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
The use of progestogens in breast cancer has been controversial. Recent preclinical studies have shown that ligand-bound progesterone receptor interacts directly with the estrogen receptor (ER) and reprograms ER transcriptional activity. Progestogen cotreatment enhances the antitumor activity of antiestrogen therapy in mouse xenografts. We report PIONEER, a 198-participant, three-arm, randomized phase 2b window-of-opportunity study for women with early-stage ER<sup>+</sup> breast cancer, which evaluated letrozole with or without megestrol at 40 mg or 160 mg daily. The primary endpoint was the change in tumor proliferation measured by Ki67 immunohistochemistry. Secondary and exploratory endpoints included a comparison of low versus higher dose of megestrol, safety, tolerability and biomarker subgroup analyses. The trial met its primary endpoint, with a greater reduction in proliferation seen when megestrol was added to letrozole. This effect was accompanied by reduced ER genomic binding at canonical binding sites in paired tumor biopsies, indicating reduced ER transcriptional activity. These results support further evaluation of low-dose megestrol, which has two mechanisms for potentially improving breast cancer outcomes in combination with standard antiestrogen therapy: alleviating hot flashes and thereby helping with treatment adherence, as well as a direct antiproliferative effect ( NCT03306472 ).
Authors
- Cleopatra Pike
- Alimu Dayimu
- Danya Cheeseman (ORCID: https://orcid.org/0000-0003-1617-1966)
- Jean Abraham (ORCID: https://orcid.org/0000-0003-0688-4807)
- C. Caldas
- Eleftheria Kleidi
- Karen Pinilla (ORCID: https://orcid.org/0000-0002-2723-0805)
- Beatrix Elsberger (ORCID: https://orcid.org/0000-0002-2864-5789)
- Lucy Satherley
- Igor Chernukhin (ORCID: https://orcid.org/0000-0002-4411-1218)
- Sanjeev Kumar (ORCID: https://orcid.org/0000-0001-6017-1117)
- Sirwan Hadad (ORCID: https://orcid.org/0000-0002-9190-021X)
- S. Govindarajulu
- Rebecca A. Burrell (ORCID: https://orcid.org/0009-0005-1314-1552)
- Elena Provenzano (ORCID: https://orcid.org/0000-0003-3345-3965)
- John R. Benson (ORCID: https://orcid.org/0000-0001-5491-1641)
- Parto Forouhi (ORCID: https://orcid.org/0000-0003-1891-2182)
- Richard D. Baird (ORCID: https://orcid.org/0000-0001-7071-6483)
- Polly King (ORCID: https://orcid.org/0000-0003-2140-9422)
- Amit Agrawal (ORCID: https://orcid.org/0000-0002-9619-7623)
- Wendi Qian (ORCID: https://orcid.org/0000-0002-4238-3471)
- S. Bell
- Vassilis Pitsinis
- Bodiere Akpuluma
- Tulay Gulsen
- Stuart A. McIntosh
- Jason S. Carroll
- Peter Schmid
Institutions
- Queen's University Belfast (GB)
- North Bristol NHS Trust (GB)
- University College London Hospitals NHS Foundation Trust (GB)
- Queen Mary University of London (GB)
- University of Aberdeen (GB)
- University of Cambridge (GB)
- Royal Cornwall Hospital Trust (GB)
- Royal Cornwall Hospital (GB)
- Aberdeen Royal Infirmary (GB)
- Southmead Hospital (GB)
- Cancer Research UK (GB)
- Ninewells Hospital (GB)
- Cancer Research UK Cambridge Center (GB)
- Chris O’Brien Lifehouse (AU)
- Addenbrooke's Hospital (GB)
- NIHR Cambridge Biomedical Research Centre (GB)
- University College London (GB)
- Cardiff University (GB)
Publication Details
- Journal
- Nature Cancer
- Published
- 2026-01-05
- DOI
- https://doi.org/10.1038/s43018-025-01087-x
- Citations
- 2
- Primary Topic
- Estrogen and related hormone effects
- Type
- article
- Field-Weighted Citation Impact
- 61.86
Funders
- Eli Lilly and Company
- Cancer Research UK
- National Institute for Health and Care Research