Comprehensive characterization and clinical impact of concomitant genomic alterations in EGFR-mutant NSCLCs treated with EGFR kinase inhibitors.

Abstract

OBJECTIVES:

Although the majority of epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) patients respond to EGFR tyrosine kinase inhibitors (TKIs), significant heterogeneity in clinical response is observed which might be attributed to the distinct sub-molecular characteristics. The present study aims to identify genetic alterations correlated with clinical outcomes and treatment response to different EGFR-TKI inhibitors.

MATERIALS AND METHODS:

We integrated the genomic data and clinical outcomes including progression-free survival (PFS) and overall survival (OS) in 179 patients with advanced EGFR-mutant NSCLC who were treated with EGFR-TKI as 1st line of treatment.

RESULTS:

We found that EGFR-mutant patients harboring concomitant TP53 mutation (OS: 21 vs. 40 months, P = 0.05), ERBB2 amplification (PFS: 6.1 vs. 12.5 months, P = 0.01) or FGF19 amplification (OS: 11.2 vs. 27.1 months, P = 0.01) were significantly associated with a poorer clinical prognosis after treated with 1st generation EGFR-TKI. In contrast, the presence of TP53 mutation did not affect the PFS nor OS of patients treated with 2nd generation EGFR-TKI. Furthermore, EGFR-mutant and TP53-wild type (WT) patients benefited more from a combinatorial treatment consisting of EGFR-TKI and bevacizumab comparing to EGFR-TKI as a single agent (PFS: 21.7 vs. 9.3 months, P < 0.01). Copy number variation (CNV) (PFS: 4.6 vs.9.4 months, p = 0.018) was identified as an unfavorable predictive factor to 3rd-generation TKI. We also revealed distinct resistance mechanisms associated with different EGFR-TKIs.

CONCLUSION:

Our study highlights the heterogeneity both in the primary molecular landscape and acquired alterations in EGFR-mutated NSCLCs, which might play a role in determining the clinical efficacy of EGFR-TKIs. We also revealed the differential prognostic role of TP53 mutation in patients treated with the 1st or 2nd generation of EGFR-TKI. Our study also suggests that EGFR-mutant and TP53-WT patients may benefit more from combinatorial treatment consisting of EGFR-TKI and bevacizumab, highlighting the importance of further stratifying EGFR-mutant patients.

• Authors: Ying Cheng, Lixia Ma, Ying Liu, Jing Zhu, Ying Xin, Xianhong Liu, Ying Wang, Tingting Zhang, Changliang Yang, Sheng Wang, Hongxia Cui, Liang Zhang, Jixin Dai, Lin Shao, Jing Lin, Junyi Ye, Hao Liu
• Journal: Lung cancer (Amsterdam, Netherlands) (Lung Cancer) Vol. 145 Pg. 63-70 (07 2020) ISSN: 1872-8332 [Electronic] Ireland
• PMID: 32408134 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2020 Elsevier B.V. All rights reserved.

Chemical References

• Protein Kinase Inhibitors
• EGFR protein, human
• ErbB Receptors

Topics

• Carcinoma, Non-Small-Cell Lung (drug therapy, genetics)
• DNA Copy Number Variations
• ErbB Receptors (genetics)
• Genomics
• Humans
• Lung Neoplasms (drug therapy, genetics)
• Mutation
• Protein Kinase Inhibitors (therapeutic use)