Abstract
Clonal architecture is fundamental for the understanding of cancer biology and therapy; however, multiregional sampling in advanced-stage cancers is not always applicable. This prospective clinical trial was to investigate whether paired tissue and circulating tumor DNA (ctDNA) could describe the clonal architecture of advanced non-small cell lung cancer (NSCLC) and its association with clinical outcome (NCT03059641).
Paired tumor and plasma ctDNA samples were sequenced by target-capture deep sequencing of 1,021 genes. Clonal dominance analysis was performed on the basis of PyClone.
Overall, 300 treatment-naïve patients with stage IIIB-IV NSCLC were recruited from 14 centers. Of the 94 patients with available ctDNA data for
clonal architecture analysis, 72 (76.6%) showed
as the dominant clone. The median progression-free survival was longer for these patients than for the 22 patients whose
was nondominant clone [11 vs. 10 months; HR, 0.46; 95% confidence interval (CI), 0.24-0.88;
= 0.02]. The difference was more significant if both tissue and ctDNA defined
as dominant clone (
= 43) versus those not (
= 8; 11 vs. 6 months; HR, 0.13; 95% CI, 0.04-0.50;
= 0.003). Moreover, multivariate Cox proportional HR analysis demonstrated
clonal architecture as an independent prognostic indicator of the efficacy of EGFR-tyrosine kinase inhibitors (TKIs).
Paired tissue and ctDNA could be analyzed for clonal architecture in advanced cancer.
mutations do not always make up a dominant clone in advanced NSCLC, which was associated with the efficacy of EGFR-TKIs in NSCLC.