title: Coexistence of p16/CDKN2A homozygous deletions and activating EGFR mutations in lung adenocarcinoma patients signifies a poor response to EGFR-TKIs.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: The State Key Laboratory of Respiratory Disease, Guangzhou Institute of Respiratory Disease, The First Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong, 510120, China.
authors.forename: Juhong
authors.initials: J
authors.lastname: Jiang
authors.affiliation: The State Key Laboratory of Respiratory Disease, Guangzhou Institute of Respiratory Disease, The First Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong, 510120, China.
authors.forename: Yingying
authors.initials: Y
authors.lastname: Gu
authors.affiliation: The State Key Laboratory of Respiratory Disease, Guangzhou Institute of Respiratory Disease, The First Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong, 510120, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Liu
authors.affiliation: The State Key Laboratory of Respiratory Disease, Guangzhou Institute of Respiratory Disease, The First Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong, 510120, China.
authors.forename: Ruibin
authors.initials: R
authors.lastname: Wu
authors.affiliation: The State Key Laboratory of Respiratory Disease, Guangzhou Institute of Respiratory Disease, The First Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong, 510120, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Fu
authors.affiliation: The State Key Laboratory of Respiratory Disease, Guangzhou Institute of Respiratory Disease, The First Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong, 510120, China.
authors.forename: Jin
authors.initials: J
authors.lastname: Zhao
authors.affiliation: Department of Radiology, The First Affiliated Hospital, Guangzhou Medical University; Guangzhou, Guangdong, 510120, China. Electronic address: yubaoguan@163.com.
authors.forename: Yubao
authors.initials: Y
authors.lastname: Guan
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D000077192:Adenocarcinoma of Lung; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000627:therapeutic use; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics*; D018572:Disease-Free Survival; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000235:genetics*; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009367:Neoplasm Staging; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D012189:Retrospective Studies
chemical_list: D000970:Antineoplastic Agents; C000614131:CDKN2A protein, human; D019941:Cyclin-Dependent Kinase Inhibitor p16; D047428:Protein Kinase Inhibitors; C512478:EGFR protein, human; D066246:ErbB Receptors
keywords: EGFR-TKI; Homozygous deletion; Lung adenocarcinoma; p16/CDKN2A