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AR Emerges as a Potential Target in Triple-Negative Breast Cancer

Allie Strickler @Alliejayes
Published: Friday, Mar 24, 2017

Michael F. Press, MD, PhD

Michael F. Press, MD, PhD

Whereas the androgen receptor (AR) is a common target in the treatment of prostate cancer, Michael F. Press, MD, PhD, shed light on the role of the receptor in breast cancer in a presentation during the 2017 Miami Breast Cancer Conference.

The reason people are particularly interested in the possibility of using the AR in breast cancer has to do with the category of triplenegative breast cancers [TNBCs],” said Press, the Harold E. Lee Chair for Cancer Research in the Department of Pathology, Norris Comprehensive Cancer Center, University of Southern California.

At present, no targeted therapies are approved for the treatment of patients with TNBC, and new treatment approaches are critically needed. “One of the potential targets is AR,” Press said, “A proportion of breast cancers that lack, ER, PR, and HER2, do show AR expression.”

Androgens are classified as male hormones, although they can also be expressed in the female body. Furthermore, they can be expressed in the breast epithelium. The hope is that AR blockers, most commonly used in the treatment of prostate cancer, could be used on breast cancers that express ARs.

“Since there are FDA-approved drugs that block the androgen receptor in men, the hope is that, if one could come up with a strategy that would demonstrate the effectiveness of these drugs in some women, that they could become clinically available for use in the clinic pretty quickly. This is under active investigation,” said Press. Current efforts to employ ARs in breast cancer are focused on 3 prostate cancer drugs.

Enzalutamide

A phase II study, presented at the 2015 ASCO Annual Meeting1 (MDV3100-11 trial), evaluated single-agent enzalutamide (Xtandi)—an AR inhibitor that impairs nuclear localization of AR—in patients with advanced AR-positive (IHC ≥10% and ≥1 post-baseline tumor assessment) TNBC. The clinical benefit rate (CBR) at 16 weeks served as the study’s primary endpoint.

Among the 75 evaluable patients, the CBR was 35% (n = 26) at 16 weeks (95% CI, 0.24-0.46) and 29% (n = 22) at 24 weeks (95% CI, 0.20-0.41). Six patients showed a complete or partial response (response rate of 8%). The researchers found a median progression-free survival (PFS) of 14.7 weeks in the evaluable population (95% CI, 8.1-19.3).

The median age of patients in the intent-to-treat population (n = 118; those who received >1 dose of enzalutamide) was 57 years. The 16-month CBR for these patients was 25%, and the 24-month CBR was 20%. The response rate was 6%, and the median PFS was 12.6 weeks. Additionally, the median overall survival was 12 months.

Overall, 61% of patients (n = 72) experienced treatmentrelated adverse events (AEs), the most common of which were fatigue (30%), nausea (22%), and decreased appetite (11%).

Thus far, this study is the largest prospective trial to date of an AR inhibitor in TNBC. Enzalutamide represents 1 of the most promising agents evaluated in this space. The drug is currently being explored in the phase III ENDEAR trial, which will evaluate enzalutamide in combination with paclitaxel or as a monotherapy versus placebo with paclitaxel in patients with locally advanced or metastatic TNBC.

In another study looking at enzalutamide, which was published in Breast Cancer Research,2 the AR antagonist was used to elucidate the role of AR in preclinical models of ER-positive and ER-negative breast cancer.

The study authors examined a cohort of 192 women with ER-positive breast cancers, assessing their nuclear AR to ER protein ratios in primary breast cancers, in relation to response to treatment with endocrine therapy. The effects of AR inhibition with enzalutamide were examined in vitro and in preclinical models of ER-positive and ER-negative breast cancers with AR expression.

The AR to ER ratio was an independent predictor of disease-free survival (HR, 4.04; 95% CI, 1.68-9.69; P = .002) and disease-specific survival (HR, 2.75; 95% CI, 1.11-6.86; P = .03). The findings demonstrated that the AR to ER ratio might influence a patient’s response to traditional endocrine therapy when being treated for breast cancer.

Bicalutamide

Bicalutamide (Casodex), another hormone-based AR antagonist, was evaluated in a phase II trial involving patients with AR-positive, ER-negative metastatic breast cancer.

The study, published in Clinical Cancer Research,3 tested tumors from patients with ER/progesterone receptor (PgR)-negative advanced breast cancer for AR by IHC (>10% nuclear staining considered positive). If either the primary or a metastatic site was positive, patients were then eligible to receive bicalutamide at a dose of 150 mg daily. The primary endpoint was CBR, defined as the total number of patients who showed a complete response, partial response, or stable disease more than 6 months. Secondary endpoints in the study included PFS and toxicity.


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