Hot flush treatment has anti-breast cancer activity, study finds
A drug mimicking the hormone progesterone has anti-cancer activity when used together with conventional anti-oestrogen treatment for women with breast cancer, a new Cambridge-led trial has found.
A low dose of megestrol acetate (a synthetic version of progesterone) has already been proven as a treatment to help patients manage hot flushes associated with anti-oestrogen breast cancer therapies, and so could help them continue taking their treatment. The PIONEER trial has now shown that the addition of low dose megestrol to such treatment may also have a direct anti-cancer effect.
Around three-quarters of all breast cancers are ER-positive. This means the tumours are abundant in a molecule known as an oestrogen receptor, ‘feeding’ on the oestrogen circulating in the body. These women are usually offered anti-oestrogens, medication that reduces level of oestrogen and hence deprives the cancer of oestrogen and inhibits its growth. However, reducing oestrogen levels can bring on menopause-like symptoms, including hot flushes, joint and muscle pain, and potential bone loss.
In the PIONEER trial, post-menopausal women with ER-positive cancers were treated with an anti-oestrogen with or without the progesterone mimic, megestrol. After two weeks of treatment, those that received the combination saw a greater decrease in tumour growth rates compared to those treated with an anti-oestrogen only.
Although further work is required in larger patient cohorts and over a longer period of time to confirm the findings, researchers at the University of Cambridge say the trial suggests that megestrol could help improve the lives of thousands of women for whom anti-oestrogen medication causes uncomfortable side-effects and can lead to some women stopping taking the medication.
PIONEER was led by Dr Richard Baird from the Department of Oncology at the University of Cambridge and Honorary Consultant Medical Oncologist at Cambridge University Hospitals NHS Foundation Trust (CUH). He said: “On the whole, anti-oestrogens are very good treatments compared to some chemotherapies. They're gentler and are well tolerated, so patients often take them for many years. But some patients experience side effects that affect their quality of life. If you’re taking something long term, even seemingly relatively minor side effects can have a big impact.”
Some ER-positive breast cancer patients also have high levels of another molecule, known as progesterone receptor (PR). This group of patients also respond better to the anti-oestrogen hormone therapy.
To explain why, Professor Jason Carroll and colleagues at the Cancer Research UK Cambridge Institute used cell cultures and mouse models to show that the hormone progesterone stops ER-positive cancer cells from dividing by indirectly blocking ER. This results in slower growth of the tumour. When mice treated with anti-oestrogen hormone therapy were also given progesterone, the tumours grew even more slowly.
Professor Carroll, who co-leads the Precision Breast Cancer Institute, said: “These were very promising lab-based results, but we needed to show that this was also the case in patients. There’s been concern that taking hormone replacement therapy – which primarily consists of oestrogen and synthetic versions of progesterone (called progestins) – might encourage tumour growth. Although we no longer think this is the case, there’s still been residual concern around the use of progesterone and progestins in breast cancer.”
To see whether targeting the progesterone receptor in combination with an anti-oestrogen could slow tumour growth in patients, Dr Baird and Professor Carroll designed the PIONEER trial, which tested adding megestrol, a progestin, to the standard anti-oestrogen treatment letrozole.
A total of 198 patients were recruited at ten UK hospitals, including Addenbrooke’s Hospital in Cambridge, and randomised into one of three groups: one group received only letrozole; one group received letrozole alongside 40mg of megestrol daily; and the third group received letrozole plus a much higher daily dose of megestrol, 160mg. In this ‘window of opportunity’ trial, treatment was given for two weeks prior to surgery to remove the tumour. The percentage of actively growing tumour cells was assessed at the start of the trial and then again before surgery.
In findings published today in Nature Cancer, the team showed that adding megestrol boosted the ability of letrozole to block tumour growth, with comparable effects at both the 40mg and 160mg doses.
Joint first author Dr Rebecca Burrell from the Cancer Research UK Cambridge Institute and CUH said: “In the two-week window that we looked at, adding a progestin made the anti-oestrogen treatment more effective at slowing tumour growth. What was particularly pleasing to see was that even the lower dose had the desired effect.
“Although the higher dose of progesterone is licenced as an anti-cancer treatment, over the long term it can have side effects including weight gain and high blood pressure. But just a quarter of the dose was as effective, and this would come with fewer side effects. We know from previous trials that a low dose of progesterone is effective at treating hot flushes for patients on anti-oestrogen therapy. This could reduce the likelihood of patients stopping their medication, and so help improve breast cancer outcomes. Megestrol – the drug we used – is off-patent, making it a cost-effective option.”
Because women in the trial were only given megestrol for a short period of time, follow-up studies will be needed to confirm whether the drug would have the same beneficial effects with reduced side-effects over a longer period of time.
Reference:
Burrell, R.A., Kumar, S., Provenzano, E. et al. Evaluating progesterone receptor agonist megestrol plus letrozole for women with early-stage estrogen-receptor-positive breast cancer: the window-of-opportunity, randomized, phase 2b, PIONEER trial. Nat Cancer (2026). https://doi.org/10.1038/s43018-025-01087-x
