Our study has several limitations: (1) we have a relatively small cohort of patients; (2) as mentioned, we lack sufficient matched primary tumor tissue biopsies for comparison; and (3) we did not perform paired leukocyte DNA sequencing thus we could not fully exclude that TP53 mutations were derived from leukocyte DNA, because somatic variants in TP53 found in ctDNA could be derived from clonal hematopoiesis [50,51]; (4) the ctDNA panel that we used is limited and does not contain all known actionable somatic alterations (e.g. mutation in TSC1/TSC2, amplification in EGFR and MET). Here, TSC1 is linked to neoplasm.