Study: Androgen Therapy Shows Promise as a Breast Cancer Treatment

Researchers at the University of Adelaide in South Australia have identified a potential new treatment for estrogen receptor-positive breast cancer that hinges on the manipulation of sex hormone levels. 

The study looks at androgens—usually thought of as male sex hormones but also found at lower levels in women—as a potential treatment for estrogen receptor-positive breast cancer. The January study was published in the journal Nature Medicine.

“Given the quality-of-life benefits and the efficacy of this treatment strategy at multiple stages of disease in our study, we hope to translate these findings into clinical trials as a new class of endocrine therapy for breast cancer,” one of the study's authors Wayne Tilley, PhD, director of the Dame Roma Mitchell Cancer Research Laboratories at Adelaide Medical School, tells Verywell.

How Sex Hormones Factor In

Hormone receptor-positive breast cancers—breast cancers that possess either estrogen receptors or progesterone receptors or both–account for about two-thirds of all breast cancers.

Estrogen, progesterone, and androgens such as testosterone and androstenedione are sex hormones, meaning they drive human sexual development and reproduction. All three are present in both men and women, just to different degrees. 

But while sex hormones are necessary for normal growth and development, they can also incite the kind of rampant cell division that causes cancer. Excessive estrogen activity, for example, is the biological basis for estrogen receptor-positive breast cancer.

The relationship has inspired many treatment approaches, including endocrine therapy. Current endocrine therapies, also known as hormone therapies, involve the use of drugs such as aromatase inhibitors to reduce estrogen or progesterone concentrations in the body. They are often prescribed to reduce the risk of recurrence.

Even so, they are far from wholly effective. Resistance to current endocrine therapies is, according to Tilley, the “major cause of breast cancer mortality.” 

Finding an Alternative Treatment

In search of an alternative, the researchers began investigating the use of androgens to treat estrogen receptor-positive breast cancer. Their work was informed by decades-old medical history. Once a first resort, androgen therapy fell out of favor after the 1980s due in part to its masculinizing effects, Tilley says. Complicating medical matters further was the existence of widespread confusion over the role of androgens in estrogen receptor-positive breast cancer development. 

In addition to estrogen receptors, estrogen receptor-positive breast cancers express androgen receptors. Once they made this discovery, scientists of the time were faced with a dilemma: Did androgens help or harm estrogen receptor-positive breast cancer? The debate over the right answer has been raging ever since.

Since estrogen and progesterone promote growth and androgens inhibit it, however, it would make sense that elevating androgen levels would have a negative effect on tumor size. 

Using both cell-line and patient-derived models, the researchers showed that androgen receptor activation had a “potent antitumor” impact on estrogen receptor-positive breast cancers, including those that had not responded adequately to endocrine therapy.

In fact, according to Tilley, “the androgen-receptor activating therapy consistently outperformed standard-of-care estrogen receptor-targeted therapy in all preclinical models.” The results of the study also show that androgen receptor deactivation had no impact on estrogen receptor-positive breast cancer, effectively resolving the debate 30 years after it first began.

“Our research published in Nature Medicine shows that the androgen receptor should be activated, not blocked, resolving a major controversy that has hindered implementation of a rational clinical strategy for the use of androgenic drugs that activate the androgen receptor as a breast cancer therapeutic,” Tilley says.

The Future of Treatment

Androgen receptors can be activated by natural androgens or androgenic (androgen-mimicking) drugs. Clinical trials of one such drug, Enobosarm, are slated for the second quarter of 2021. In addition to preventing estrogen receptor-positive breast cancer progression, androgenic drugs can improve mental health, strengthen bone, and build muscle.

As such, androgen therapy represents “a new form of endocrine therapy that works without the debilitating side effects of current standard-of-care endocrine therapies” such as joint pain and hot flashes, Tilley says. It will initially have to be used in combination with “standard-of-care endocrine or CDK4/6 [enzyme] inhibitors,” he adds. 

When it becomes widely available, androgen therapy seems likely to be welcomed with open arms. People who have undergone treatment for or have survived estrogen receptor-positive breast cancer say there is a dire need for additional treatment options. If the results of this new study eventually yield new treatments, ones for other estrogen-fuelled medical conditions, including stroke, blood clotting, and heart disease, could follow.