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Androgen Receptor Function and Androgen Receptor–Targeted Therapies in Breast CancerA Review

Educational Objective
To learn the role of androgen receptor and the effects of androgen receptor blockade in breast cancer.
1 Credit CME
Abstract

Importance  The androgen receptor (AR) pathway is emerging as a potential therapeutic target in breast cancer. To date, AR-targeted drugs have been approved only for treatment of prostate cancer; however, AR-targeted treatment for breast cancer is an area of active investigation. Through review of preclinical studies, retrospective clinical studies, and clinical trials, we examined the biology of AR and AR-related pathways, the potential for AR-targeted therapies in breast cancer, and potential biomarkers for AR-targeted treatments.

Observations  The rate of AR positivity in breast cancer is about 60% to 80%. Biologically, the AR pathway has cross-talk with several other key signaling pathways, including the PI3K/Akt/mTOR and MAPK pathways, and with other receptors, including estrogen receptor and human epidermal growth factor receptor-2. The value of AR positivity as a prognostic marker has not yet been defined. Androgen receptor–targeted therapies, including AR agonists, AR antagonists, and PI3K inhibitors, have shown promising results in clinical trials in patients with breast cancer, and combinations of AR-targeted therapies with other agents have been investigated for overcoming resistance to AR-targeted therapies. Biomarkers to stratify patients according to the likelihood of response to AR-targeted drugs are yet to be established. Potential biomarkers of response to AR inhibitors include AR phosphorylation and AR gene expression.

Conclusions and Relevance  Androgen receptor–targeted treatments for breast cancer are in development and have shown promising preliminary results. In-depth understanding of AR and AR-related signaling pathways would improve the treatment strategies for AR-positive breast cancer. Further preclinical and clinical studies of AR-targeted drugs alone and in combination with other drugs are justified and warranted to clarify the biology of AR and inform the development of AR-targeted therapies to improve survival outcome in patients with breast cancer.

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Article Information

Corresponding Author: Naoto T. Ueno, MD, PhD, FACP, Section of Translational Breast Cancer Research, Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Unit 1354, Houston, TX 77030 (nueno@mdanderson.org).

Accepted for Publication: September 12, 2016.

Published Online: March 16, 2017. doi:10.1001/jamaoncol.2016.4975

Author Contributions: Dr Ueno had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Drs Kono and Fujii contributed equally to this work.

Concept and design: Kono, Fujii, Ueno.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Kono, Fujii, Karuturi, Tripathy.

Critical revision of the manuscript for important intellectual content: All authors.

Administrative, technical, or material support: Tripathy, Ueno.

Study supervision: Kono, Fujii, Lim, Karuturi, Ueno.

Conflict of Interest Disclosures: Dr Karuturi has received research grants from Novartis and AstraZeneca for work unrelated to this manuscript. No other disclosures are reported.

Funding/Support: This work was supported by the Morgan Welch Inflammatory Breast Cancer Research Program; a grant from the State of Texas Rare and Aggressive Breast Cancer Research Program; MD Anderson’s Cancer Center support grant from the National Cancer Institute, CA016672, which supports the Biostatistics Shared Resource; National Cancer Institute grant CA079466; and an award from the Japan Cancer Society.

Role of the Funder/Sponsor: The funders had no role in the design or conduct of the study; collection, management, analysis, or interpretation of the data; preparation, review, or approval of the manuscript; or decision to submit the manuscript for publication.

Additional Contributions: Stephanie P. Deming, BA, of the Department of Scientific Publications at MD Anderson Cancer Center provided scientific editing services. Greg Pratt, DDS, clinical librarian of the Research Medical Library at MD Anderson Cancer Center, conducted the literature search. They received no additional compensation beyond their regular salaries.

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