title: Change in serum KL-6 level from baseline is useful for predicting life-threatening EGFR-TKIs induced interstitial lung disease.
abstract: BACKGROUND
  A high incidence of interstitial lung disease (ILD) has been reported in patients with advanced non-small cell lung cancer (NSCLC) treated with epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs), particularly in Japanese populations. A previous report from our laboratory demonstrated that KL-6 was a useful serum biomarker to assess the severity of drug-induced pneumonitis. Based on these observations, this study was conducted to evaluate the risk factors of EGFR-TKIs induced ILD and the usefulness of monitoring serum KL-6 levels in patients who developed EGFR-TKIs induced ILD in a large multi-institutional setting.
  
  
  METHODS
  We retrospectively reviewed clinical records and radiographies of 341 patients with advanced NSCLCs who were treated with EGFR-TKIs, and analyzed risk factors for the development of EGFR-TKIs induced ILD. Changes of circulating levels of KL-6 were also evaluated in the patients who developed EGFR-TKIs induced ILD.
  
  
  RESULTS
  Among the 341 patients included in this study, 20 (5.9%) developed EGFR-TKIs induced ILD, and 9 (2.6%) died from ILD. Univariate analyses revealed that only preexisting pulmonary fibrosis was a significant risk factor for the development of EGFR-TKIs induced ILD (p = 0.003). Absolute levels of circulating KL-6 at neither baseline nor the onset of ILD could discriminate between life-threatening and non-life threatening EGFR-TKIs induced ILDs. However, we found that the ratios of serum KL-6 levels just after the onset of EGFR-TKIs induced ILD to those at baseline could quite precisely distinguish survivors from non-survivors (p = 0.006) as well as acute interstitial pneumonia (AIP) pattern from non-AIP pattern (p = 0.005).
  
  
  CONCLUSIONS
  The results of this study strongly support the potential of KL-6 as a diagnostic biomarker for life-threatening EGFR-TKIs induced ILD. Monitoring of KL-6 is also useful to evaluate the progression and severity of EGFR-TKIs induced ILD.
authors.affiliation: Department of Molecular and Internal Medicine, Graduate School of Biomedical Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8551, Japan.
authors.forename: Shigeo
authors.initials: S
authors.lastname: Kawase
authors.forename: Noboru
authors.initials: N
authors.lastname: Hattori
authors.forename: Nobuhisa
authors.initials: N
authors.lastname: Ishikawa
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Horimasu
authors.forename: Kazunori
authors.initials: K
authors.lastname: Fujitaka
authors.forename: Osamu
authors.initials: O
authors.lastname: Furonaka
authors.forename: Takeshi
authors.initials: T
authors.lastname: Isobe
authors.forename: Seigo
authors.initials: S
authors.lastname: Miyoshi
authors.forename: Hironobu
authors.initials: H
authors.lastname: Hamada
authors.forename: Takashi
authors.initials: T
authors.lastname: Yamane
authors.forename: Akihito
authors.initials: A
authors.lastname: Yokoyama
authors.forename: Nobuoki
authors.initials: N
authors.lastname: Kohno
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000009:adverse effects*; D015415:Biomarkers / Q000097:blood; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D016903:Drug Monitoring / Q000379:methods; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D005260:Female; D006801:Humans; D007564:Japan; D017563:Lung Diseases, Interstitial / Q000139:chemically induced / Q000000981:diagnostic imaging / Q000276:immunology* / Q000401:mortality; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D008297:Male; D008875:Middle Aged; D018396:Mucin-1 / Q000097:blood*; D009154:Mutation; D016017:Odds Ratio; D011237:Predictive Value of Tests; D047428:Protein Kinase Inhibitors / Q000009:adverse effects*; D011658:Pulmonary Fibrosis / Q000150:complications; D012189:Retrospective Studies; D018570:Risk Assessment; D012307:Risk Factors; D012720:Severity of Illness Index; D014057:Tomography, X-Ray Computed
chemical_list: D000970:Antineoplastic Agents; D015415:Biomarkers; C060192:MUC1 protein, human; D018396:Mucin-1; D047428:Protein Kinase Inhibitors; C512478:EGFR protein, human; D066246:ErbB Receptors