Abstract
Interstitial lung disease (ILD) events have been reported in Japanese non-small-cell lung cancer (NSCLC) patients receiving EGFR tyrosine kinase inhibitors. We investigated proteomic biomarkers for mechanistic insights and improved prediction of ILD. Blood plasma was collected from 43 gefitinib-treated NSCLC patients developing acute ILD (confirmed by blinded diagnostic review) and 123 randomly selected controls in a nested case-control study within a pharmacoepidemiological cohort study in Japan. We generated ∼7 million tandem mass spectrometry (MS/MS) measurements with extensive quality control and validation, producing one of the largest proteomic lung cancer datasets to date, incorporating rigorous study design, phenotype definition, and evaluation of sample processing. After alignment, scaling, and measurement batch adjustment, we identified 41 peptide peaks representing 29 proteins best predicting ILD. Multivariate peptide, protein, and pathway modeling achieved ILD prediction comparable to previously identified clinical variables; combining the two provided some improvement. The acute phase response pathway was strongly represented (17 of 29 proteins, p = 1.0×10−25), suggesting a key role with potential utility as a marker for increased risk of acute ILD events. Validation by Western blotting showed correlation for identified proteins, confirming that robust results can be generated from an MS/MS platform implementing strict quality control.
Highlights
Interstitial lung disease (ILD) affects the pulmonary parenchyma or alveolar region [1]
Characteristics of the study population The non-randomized cohort included 3,166 Japanese patients with advanced/recurrent non-small-cell lung cancer (NSCLC) who were followed for 12 weeks after initiating gefitinib (n = 1,872 treatment periods) or chemotherapy (n = 2,551)
Exploratory analysis of liquid chromatography (LC)-MS/MS data generated under quality controlled conditions reveals large batch variation that needs to be controlled in subsequent statistical analyses
Summary
Interstitial lung disease (ILD) affects the pulmonary parenchyma or alveolar region [1]. When associated with drug treatment, it can present precipitously as acute diffuse alveolar damage (DAD), sometimes with a fatal outcome [2]. Acute ILD events may develop de novo, but an existing chronic ILD condition increases the risk considerably [3], as observed in recent studies of patients with idiopathic pulmonary fibrosis (IPF), the most common chronic form [4]. ILD, especially IPF, is a known co-morbidity in patients with non-small-cell lung cancer (NSCLC) [5]. Acute ILD events have been reported with many lung cancer therapies at rates up to ,10% [6,7,8,9,10,11]. ILD is recognized as more common in Japan than elsewhere, both in the population and among patients with NSCLC [5,6,12,13], it is unclear why
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
