title: Effectiveness of Tyrosine Kinase Inhibitors in Japanese Patients with Non-small Cell Lung Cancer Harboring Minor Epidermal Growth Factor Receptor Mutations: Results from a Multicenter Retrospective Study (HANSHIN Oncology Group 0212).
abstract: OBJECTIVE
  Non-small cell lung cancer (NSCLC) with minor mutations in the epidermal growth factor receptor (EGFR) gene, except for the common 15 base-pair deletions in exon 19 and the L858R mutation in exon 21, is rare, and only few data exist on this patient population. The aim of the present study was to describe the clinical characteristics and to clarify the efficacy of EGFR-tyrosine kinase inhibitors (TKIs) in patients with NSCLC harboring minor mutations of the EGFR gene.
  
  
  METHODS
  This was a multicenter, retrospective study that analyzed specimens from patients with NSCLC who had minor EGFR gene mutations and were treated with EGFR-TKIs between June 2002 and March 2012.
  
  
  RESULTS
  Out of 56 patients with minor mutations of the EGFR gene, 44 were treated with either gefitinib or erlotinib. Mutation sites were G719X in exon 18 (n=35), L861Q in exon 21 (n=11), and G874S in exon 21 (n=1). Three patients had both the G719S and the L861Q mutation. The response rate to TKI treatment was 29.5%, and the disease control rate was 63.6%. The median progression-free survival (PFS) was 6.7 months [95% confidence interval (CI)=2.06-8.66 months]. The median PFS was 7.2 months (95% CI=4.23-12.3 months) in 32 patients who received first- or second-line treatment with EGFR-TKIs, whereas the median PFS was 1.57 months (95% CI=0.73-3.8 months) in 12 patients treated with EGFR-TKIs as a third-line or later treatment. In multivariate Cox analysis, erlotinib therapy was associated with a longer PFS than gefitinib (p=0.025).
  
  
  CONCLUSIONS
  Patients with NSCLC harboring minor mutations of the EGFR gene exhibited a modest response to EGFR-TKI treatment. Treatment with first-generation EGFR-TKIs, in particular erlotinib, may be considered a first- or second-line option for patients with NSCLC with minor EGFR mutations.
authors.affiliation: Department of Thoracic Oncology, National Hospital Organization Toneyama National Hospital, Toyonaka, Japan Department of Respiratory Medicine, Allergy, and Rheumatic Diseases, Osaka University Graduate School of Medicine, Suita, Japan.
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Otsuka
authors.affiliation: Department of Thoracic Oncology, National Hospital Organization Toneyama National Hospital, Toyonaka, Japan mmori@toneyama.go.jp.
authors.forename: Masahide
authors.initials: M
authors.lastname: Mori
authors.affiliation: Department of Thoracic Oncology, National Hospital Organization Toneyama National Hospital, Toyonaka, Japan.
authors.forename: Yukihiro
authors.initials: Y
authors.lastname: Yano
authors.affiliation: Department of Thoracic Oncology, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka, Japan.
authors.forename: Junji
authors.initials: J
authors.lastname: Uchida
authors.affiliation: Department of Thoracic Oncology, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka, Japan.
authors.forename: Kazumi
authors.initials: K
authors.lastname: Nishino
authors.affiliation: Division of Integrated Oncology, Institute of Biomedical Research and Innovation, Kobe, Japan.
authors.forename: Reiko
authors.initials: R
authors.lastname: Kaji
authors.affiliation: Division of Integrated Oncology, Institute of Biomedical Research and Innovation, Kobe, Japan.
authors.forename: Akito
authors.initials: A
authors.lastname: Hata
authors.affiliation: Department of Thoracic Oncology, Hyogo Cancer Center, Akashi, Japan.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Hattori
authors.affiliation: Department of Thoracic Oncology, Hyogo Cancer Center, Akashi, Japan.
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Urata
authors.affiliation: Department of Respiratory Medicine, Kobe City Medical Center West Hospital, Kobe, Japan.
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Kaneda
authors.affiliation: Department of Respiratory Medicine, Kobe University Graduate School of Medicine, Kobe, Japan.
authors.forename: Motoko
authors.initials: M
authors.lastname: Tachihara
authors.affiliation: Department of Thoracic Oncology, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka, Japan.
authors.forename: Fumio
authors.initials: F
authors.lastname: Imamura
authors.affiliation: Division of Integrated Oncology, Institute of Biomedical Research and Innovation, Kobe, Japan.
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Katakami
authors.affiliation: Department of Medical Oncology, Hyogo Cancer Center, Akashi, Japan.
authors.forename: Shunichi
authors.initials: S
authors.lastname: Negoro
authors.affiliation: Department of Biomedical Statistics and Bioinformatics, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Morita
authors.affiliation: Department of Thoracic Oncology, National Hospital Organization Toneyama National Hospital, Toyonaka, Japan.
authors.forename: Soichiro
authors.initials: S
authors.lastname: Yokota
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000494:pharmacology; D044466:Asian People / Q000235:genetics; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D018572:Disease-Free Survival; D066246:ErbB Receptors / Q000235:genetics*; D000069347:Erlotinib Hydrochloride; D005091:Exons / Q000187:drug effects / Q000235:genetics; D005260:Female; D000077156:Gefitinib; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000187:drug effects / Q000235:genetics; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D011799:Quinazolines / Q000627:therapeutic use; D012189:Retrospective Studies; D017384:Sequence Deletion / Q000187:drug effects / Q000235:genetics
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D000069347:Erlotinib Hydrochloride; D066246:ErbB Receptors; D011505:Protein-Tyrosine Kinases; D000077156:Gefitinib
keywords: EGFR-TKI; erlotinib; gefitinib; minor EGFR mutation; non-small-cell lung cancer