title: Nested case control study of proteomic biomarkers for interstitial lung disease in Japanese patients with non-small-cell lung cancer treated with erlotinib: a multicenter phase IV study (JO21661).
abstract: BACKGROUND
  Interstitial lung disease (ILD) is a serious adverse drug reaction associated with epidermal growth factor receptor tyrosine-kinase inhibitors (EGFR TKIs). Its risk factors are yet to be fully elucidated. We sought to identify proteomic biomarkers associated with ILD development in erlotinib-treated Japanese patients with non-small-cell lung cancer (NSCLC) to build predictive models.
  
  
  METHODS
  We conducted a nested case-control study. The participants were patients with NSCLC enrolled in a phase IV study of erlotinib in whom ILD developed within 120 days after erlotinib administration. The controls were randomly selected patients without ILD from the overall study cohort who were also treated with erlotinib. Serum samples were obtained before the first administration of erlotinib and were assayed by liquid chromatography-mass spectroscopy/mass spectroscopy (LC-MS/MS). Logistic regression analysis was performed to identify the peptide and proteins associated with ILD.
  
  
  RESULTS
  A total of 645 patients were enrolled in the cohort; 15 case patients and 64 controls were analyzed. When multiplicity was taken into account, we were unable to statistically verify any genuine association between individual markers and ILD. Investigation of the predictive power based on leave-one-out cross-validation (LOOCV) showed that the area under the receiver operating characteristic curve was 0.73 at a maximum. Additional analysis suggested that 3 proteins (C3, C4A/C4B, and APOA1) have a stronger association with ILD than do the other proteins tested.
  
  
  CONCLUSIONS
  We were unable to demonstrate predictive serum protein markers for ILD development. However, C3, C4A/C4B, and APOA1 are worthy of further investigation.
authors.affiliation: Department of Thoracic Oncology, National Hospital, Organization Kinki-chuo Chest Medical Center, Sakai, Japan. s-atagi@kch.hosp.go.jp
authors.forename: Shinji
authors.initials: S
authors.lastname: Atagi
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Katakami
authors.forename: Hiroshige
authors.initials: H
authors.lastname: Yoshioka
authors.forename: Masahiro
authors.initials: M
authors.lastname: Fukuoka
authors.forename: Shoji
authors.initials: S
authors.lastname: Kudoh
authors.forename: Atsushi
authors.initials: A
authors.lastname: Ogiwara
authors.forename: Masato
authors.initials: M
authors.lastname: Imai
authors.forename: Masamichi
authors.initials: M
authors.lastname: Ueda
authors.forename: Shigeyuki
authors.initials: S
authors.lastname: Matsui
mesh_terms: D000230:Adenocarcinoma / Q000150:complications / Q000188:drug therapy / Q000378:metabolism; D000368:Aged; D014408:Biomarkers, Tumor / Q000097:blood*; D002289:Carcinoma, Non-Small-Cell Lung / Q000150:complications* / Q000188:drug therapy / Q000378:metabolism; D002294:Carcinoma, Squamous Cell / Q000150:complications / Q000188:drug therapy / Q000378:metabolism; D016022:Case-Control Studies; D066246:ErbB Receptors / Q000037:antagonists & inhibitors; D000069347:Erlotinib Hydrochloride; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D017563:Lung Diseases, Interstitial / Q000097:blood / Q000139:chemically induced / Q000175:diagnosis*; D008175:Lung Neoplasms / Q000150:complications* / Q000188:drug therapy / Q000378:metabolism; D008297:Male; D009367:Neoplasm Staging; D011379:Prognosis; D047428:Protein Kinase Inhibitors / Q000009:adverse effects; D040901:Proteomics; D011799:Quinazolines / Q000009:adverse effects*; D053719:Tandem Mass Spectrometry
chemical_list: D014408:Biomarkers, Tumor; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D000069347:Erlotinib Hydrochloride; D066246:ErbB Receptors