The potential of androgens in breast cancer treatment

New evidence of the positive role of androgens in breast cancer treatment has been uncovered by University of Adelaide researchers, with immediate implications for women with oestrogen receptor-driven metastatic disease.

The international study — conducted in collaboration with the Garvan Institute of Medical Research — examined the role of androgens as a potential treatment for oestrogen-receptor-positive breast cancer. Androgens are commonly thought of as male sex hormones but are also found at lower levels in women. The results of the study are published in Nature Medicine.

In normal breast development, oestrogen stimulates and androgen inhibits growth at puberty and throughout adult life. Abnormal oestrogen activity is responsible for the majority of breast cancers, but the role of androgen activity has been controversial.

Androgens were historically used to treat breast cancer, but knowledge of hormone receptors in breast tissue was rudimentary at the time and the treatment’s efficacy misunderstood. Androgen therapy was discontinued due to virilising side effects and the advent of anti-oestrogenic endocrine therapies.

While endocrine therapy is the standard of care for oestrogen-receptor-positive breast cancer, resistance to these drugs is the major cause of breast cancer mortality.

Study leads Professor Wayne Tilley — Director of the Dame Roma Mitchell Cancer Research Laboratories — and Associate Professor Theresa Hickey — Head of the Breast Cancer Group — said the need for alternative treatment strategies has renewed interest in androgen therapy for breast cancer. They explained that previous studies produced conflicting evidence on how best to therapeutically target the androgen receptor for treatment of breast cancer, which caused widespread confusion and hampered clinical application.

Study leads Professor Wayne Tilley and Associate Professor Theresa Hickey said the need for alternative treatment strategies has renewed interest in androgen therapy for breast cancer.

Androgen receptor activation

Using cell-line and patient-derived models, a global team, including researchers at the University of Adelaide and the Garvan Institute, demonstrated that androgen receptor activation by natural androgen or a new androgenic drug had potent anti-tumour activity in all oestrogen-receptor-positive breast cancers, even those resistant to current standard-of-care treatments. In contrast, androgen receptor inhibitors had no effect.

“This work has immediate implications for women with metastatic oestrogen-receptor-positive breast cancer, including those resistant to current forms of endocrine therapy,’’ Associate Professor Theresa Hickey said.

Professor Tilley added, “We provide compelling new experimental evidence that androgen-receptor-stimulating drugs can be more effective than existing (eg, Tamoxifen) or new (eg, Palbociclib) standard-of-care treatments and, in the case of the latter, can be combined to enhance growth inhibition.

“Moreover, currently available selective androgen-receptor-activating agents lack the undesirable side effects of natural androgens, and can confer benefits in women including promotion of bone, muscle and mental health.”

Breast oncologist and Head of the Connie Johnson Breast Cancer Research Lab at the Garvan Institute Associate Professor Elgene Lim said, “The new insights from this study should clarify the widespread confusion over the role of the androgen receptor in oestrogen-receptor-driven breast cancer. Given 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.”

Dr Stephen Birrell, a breast cancer specialist and pioneer in androgens and women’s health who was part of the Adelaide-based team, pointed out that the finding has application beyond the treatment of breast cancer, including breast cancer prevention and treatment of other disorders also driven by oestrogen.

An international phase 3 registration clinical trial evaluating the androgen-receptor-activating agent Enobosarm in patients with androgen-receptor- and oestrogen-receptor-positive metastatic breast cancer who failed endocrine therapy and a CDK 4/6 inhibitor will commence in the second quarter of 2021.

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