EGFR intron 1 dinucleotide repeat polymorphism is associated with the occurrence of skin rash with gefitinib treatment

Background: Skin rash is the most common toxicity of epidermal growth factor receptor (EGFR)-targeted therapy. This study investigated the clinical and genetic factors associated with this skin rash. Methods: Fifty-two non-small cell lung cancer patients enrolled in a clinical trial of first-line gefitinib treatment were genotyped for EGFR intron I CA repeat ([CA]n) polymorphism and single nucleotide polymorphisms at G-216T, C-191A, and R521 K. The severity of skin rash was correlated with the genotypic and clinicopathological features. Results: Seventeen patients (32.7%) developed grade 2-3 skin rashes within 4 weeks of treatment (early G2/3 rash). In the multivariate logistic regression analysis, only the [CA]n genotype was correlated with early G2/3 rash; and this relationship was modified by age. Early G2/3 rash developed in 21% of patients with homozygous long allele (19-22 repeats, L) genotype, 31% with heterozygous short allele (15-18 repeats, S)/L genotype, and 71% with S/S genotype, respectively. The estimated logarithm of odds ratio (in OR) for early G2/3 rash, as compared to S/S genotype, for S/L genotype was -0.038 multiplied by age (P=0.011): and the In OR for L/L genotype was -0.050 multiplied by age (P=0.004). Early G2/3 rash was correlated with tumor response in the multiple logistic regression analysis (P=0.027). However, the [CA]n genotype was not significantly correlated with tumor response (P=0.35). Conclusions: EGFR [CA]n genotype appears to be a useful predictive marker of the development of skin rashes with gefitinib treatment. (C) 2008 Elsevier Ireland Ltd. All rights reserved.