Abstract 1662: Association of EGFR and ABCG2 polymorphisms with gefitinib toxicity in non-small cell lung cancer patients

Abstract

Abstract The use of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), such as gefitinib and erlotinib, in non-small-cell lung cancer (NSCLC) patients is commonly associated with gastrointestinal (diarrhea) and skin (rash) toxicity. These adverse effects have a high interindividual variability, which might be partially explained by pharmacogenetic determinants. In particular, polymorphisms in EGFR and in ABCG2, an efflux transporter higly expressed in the gastrointestinal tract and able to transport gefitinib and other EGFR TKIs, might have an impact on gefitinib-associated toxicity. Therefore, the aim of our study was to evaluate associations between EGFR and ABCG2 polymorphisms with diarrhea and skin rash in gefitinib-treated NSCLC patients. Four polymorphisms in EGFR (CA repeat length in the intron-1 (CA)n, EGFR −191C/A, EGFR −216G/T and EGFR R497K) and one in ABCG2 (ABCG2 421C/A) were assessed in DNA isolated from blood samples and/or paraffin-embedded tumor tissue from 96 NSCLC patients treated with gefitinib. Significant associations between EGFR and ABCG2 variants and toxicity were evaluated using the Fisher's exact test. In total, 87 and 85 patients had available data on polymorphisms and skin and gastrointestinal toxicity, respectively. Diarrhea occurred in 33 (38.8%) of the 85 patients, with 6 of them experiencing high toxicity (grade=2-3 diarrhea). Skin rash was reported for 46 (52.9%) of the 87 patients, with 22 patients having grade>1. The EGFR −191C/A polymorphism was strongly associated with grade>1 diarrhea (P<0.01). Five (33.3%) of the 15 patients carrying the CA or AA genotype developed severe diarrhea compared with only 1 (1.4%) of the 70 CC patients. The EGFR −216G/T polymorphism was also associated with high grade (>1) diarrhea as all the patients who experienced grade 2 or 3 diarrhea carried the GG variant, while only 30.4% (24 out of 79) of the patients with low toxicity carried this variant (P<0.01). Similar findings were found for the EGFR R497K polymorphism, with severe diarrhea being observed in 3 (30%) of the 10 patients with the AA genotype and in 3 (4.1%) of the 74 patients carrying the GG or GA variants (P=0.02). In contrast, none of these EGFR polymorphisms had a significant association with skin toxicity. Additionally, we found no association between EGFR (CA)n and the ABCG2 421C/A polymorphism with either gastrointestinal or skin toxicity. In conclusion, our results demonstrate a clear association between the EGFR −191C/A, −216G/T and R497K with diarrhea in gefitinib-treated NSCLC patients, suggesting that these polymorphisms might be useful as pharmacogenetic markers for the selection of patients for treatment. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1662.