A Window of Opportunity Study of Pre-operative Endocrine Therapy With and Without Prometrium in Postmenopausal Women With Early Stage Breast Hormone Receptor Positive (HR+) Human Epidermal Receptor 2 Negative (HER2-) Breast Cancer.

A Window of Opportunity Study of Endocrine Therapy With and Without Prometrium in Postmenopausal Women With Early Stage Hormone Receptor-positive Breast Cancer.

A phase II randomised, open label study of pre-operative endocrine therapy with & without prometrium in postmenopausal women with early stage breast hormone receptor positive (HR+) human epidermal receptor 2 negative (HER2-) breast cancer.

There is bidirectional interplay between the progesterone receptor (PR) and oestrogen receptor (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 2.5mg 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 definitive surgery.

Inclusion Criteria:

1. Histologically confirmed ER+ and PR+ breast cancer (defined as ≥10% positive staining cells)
2. Histologically confirmed HER2-negative breast cancer (defined as IHC 0-1 and/or FISH/CISH <2.2)
3. Tumour size ≥1 cm as measured by ultrasound and/or mammogram
4. Ability to understand all patient information and informed-consent documents, written informed consent to participate in the trial, and to avail tissue and blood samples for research
5. Aged 18 years or older

Exclusion Criteria:

1. Women currently on hormone therapies, including hormone replacement therapy and oral contraceptive pill
2. Locally advanced/inoperable and inflammatory breast cancer
3. Planned for a mastectomy (due to increased risk of venous thromboembolism)
4. Clinical evidence of metastatic disease
5. Patients treated with other preoperative systemic therapies
6. Nut allergy (prometrium contains peanut oil)
7. Prior history of uterine cancer, deep vein thrombosis, pulmonary embolism or clotting disorder
8. Women who are pregnant or breast-feeding