SummaryBreast cancer (BC) remains a primary cause of cancer-related illness and death among women worldwide. Molecular biomarkers have been proposed as valuable tools for the early identification and improved risk assessment of both BC. Recent research has highlighted several blood-based protein biomarkers that could improve the identification of individuals at high risk for BC screening. These proteins are suggested to have a possible causal link to BC risk, making them potentially useful for predicting BC risk and facilitating early screening efforts. However, only a handful of these protein biomarkers have demonstrated promising re-sults in detecting asymptomatic BC. Recent advances in proteomics technology have opened new avenues for comprehensive proteomic profil-ing, which may provide an exceptional opportunity to discover protein signatures that perform well in early detection and risk prediction of BC. By utilizing baseline samples from the female BC cases detected during the first follow-up (after 2-years) of the large-scale prospective German Nationale Kohorte (NAKO) Health Study, we aim to identify, as well as evaluate the relevance of protein biomarkers assessed closer to the point of cancer diagnosis for early detection of asymptomatic disease. A nested case-control study will be use as it is an efficient design for biomarker discovery within large prospective cohorts and it leverages pre-diagnosis samples, reducing costs while maintaining the advantages of a cohort study. Cases will be wom-en who develop incident breast cancer during follow-up, while three controls will be randomly selected from women who have no history of cancer and are cancer-free at the time of case diagnosis. Incident BC cases will be based on data from the German cancer registries. To ensure that controls represent the exposure distribution in the risk set, controls will be identified at each case's diagnosis timepoint, matched by age at blood draw (+/-2 years). Based on the recent BC incident rates in Germany, as reported by the Robert Koch Institute, we estimate that in the age groups 40 – 70 years, there will be 201 incident cases of female BC available for analysis in this project. The total number of controls will be 3*201=603. The proposed study will require a total of 100 µL of plasma for BC cases and controls and related covariate data from a total of 804 female participants from the NAKO study. With this data, we aim to achieve the following research objectives: 1. To identify the most promising protein marker signature for early detection and risk stratification of BC. 2. To externally validate the identified protein signature for early detection and risk stratification of BC in the UK Biobank cohort.

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InstitutionsDeutsches Krebsforschungszentrum, German Cancer Research Center (DKFZ), German Cancer Research Center