title: Distinct Epidemiology and Clinical Consequence of Classic Versus Rare EGFR Mutations in Lung Adenocarcinoma.
abstract: BACKGROUND
  Although classic sensitizing mutations of epidermal growth factor receptor (EGFR) are positive predictive markers for EGFR tyrosine kinase inhibitors (TKIs) in lung adenocarcinoma, there are rare EGFR mutations with unknown epidemiology and influence on prognosis and TKI response.
  
  
  METHODS
  Eight hundred and fourteen lung adenocarcinoma patients with KRAS and/or EGFR mutation analyses for TKI therapy indication were identified. Six hundred and forty-five patients were included in the epidemiological analysis. The clinical outcome was analyzed in 419 advanced-stage patients with follow-up data.
  
  
  RESULTS
  Four hundred and eighty (59%) KRAS/EGFR double wild-type, 216 (27%) KRAS mutant, 42 (5%) classic, 49 (6%) rare, and 27 (3%) synonymous EGFR mutant cases were identified. Twenty previously unpublished non-synonymous mutations were found. Rare EGFR mutations were significantly associated with smoking (vs. classic EGFR mutations; p = 0.0062). Classic EGFR mutations but not rare ones were independent predictors of increased overall survival (hazard ratios, 0.45; 95% confidence intervals, 0.25-0.82; p = 0.009). TKI therapy response rate of patients harboring classic EGFR mutations was significantly higher (vs. rare EGFR mutations; 71% vs. 37%; p = 0.039). Patients with classic or sensitizing rare (G719x and L861Q) EGFR mutations had significantly longer progression-free survival when compared with the remaining rare mutation cases (12 vs. 6.2 months; p = 0.048).
  
  
  CONCLUSIONS
  The majority of rare EGFR mutations was associated with smoking, shorter overall survival, and decreased TKI response when compared with classic EGFR mutations. However, studies characterizing the TKI sensitizing effect of individual rare mutations are indispensable to prevent the exclusion of patients with sensitizing rare EGFR mutations who may benefit from anti-EGFR therapy.
authors: Department of Tumor Biology, National Koranyi Institute of Pulmonology, Budapest, Hungary; Translational Thoracic Oncology Laboratory, Division of Thoracic Surgery, Department of Surgery, Comprehensive Cancer Center, Medical University of Vienna, Austria; Department of Thoracic Surgery, National Institute of Oncology-Semmelweis University, Budapest, Hungary.
authors: Zoltan
authors: Z
authors: Lohinai
authors: Translational Thoracic Oncology Laboratory, Division of Thoracic Surgery, Department of Surgery, Comprehensive Cancer Center, Medical University of Vienna, Austria.
authors: Mir Alireza
authors: MA
authors: Hoda
authors: Department of Pulmonology, Semmelweis University, Budapest, Hungary.
authors: Katalin
authors: K
authors: Fabian
authors: Department of Tumor Biology, National Koranyi Institute of Pulmonology, Budapest, Hungary.
authors: Gyula
authors: G
authors: Ostoros
authors: Second Department of Pathology, Semmelweis University, Budapest, Hungary; Molecular Oncology Research Group, Hungarian Academy of Sciences-Semmelweis University, Budapest, Hungary.
authors: Erzsebet
authors: E
authors: Raso
authors: Second Department of Pathology, Semmelweis University, Budapest, Hungary.
authors: Tamas
authors: T
authors: Barbai
authors: Second Department of Pathology, Semmelweis University, Budapest, Hungary; Molecular Oncology Research Group, Hungarian Academy of Sciences-Semmelweis University, Budapest, Hungary.
authors: Jozsef
authors: J
authors: Timar
authors: First Department of Pathology, Experimental Cancer Research, Semmelweis University, Budapest, Hungary.
authors: Ilona
authors: I
authors: Kovalszky
authors: Department of Tumor Biology, National Koranyi Institute of Pulmonology, Budapest, Hungary.
authors: Mihaly
authors: M
authors: Cserepes
authors: Department of Tumor Biology, National Koranyi Institute of Pulmonology, Budapest, Hungary; Translational Thoracic Oncology Laboratory, Division of Thoracic Surgery, Department of Surgery, Comprehensive Cancer Center, Medical University of Vienna, Austria.
authors: Anita
authors: A
authors: Rozsas
authors: Translational Thoracic Oncology Laboratory, Division of Thoracic Surgery, Department of Surgery, Comprehensive Cancer Center, Medical University of Vienna, Austria.
authors: Viktoria
authors: V
authors: Laszlo
authors: Department of Internal Medicine I, Institute of Cancer Research and Comprehensive Cancer Center, Medical University of Vienna, Austria.
authors: Michael
authors: M
authors: Grusch
authors: Department of Internal Medicine I, Institute of Cancer Research and Comprehensive Cancer Center, Medical University of Vienna, Austria.
authors: Walter
authors: W
authors: Berger
authors: Translational Thoracic Oncology Laboratory, Division of Thoracic Surgery, Department of Surgery, Comprehensive Cancer Center, Medical University of Vienna, Austria.
authors: Walter
authors: W
authors: Klepetko
authors: Department of Pulmonology, Semmelweis University, Budapest, Hungary.
authors: Judit
authors: J
authors: Moldvay
authors: Department of Tumor Biology, National Koranyi Institute of Pulmonology, Budapest, Hungary; Translational Thoracic Oncology Laboratory, Division of Thoracic Surgery, Department of Surgery, Comprehensive Cancer Center, Medical University of Vienna, Austria; Department of Thoracic Surgery, National Institute of Oncology-Semmelweis University, Budapest, Hungary. Electronic address: balazs.dome@meduniwien.ac.at.
authors: Balazs
authors: B
authors: Dome
authors: Translational Thoracic Oncology Laboratory, Division of Thoracic Surgery, Department of Surgery, Comprehensive Cancer Center, Medical University of Vienna, Austria; Molecular Oncology Research Group, Hungarian Academy of Sciences-Semmelweis University, Budapest, Hungary. Electronic address: balazs.hegedus@meduniwien.ac.at.
authors: Balazs
authors: B
authors: Hegedus
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000453:epidemiology* / Q000235:genetics*; D000368:Aged; D004252:DNA Mutational Analysis; D018572:Disease-Free Survival; D066246:ErbB Receptors / Q000235:genetics*; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000453:epidemiology* / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D017720:Molecular Epidemiology; D009154:Mutation; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics; D012189:Retrospective Studies; D012907:Smoking / Q000453:epidemiology / Q000235:genetics; D015996:Survival Rate
chemical_list: C117307:KRAS protein, human; D047428:Protein Kinase Inhibitors; D066246:ErbB Receptors; D016283:Proto-Oncogene Proteins p21(ras)