Results of the window-of-opportunity PIONEER trial evaluating addition of the progesterone receptor (PR) agonist megestrol to letrozole for early-stage estrogen receptor (ER) positive breast cancer: exploiting ER-PR interaction

The use of progestogens in breast cancer has been controversial. Recent preclinical studies have shown that progestogen-bound PR interacts directly with ER and reprograms ER transcriptional activity. Progestogen co-treatment also enhances the anti-tumor activity of anti-estrogen therapy in mouse xenografts. We report PIONEER (NCT03306472), a 198 patient, 3-arm, randomised phase IIb pre-operative window of opportunity study, which evaluated the anti-estrogen letrozole with or without megestrol at 40mg or 160mg daily. The trial met its primary endpoint, with a greater reduction in proliferation seen when megestrol was added to letrozole. Mechanistically, this effect was accompanied by reduced ER genomic binding at canonical binding sites, indicating reduced ER transcriptional activity. These results support further evaluation of low dose megestrol, which has two parallel mechanisms for potentially improving breast cancer outcomes in combination with standard anti-estrogen therapy: alleviating. In addition to helping patients experiencing hot flashes as a side effect of treatmentand thereby helping with treatment adherence, megestrol has a and also a direct anti-proliferative effect. in breast cancer patients, when combined with standard anti-estrogen therapy.