Early-stage Breast Cancer, Hormone Receptor Positive Tumor
Conditions
Keywords
early stage breast cancer, prometrium, progesterone, post-menopausal, endocrine therapy
Brief summary
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
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.
Interventions
DRUGLetrozole
PO daily for 14 days
DRUGLetrozole and Prometrium
PO daily for 14 days
DRUGTamoxifen and Prometrium
PO daily for 14 days
Sponsors
St Vincent's Hospital
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Geometric mean suppression of proliferation marker Ki67 | After two weeks of intervention, compared with baseline | The geometric mean suppression of the centrally assessed proliferation marker Ki67, after two weeks of intervention, compared with baseline |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Safety and tolerability: number of participants with treatment-related adverse events as assessed by CTCAE v4.0 | 2 years | Safety and tolerability of combination therapy (NCI-CTCAE v4.0) |
Other
| Measure | Time frame | Description |
|---|---|---|
| Define a gene set as a predictive biomarker for a reduction in Ki67 | 4 years | Expression of gene signature will be tested in the pre- and post-intervention tissues using the Nanostring nCounter system |
| Evaluate changes in the apoptotic markers Bcl-2 and Caspase 3 in the tumors following intervention | 4 years | Immunohistochemistry of the pre and post intervention tissue samples |
| Evaluate changes in ER, PR, AR, FoxA1, Cyclin D1 protein and mRNA expression in the tumors following intervention | 4 years | Immunohistochemistry of the pre and post intervention tissue samples |
Countries
Australia
Contacts
Primary ContactRobert Kent
Outcome results
None listed