There is bidirectional interplay between PR and ER in breast cancers (Lim et al, Endo Rel Can 2016). There is evidence for a reprogramming of ER chromatin binding sites with 470 genes differentially regulated by dual treatment with oestrogen plus progestogen compared to oestrogen alone in breast cancer cell lines (Mohammed et al, Nature 2015). 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 2.5mg PO daily (arm 1), letrozole 2.5mg + prometrium 300mg PO daily (arm 2) or tamoxifen 20mg + prometrium 300mg PO daily (arm 3), between diagnosis of breast cancer and definite surgery.
Australian Clinical Trials Registry: ACTRN1261800092813
1. Primary Endpoint
The geometric mean suppression of the centrally assessed proliferation marker Ki67, compared with baseline. Obtained by comparing the mean difference in Ki67 staining between pre and post-treated samples.
2. Secondary Endpoint
Safety and tolerability of combination therapy (NCI-CTCAE v4.0)
3. Translational Endpoints
Define a gene set as a predictive biomarker for a reduction in Ki67, evaluate changes in the apoptotic markers Bcl-2 and Caspase 3 and evaluate changes in ER, PR, AR, FoxA1, Cyclin D1 protein and mRNA expression.
The IMPACT study reported a geometric mean reduction in Ki67 after 2 weeks of preoperative tamoxifen of 59.5% and anastrazole of 76% (Dowsett et al, JNCI 2007). 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. For the third possible comparison of Arm 2 vs Arm 3, there is no prior evidence, therefore this as a purely exploratory comparison. With a total 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.
Present: 7 (1 site open)
Target: 200 (8 sites total)