title: Pharmacogenetic predictors for EGFR-inhibitor-associated skin toxicity.
abstract: The aim of this study was to investigate pharmacogenetic determinants of skin rash associated with epidermal growth factor receptor (EGFR) inhibitor treatment. A total of 109 prospectively sampled cancer patients, receiving the first treatment with an EGFR inhibitor, were genotyped for functional EGFR polymorphisms and tagging variants in genes involved in receptor downstream signaling. Skin rash was absent in 26 (23.9%) patients and associated with shorter overall survival compared with patients presenting skin rash (P=0.005). The EGFR polymorphisms, 497G/A (P=0.008), and the haplotypes of the promoter variants, EGFR-216G/T and -191C/A (P=0.029), were associated with the appearance of skin rash. In addition, a common haplotype in the PIK3CA gene was associated with skin rash (P=0.045) and overall survival (P=0.009). In conclusion, genetic variation within the EGFR gene and its downstream signaling partner PIK3CA might predict EGFR-inhibitor-related skin rash.
authors.affiliation: Institute of Pharmacology of Natural Products and Clinical Pharmacology, University of Ulm, Helmholtzstrasse 20, Ulm, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Parmar
authors.forename: C
authors.initials: C
authors.lastname: Schumann
authors.forename: S
authors.initials: S
authors.lastname: Rüdiger
authors.forename: S
authors.initials: S
authors.lastname: Boeck
authors.forename: V
authors.initials: V
authors.lastname: Heinemann
authors.forename: V
authors.initials: V
authors.lastname: Kächele
authors.forename: A
authors.initials: A
authors.lastname: Seeringer
authors.forename: T
authors.initials: T
authors.lastname: Paul
authors.forename: T
authors.initials: T
authors.lastname: Seufferlein
authors.forename: J C
authors.initials: JC
authors.lastname: Stingl
mesh_terms: D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000009:adverse effects; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage / Q000009:adverse effects; D000068818:Cetuximab; D058534:Class I Phosphatidylinositol 3-Kinases; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics*; D000069347:Erlotinib Hydrochloride; D005076:Exanthema / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology; D005260:Female; D000077156:Gefitinib; D056726:Genetic Association Studies; D006239:Haplotypes; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D000077544:Panitumumab; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects*; D011799:Quinazolines / Q000008:administration & dosage / Q000009:adverse effects
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D000077544:Panitumumab; D000069347:Erlotinib Hydrochloride; D019869:Phosphatidylinositol 3-Kinases; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human; C512478:EGFR protein, human; D066246:ErbB Receptors; D000068818:Cetuximab; D000077156:Gefitinib