Liverpool cancer researchers have contributed to important new findings about the positive role of androgens in breast cancer treatment, with immediate implications for women with oestrogen receptor-positive (ER-positive) advanced disease.
ER-positive breast cancer is the most common type of breast cancer diagnosed today, accounting for around 75 out of every 100 cases.
Published today in Nature Medicine, an international study led by the University of Adelaide, looked at the role of androgens – commonly thought of as male sex hormones but also found in lower levels in women – as a potential treatment for ER-positive breast cancer.
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 in this disease 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 standard-of-care for ER-positive breast cancer, resistance to these drugs are the major cause of breast cancer mortality.
Using cell-line and patient-derived models, a global team, including Professor Carlo Palmieri from the University of Liverpool and Clatterbridge Cancer Centre NHS Foundation Trust, 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.
Professor Wayne Tilley, Director of the Dame Roma Mitchell Cancer Research Laboratories at the University of Adelaide, said: “We provide compelling new experimental evidence that androgen receptor stimulating drugs can be more effective than existing (Tamoxifen) or new (Palbociclib) standard-of-care treatments and, in the case of the latter, can be combined to enhance growth inhibition.”
Moreover, currently available androgen receptor-targeted therapies lack the undesirable side-effects of natural androgens, and can confer health benefits in women including promotion of bone, muscle and mental health.
The new research findings are reinforced by recent positive data from a phase 2 trial of enobosarm, an oral, novel selective androgen receptor (AR) targeting agent, for the treatment of ER-positive metastatic breast cancer.
The results of the trial (sponsored by VERU, Inc) were presented by Professor Palmieri at the 2020 San Antonio Breast Cancer Symposium in December.
Professor Palmieri, said: “These data are very exciting and clearly demonstrate the important role that the male sex hormone receptor, the androgen receptor, plays in hormone driven breast cancer. Crucially, the results seen in the laboratory play out in the clinic, with enobosarm showing activity when given to women with advanced breast cancer. Importantly for a new drug it was also well tolerated and improved quality of life.”
“Taken together these data open up a potentially new chapter in the treatment of hormone driven breast cancer, one which is focused on stimulating the androgen receptor rather than blocking the female sex hormone receptor (so-called oestrogen receptor) and it is hoped, given how they work, that they will have less side effects than treatments which block the oestrogen receptor.”
An international Phase 3 registration clinical trial evaluating enobosarm in patients with androgen receptor and oestrogen receptor positive metastatic breast cancer who failed endocrine therapy and a CDK 4/6 inhibitor (e.g. palbociclib), will commence in the second quarter of 2021.
Watch a video explainer about the new study at – https://youtu.be/NYalzv4C35U
Hickey, T.E., Selth, L.A., Chia, K.M. et al. The androgen receptor is a tumor suppressor in estrogen receptor-positive breast cancer. Nat Med(2021). https://doi.org/10.1038/s41591-020-01168-7