Combined Chemotherapy Trials Require Combined Pharmacogenetic Approaches
Authors: Michael Steiner, Peter Schuff-Werner, Mathias Freund, Claus-Henning Köhne, James P. Stevenson, Alexander S. Whitehead, Peter J. O’Dwyer
Journal: Journal of Clinical Oncology (2002)

Article Tools SPECIAL DEPARTMENTS Article Tools OPTIONS & TOOLS Export Citation Track Citation Add To Favorites Rights & Permissions COMPANION ARTICLES No companion articles ARTICLE CITATION DOI: 10.1200/JCO.2002.20.5.1425 Journal of Clinical Oncology - published online before print September 21, 2016 PMID: 11870191 Combined Chemotherapy Trials Require Combined Pharmacogenetic Approaches Michael SteinerxMichael SteinerSearch for articles by this author , Peter Schuff-WernerxPeter Schuff-WernerSearch for articles by this author , Mathias FreundxMathias FreundSearch for articles by this author , Claus-Henning KöhnexClaus-Henning KöhneSearch for articles by this author James P. StevensonxJames P. StevensonSearch for articles by this author , Alexander S. WhiteheadxAlexander S. WhiteheadSearch for articles by this author , Peter J. O’DwyerxPeter J. O’DwyerSearch for articles by this author Show More University of Rostock, Rostock, GermanyTechnical University of Dresden, Dresden, GermanyUniversity of Pennsylvania, Philadelphia, PA https://doi.org/10.1200/JCO.2002.20.5.1425 First Page Full Text PDF Figures and Tables © 2002 by American Society of Clinical OncologyjcoJ Clin OncolJournal of Clinical OncologyJCO0732-183X1527-7755American Society of Clinical OncologyResponse01032002In Reply:Our initial intent to study the methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism was based on the fact that a large body of data already existed regarding its effect on folate physiology and its obvious potential impact in patients receiving antifolate thymidylate synthase inhibitors such as raltitrexed. This was an exploratory analysis, and because there were no ongoing raltitrexed monotherapy trials, we chose to focus on the toxicities most likely to be associated with raltitrexed in our irinotecan combination study.1 We reasoned that the lack of substantial overlapping toxicity between irinotecan and raltitrexed would allow us to discern a relationship of toxicity to the polymorphism. Notwithstanding the potential for confounding effects, the C677T homozygotes clearly had minimal chemotherapy-associated toxicity. We are prospectively studying the A1298C methylenetetrahydrofolate reductase genotype as well as other polymorphic variants of enzymes involved in the folate/homocysteine axis in additional cohorts of patients.We are aware of the data regarding UGT1A1 TATA promoter polymorphisms and irinotecan-induced diarrhea. However, we would note that a recent report by White et al2 found no association between those heterozygous or homozygous for the mutant (TA)7 allele and diarrhea in 63 patients receiving irinotecan. We suspect that individual variation in other enzymes involved in irinotecan biotransformation, such as carboxylesterases, CYP3A, and beta-glucuronidases, may influence irinotecan toxicity as well.Dr Steiner and colleagues raise valid points regarding pharmacogenetic end points. Our hypothesis was that polymorphisms in folate metabolism would be a determinant of toxicity. Additional studies may find that such effects are multifactorial. One can envision the use of pharmacogenetic “panels” designed for specific classes of agents that would be easily applied to patient DNA samples, especially with the use of the multiplexed heteroduplexing method.3 We believe our results add to the mounting evidence in support of a genetic basis for individual variation in the pharmacology of cancer chemotherapeutics.1. Stevenson JP, Redlinger M, Kluijtmans LAJ, et al: Phase I clinical and pharmacogenetic trial of irinotecan and raltitrexed administered every 21 days to patients with cancer. J Clin Oncol 19:: 4081,2001-4087, Link, Google Scholar2. White SC, Gurtler V, Eades S, et al: CPT-11 (irinotecan) and polymorphism in the promoter of UDP-glucuronosyltransferase 1 gene. Proc Am Soc Clin Oncol 20:: 74a,,2001 (abstr 294) Google Scholar3. Barbaux S, Kluijtmans LA, Whitehead AS: Accurate and rapid “multiplex heteroduplexing” method for genotyping key enzymes involved in folate/homocysteine metabolism. Clin Chem 46:: 907,2000-912, Medline, Google Scholar