Epidermal growth factor receptor polymorphisms and risk for toxicity in paediatric patients treated with gefitinib |
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| Authors: | Trevor McKibbin Wei Zhao Michael Tagen Najat C Daw Wayne L Furman Lisa M McGregor J Russell Geyer Jeffrey W Allen Clinton F Stewart |
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| Institution: | 1. Department of Clinical Pharmacy, University of Tennessee, Memphis, TN, United States;2. Department of Biostatistics, St. Jude Children’s Research Hospital, Memphis, TN, United States;3. Department of Pharmaceutical Sciences, St. Jude Children’s Research Hospital (SJCRH), Memphis, TN, United States;4. Department of Oncology, St. Jude Children’s Research Hospital, Memphis, TN, United States;5. Children’s Hospital and Medical Center, Seattle, WA, United States;6. University of Tennessee Cancer Institute, Memphis, TN, United States;1. School of Pharmacy and Graduate Institute, College of Pharmacy, China Medical University, Taichung, Taiwan, ROC;2. Department of Pharmacy, China Medical University Hospital, Taichung, Taiwan, ROC;3. Department of Cosmetic Science, Providence University, Taichung, Taiwan, ROC;1. Laboratory for Medical Microbiology and Medical Immunology, Meander Medical Centre, Amersfoort, The Netherlands;2. University of Groningen, University Medical Centre Groningen, Department of Medical Microbiology and Infection Prevention, Groningen, The Netherlands;3. Department of Hygiene and Infection Prevention, Meander Medical Centre, Amersfoort, The Netherlands;4. Department of Pathology, University of Utah School of Medicine, Salt Lake City, UT, USA;1. Department of Radiation Oncology, National Cancer Institute-Designated Comprehensive Cancer Center, University of California Davis School of Medicine, Sacramento, CA 95817, USA;2. Department of Medical Microbiology and Immunology, University of California Davis, Davis, CA 95616, USA;3. Departments of Biochemistry and Molecular Medicine and Psychiatry and Behavioral Sciences, University of California Davis School of Medicine, Davis, CA 95616, USA;4. Department of Radiation Oncology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA;5. Department of Radiation and Cellular Oncology, University of Chicago, Chicago, IL 60637, USA;1. Department of Pathology, The Johns Hopkins University, Baltimore, MD 21287, USA;2. Department of Oncology, The Johns Hopkins University, Baltimore, MD 21287, USA;3. Department of Gynecology and Obstetrics, The Johns Hopkins University, Baltimore, MD 21287, USA |
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| Abstract: | PurposeTo investigate associations between germline genetic variations in the epidermal growth factor receptor (EGFR) and toxicity in paediatric patients treated with gefitinib.Patients and methodsGefitinib treatment and toxicity data from five paediatric clinical trials were combined. EGFR genotypes evaluated included –191C>A, –216G>T, Arg497Lys and intron 1 CA sequence repeat number. The genetic variations were evaluated for associations with grade one or greater rash or diarrhoea during the first course of treatment.ResultsThe analysis included 110 patients, 60 (55%) with grade one or greater rash and 47 (43%) with grade one or greater diarrhoea. Among patients with the –216 GG (n = 51), GT (n = 41) and TT (n = 16) genotypes, grade one or greater rash occurred in 52.9%, 46.3% and 87.5% of patients (p = 0.003, recessive model), respectively. Diarrhoea occurred in 27.5%, 58.5% and 43.8% of patients with respective GG, GT and TT genotypes (p = 0.004, dominant model). The –191C>A, intron 1 CA repeat number and Arg497Lys genotypes were not significantly associated with either rash or diarrhoea. EGFR –216 and –191 polymorphisms were in linkage disequilibrium (D′ = 0.66, p = 0.01). The haplotype (–191C, –216T) was associated with increased risk for rash (p = 0.049), but was not more predictive of rash than the single –216 polymorphism.ConclusionThese findings indicate that EGFR –216G>T genotype is a predictive marker for the development of skin rash and diarrhoea in paediatric patients treated with gefitinib. Continued investigation of relationships between germline EGFR polymorphisms and the efficacy of EGFR inhibitors in paediatric patients is warranted. |
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