title: Dosing to rash?--The role of erlotinib metabolic ratio from patient serum in the search of predictive biomarkers for EGFR inhibitor-mediated skin rash.
abstract: OBJECTIVE
  The aim of this study was to investigate if biomarkers of individual drug metabolism, respectively, the erlotinib/O-desmethyl-erlotinib metabolic ratio, may be a predictive factor for the severity of erlotinib-mediated skin rash in epidermal growth factor receptor (EGFR) inhibitor-treated patients suffering from epithelial cancers. This is especially important since it is known that the severity of skin rash has a prognostic value on outcome and survival in cancer patients experiencing skin rash under treatment with EGFR inhibitors.
  
  
  METHODS
  From 2008 to 2014, 96 patients, n = 63 suffering from histologically confirmed non-small-cell lung cancer and n = 33 from pancreatic adenocarcinoma were observed for the occurrence and severity of skin rash after the onset of treatment with erlotinib. The primary end-points (occurrence and severity of skin rash, progression-free survival [PFS] and overall survival [OS]) were analysed with regard to erlotinib and its metabolite O-desmethyl-erlotinib trough serum concentrations measured at 4 weeks after onset of therapy by the use of correlation, multiple regression and survival analysis.
  
  
  RESULTS
  Occurrence of skin rash was associated with PFS (p = 0.0042) and OS (p = 0.017) in the overall cohort of erlotinib-treated cancer patients. Drug-metabolising activity assessed by the erlotinib/O-desmethyl-erlotinib metabolic ratio was correlated with severity of skin rash (p = 0.023) and as well highly associated with both PFS (p = 2.1 × 10(-4)) and OS (p = 5.8 × 10(-5)).
  
  
  CONCLUSIONS
  The erlotinib/O-desmethyl-erlotinib metabolic ratio reflecting the individual metabolic activity of erlotinib correlated with the severity of skin rash and outcome in patients treated with EGFR tyrosine kinase inhibitors. The metabolic ratio determined in serum may be used for therapeutic monitoring in erlotinib treatment and decisions on individual dosing to rash in rash-negative patients.
authors.affiliation: Research Division, Federal Institute for Drugs and Medical Devices, Bonn, Germany; Centre for Translational Medicine, University Bonn Medical Faculty, Bonn, Germany. Electronic address: michael.steffens@bfarm-research.de.
authors.forename: Michael
authors.initials: M
authors.lastname: Steffens
authors.affiliation: Institute of Pharmacology of Natural Products and Clinical Pharmacology, University of Ulm, Ulm, Germany.
authors.forename: Tanusree
authors.initials: T
authors.lastname: Paul
authors.affiliation: Research Division, Federal Institute for Drugs and Medical Devices, Bonn, Germany; Centre for Translational Medicine, University Bonn Medical Faculty, Bonn, Germany.
authors.forename: Vivien
authors.initials: V
authors.lastname: Hichert
authors.affiliation: Research Division, Federal Institute for Drugs and Medical Devices, Bonn, Germany; Centre for Translational Medicine, University Bonn Medical Faculty, Bonn, Germany.
authors.forename: Catharina
authors.initials: C
authors.lastname: Scholl
authors.affiliation: Research Division, Federal Institute for Drugs and Medical Devices, Bonn, Germany; Centre for Translational Medicine, University Bonn Medical Faculty, Bonn, Germany.
authors.forename: Dirk
authors.initials: D
authors.lastname: von Mallek
authors.affiliation: IBMP-Institute for Biomedical and Pharmaceutical Research, Nürnberg, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Stelzer
authors.affiliation: IBMP-Institute for Biomedical and Pharmaceutical Research, Nürnberg, Germany; Department of Pharmacology, University of Duisburg-Essen, Essen, Germany.
authors.forename: Fritz
authors.initials: F
authors.lastname: Sörgel
authors.affiliation: Institute of Pharmacology of Natural Products and Clinical Pharmacology, University of Ulm, Ulm, Germany.
authors.forename: Bärbel
authors.initials: B
authors.lastname: Reiser
authors.affiliation: Department of Internal Medicine II, University of Ulm, Ulm, Germany; Pneumology, Thoracic Oncology, Sleep- and Respiratory Critical Care Medicine, Clinics Kempten-Oberallgäu, Kempten, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Schumann
authors.affiliation: Department of Internal Medicine II, University of Ulm, Ulm, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Rüdiger
authors.affiliation: Department of Internal Medicine III and Comprehensive Cancer Center, Ludwig-Maximilians-University of Munich, Munich, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Boeck
authors.affiliation: Department of Internal Medicine III and Comprehensive Cancer Center, Ludwig-Maximilians-University of Munich, Munich, Germany.
authors.forename: Volker
authors.initials: V
authors.lastname: Heinemann
authors.affiliation: Department of Internal Medicine I, University of Ulm, Ulm, Germany.
authors.forename: Volker
authors.initials: V
authors.lastname: Kächele
authors.affiliation: Department of Internal Medicine I, University of Ulm, Ulm, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Seufferlein
authors.affiliation: Research Division, Federal Institute for Drugs and Medical Devices, Bonn, Germany; Centre for Translational Medicine, University Bonn Medical Faculty, Bonn, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Stingl
mesh_terms: D000230:Adenocarcinoma / Q000097:blood / Q000188:drug therapy* / Q000201:enzymology / Q000401:mortality / Q000473:pathology; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects* / Q000097:blood / Q000493:pharmacokinetics; D001711:Biotransformation; D002289:Carcinoma, Non-Small-Cell Lung / Q000097:blood / Q000188:drug therapy* / Q000201:enzymology / Q000401:mortality / Q000473:pathology; D003640:Dealkylation; D018450:Disease Progression; D018572:Disease-Free Survival; D054796:Drug Dosage Calculations; D016903:Drug Monitoring / Q000379:methods; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000069347:Erlotinib Hydrochloride / Q000008:administration & dosage / Q000009:adverse effects* / Q000097:blood / Q000493:pharmacokinetics; D005076:Exanthema / Q000139:chemically induced* / Q000175:diagnosis; D005260:Female; D005858:Germany; D006801:Humans; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000201:enzymology / Q000401:mortality / Q000473:pathology; D008297:Male; D008875:Middle Aged; D010190:Pancreatic Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000201:enzymology / Q000401:mortality / Q000473:pathology; D011237:Predictive Value of Tests; D016016:Proportional Hazards Models; D011446:Prospective Studies; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects* / Q000097:blood / Q000493:pharmacokinetics; D012720:Severity of Illness Index
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D000069347:Erlotinib Hydrochloride; C512478:EGFR protein, human; D066246:ErbB Receptors
keywords: EGFR inhibitor-induced skin rash; Erlotinib metabolic ratio; Erlotinib/O-desmethyl-erlotinib ratio; Predictive biomarker