Low-dose megestrol strengthens hormone therapy in ER-positive breast cancer

By Dr. Liji Thomas, MDReviewed by Lauren HardakerJan 7 2026

A preoperative trial shows that activating the progesterone receptor with low-dose megestrol can deepen estrogen blockade and curb tumor proliferation, without added toxicity, pointing to a simpler way to strengthen hormone therapy for ER-positive breast cancer.

Study: 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. Image credit: Gorodenkoff/Shutterstock.com

Breast cancer causes 670,000 deaths each year, according to the World Health Organization (WHO). About three-fourths of these cancers express estrogen receptors (ER), and these are primarily treated with antiestrogens in the adjuvant and metastatic settings. A recent paper in Nature Cancer reported on the PIONEER study, which examined the effect of adding the progesterone receptor (PR) agonist megestrol acetate, a synthetic progestogen, to this therapy in a short preoperative window-of-opportunity trial.

Reassessing progestogens after decades of clinical controversy

Antiestrogens like the aromatase inhibitor letrozole are the primary choice for ER-positive breast cancer. Treatment failure does occur, as do adverse effects severe enough to necessitate stopping treatment. These include intolerable hot flushes and other perimenopausal symptoms.

Some of these could be alleviated by progestogens acting on the PR. Megestrol acetate is a progestogen approved for metastatic ER-positive breast cancer at 160 mg per day. At this high dose, its potentially dangerous side effects include hypertension, weight gain, and venous thromboembolism (VTE). Lower doses of megestrol (20 to 40 mg per day) reduce hot flushes in women on antiestrogens as shown in prior randomized trials, but are not yet approved for this use.

Some trials suggested that progestins increased breast cancer risk. Notably, early data from the Women’s Health Initiative on menopausal hormone therapy implicated the progestogen medroxyprogesterone acetate. However, 18-year follow-up data showed no difference in overall mortality attributable to the inclusion of a progestin, and the association with breast cancer incidence remains debated.

More recent studies on combination hormone therapy, using progestogens like dydrogesterone and progesterone, contradict this association. Premenopausal women with higher endogenous progesterone levels have a reduced breast cancer risk.

In vitro studies of breast cancer also indicate dramatic shifts in ER-mediated target gene transcription following progesterone exposure. As a result, a combination of antiestrogens with progesterone induces a greater antiproliferative effect than with either agent alone. This effect could mirror both PR activation, mediated by ER reprogramming, and PR, ER interactions that reduce ER binding to canonical target genes.

The current PIONEER study, a preoperative-window study of letrozole plus PR agonist megestrol acetate versus letrozole alone in postmenopausal women with ER-positive breast cancer, aims to examine tumor activity in postmenopausal operable ER-positive human epidermal growth factor receptor 2 (HER2, also known as ERBB2)-negative breast cancer with combined letrozole–megestrol therapy versus letrozole alone. Two doses of megestrol were used, namely, the higher 160 mg dose, which is approved as an anticancer drug for metastatic ER-positive breast cancer, and the lower 40 mg dose, which is safer and better tolerated, but not approved as an antiproliferative agent in this condition.

Comparing low- and high-dose megestrol with letrozole

The PIONEER study randomized 244 participants, of whom 198 were evaluable for the primary endpoint, in a three-arm randomized controlled trial (RCT). The aim was to compare early-stage ER-positive breast cancer treated with letrozole with and without megestrol at 40 mg or 160 mg per day. Tumor proliferation was observed for any change, based on Ki67 expression, Ki67 being a protein marker of cell proliferation used as an early pharmacodynamic biomarker rather than a clinical outcome.

Study findings

Megestrol inhibits proliferation

The combination of megestrol with letrozole was associated with a larger drop in tumor cell proliferation compared to letrozole alone. This finding persisted after adjusting for tumor grade. Megestrol dosage did not alter the final antiproliferative effect.

These effects were confirmed using aurora kinase A (AURKA) assays, which were highly correlated with the Ki67 results. This validates the alternative use of AURKA as a measure of proliferative activity.

At the end of treatment, the mean Ki67 levels were 30 % lower with combined letrozole–megestrol treatment, irrespective of dosage, compared to letrozole alone. An excellent response to treatment, as signaled by a Ki67 value of 10 % or less, was achieved in approximately 65 % of participants on letrozole alone, but in approximately 80 % of the other two combined-treatment arms. Similarly, complete cell cycle arrest was observed in approximately 27 % of monotherapy versus approximately 40 % of combination therapy recipients.

Megestrol represses PR

Megestrol resulted in PR repression with comparable efficacy at both dosages. Of 196 participants with complete PR data, 174 were PR-positive, and 25 % of these, 44 participants, had less than 1 % PR-positive cells after completing treatment. Interestingly, 91 % of them received megestrol.

Again, 61 % of PR-positive tumors had 10 % or more PR-positive cells at the end of treatment, with 66 % of these tumors being in combination therapy arms. The highest ER-positive and PR-positive expression levels predict an exceptional response to aromatase inhibitors, based on exploratory subgroup analyses, outlining a subgroup that may not require added megestrol.

These findings emphasize the importance of using diagnostic histology from core biopsy, rather than surgical histology, to guide adjuvant treatment for preoperative antiestrogen therapy.

Megestrol impairs ER genomic binding

Tumor biopsies showed megestrol-induced reduced ER binding at key ER-binding regulatory sites adjacent to canonical ER target genes. This resulted in ER repression. This corroborates prior preclinical study findings and suggests that megestrol activates PR, leading to functional ER suppression and reprogramming; however, additional nuclear receptor-mediated effects cannot be excluded, regardless of the megestrol dosage.

Adverse effects were similar across all three arms; however, the trial duration was too short to allow for proper safety assessments. Joint pain, tiredness, headache, and nausea were the most common, though megestrol inclusion caused dry mouth, dyspnea, and vaginal bleeding in 10 % or less of recipients. Treatment-emergent hypertension was observed in the 160 mg arm but not in the 40 mg or letrozole-only arms. Postoperative venous thromboembolism rates were not above expected levels, though attribution to megestrol could not be determined.

Low-dose megestrol reduces hot flushes in women on antiestrogen therapy, as shown in earlier studies, encouraging treatment compliance and thus improving outcomes. Additionally, it directly inhibits tumor cell proliferation, most likely through PR activation with downstream suppression of ER activity rather than through PR repression itself, as reflected by short-term biomarker changes.

Cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6) like abemaciclib are being routinely used at present as adjuvant treatment of high-risk tumors. If poorly tolerated or inaccessible, they could potentially be complemented or selectively substituted by megestrol in carefully selected patients, pending confirmation of long-term clinical benefit in future trials, which is also more cost-effective.

Low-dose PR activation strengthens endocrine therapy signals

The study suggests that combining low-dose megestrol with letrozole enhances therapeutic efficacy at the level of tumor proliferation biomarkers. Besides relieving hot flushes, as previously reported in other trials, thus improving treatment adherence and enhancing patient outcomes, it is here shown to have a direct antiproliferative effect, mediated by PR activation and ER reprogramming, a hypothesis that will require validation in longer-term outcome-driven studies.

Download your PDF copy now!