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)

The first case-control study to identify the risk factors of interstitial lung disease (ILD) has been performed in patients with non-small-cell lung cancer (NSCLC) who were treated with erlotinib in Japan, where drug-induced ILD is observed more frequently than in other countries. The proteomic analysis comparing 15 patients with ILD and 64 controls was unable to identify any statistically significant predictive serum proteins for ILD but suggested an association of 3 proteins (C3, C4A/C4B, and APOA1) with ILD, which deserves further study. 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. Patients and 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. Conclusion: We were unable to demonstrate predictive serum protein markers for ILD development. However, C3, C4A/C4B, and APOA1 are worthy of further investigation. (C) 2013 Elsevier Inc. All rights reserved.