Three new disease-progression modes in NSCLC patients after EGFR-TKI treatment by next-generation sequencing analysis

Most non-small-cell lung cancer (NSCLC) patients who exhibit good clinical responses to EGFR-tyrosine kinase inhibitors (EGFR-TKIs) will inevitably develop disease progression. Herein, through next-generation sequencing (NGS), we aimed to investigate three new disease-progression modes of NSCLC patients after EGFR-TKI treatment.

Patients with sensitive EGFR-mutations who acquired resistance to EGFR-TKIs and whose tissues were subjected to post-progression NGS were enrolled. The clinical characteristics, progression-free survival (PFS), genomic alterations and expression of EGFR-mutations among the three disease-progression modes were retrospectively analyzed.

The sites of disease progression were as follows: primary foci in 19.5% (8/41) (Mode 1), metastatic foci in 31.7% (13/41) (Mode 2), and both primary and metastatic foci in 48.8% (20/41) (Mode 3). The median PFS in Mode 1 was 6 months (95% CI 1-8), which was significantly shorter than the 11 months (95% CI 8-14) in Mode 2 and the 10 months (95% CI 3-16) in Mode 3 (p = 0.0084). The expression of Del19 was significantly different among the three modes (p = 0.02). The numbers and species of mutant genes in Mode 3 were obviously greater than those in Modes 1 and 2, and no gene amplifications were observed in Mode 2. Mutations in the TP53 gene were the most frequent genetic alteration found in our study, and these accounted for 48.8% (20/41) of all alterations. TP53 mutations in Mode 1 were mainly in exons 6 and 8, while in Mode 2 and Mode 3, all mutations were located from exon 4 to exon 8. A significant benefit in PFS was observed in the metastatic foci progression mode and in the dual primary and metastatic foci progression mode rather than in the primary foci progression mode, which had significant value in the design of therapeutic strategies.