Oncology Abstracts

Background: Published preclinical findings from our lab (Cambridge Institute, CRUK) provided new insights into the functional ‘cross-talk’ between the oestrogen receptor alpha (ERα) and the progesterone receptor (PR) in breast cancer (Mohammed et al., Nature, 2015). Addition of a PR agonist to anti-oestrogens directly modifies ERα chromatin binding and the transcriptional response in breast cancer cells, and is anti-proliferative in vitro and in vivo.

PIONEER Clinical 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 Megestrol Acetate (MA, an off-patent semi-synthetic derivative of progesterone) 40 mg, or LET plus MA 160 mg in postmenopausal women with newly diagnosed, ER+ HER2- invasive primary breast cancer. >60 patients have been recruited in Cambridge, London (Guys and St Thomas’ and St Bart’s), Cornwall, Belfast, Bristol and Birmingham, with 3 other UK sites in active set up. 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 AR/PR/EMT markers by IHC; and safety endpoints. Exploratory endpoints include: transcription factor mapping (ChIP-seq) on paired fresh-frozen tumour samples. 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 (40 mg vs 160 mg). Primary endpoint data and correlative ChIP-seq findings for an initial cohort of recruited patients will be presented.

Preclinical work: Other novel, more potent progestins are also being characterised in the lab, including Trimegestone (EC214), in cell lines, as well as ex vivo (PDX and primary tumour explants) and in vivo models. The role of progestins in the setting of the most common ESR1 mutations (Y537S and D538G) is also being explored preclinically using CRISPR-derived MCF7 and T47D mutant clones. Growth data in these cell lines after treatment with a panel of progestins will be presented, as well as ERα and PR ChIP-seq data, as well as plans for in vivo work with cell line xenograft models (in collaboration with Simak Ali).