Abstract OT1-01-03: The WinPro study: A window of opportunity study of endocrine therapy with and without prometrium in postmenopausal women with early stage hormone receptor-positive breast cancer
Authors: Carson E , Segara D , Parker A , O'Toole S , Coates A , Mann B , Lindeman G , Tilley W , Lim E 
Published: May 2019

Abstract
Background
There is bidirectional interplay between PR and ER in human 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 estrogen plus progestogen compared to estrogen 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.
Trial Design
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
Eligibility Criteria
Inclusion Criteria
a) Histologically confirmed ER+ and PR+ breast cancers (≥10% positive staining cells)
b) HER2/CEP17 ratio of &lt;2 and mean HER2 copy number &lt;6 (ASCO CAP 2013 guidelines)
c) Tumour size ≥1cm on ultrasound and/or mammogram
d) Aged ≥18 years
Exclusion Criteria
a) Currently on hormone therapies (HRT and OCP)
b) Locally advanced/inoperable and inflammatory breast cancer
c) Clinical evidence of metastatic disease
d) Received other preoperative systemic therapies
e) Nut allergy (prometrium contains peanut oil)
f) Prior history of uterine cancer, deep vein thrombosis, pulmonary embolism or clotting disorder
g) Women who are pregnant/breast feeding
Specific Aims
a) Primary Endpoint
The geometric mean suppression of the centrally assessed proliferation marker Ki67, after two weeks of intervention, compared with baseline. This will be obtained by comparing the mean difference in Ki67 staining between pre and post-treated samples in each intervention arm.
b) Secondary Endpoint
Safety and tolerability of combination therapy (NCI-CTCAE v4.0)
c) Translational Endpoints
1. Define a gene set as a predictive biomarker for a reduction in Ki67
2. Evaluate changes in the apoptotic markers Bcl-2 and Caspase 3 in the tumors following intervention
3. Evaluate changes in ER, PR, AR, FoxA1, Cyclin D1 protein and mRNA expression in the tumors following intervention
Statistical Methods
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 trial 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.
Accrual
Present: 5 (1 site open)
Target: 200 (8 sites total)
Contact Information
Elgene Lim, MBBS, FRACP, PhD. e.lim@garvan.com.au
Citation Format: Carson E, Segara D, Parker A, O'Toole S, Coates A, Mann B, Lindeman G, Tilley W, Lim E. The WinPro study: A window of opportunity study of endocrine therapy with and without prometrium in postmenopausal women with early stage hormone receptor-positive breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr OT1-01-03.