A new clinical trial led by researchers in Cambridge, United Kingdom, suggests that low-dose megestrol acetate, a synthetic progesterone, may not only ease the side effects of anti-estrogen therapy but also slow the growth of estrogen-receptor (ER) positive breast tumors.
Breast cancer is the most common cancer among women worldwide, with approximately 2.3 million diagnoses annually, according to the World Health Organization. While less than 1% of cases occur in men, ER-positive breast cancers—where tumor cells grow in response to estrogen—account for around 75% of all cases. Standard treatment often includes anti-estrogen medications, such as letrozole, which reduce estrogen production but can cause menopausal-like side effects, including hot flashes, joint pain, and bone loss.
The PIONEER trial, recently published in Nature Cancer, examined whether adding megestrol acetate could improve both treatment tolerability and tumor control. The study involved 244 women with early-stage ER-positive breast cancer from 10 hospitals across the UK. Participants were randomly assigned to three groups before surgery: 62 received letrozole alone, 91 received letrozole plus 40 mg of megestrol, and 91 received letrozole plus 160 mg of megestrol.
Of the participants, 198 completed the two-week treatment course and had tumor samples suitable for proliferation analysis. Researchers found that megestrol enhanced the anti-proliferative effect of letrozole at both low and high doses, with no significant difference between the two megestrol groups.
“These findings could have significant clinical impact by improving treatment adherence while positively impacting tumor control. However, further studies will be required to substantiate these claims,” said Dr. Esha Sachdev, breast medical oncologist at MemorialCare Todd Cancer Institute in Long Beach, California, who was not involved in the study.
Tackling Side Effects of Anti-Estrogen Therapy
Letrozole, commonly prescribed to post-menopausal women following initial breast cancer treatment, works by reducing estrogen production to prevent cancer recurrence. However, the therapy often triggers uncomfortable symptoms, including hot flashes, joint pain, reduced bone density, and increased cholesterol. Megestrol acetate, marketed as Megace in the U.S., has been used to alleviate these side effects, even at low doses.
“The lower dose of megestrol was as effective at slowing tumor growth as the higher dose, suggesting patients could benefit from its protective effects while minimizing adverse side effects like weight gain, high blood pressure, and blood clots,” said Dr. Richard Baird, corresponding author of the study and oncologist at Cambridge University Hospitals NHS Foundation Trust.
Potential Mechanisms
Experts propose two ways megestrol may benefit patients. First, by reducing hot flashes, it helps improve adherence to long-term anti-estrogen therapy. Second, it may exert a direct anti-proliferative effect by reducing estrogen receptor (ER) binding in tumor cells, thereby slowing cell growth. Low doses may be sufficient to achieve this effect without increasing the risk of side effects.
Next Steps
While results are promising, the study involved fewer than 200 patients and lasted only two weeks. Researchers stress that larger, longer-term trials are needed to validate these findings before they can inform clinical practice.
“A randomized phase 3 trial comparing letrozole plus megestrol versus letrozole alone is essential to determine long-term clinical benefits, including disease-free survival,” Dr. Sachdev said. “Additionally, a dose-finding study over an extended period would help assess safety and tolerability alongside efficacy.”
The PIONEER trial highlights the potential of low-dose megestrol to improve both patient comfort and tumor control in ER-positive breast cancer, representing a promising avenue for future research.
