Identification of genetic alterations associated with primary resistance to EGFR-TKIs in advanced non-small-cell lung cancer patients with EGFR sensitive mutations.

Abstract

BACKGROUND:

Identification of activated epidermal growth factor receptor (EGFR) mutations and application of EGFR-tyrosine kinase inhibitors (EGFR-TKIs) have greatly changed the therapeutic strategies of non-small-cell lung cancer (NSCLC). However, the long-term efficacy of EGFR-TKI therapy is limited due to the development of drug resistance. The aim of this study was to investigate the correlation between the aberrant alterations of 8 driver genes and the primary resistance to EGFR-TKIs in advanced NSCLC patients with activated EGFR mutations.

METHODS:

We retrospectively reviewed the clinical data from 416 patients with stage III/IV or recurrent NSCLC who received an initial EGFR-TKI treatment, from April 2004 and March 2011, at the Sun Yat-sen University Cancer Center. Several genetic alterations associated with the efficacy of EGFR-TKIs, including the alterations in BIM, ALK, KRAS, PIK3CA, PTEN, MET, IGF1R, and ROS1, were detected by the routine clinical technologies. The progression-free survival (PFS) and overall survival (OS) were compared between different groups using Kaplan-Meier survival analysis with the log-rank test. A Cox regression model was used to estimate multivariable-adjusted hazard ratios (HRs) and their 95% confidence intervals (95% CIs) associated with the PFS and OS.

RESULTS:

Among the investigated patients, 169 NSCLC patients harbored EGFR-sensitive mutations. EGFR-mutant patients having PTEN deletion had a shorter PFS and OS than those with intact PTEN (P = 0.003 for PFS, and P = 0.034 for OS). In the combined molecular analysis of EGFR signaling pathway and resistance genes, we found that EGFR-mutant patients coexisted with aberrant alterations in EGFR signaling pathway and those having resistant genes had a statistically poorer PFS than those without such alterations (P < 0.001). A Cox proportional regression model determined that PTEN deletion (HR = 4.29,95% CI = 1.72-10.70) and low PTEN expression (HR = 1.96, 95% CI = 1.22-3.13), MET FISH + (HR = 2.83,95% CI = 1.37-5.86) were independent predictors for PFS in patients with EGFR-TKI treatment after adjustment for multiple factor.

CONCLUSIONS:

We determined that the coexistence of genetic alterations in cancer genes may explain primary resistance to EGFR-TKIs.

• Authors: Fang Wang, Xia-Yao Diao, Xiao Zhang, Qiong Shao, Yan-Fen Feng, Xin An, Hai-Yun Wang
• Journal: Cancer communications (London, England) (Cancer Commun (Lond)) Vol. 39 Issue 1 Pg. 7 (03 02 2019) ISSN: 2523-3548 [Electronic] United States
• PMID: 30823937 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Protein Kinase Inhibitors
• Erlotinib Hydrochloride
• EGFR protein, human
• ErbB Receptors
• Gefitinib

Topics

• Antineoplastic Agents (therapeutic use)
• Carcinoma, Non-Small-Cell Lung (drug therapy, genetics)
• DNA Copy Number Variations
• Drug Resistance, Neoplasm (genetics)
• ErbB Receptors (antagonists & inhibitors, genetics)
• Erlotinib Hydrochloride (therapeutic use)
• Female
• Gefitinib (therapeutic use)
• Humans
• Kaplan-Meier Estimate
• Lung Neoplasms (drug therapy, genetics)
• Male
• Middle Aged
• Mutation
• Proportional Hazards Models
• Protein Kinase Inhibitors (therapeutic use)