Multicenter phase 2b trial of letrozole with or without megestrol for early-stage ER-positive breast cancer

In mouse xenografts, progestogen cotreatment enhances the antitumor activity of antiestrogen therapy for breast cancer. The multicenter phase 2b PIONEER trial in the UK evaluated letrozole with or without megestrol in women with early-stage ER-positive breast cancer. A total of 244 patients were randomized 2:3:3 to letrozole only (arm A; n=62), letrozole plus megestrol 40 mg (arm B; n=91), or letrozole plus megestrol 160 mg (arm C; n=91). The primary endpoint was change in tumor proliferation measured by Ki67 immunohistochemistry. 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. The authors conclude that 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.