Juhong Jiang1, Yingying Gu1, Jing Liu1, Ruibin Wu1, Lin Fu1, Jin Zhao1, Yubao Guan2. 1. The State Key Laboratory of Respiratory Disease, Guangzhou Institute of Respiratory Disease, The First Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong, 510120, China. 2. Department of Radiology, The First Affiliated Hospital, Guangzhou Medical University; Guangzhou, Guangdong, 510120, China. Electronic address: yubaoguan@163.com.
Abstract
OBJECTIVES: Activating mutations in the epidermal growth factor receptor (EGFR) are strongly predictive of EGFR-tyrosine kinase inhibitor (TKI) activity in non-small cell lung cancer (NSCLC). However, primary resistance to EGFR-TKIs occurs in approximately 20-30% of NSCLC patients with EGFR mutations. The goal of this study was to determine whether p16/CDKN2A homozygous deletion (HD) is associated with primary resistance to EGFR-TKIs in lung adenocarcinoma patients with EGFR activating mutations. METHODS: We investigated 127 patients with stage IIIB or IV lung adenocarcinoma harboring activating EGFR mutations, and who had received EGFR-TKIs as first-line therapy. Dual-color fluorescence in situ hybridization for p16/CDKN2A and chromosome 9 was performed in tumor biopsy samples obtained before initiation of EGFR-TKI treatment. RESULTS: p16/CDKN2A HD was detected in 24.4% (31/127) of patients, and the overall response rate in patients with and without this mutation was 48.4% and 78.1%, respectively (P=0.0027). The median progression-free survival was 5.3 months (95% confidence interval [CI]: 4.582-6.018) for patients with p16/CDKN2A HD and 10.5 months (95% CI: 9.365-11.635 months) for patients without the mutation (P=0.001). No correlations between p16/CDKN2A HD and patient characteristics including gender, age, smoking history, EGFR mutation type, tumor-node-metastasis stage, and performance status were found. CONCLUSIONS: Our study demonstrates that the coexistence of p16/CDKN2A HDs and activating EGFR mutations in lung adenocarcinoma patients signifies a poor response to EGFR-TKI therapy.
OBJECTIVES: Activating mutations in the epidermal growth factor receptor (EGFR) are strongly predictive of EGFR-tyrosine kinase inhibitor (TKI) activity in non-small cell lung cancer (NSCLC). However, primary resistance to EGFR-TKIs occurs in approximately 20-30% of NSCLCpatients with EGFR mutations. The goal of this study was to determine whether p16/CDKN2A homozygous deletion (HD) is associated with primary resistance to EGFR-TKIs in lung adenocarcinomapatients with EGFR activating mutations. METHODS: We investigated 127 patients with stage IIIB or IV lung adenocarcinoma harboring activating EGFR mutations, and who had received EGFR-TKIs as first-line therapy. Dual-color fluorescence in situ hybridization for p16/CDKN2A and chromosome 9 was performed in tumor biopsy samples obtained before initiation of EGFR-TKI treatment. RESULTS:p16/CDKN2AHD was detected in 24.4% (31/127) of patients, and the overall response rate in patients with and without this mutation was 48.4% and 78.1%, respectively (P=0.0027). The median progression-free survival was 5.3 months (95% confidence interval [CI]: 4.582-6.018) for patients with p16/CDKN2AHD and 10.5 months (95% CI: 9.365-11.635 months) for patients without the mutation (P=0.001). No correlations between p16/CDKN2AHD and patient characteristics including gender, age, smoking history, EGFR mutation type, tumor-node-metastasis stage, and performance status were found. CONCLUSIONS: Our study demonstrates that the coexistence of p16/CDKN2A HDs and activating EGFR mutations in lung adenocarcinomapatients signifies a poor response to EGFR-TKI therapy.
Authors: Sarwat Naz; Anastasia Sowers; Rajani Choudhuri; Maria Wissler; Janet Gamson; Askale Mathias; John A Cook; James B Mitchell Journal: Clin Cancer Res Date: 2018-05-01 Impact factor: 12.531