Association between single-nucleotide polymorphisms and adverse events in nivolumab-treated non-small cell lung cancer patients

• Published in: British journal of cancer Vol. 118; no. 10; pp. 1296 - 1301
• Main Authors: Bins, Sander, Basak, Edwin A., el Bouazzaoui, Samira, Koolen, Stijn L. W., Oomen – de Hoop, E., van der Leest, Cor H., van der Veldt, Astrid A. M., Sleijfer, Stefan, Debets, Reno, van Schaik, Ron H. N., Aerts, Joachim G. J. V., Mathijssen, Ron H. J.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.05.2018; Nature Publishing Group
• Subjects: 631/67/1059/2325; 692/4028/67/1612/1350; Biomarkers; Biomedical and Life Sciences; Biomedicine; Cancer Research; Drug Resistance; Epidemiology; Immune checkpoint; Immunotherapy; Lung cancer; Lymphocytes T; Molecular Medicine; Monoclonal antibodies; Non-small cell lung carcinoma; Oncology; Patients; PD-1 protein; Polymorphism; Single-nucleotide polymorphism; Targeted cancer therapy; Toxicity; ZAP-70 protein
• ISSN: 0007-0920; 1532-1827
• DOI: 10.1038/s41416-018-0074-1

Background Treatment with PD-1 inhibitors can be hampered by severe auto-immune-related toxicities. Our objective was to identify single-nucleotide polymorphisms (SNPs) in genes previously associated with auto-immunity, which are associated with toxicities in nivolumab-treated NSCLC patients. This was in order to identify patients prone to develop severe toxicities and to gain more insight into the underlying pathobiology. Methods We analysed 322 nivolumab-treated patients and assessed the association with toxicities for seven SNPs in four genes, which are considered contributors to PD-1-directed T-cell responses, i.e., PDCD1 , PTPN11 , ZAP70 and IFNG . Every SNP was tested for its association with toxicity endpoints. Significant associations were tested in a validation cohort. Results A multivariable analysis in the exploration cohort showed that homozygous variant patients for PDCD1 804C>T (rs2227981) had decreased odds for any grade treatment-related toxicities ( n  = 96; OR 0.4; 95% CI 0.2–1.0; p  = 0.039). However, this result could not be validated ( n  = 85; OR 0.9; 95% CI 0.4–1.9; p  = NS). Conclusions Our results show that it is unlikely that the investigated SNPs have a clinical implication in predicting toxicity. A finding, even though negative, that is considered timely and instructive towards further research in biomarker development for checkpoint inhibitor treatments.