Novel biomarkers in the risk stratification, surveillance and treatment of young breast cancer patients and germline carriers of pathogenic variants in TP53.

With the expanding therapeutic options in early breast cancer, there is an urgent need for more precise prognostic and predictive biomarkers. Emerging evidence reveals that adaptations of cellular metabolism in cancer determine therapy resistance, and that plasma and tissue metabolite signatures offer potential as biomarkers to predict therapy response and disease outcome. We will evaluate the metabolomics profile of a large cohort of early breast cancer patients and correlate this with treatment response and long-term outcome with the goal to develop a metabolomics signature on liquid biopsy as a prognostic and predictive biomarker in early breast cancer. In individuals with a hereditary cancer syndrome with high penetrance for various cancer types such as carriers of germline pathogenic TP53 variants (Li-Fraumeni syndrome), there is an urgent need for more accurate variant-specific risk prediction and for more prospective data on cancer surveillance programs. New early cancer detection methods based on genome-wide imbalances in copy number alterations in plasma cell-free DNA (cfDNA) have, combined with cfDNA methylation profiling, the additional potential of tracing the organ of origin and could therefore become a highly relevant emerging screening modality in this population. We propose a national prospective observational study in germline carriers of pathogenic TP53 variants. In the context of this observational trial, a national registry for this population will be established. Moreover, we offer optional participation to an interventional part that consists of longitudinal cfDNA sampling and assessment of the individual carrier TP53 variant pathogenicity by performing a functional p53 assay based on lymphocyte cultures for the evaluation of protein function in response to genotoxic stress. The aim of the interventional part is to evaluate new early detection techniques and knowledge of genotype-phenotype relationship in this high-risk population. In young breast cancer patients, we need to better understand the specific clinical and histopathological characteristics, patterns of care and outcomes according to age at diagnosis and hereditability. In patients with familial breast cancer without known monogenetic breast cancer susceptibility, there are important uncertainties with regard to risk stratification that have major impact on patient surveillance. Recently, polygenic risk scores (PRS) have been found to explain a significant part of the familial breast cancer risk, but it is unknown what the relation is between PRS and age of breast cancer onset. We plan a large international retrospective hospital-based study to address these questions. With this combination of work packages, we aim to address several relevant basic, translational and clinical research objectives in the context of this PhD project.