Interstitial Lung Disease in Gefitinib-Treated Japanese Patients with Non-Small-Cell Lung Cancer: Genome-Wide Analysis of Genetic Data

Abstract

Aim: To investigate potential relationships between SNPs and acute interstitial lung disease (ILD) events in Japanese non-small-cell lung cancer patients receiving gefitinib. Materials & methods: Japanese non-small-cell lung cancer patients treated with gefitinib from a prospective pharmacoepidemiological cohort with a nested case–control study component (‘CCS‘; 52 ILD cases, 139 controls) and a retrospective study (28 ILD cases, 55 controls) were genotyped for nearly 500,000 SNPs. Associations between genotype and ILD were evaluated using Fisher‘s exact test and logistic regression modeling, and false discovery rate analysis was used to adjust for the large number of statistical tests. Results: The CCS data provided some false discovery rate evidence that the significance of top-ranking SNPs exceeded levels expected by chance, suggesting some genuine associations. However, replication analyses using retrospective study data were not supportive and there was little evidence of strong genetic associations from a combined analysis. Adjustment of CCS analyses for clinical variables provided little additional convincing evidence. Significant gene–gene interactions between SNP pairs using CCS data were not confirmed in retrospective study replication analyses. Conclusion: Although it is not possible to exclude genetic influences in ILD etiology, common sequence variation is unlikely to explain a major component of ILD risk. Our top results may provide a useful hypothesis-generating starting point for further research.

Presented, in part, at the 26th ICPE: International Conference on Pharmacoepidemiology & Therapeutic Risk Management, Brighton, UK, 19–22 August 2010.

Original submitted 1 December 2010; Revision submitted 22 February 2011

KEYWORDS::

• gefitinib
• genome-wide association
• interstitial lung disease
• non-small-cell lung cancer
• pharmacogenomics

Acknowledgements

The authors thank the patients, investigators and study personnel who participated in these studies (investigators and key study personnel are listed under Study Organization in the Supplementary Material ); Iain McKendrick and Catriona Tate of Discovery Information, AstraZeneca R&D , for bioinformatics support to the genetic analyses; and Annette Smith, from Complete Medical Communications, who provided medical writing support funded by AstraZeneca.

Financial & competing interests disclosure

The prospective study was sponsored and funded by AstraZeneca. AstraZeneca also provided funding for the retrospective study, which was a collaborative research effort between AstraZeneca and Tokyo University. Fredrik Nyberg, Ansar Jawaid, Shuji Hada, Takaaki Umemura, Ruth March and Bryan J Barratt are employees of AstraZeneca. Fredrik Nyberg and Bryan J Barratt have stock ownership of AstraZeneca. Masahiro Fukuoka has received honoraria from AstraZeneca. The other coauthors have no potential conflicts of interest to disclose. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Medical writing assistance was provided by Annette Smith, Complete Medical Communications, funded by AstraZeneca.

Ethical conduct of research

The authors state that they have obtained appropriate institutional review board approval or have followed the principles outlined in the Declaration of Helsinki for all human or animal experimental investigations. In addition, for investigations involving human subjects, informed consent has been obtained from the participants involved.

Additional information

Funding

The prospective study was sponsored and funded by AstraZeneca. AstraZeneca also provided funding for the retrospective study, which was a collaborative research effort between AstraZeneca and Tokyo University. Fredrik Nyberg, Ansar Jawaid, Shuji Hada, Takaaki Umemura, Ruth March and Bryan J Barratt are employees of AstraZeneca. Fredrik Nyberg and Bryan J Barratt have stock ownership of AstraZeneca. Masahiro Fukuoka has received honoraria from AstraZeneca. The other coauthors have no potential conflicts of interest to disclose. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. Medical writing assistance was provided by Annette Smith, Complete Medical Communications, funded by AstraZeneca.