- and ER-positive. Correlations between PET uptake and semiquantitative immunohistochemical scoring (percentage positive cells × intensity) were calculated. The optimum threshold of SUV to discriminate positive and negative lesions for both AR and ER was determined by receiver-operating-characteristic analysis. In the 13 evaluable patients, correlation ( ) between semiquantitative AR expression and F-FDHT uptake was 0.47 ( = 0.01) and between semiquantitative ER expression and F-FES uptake 0.78 ( = 0.01). The optimal cutoff for AR-positive lesions was an SUV of 1.94 for F-FDHT PET, yielding a sensitivity of 91% and a specificity of 100%; the optimal cutoff was an SUV of 1.54 for F-FES PET, resulting in a sensitivity and specificity of 100% for ER.F-FDHT and F-FES uptake correlate well with AR and ER expression levels in representative biopsies. These results show the potential use of whole-body imaging for receptor status assessment, particularly in view of biopsy-associated sampling errors and heterogeneous receptor expression in breast cancer metastases.

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Section: Discussionmentioning

confidence: 99%

Androgen and Estrogen Receptor Imaging in Metastatic Breast Cancer Patients as a Surrogate for Tissue Biopsies

et al. 2017

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“…Enobosarm is a potent AR agonist with reduced capacity for androgenization and without estrogenic properties (Coss et al 2014). A small proof-of-concept study confirmed activity and tolerability in a cohort of heavily pretreated ER/AR + patients with metastatic breast cancer (Overmoyer et al 2014), and results from a follow-up phase II trial are awaited (NCT02463032). These recent findings support a role for AR agonists as anti-proliferative agents in ER + breast cancer contexts.…”

Section: Cross-talk Between Er and Other Steroid Hormone Receptorsmentioning

confidence: 99%

Signaling pathways and steroid receptors modulating estrogen receptor α function in breast cancer

2018

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Estrogen receptor α (ER) is the major driver of ∼75% of breast cancers, and multiple ER targeting drugs are routinely used clinically to treat patients with ER breast cancer. However, many patients relapse on these targeted therapies and ultimately develop metastatic and incurable disease, and understanding the mechanisms leading to drug resistance is consequently of utmost importance. It is now clear that, in addition to estrogens, ER function is modulated by other steroid receptors and multiple signaling pathways (e.g., growth factor and cytokine signaling), and many of these pathways affect drug resistance and patient outcome. Here, we review the mechanisms through which these pathways impact ER function and drug resistance as well as discuss the clinical implications.

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“…Some studies have reported that AR is prognostically beneficial irrespective of ER [ 4 ], but the results regarding the role of AR expression in the ER negative (ER−) setting diverge [ 2 , 4 – 8 ]. Ongoing clinical trials are evaluating anti-androgens and selective androgen receptor modulators across different breast cancer subtypes [ 2 , 9 , 10 ]. It is essential to better define AR’s prognostic role in different breast cancer subtypes.…”

Section: Introductionmentioning

confidence: 99%

Androgen receptor expression and breast cancer mortality in a population-based prospective cohort

Elebro

Bendahl

Jernström

et al. 2017

Breast Cancer Res Treat

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PurposeThe increase in clinical trials with androgen receptor (AR)-targeting drugs emphasizes the need of clarifying the role of AR expression in different breast cancer subtypes. AR confers good prognosis in estrogen receptor positive (ER+) breast cancer, but its role in ER-negative (ER−) breast cancer is unclear. The aim of this study was to elaborate on previous findings of a differential prognostic role for AR depending on ER status, using breast cancer mortality (BCM) as endpoint, in a population-based cohort from the Malmö Diet and Cancer Study.MethodsImmunohistochemical AR expression was assessed in 910 women with invasive breast cancer diagnosed 1991–2010, supplemented with clinicopathological information, vital status, and cause of death, with the last follow-up in December 2014 (median 10 years). Survival analyses according to AR status and AR/ER combinations were performed.ResultsAR expression was available for 671 tumors. AR+ (n = 573, 85%) was associated with favorable established tumor markers and lower BCM in univariable analysis, especially during the first 5 years following diagnosis [HR 0.4; 95% confidence intervals (CI) 0.2–0.7]. Multivariable analysis for short-term follow-up indicated higher BCM among patients with AR+ER− tumors (HR 3.5; 95% CI 1.4–9.1) than other AR and ER combinations.ConclusionsAR expression added prognostic information to ER expression with respect to short-term prognosis. The worst prognosis was seen for patients with AR+/ER− tumors in short-term follow-up, supporting the pre-specified hypothesis. However, larger cohorts are needed for further characterization of the role of AR expression in ER− breast cancer.

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Enobosarm: A targeted therapy for metastatic, androgen receptor positive, breast cancer.

Cited by 21 publications

References 0 publications

Androgen and Estrogen Receptor Imaging in Metastatic Breast Cancer Patients as a Surrogate for Tissue Biopsies

Androgen and Estrogen Receptor Imaging in Metastatic Breast Cancer Patients as a Surrogate for Tissue Biopsies

Signaling pathways and steroid receptors modulating estrogen receptor α function in breast cancer

Androgen receptor expression and breast cancer mortality in a population-based prospective cohort

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