A drug that mimics the hormone progesterone may enhance the effectiveness of standard anti-estrogen therapies for women with certain types of breast cancer, according to new research led by the University of Cambridge.
The medication, megestrol acetate, is already prescribed at low doses to ease side effects of anti-estrogen treatments—such as hot flashes—in patients with estrogen receptor–positive (ER-positive) breast cancer. But findings from a new clinical trial suggest it may also have a direct anticancer effect when combined with conventional hormone therapy.
The study, known as the PIONEER trial, was recently published in Nature Cancer.
“These findings could have significant clinical impact by improving treatment adherence while positively impacting tumor control,” said Dr. Esha Sachdev, a breast medical oncologist at the MemorialCare Todd Cancer Institute in Long Beach, California, who was not involved in the research. “However, further studies will be required to substantiate these claims.”
Dr. Debra Patt, executive vice president of public policy and strategy at Texas Oncology, also welcomed the results.
“I think the study is exciting and should be expanded so we know how it might impact long-term outcomes in women with breast cancer,” Patt told Healthline.
Potential Anticancer Effects of a Progesterone Mimic
Roughly 75% of all breast cancers are classified as ER-positive, meaning the cancer cells have receptors that bind to estrogen and use it to fuel tumor growth. Tumor samples taken during biopsy or surgery are routinely tested for estrogen and progesterone receptors to guide treatment decisions.
Patients with ER-positive breast cancer are commonly prescribed anti-estrogen medications, which reduce estrogen levels and help slow cancer growth. However, these drugs can cause menopause-like side effects, including hot flashes, bone loss, and joint or muscle pain—symptoms that can interfere with long-term treatment adherence.
“One proposed mechanism as to why the megestrol reduces tumor growth is through improving adherence to adjuvant endocrine therapy by alleviating hot flashes,” Sachdev explained. “A second mechanism is the direct antiproliferative effect on tumor cells mediated by reduced ER genomic binding, subsequently antagonizing estrogen signaling.”
She added that even a lower dose of megestrol may be enough to saturate hormone receptors and limit estrogen-driven tumor activity.
Inside the PIONEER Trial
The PIONEER study enrolled 198 postmenopausal women with ER-positive breast cancer from 10 hospitals across the United Kingdom. Participants were randomly assigned to one of three treatment groups:
- Letrozole alone (an anti-estrogen medication commonly used for ER-positive breast cancer)
- Letrozole plus 40 mg of megestrol daily
- Letrozole plus 160 mg of megestrol daily
Each patient received treatment for two weeks prior to surgery to remove the tumor. Researchers measured the percentage of actively growing tumor cells at the start of the trial and again just before surgery.
After two weeks, patients who received the combination of letrozole and megestrol showed a greater reduction in tumor growth rates compared with those who received letrozole alone.
“In the two-week window that we looked at, adding a progestin made the anti-oestrogen treatment more effective at slowing tumour growth,” said Rebecca Burrell, joint first author of the study and a clinical research associate with Cambridge University Hospitals and the Cancer Research UK Cambridge Institute. “What was particularly pleasing to see was that even the lower dose had the desired effect.”
Burrell noted that while higher doses of progesterone-like drugs are already licensed as cancer treatments, they can cause side effects such as weight gain and high blood pressure when used long term.
“But just a quarter of the dose was as effective, and this would come with fewer side effects,” she said.
What This Means for the Future of Breast Cancer Care
Researchers caution that more work is needed before the findings can change standard clinical practice. Larger studies with longer follow-up periods will be required to confirm both the safety and long-term effectiveness of combining megestrol with anti-estrogen therapy.
“Several additional studies are needed to strengthen and validate the results from this trial,” Sachdev said. “A longer duration is necessary to assess safety and tolerability in conjunction with efficacy.”
Still, experts say the results highlight an encouraging direction for breast cancer research.
“We are in a time of incredible research in breast cancer, and breast cancer patients have every reason to be optimistic about their future,” Patt said. “As multidisciplinary cancer care continues to evolve, we can do more and more to help women live long and healthy lives.”
