Clinical trial NCT03906669: 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.
Official title: A Window of Opportunity Study of Endocrine Therapy With and Without Prometrium in Postmenopausal Women With Early Stage Hormone Receptor-positive Breast Cancer.
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Early-stage Breast Cancer
Hormone Receptor Positive Tumor
Keywords: early stage breast cancer
prometrium
progesterone
post-menopausal
endocrine therapy
Lead sponsor: St Vincent's Hospital
Sponsor class: OTHER
First posted: 2019-04-08
Enrollment: 200
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility criteria: 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

Primary outcomes:
measure: Geometric mean suppression of proliferation marker Ki67
timeFrame: After two weeks of intervention, compared with baseline
Secondary outcomes:
measure: Safety and tolerability: number of participants with treatment-related adverse events as assessed by CTCAE v4.0
timeFrame: 2 years
Other outcomes:
measure: Define a gene set as a predictive biomarker for a reduction in Ki67
timeFrame: 4 years
measure: Evaluate changes in the apoptotic markers Bcl-2 and Caspase 3 in the tumors following intervention
timeFrame: 4 years
measure: Evaluate changes in ER, PR, AR, FoxA1, Cyclin D1 protein and mRNA expression in the tumors following intervention
timeFrame: 4 years
Locations:
city: Sydney
country: Australia
facility: St Vincent's Hospital
state: New South Wales
Study officials:
affiliation: Garvan Research Institute
name: Elgene Lim, MBBS FRACP PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Mohammed H, Russell IA, Stark R, Rueda OM, Hickey TE, Tarulli GA, Serandour AA, Birrell SN, Bruna A, Saadi A, Menon S, Hadfield J, Pugh M, Raj GV, Brown GD, D'Santos C, Robinson JL, Silva G, Launchbury R, Perou CM, Stingl J, Caldas C, Tilley WD, Carroll JS. Progesterone receptor modulates ERalpha action in breast cancer. Nature. 2015 Jul 16;523(7560):313-7. doi: 10.1038/nature14583. Epub 2015 Jul 8.
citation: Lim E, Tarulli G, Portman N, Hickey TE, Tilley WD, Palmieri C. Pushing estrogen receptor around in breast cancer. Endocr Relat Cancer. 2016 Dec;23(12):T227-T241. doi: 10.1530/ERC-16-0427. Epub 2016 Oct 11.