title: Expression of insulin-like growth factor 1 receptor (IGF-1R) predicts poor responses to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors in non-small cell lung cancer patients harboring activating EGFR mutations.
abstract: OBJECTIVE
  Expression of insulin-like growth factor 1 receptor (IGF-1R) in non-small cell lung cancer (NSCLC) is associated with poor prognosis. The IGF-1R pathway activates downstream targets that bypass dependency in signals from the epidermal growth factor receptor (EGFR), which mediates resistance to EGFR tyrosine kinase inhibitors (TKIs). The aim of the present study was to determine the predictive role of IGF-1R expression in the response to EGFR-TKIs of NSCLC patients harboring activating EGFR mutations.
  
  
  METHODS
  We retrospectively studied 62 NSCLC patients who had activating EGFR mutations and received TKIs. Protein expression of IGF-1R, vascular endothelial growth factor (VEGF), and human epidermal growth factor receptor 2 (HER2) were measured by immunohistochemical staining. Univariate and multivariate analyses were performed to identify predictive factors associated with the responses to EGFR-TKIs. The relationship of progression-free survival (PFS) with IGF-1R expression and the presence of diabetes mellitus (DM) were examined.
  
  
  RESULTS
  Of 62 EGFR mutation positive patients, 26 expressed IGF-1R, and 13 had DM. In the multivariate analysis, young age, squamous cell carcinoma, and IGF-1R expression were independently associated with a shorter PFS after treatment with EGFR-TKIs. Patients expressing IGF-1R showed a significantly shorter PFS in response to EGFR-TKIs compared with those lacking IGF-1R expression (9.1 vs. 20.1 months, p=0.005). The 13 patients with DM were more likely to express IGF-1R (p=0.001) and had shorter PFS times when treated with first-line EGFR-TKIs (7.6 vs. 18.6 months, p=0.005), compared with those without DM.
  
  
  CONCLUSIONS
  IGF-1R expression was a negative predictive factor for a response to EGFR-TKIs in NSCLC patients harboring activating EGFR mutations. Moreover, patients with DM highly expressed IGF-1R in tumor tissues, which was associated with a poor response to first-line TKI therapy. Further studies aimed at overcoming EGFR-TKI resistance will need to also address IGF-1R pathways.
authors.affiliation: Division of Pulmonology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.
authors.forename: Chang Dong
authors.initials: CD
authors.lastname: Yeo
authors.affiliation: Division of Pulmonology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.
authors.forename: Ki Hoon
authors.initials: KH
authors.lastname: Park
authors.affiliation: Division of Pulmonology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.
authors.forename: Chan Kwon
authors.initials: CK
authors.lastname: Park
authors.affiliation: Division of Pulmonology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.
authors.forename: Sang Haak
authors.initials: SH
authors.lastname: Lee
authors.affiliation: Division of Pulmonology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.
authors.forename: Seung Joon
authors.initials: SJ
authors.lastname: Kim
authors.affiliation: Division of Pulmonology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.
authors.forename: Hyung Kyu
authors.initials: HK
authors.lastname: Yoon
authors.affiliation: Department of Hospital Pathology, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.
authors.forename: Youn Soo
authors.initials: YS
authors.lastname: Lee
authors.affiliation: Department of Hospital Pathology, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.
authors.forename: Eun Jung
authors.initials: EJ
authors.lastname: Lee
authors.affiliation: Department of Hospital Pathology, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.
authors.forename: Kyo Young
authors.initials: KY
authors.lastname: Lee
authors.affiliation: Department of Hospital Pathology, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea. Electronic address: kimecho@catholic.ac.kr.
authors.forename: Tae-Jung
authors.initials: TJ
authors.lastname: Kim
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality* / Q000473:pathology; D015897:Comorbidity; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics*; D005260:Female; D015870:Gene Expression; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D063868:Patient Outcome Assessment; D011379:Prognosis; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D017526:Receptor, IGF Type 1 / Q000235:genetics*; D012307:Risk Factors; D016019:Survival Analysis
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D066246:ErbB Receptors; D017526:Receptor, IGF Type 1
keywords: DM; EGFR mutation; IGF-1R; Non-small cell lung cancer; Progression-free survival; TKI