213TiPPIONEER- Pre-operative wIndOw study of letrozole plus PR agonist megestrol acetate versus letrozole aloNE in post-menopausal patients with ER-positive breast cancer

Background: Recent preclinical findings have been published which provide new insights into the functional cross-talk between the estrogen receptor (ER) and the progesterone receptor (PR) in breast cancer (Mohammed et al., Nature, 2015). Addition of a PR agonist to anti-estrogens directly modifies ERa chromatin binding and the transcriptional response in breast cancer cells, and is anti-proliferative in vitro and in vivo. Megestrol Acetate (MA), an off-patent semi-synthetic derivative of progesterone, has been licensed for many years as a treatment for ER+ metastatic breast cancer. There is also good evidence for the effectiveness of MA as a supportive therapy to ameliorate endocrine therapy-related hot flushes. Trial design: PIONEER is a three-arm, open label, multi-centre randomised phase II pre-surgical window trial evaluating effects of 15 days of preoperative therapy with Letrozole (LET), or LET plus MA 40mg, or LET plus MA 160mg in postmenopausal women with newly diagnosed, ER+ HER2- invasive primary breast cancer. Patients are being recruited in Cambridge, with 5-6 other UK sites due to open in q3/4 2017.Table213TiP 3-arm randomisationArm ALET 2.5mg dailyArm BLET 2.5mg daily + MA 40mg dailyArm CLET 2.5mg daily + MA 160mg daily Open table in a new tab The primary endpoint is % change in proliferation between baseline and day 15 tumour biopsies, measured by Ki67 immunohistochemical (IHC) assessment. Secondary endpoints include: expression of Aurora Kinase A, Caspase 3 and Androgen receptor/PR/EMT markers by IHC; and safety endpoints. Exploratory endpoints include: transcription factor mapping (ChIP-seq) on paired fresh-frozen tumour samples. Patients are randomised in a 1: 1.5: 1.5 ratio for arms A: B: C. Based on results from previous clinical trials, a mean 66% reduction in Ki67 is anticipated for LET alone (arm A), and a 77.5% reduction for combination arms B and C, based on preclinical data. A recruitment total of 189 patients is required. Pioneer will help determine if there is value in conducting a follow-on adjuvant study to investigate the longer term benefit of combining an aromatase inhibitor with MA, and if so, at what dose (40mg vs. 160mg). Clinical trial identification: EudraCT Number: 2016-003752-79 MHRA/REC number: v2.0 5th June 2017 Legal entity responsible for the study: Cambridge University Hospitals NHS Foundation Trust and the University of Cambridge Funding: Anticancer Fund Disclosure: All authors have declared no conflicts of interest.