A University of Cambridge-led trial has found that a drug mimicking the hormone progesterone has anti-cancer activity when it is used together with conventional anti-oestrogen treatment for women with breast cancer.
A low dose of megestrol acetate, which is a synthetic version of progesterone, is already proven as a treatment to help patients manage the hot flushes that can be associated with anti-oestrogen breast cancer therapies.
A mammogram. Picture: iStock
The PIONEER trial has now shown it may also have a direct anti-cancer effect.
About three-quarters of all breast cancers are ER-positive, meaning the tumours are abundant in a molecule known as an oestrogen receptor, that ‘feeds’ on oestrogen circulating in the body.
Women with these cancers are usually offered anti-oestrogens to deprive the cancer of oestrogen and inhibit its growth. But reducing oestrogen levels can bring on menopause-like symptoms, including hot flushes, joint and muscle pain, and potential bone loss.
During 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, those who received the combination saw a greater decrease in tumour growth compared to those treated with an anti-oestrogen only.
The researchers say further work is required in larger patient cohorts and over a longer period of time to confirm the findings, but the trial suggests megestrol could help improve the lives of thousands of women for whom anti-oestrogen medication causes uncomfortable side-effects, which can lead some women to stop taking the medication.
Dr Richard Baird, from the Department of Oncology and honorary consultant medical oncologist at Cambridge University Hospitals, who led the trial, 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.”
Megestrol acetate (a synthetic version of progesterone) has already been proven as a treatment to help patients manage hot flushes. Picture: iStock
Some ER-positive breast cancer patients also have high levels of progesterone receptor (PR) and they also respond better to the anti-oestrogen hormone therapy.
Prof Jason Carroll and colleagues at the Cancer Research UK Cambridge Institute used cell cultures and mouse models to explore why. They showed that the hormone progesterone stops ER-positive cancer cells from dividing by indirectly blocking ER, leading to slower growth of the tumour. When mice were treated with anti-oestrogen hormone therapy were also given progesterone, the tumours grew even more slowly.
Clare College fellow Prof 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 study whether targeting the progesterone receptor in combination with an anti-oestrogen could slow tumour growth in patients, Dr Baird and Prof Carroll designed the PIONEER trial.
It tested the addition of megestrol, a progestin, to the standard anti-oestrogen treatment, letrozole.
Some 198 patients were recruited at 10 UK hospitals, including Addenbrooke’s in Cambridge for the ‘window of opportunity’ trial, during which treatment was given for two weeks prior to surgery to remove the tumour. They found adding megestrol boosted the ability of letrozole to block tumour growth, with comparable effects at both 40mg and 160mg doses.
Dr Rebecca Burrell, from the Cancer Research UK Cambridge Institute and CUH, joint first author of the study published in Nature Cancer, said: “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.”
Follow-up studies over more time are needed to confirm the impact.