Tumor volume determines the feasibility of cell-free DNA sequencing for mutation detection in non–small cell lung cancer

Summary

Next-generation sequencing (NGS) and digital polymerase chain reaction (PCR) technologies allow analysis of the mutational profile of circulating cell-free DNA (cfDNA) in individuals with advanced lung cancer. We have now evaluated the feasibility of cfDNA sequencing for mutation detection in patients with non–small cell lung cancer (NSCLC) at earlier stages. A total of 150 matched tumor and serum samples were collected from NSCLC patients at stages IA–IIIA. Amplicon sequencing with DNA extracted from tumor tissue detected frequent mutations in EGFR (37% of patients), TP53 (39%), and KRAS (10%), consistent with previous findings. In contrast, NGS of cfDNA identified only EGFR, TP53, and PIK3CA mutations in three, five, and one patients, respectively, even though adequate amounts of cfDNA were extracted (median of 4,936 copies per milliliter of serum). NGS showed a high accuracy (98.8%) compared with droplet digital PCR for cfDNA mutation detection, suggesting that the low frequency of mutations in cfDNA was not due to a low assay sensitivity. Whereas the yield of cfDNA did not differ among tumor stages, the cfDNA mutations were detected in seven patients at stages IIA–IIIA and at T2b or T3. Tumor volume was significantly higher in the cfDNA mutation–positive patients than in the negative patients at stages T2b–T4 (159.1 ± 58.0 versus 52.5 ± 9.9 cm³, p = 0.014). Our results thus suggest that tumor volume is a determinant of the feasibility of mutation detection with cfDNA as the analyte.

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