Tamoxifen prevents breast cancer in some high-risk women but not others, and a new study will dissect the biological differences between those who respond and those who do not. Breast cancer is the leading cause of death in UK women aged 35–64. Tamoxifen reduces incidence but does not cut mortality, and it fails entirely against oestrogen-receptor-negative tumours. The researchers have already identified that some women’s breast tissue shows reduced cell proliferation on tamoxifen, while others are resistant. This project aims to uncover the mechanisms driving that resistance. The team will analyse matched tissue biopsies taken before and after three months of tamoxifen from 12 women—six responders and six non-responders. They will combine X-ray imaging, spatial proteomics, mass cytometry, and gene-expression mapping, then use machine learning to link tissue features to mammogram patterns in large datasets (57,000 and 140,000 women). They will also recruit new participants for fresh biopsies and single-cell analyses. If successful, the work could yield imaging or genomic biomarkers that predict tamoxifen response, and identify new drug targets for women who currently get no preventive benefit. This is translational research with a clear pathway toward a prospective validation study and, eventually, tailored prevention strategies.
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Background: Breast cancer (BC) is the leading cause of death in UK women aged 35-64. Women at increased risk are offered tamoxifen as prevention therapy, which reduces BC incidence. However, tamoxifen may not reduce BC mortality, and does not prevent oestrogen receptor negative cancers. Our Biomarkers of Breast Cancer Prevention (BBCP) study has identified differential epithelial responses to preventive tamoxifen therapy, with some women responding to tamoxifen with reduced proliferation, whilst others are resistant. We want to define the biological mechanisms behind these different responses and find novel prevention targets for women who are resistant to tamoxifen. Aims 1. Identify the biological features of resistance to preventive tamoxifen. 2. Determine how these features can be identified by mammographic imaging and genomic biomarkers. 3. Translate tamoxifen resistant biology into novel preventive approaches Methods: We will use existing samples and ongoing recruitment from BBCP. Premenopausal women at increased BC risk have a baseline vacuum assisted biopsy (VAB) prior to commencing preventive tamoxifen followed by contralateral VAB after 3 months. We will characterise 12 matched VAB pairs, 6 that respond (EResponse) and 6 resistant (EResist), by 2D X-ray projection, 3D X-ray microtomography (µCT), spatial proteomics, multiplexed imaging mass cytometry, and spatial transcriptomics. We will use machine learning to identify features within the breast that predict tamoxifen response. We will use Machine Learning to identify mammographic features that predict BC risk and response to preventive tamoxifen, including for BC subtypes. We will use training and validation datasets (PROCAS n=57,000 and Grampian n=140,000). Subgroup analyses will be performed at points of hormonal fluctuation; menopause and HRT use before evaluation in a dataset of n=240 premenopausal participants receiving tamoxifen in our prior studies. Oncoarray data will be used to explore associations between SNPs, mammogram features and tissue response. We will examine the transcriptional regulation of tamoxifen response in newly recruited participants to BBCP. Fresh samples will be subjected to ChIP-seq, qPLEX-RIME and single-cell ATAC-seq and retrospectively classified as EResponse or EResist. Potential gene regulatory networks will be verified on tissue samples using tissue microarray and RNAScope-based RNA-FISH analyses. Key transcriptional programmes, differentially regulated in EResist will be validated in explant culture in vitro. How this research will be used: Identification of biological markers of tamoxifen response will allow us to: - design a prospective cohort study to validate predictive biomarkers of tamoxifen response - develop novel strategies for BC prevention in those women resistant to tamoxifen.
Prevention and Population Research Committee - Project
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