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Clonal Architecture of EGFR Mutation Predicts the Efficacy of EGFR-Tyrosine Kinase Inhibitors in Advanced NSCLC: A Prospective Multicenter Study
55 Pages Posted: 18 Aug 2020
More...Abstract
Background: Although EGFR mutations in lung cancer are identified most often as trunk mutations in the early stage, cancer evolution often follows a branched trajectory. Whether EGFR would always be the dominant clone in the advanced stage is unknown.
Methods: This prospective multicenter clinical trial recruited treatment naïve patients with stage IIIB-IV non–small cell lung cancer from 14 centers in China. Paired tumor and plasma ctDNA samples were sequenced by target-capture deep sequencing of 1021 genes. Clonal dominance analysis was performed on the basis of PyClone.
Findings: Overall, 300 patients were recruited and 132 patients treated with first line targeted therapy were followed. The median follow-up time was 10 months (IQR 6–13). Of the 94 patients with available ctDNA data for EGFR clonal architecture analysis, 72 (76.6%) showed EGFR as the dominant clone. The mPFS was longer for these patients than for the 22 patients who had EGFR non-dominant clone (11 months vs 10 months, hazard ratio [HR] 0.46, 95% CI 0.24–0.88, p = 0.02). The difference was more significant if patients who were defined as having EGFR dominant clone by both tumor tissue and plasma (n = 43) versus those not (n = 8) (11 vs 6 months, HR = 0.13, 95% CI 0.04–0.50, p = 0.003). Moreover, multivariate cox proportional hazard ratio analysis demonstrated EGFR clonal architecture as an independent prognostic indicator of the efficacy of EGFR-tyrosine kinase inhibitors.
Interpretation: In advanced NSCLC,EGFR mutations do not always make up a dominant clone. Clonal architecture of EGFR in the pretreatment ctDNA is associated with the efficacy of EGFR-TKIs in NSCLC.
Trial Registration: The trial has been registered with the number NCT03059641.
Funding Statement: Geneplus-Beijing Co. Ltd.
Declaration of Interests: RC, PL, LC and XY were employees of Geneplus-Beijing Co. Ltd. All other authors declare no conflict of interests.
Ethics Approval Statement: This study was performed under a protocol (KS1707) approved by the Institutional Review Board of Shanghai Chest hospital (Shanghai, China).
Keywords: clonal architecture, EGFR, NSCLC, ctDNA
Suggested Citation: Suggested Citation