Importance There has been great enthusiasm for the emerging technology of molecular-based tests to detect and quantify tumor DNA circulating in the bloodstream, colloquially known as a liquid biopsy. However, less attention has been given to how their clinical utility depends on the indication for testing, which includes a range of clinical situations, each presenting unique challenges.Observations Five indications for circulating tumor DNA (ctDNA) blood testing were considered. (1) For therapy selection, ctDNA tests can identify genetic alterations in patients with cancer amenable to targeted therapy, but most patients do not have a targetable alteration. (2) For response to therapy, the absence of residual tumor DNA following cancer surgery could reduce the use of adjuvant chemotherapy, but it is unclear that this will happen in practice. (3) For disease surveillance following cancer treatment, ctDNA tests may well detect cancer recurrence before symptoms appear, yet earlier intervention may have no effect on mortality. (4) For diagnosis of suspected cancer, ctDNA tests are able to identify some symptomatic cancers, but how they add to the conventional diagnostic evaluation is unknown. (5) For screening for cancer, multicancer tests can detect many types of cancer, but their low sensitivity for early-stage tumors raises questions as to whether screening can help patients live longer or live better.Conclusions and Relevance Circulating tumor DNA tests are being promoted for multiple indications. Numerous studies are ongoing, but randomized clinical trials of their effect on patient-centered outcomes are rare. While these tests have the potential to improve care in selected indications, this must be proven, as they will add cost, complexity, and unintended adverse effects for patients.
