Development of a multiomics pipeline to deliver a precision oncology approach in breast cancer

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Breast cancer is the most diagnosed, and leading cause of cancer-related mortality worldwide among women with an estimate of 2.3 million new cases in 2021. If diagnosed soon enough it is curable in 70-80% of patients with early stage, non-metastatic disease, but advanced forms that have metastasized to distant organs are considered incurable with current therapeutic options. The underlying aetiology of breast cancer represents a heterogeneous group of diseases classified across several histological/intrinsic subtypes alongside hormone receptor expression profiles. Approximately 10% of all breast cancers correlate with familial genetic predisposition and associated protein/metabolic reprogramming are regarded as primary expressed hallmarks of the disease. This reflects biomolecular changes underpinning the abnormal development of cell malignancy. These molecular characteristics have vital implications for detection and therapy. Thus, by understanding the combined biomolecular adaptations and new dependencies of breast cancer it is possible to bimolecularly classify subtypes of the disease and design disease subtype biomarkers and far more precise therapeutic strategies. Elements of this precision approach are already in action in the clinic, with tumour histology already being used to stratify the disease according to cellular architectural changes and any metastatic presence in lymph nodes. When combined with breast cancer susceptibility genes measurement (that can include BRCA1/2, Ki67, ATM, CHEK2, PALB2, PTEN, STK11 and TP53), alongside hormone receptor and HER2 status, it is possible to further stratify the disease in to the 5 main molecular types of the disease. But, with 19 subtypes of the disease known to exist, there is still a huge gap in our knowledge of how biomolecular changes translate up to pathophysiological presentation and further refinement of diagnostic and therapeutic practise. The multiomics approach (the combination of gene/protein/metabolite screening tools that analyse different layers of the chemistry pertained within the central dogma of molecular biology) is primed to make a step change in our understanding of how different subtypes of breast cancer are expressed and manifest within the body. By being able to documents the complex protein (proteomics) and metabolite (metabolomics) landscape present in different breast tumour samples it is possible to build exquisitely detailed molecular maps that highlight differentially expressed biomolecular pathways. From these pathways, not only can new hypotheses for new therapeutic targets begin to be developed, but, when combined with matched blood-based analyses, it is possible to develop far less invasive ways to detect and classify subtypes of breast cancer. Aims: The primary outcome of the study is to establish the differential biomolecular signatures of breast cancer subtypes as a function of tumor clinicopathologic parameters using tumor biopsy/serum samples in tandem with online omics data from the UK Biobank. This information will be used to establish whether stratification of breast tumors can be achieved using an untargeted mass spectrometry approach. Results will then be correlated to signatures from matched patient sera to determine if detectable circulating biomarkers can be used to define molecular tumors sub-phenotype without surgical biopsy. Project tissue samples will come from the UoS/NHS-L biobank and mass spectrometry analysis will be performed within the Strathclyde Centre for Molecular Biosciences.