212 Chapter 8 Figure 1: Roadmap indicating the state of readiness for the integration of blood- and urine-based liquid biopsy tests into clinical practice using five navigators in the translational research phase. Urine-based tests developed in this thesis are marked in the context of blood-based multi-cancer early detection tests developed by large consortia and biotech companies and the blood-based FDA-approved Cobas® EGFR Mutation Test v2. Partly adapted from IJzerman et al (11). Created with BioRender.com. The FDA-approved Cobas® EGFR Mutation Test v2 (12) is an example of an implemented liquid biopsy test. This PCR-based test is currently used as a diagnostic test to detect targetable EGFR mutations in NSCLC patients and guide therapy selection. At present, blood-based multi-cancer early detection tests are being developed by large consortia and biotech companies, such as the GRAIL Galleri (13) and CancerSEEK tests (14). The GRAIL Galleri test is also based on the targeted methylation analysis of cfDNA, whereas the CancerSEEK test evaluates the presence of mutations and elevated cancerassociated protein levels. While the clinical potential of multi-cancer early detection tests is evident, there is a need for further improvements to realize their ultimate goal of early cancer detection. Both the GRAIL Galleri and CancerSEEK tests lack sensitivity, particularly for the detection of early-stage cancers (13, 15, 16). Toward implementation of patient-friendly cancer detection methods in routine clinical practice • Biomarker testing in patient-friendly samples could be valuable to detect primary and recurrent cancer early, alleviate stringent routine follow-up regimens, and restrict invasive procedures to individuals with a high cancer risk. • Current work shows technical feasibility and marks the starting point for the continued development of urine-based cancer detection methods. 8.2 Challenges of cancer-specific DNA methylation marker testing in urine Work presented in this thesis underlines the high clinical potential of urine as a liquid biopsy for different cancer types, including endometrial (Chapters 2 to 4), ovarian (Chapter 5), and lung cancer (Chapters 6 and 7). Urine offers an attractive sample type for diagnostics,
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