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Cancer Commun (Lond). 2019 Mar 2;39(1):7. doi: 10.1186/s40880-019-0354-z.

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

Author information

1
State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, 510060, Guangdong, P.R. China. wangfang@sysucc.org.cn.
2
Department of Molecular Diagnostics, Sun Yat-sen University Cancer Center, No. 651 Dongfeng Road East, Guangzhou, 510060, Guangdong, P.R. China. wangfang@sysucc.org.cn.
3
Department of Urology, Sun Yat-sen Memorial Hospital, Guangzhou, 510120, Guangdong, P.R. China.
4
Department of Molecular Diagnostics, Sun Yat-sen University Cancer Center, No. 651 Dongfeng Road East, Guangzhou, 510060, Guangdong, P.R. China.
5
State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, 510060, Guangdong, P.R. China.
6
Department of Pathology, Sun Yat-sen University Cancer Center, Guangzhou, 510060, Guangdong, P.R. China.
7
Department of Medical Oncology, Sun Yat-sen University Cancer Center, Guangzhou, 510060, Guangdong, P.R. China.
8
State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, 510060, Guangdong, P.R. China. wanghy29@mail3.sysu.edu.cn.
9
Department of Molecular Diagnostics, Sun Yat-sen University Cancer Center, No. 651 Dongfeng Road East, Guangzhou, 510060, Guangdong, P.R. China. wanghy29@mail3.sysu.edu.cn.

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.

KEYWORDS:

Epidermal growth factor receptor; Non-small-cell lung cancer; Resistance; Tyrosine kinase inhibitors

PMID:
30823937
DOI:
10.1186/s40880-019-0354-z
Free PMC Article

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