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Circulating tumor DNA (ctDNA), accurately described by the term liquid profiling (LP), enables real-time assessment of the tumor mutational profile as a minimally invasive test and has therefore rapidly gained traction, particular for the management of cancer patients. By LP, tumor-specific genetic alterations can be determined as part of companion diagnostics to guide selection of appropriate targeted therapeutics. Because LP facilitates longitudinal monitoring of cancer patients, it can be used to detect acquired resistant mechanisms or as a personalized biomarker for earlier detection of disease recurrence, among other applications. However, LP is not yet integrated into routine care to the extent that might be expected. This is due to the lack of harmonization and standardization of preanalytical and analytical workflows, the lack of proper quality controls, limited evidence of its clinical utility, heterogenous study results, the uncertainty of clinicians regarding the value and appropriate indications for LP and its interpretation, and finally, the lack of reimbursement for most LP tests. In this review, the value proposition of LP for cancer patient management and treatment optimization, the current status of implementation in standard care, and the main challenges that need to be overcome are discussed in detail.

The liquid profiling approach is currently at the threshold of translation from research application in various clinical trials to introduction into the management of cancer patients in the context of clinical care. Routine application has focused primarily on the analysis of single blood-based biomarkers for companion diagnostics. However, liquid profiling promises much broader diagnostic potential, which is discussed and illustrated in this manuscript through several case reports. These clinical cases range from identification of druggable targets to the detection of subclonal resistance mechanisms. In addition, liquid profiling can be used in clinical practice to identify complex molecular patterns or as a personalized tumor marker for patient-specific monitoring of response to treatment. These examples highlight both the value and limitations of liquid profiling in various clinical settings, which could be overcome by an integrative diagnostic approach with imaging techniques. The complementary advantages of both diagnostics approaches will allow combining high sensitivity with genetic tumor profiling and topologic assignment. Therefore, we advocate interdisciplinary integrated collaboration between laboratory and imaging experts to unravel the potentials of precision diagnostics in cancer care.