Clonal Architecture ofEGFRMutation Predicts the Efficacy of EGFR-Tyrosine Kinase Inhibitors in Advanced NSCLC: A Prospective Multicenter Study (NCT03059641)

Abstract

Purpose: 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).Patients and Methods: 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.Results: Overall, 300 treatment-na€ ve patients with stage IIIB-IV NSCLC were recruited from 14 centers. Of the 94 patients with available ctDNA data for EGFR clonal architecture analysis, 72 (76.6%) showed EGFR as the dominant clone. The median progression-free survival was longer for these patients than for the 22 patients whose EGFR was nondominant clone [11 vs. 10 months; HR, 0.46; 95% confidence interval (CI), 0.24-0.88; P ¼ 0.02]. The difference was more significant if both tissue and ctDNA defined EGFR as dominant clone (n ¼ 43) versus those not (n ¼ 8; 11 vs. 6 months; HR, 0.13; 95% CI, 0.04-0.50; P ¼ 0.003). Moreover, multivariate Cox proportional HR analysis demonstrated EGFR clonal architecture as an independent prognostic indicator of the efficacy of EGFR-tyrosine kinase inhibitors (TKIs).Conclusions: Paired tissue and ctDNA could be analyzed for clonal architecture in advanced cancer. EGFR mutations do not always make up a dominant clone in advanced NSCLC, which was associated with the efficacy of EGFR-TKIs in NSCLC.

Genomic comparison between cerebrospinal fluid and primary tumor revealed the genetic events associated with brain metastasis in lung adenocarcinoma

“…At present, several studies had confirmed that EGFR targeted therapy dramatically improved the prognosis of patients with NSCLC BMs [ 36 , 37 ]. However, concomitant genetic alterations (such as CDKN2A copy number loss) [ 38 ] and the number of EGFR subclones [ 39 ] are associated with worse clinical outcomes in EGFR mutant NSCLC patients under TKIs treatment. In our study, CDKN2A loss and EGFR subclone number were frequently increased in EGFR -CSF patients, which might be one of the reasons for the poor prognosis of LUAD patients with BM.…”

Genetic and treatment profiles of patients with concurrent Epidermal Growth Factor Receptor (EGFR) and Anaplastic Lymphoma Kinase (ALK) mutations

“…The sensitivity and specificity of Nextseq CN500 were 100% when compared with HiSeq3000 and NovaSeq6000. It also shows good performance on clinical practice and research [ 23 , 24 ].…”

Pyrotinib Treatment in Patients With HER2-positive Metastatic Breast Cancer and Brain Metastasis: Exploratory Final Analysis of Real-World, Multicenter Data

“…Circulating tumor DNA (ctDNA) sequencing was used to calculate genetic mutation and tumor mutation burden (TMB). The TMB was calculated as the number of somatic nonsynonymous single-nucleotide variants (SNVs) and small insertions/deletions per megabase in the coding region ([mutations per megabase [mut/Mb]] with ≥ 0.005 for ctDNA) and by integrated mutation profiling testing of actionable cancer targets within the same gene panel in the samples from the Geneplus database [20][21][22] . The categorization of TMB-high and TMB-low was explained in the preceding paper 17 .…”