There is bidirectional interplay between PR and ER in human breast cancers. There is evidence for a reprogramming of ER chromatin binding sites with 470 genes differentially regulated by dual treatment with estrogen plus progestogen compared to estrogen alone in breast cancer cell lines. Functionally, there was an additive anti-cancer effect with the addition of natural progesterone to endocrine therapy in preclinical breast cancer models. This is a phase II multi-site, randomised, open-label, three-arm, study in 200 postmenopausal women with early-stage ER+, PR+, HER2-negative breast cancer. Eligible patients will be randomised 1:1:1 to receive 14 days of intervention with either letrozole 2.5 mg PO daily, letrozole 2.5 mg + prometrium 300 mg PO daily or tamoxifen 20 mg + prometrium 300 mg PO daily, between diagnosis of breast cancer and definite surgery. The primary endpoint of this study is to determine geometric mean suppression of the centrally assessed proliferation marker Ki67 after two weeks of intervention, compared with baseline. Secondary endpoint is safety and tolerability of combination therapy. Translational endpoints including evaluating a gene set as a predictive biomarker for a reduction in Ki67, changes in the apoptotic markers Bcl-2 and Caspase 3 in the tumours following intervention and changes in ER, PR, AR, FoxA1, Cyclin D1 protein and mRNA expression in the tumours following intervention will also be assessed. The IMPACT study reported a geometric mean reduction in Ki67 after 2 weeks of preoperative tamoxifen of 59.5% and anastrazole of 76%. This allows estimation of power to detect differences between Arm 1 and either Arm 2 or Arm 3 with a p-value of 0.025. With a total trial recruitment of 200 and allowing 4% dropouts, this would give 80% power to detect an improvement in Ki67 suppression from 76% in the letrozole alone control arm to 92% in either experimental arm.
17 Mar 2019 - 20 Mar 2019