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

Abstract

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 1 CA repeat ([CA]n) polymorphism and single nucleotide polymorphisms at G-216T, C-191A, and R521K. 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 (ln 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 ln 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.