Progesterone mimic plus anti-estrogen treatment slows tumor growth in breast cancer patients

A drug mimicking the hormone progesterone has anti-cancer activity when used together with conventional anti-estrogen 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-estrogen 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 tumors are abundant in a molecule known as an estrogen receptor, 'feeding' on the estrogen circulating in the body. These women are usually offered anti-estrogens, medication that reduces level of estrogen and hence deprives the cancer of estrogen and inhibits its growth. However, reducing estrogen 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-estrogen with or without the progesterone mimic, megestrol. After two weeks of treatment, those that received the combination saw a greater decrease in tumor growth rates compared to those treated with an anti-estrogen 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-estrogen 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-estrogens 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-estrogen 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 tumor. When mice treated with anti-estrogen hormone therapy were also given progesterone, the tumors 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 estrogen and synthetic versions of progesterone (called progestins) – might encourage tumor 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-estrogen could slow tumor growth in patients, Dr Baird and Professor Carroll designed the PIONEER trial, which tested adding megestrol, a progestin, to the standard anti-estrogen 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 tumor. The percentage of actively growing tumor 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 tumor growth, with comparable effects at both the 40mg and 160mg doses.

In the two-week window that we looked at, adding a progestin made the anti-estrogen treatment more effective at slowing tumor 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-estrogen 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."

Dr. Rebecca Burrell, joint first author from the Cancer Research UK Cambridge Institute and CUH 

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.

The research was funded by Anticancer Fund, with additional support from Cancer Research UK, Addenbrooke's Charitable Trust and the National Institute for Health and Care Research Cambridge Biomedical Research Centre.

Personalized and precise cancer treatments underpin the focus of care at the future Cambridge Cancer Research Hospital. The specialist facility planned for the Cambridge Biomedical Campus will bring together world-leading researchers from the University of Cambridge and its Cancer Research UK Cambridge Centre and clinical excellence from Addenbrooke's Hospital under one roof in a brand-new NHS hospital.