Genomic alterations in circulating tumor DNA from diverse cancer patients identified by next-generation sequencing

Non-invasive genomic profiling of tumors may be possible with next-generation sequencing (NGS) of blood-derived circulating tumor DNA (ctDNA), but proof of concept in a large cohort

of patients with diverse cancers has yet to be reported. Here we report the results of an analysis of plasma-derived ctDNA from 670 patients with diverse cancers.

The tumors represented in the patient cohort were mainly gastrointestinal (31.8%), brain (22.7%) or lung (20.7%). ctDNA obtained from most patients (N = 423 (63%)) displayed at least 1 alteration. The most frequent alterations seen, as characterized mutations or variations of unknown significance, occurred in TP53 (32.5% of patients), EGFR (13%), KRAS (12.5%) and PIK3CA (9.1%); for characterized alterations, 30.7% (TP53), 7.6% (EGFR), 12.2% (KRAS), and 7.7% (PIK3CA). We found that 32% of brain tumors had at least 1 ctDNA alteration. Head and neck tumors were independently associated with a higher number of alterations in a multivariable analysis (P=0.019). Notably, 320/670 (48%) of patients displayed potentially actionable alterations with 241 patients possible candidates for on-label or off-label treatment with an FDA-approved drug. Several illustrations of the clinical utility of the information obtained for improving treatment of specific patients is provided. Our findings demonstrate the feasibility and impact of genomic profiling of tumors by ctDNA next-generation sequencing, greatly encouraging broader investigations of the application of this technology for precision medicine in cancer management.

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