Megestrol Acetate’s Role in Early-Stage ER-Positive Breast Cancer

Estrogen receptor-positive (ER+) breast cancer accounts for the majority of breast cancer diagnoses and is completely treated with endocrine therapies such as aromatase inhibitors (AIs). Although these drugs are effective, they often lead to menopausal symptoms such as hot flashes, which can impact adherence to treatment strategies. Recently, emerging evidence indicates that megestrol acetate, a synthetic progestogen used for symptom management, has anticancer properties as an adjunct to endocrine therapy, raising new clinical considerations for oncology pharmacists.^1,2

Endocrine Therapy and the Burden of Vasomotor Symptoms

Als such as letrozole result in the inhibition of estrogen production, therefore inhibiting the growth of tumors fueled by estrogen in ER+ breast cancer. However, deprivation of estrogen is closely linked to hot flashes, night sweats, and sleep disturbances, which rank among the most frequent adverse effects of endocrine therapy. These symptoms are not benign; they are a leading cause of non-adherence to treatment and early treatment discontinuation, which have been linked to worse disease outcomes.¹ Pharmacists commonly encounter patients with difficulties when taking endocrine therapy, or they are usually among the first to offer advice on how to handle these symptoms.

Megestrol Acetate: From Symptom Control to Tumor Suppression

Megestrol acetate has been widely used in a low-dose regimen for the treatment of hot flushes associated with anti-estrogen therapy. More recently, there have been attempts to investigate its use as a possible source of further anti-cancer activity, apart from its analgesic efficacy. The phase 2b PIONEER trial (NCT03306472) assessed a combination of megestrol acetate with letrozole in postmenopausal patients suffering from early-stage ER+ breast cancer.¹

In this window-of-opportunity study, tumor proliferation was assessed using the Ki-67 biomarker, a well-established indicator of cancer cell growth and relapse risk. Patients receiving the combination of megestrol and letrozole demonstrated significantly greater suppression of Ki-67 than those receiving letrozole alone.¹ These findings suggest that megestrol acetate may enhance the antiproliferative effects of standard endocrine therapy, supporting a potential dual role in symptom management and cancer control.

Biological Rationale and Clinical Implications

Progesterone receptor signaling exhibits a complex interaction with estrogen signaling in the breast tissue. Investigators hypothesize that progesterone receptors’ engagement can potentially mitigate estrogen-driven proliferative activity, thus modulating tumor behavior and inhibiting tumor growth.¹^,² Importantly, the doses of megestrol administered in the PIONEER trial were comparable to the traditional doses for treating hot flashes in women with breast cancer, which are known to be toxic at higher doses in the metastatic population.

The low-dose approaches may combine favorable effectiveness and safety profiles with reduced risks such as weight gain and thromboembolic events. Pharmacists are well-positioned to help clinicians navigate dosing strategies and patient selection based on evolving evidence.

The Pharmacist’s Role in Clinical Integration

Pharmacists can significantly help optimize outcomes of endocrine therapy by focusing on adverse reactions, which can compromise patient adherence. There is a renewed focus on the complementary effects of megestrol acetate, which can provide pharmacists with a proactive approach to oncologists for patients who continue to experience vasomotor symptoms.

This may include counseling regarding expected symptom improvement, reinforcing the need to continue endocrine therapy, and monitoring for progestogen-related adverse effects. Previous studies have shown that pharmacist-led interventions in the treatment of hot flashes can enhance symptom burden as well as continuation of cancer therapy.³ Such roles may be more critical in the future as new indications for existing medications are identified.

Additionally, pharmacists can help contextualize emerging research for patients, addressing concerns about adding another agent to their regimen and explaining the potential oncologic rationale in accessible terms.

Looking Ahead: Research and Practice Considerations

Although early results are promising, larger-scale research is warranted to assess whether the antiproliferative properties demonstrated with megestrol translate into improved survival.² Future research should also aid in defining an optimal dose as well as how long an individual should undergo treatment.

While the evidence is continually evolving, pharmacists should remain part of the discussion among the various disciplines involved in optimizing endocrine therapy. The potential of a drug with a long history of helping control symptoms to improve the effectiveness of cancer therapies can certainly emphasize the value of pharmacists’ knowledge and expertise.

REFERENCES

1. Burrell, R.A., 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). https://doi.org/10.1038/s43018-025-01087-x

2. Undeberg MR, Barash A, McKeirnan KC. Role of the pharmacist in the management of postmenopausal breast cancer treatment with vasomotor symptoms: A case report. Explor Res Clin Soc Pharm. 2023;11:100324. Published 2023 Aug 24. doi:10.1016/j.rcsop.2023.100324

3. Hot flush treatment has anti-breast cancer activity, study finds. University of Cambridge. Accessed January 7, 2026. https://www.cam.ac.uk/research/news/hot-flush-treatment-has-anti-breast-cancer-activity-study-finds