Liquid biopsies represent a transformation in the management of cancer as they have the potential to detect, characterize, and monitor cancers earlier than can be achieved with conventional diagnostic modalities. Specifically, analyses of circulating tumor DNA have shown promise in capturing tumor burden dynamics during therapeutic intervention, with the potential to allow patients with primary resistance to be rapidly identified and redirected to alternative therapies. However, cell-free DNA-based alterations can be derived from the tumor, germline, or may be associated with clonal hematopoiesis, which can confound non-invasive tumor profiling, molecular response assessment, and clonal evolution analyses through inaccurate variant classification.