Low-dose megestrol enhances anti-oestrogen therapy in breast cancer

Researchers from the University of Cambridge have identified anti-cancer activity from a drug mimicking progesterone when used alongside conventional anti-oestrogen treatment in women with breast cancer, publishing their findings in Nature Cancer.¹

The researchers evaluated the efficacy of megestrol acetate, a synthetic version of progesterone that has been shown to successfully manage hot flashes linked to anti-oestrogen breast cancer therapies. Based on this new data, adding a low dose megestrol to anti-oestrogen treatment may also directly reduce cancer activity.

“Although the higher dose of progesterone is licensed 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,” said Rebecca Burrell, PhD, researcher at Cancer Research UK Cambridge Institute.

Treatment arms and study procedures

The randomized phase 2b trial was conducted to assess the therapeutic outcomes of combined progesterone and antiestrogen therapy.² Participants included premenopausal women with treatment-naive early-stage estrogen receptor (ER)positive breast cancer scheduled for primary surgery or endocrine surgery.

Menopause was determined by 12 months of natural amenorrhea and an appropriate clinical profile, or 6 months of spontaneous amenorrhea with serum follicle-stimulating hormone and estradiol levels consistent with postmenopause. Patients with known distant metastatic, hormone replacement therapy use, or recurrent breast cancer were excluded.

Participants were randomized 2:2:3 to either a control group, letrozole 2.5 mg only group, or letrozole 2.5 mg plus lower-dose megestrol group. The latter 2 groups were referred to as research arm 1 and research arm 2, respectively. Patients received treatment for 15 days before tumor excision or core biopsy.

Assessing tumor proliferation

The change in tumor proliferation as measured by Ki67 between baseline and end of treatment (EOT) was recorded as the primary outcome, compared in the research arms vs the control arm. Patients provided core biopsies at both baseline and EOT, which were stored at −80 °C until processed.

Immunohistochemistry was also used to assess tumor proliferation. Investigators obtained blood samples from patients to isolate and quantify DNA samples.

There were 198 patients who completed at least 13 days of treatment and were included in the final analysis. Of these, 51 were in the control arm, 74 research arm 1, and 73 in research arm 2. No significant variations in baseline characteristics were reported across treatment arms.

An ER Allrede score of 7 to 8 was given to 98% of tumors, with 11% defined as progesterone receptor (PR)negative. Additionally, 22% had a PR Allred score of 0 to 3.

Ki67 suppression

Ki67 was significantly reduced in both research arms vs the control arm, with a ratio of geometric mean (GMR) proportional change in Ki67 of 0.71 for megestrol combinations vs letrozole alone. In patients taking letrozole alone, the mean Ki67 suppression was 71.4%, vs 79.5% for letrozole + 40 mg megestrol and 80% for letrozole + 160 mg megestrol.

Following adjustments for tumor grade, suppression remained significant, with a GMR proportional change of 0.74. Ki67 suppression did not significantly differ between the 2 research arms, indicating efficacy toward reducing breast cancer cell proliferation from both higher and lower doses of megestrol.

Adverse event rates did not significantly differ between groups, with a prevalence of 58.3% in the control arm, 60.7% in research arm 1, and 66.3% in research arm 2. Overall, the data highlighted superior antiproliferative activity from a combination of megestrol alongside conventional anti-oestrogen treatment vs conventional treatment alone.

“These data support an evaluation of lower-dose megestrol combination therapy in further clinical trials, given its potential as a means of enhancing both the efficacy and the tolerability of [aromatase inhibitor] therapy for persons with breast cancer,” wrote investigators.

References

1. Hot flush treatment has anti-breast cancer activity, study finds. University of Cambridge. January 5, 2026. Accessed January 9, 2026. https://www.eurekalert.org/news-releases/1111390
2. Burrell RA, 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. doi.org:10.1038/s43018-025-01087-x