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.

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

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

Conditions
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Early-stage Breast Cancer, Hormone Receptor Positive Tumor

Intervention / Treatment
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* Drug: Letrozole
* Drug: Letrozole and Prometrium
* Drug: Tamoxifen and Prometrium


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed ER+ and PR+ breast cancer (defined as ≥10% positive staining cells) Histologically confirmed HER2-negative breast cancer (defined as IHC 0-1 and/or FISH/CISH <2.2) Tumour size ≥1 cm as measured by ultrasound and/or mammogram 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 Aged 18 years or older Exclusion Criteria: Women currently on hormone therapies, including hormone replacement therapy and oral contraceptive pill Locally advanced/inoperable and inflammatory breast cancer Planned for a mastectomy (due to increased risk of venous thromboembolism) Clinical evidence of metastatic disease Patients treated with other preoperative systemic therapies Nut allergy (prometrium contains peanut oil) Prior history of uterine cancer, deep vein thrombosis, pulmonary embolism or clotting disorder Women who are pregnant or breast-feeding

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Letrozole<br>Letrozole 2.5mg PO daily for 14 days between diagnosis of breast cancer and definite surgery | Drug: Letrozole<br>* PO daily for 14 days<br>|
| Experimental: Letrozole and Prometrium<br>Letrozole 2.5mg PO daily and Prometrium 300mg PO daily for 14 days between diagnosis of breast cancer and definite surgery | Drug: Letrozole and Prometrium<br>* PO daily for 14 days<br>|
| Experimental: Tamoxifen and Prometrium<br>Tamoxifen 20mg PO daily and Prometrium 300mg PO daily for 14 days between diagnosis of breast cancer and definite surgery | Drug: Tamoxifen and Prometrium<br>* PO daily for 14 days<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Geometric mean suppression of proliferation marker Ki67 | The geometric mean suppression of the centrally assessed proliferation marker Ki67, after two weeks of intervention, compared with baseline | After two weeks of intervention, compared with baseline | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety and tolerability: number of participants with treatment-related adverse events as assessed by CTCAE v4.0 | Safety and tolerability of combination therapy (NCI-CTCAE v4.0) | 2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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prometrium, early stage breast cancer, progesterone, post-menopausal, endocrine therapy