A low-dose synthetic version of the hormone progesterone may not only relieve menopausal-like side effects but also enhance the effectiveness of standard anti-oestrogen therapies for breast cancer, according to new research led by the University of Cambridge.
The PIONEER trial, supported by the NIHR Cambridge Biomedical Research Centre (BRC), tested megestrol acetate—a synthetic progesterone already used to manage hot flushes in patients on anti-oestrogen therapy—alongside conventional treatment in post-menopausal women with oestrogen receptor (ER)-positive breast cancer.
ER-positive cancers, which account for roughly three-quarters of all breast cancers, rely on oestrogen to grow. Anti-oestrogen medications, such as letrozole, reduce oestrogen levels to slow tumour growth. However, these therapies often cause menopause-like symptoms including hot flushes, joint pain, and potential bone loss, which can lead some patients to discontinue treatment.
In the PIONEER trial, 198 women across ten UK hospitals, including Addenbrooke’s Hospital in Cambridge, were randomly assigned to one of three groups: letrozole alone, letrozole plus 40mg daily of megestrol, or letrozole plus 160mg daily of megestrol. Over a two-week period prior to surgery, the team measured the proportion of actively dividing tumour cells.
Results, published in Nature Cancer, showed that adding megestrol—at both low and high doses—significantly enhanced the anti-cancer effects of letrozole, slowing tumour growth more than letrozole alone. Notably, the lower 40mg dose, previously proven to manage hot flushes, was as effective as the higher 160mg dose, suggesting a safer, better-tolerated option for patients.
Dr. Richard Baird, lead investigator and Honorary Consultant Medical Oncologist at Cambridge University Hospitals NHS Foundation Trust, said: “Anti-oestrogens are effective and generally well-tolerated, but side effects can affect quality of life. Even minor long-term effects can be significant. Our findings suggest that a low dose of megestrol could help patients stay on therapy while also boosting treatment efficacy.”
Laboratory studies conducted by Professor Jason Carroll and colleagues at the Cancer Research UK Cambridge Institute previously showed that progesterone indirectly blocks ER activity, slowing the division of cancer cells. The PIONEER trial now demonstrates that this effect translates to real-world patients.
While the trial’s two-week duration limits conclusions about long-term outcomes, researchers are optimistic. Dr. Rebecca Burrell, joint first author, noted: “The lower dose of megestrol provides anti-cancer benefits while reducing risks such as weight gain and high blood pressure, and it may also improve adherence to anti-oestrogen therapy, ultimately enhancing outcomes.”
Megestrol is off-patent, offering a cost-effective adjunct to standard therapy. The study received funding from Anticancer Fund, Cancer Research UK, Addenbrooke’s Charitable Trust, and the NIHR Cambridge BRC.
The research aligns with the vision for the future Cambridge Cancer Research Hospital, which will integrate world-class research and clinical care at the Cambridge Biomedical Campus to advance precision cancer treatment.
