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© 2002 American Society for Clinical Oncology
Combined Chemotherapy Trials Require Combined Pharmacogenetic Approaches
University of Rostock, Rostock, Germany
To the Editor:The topoisomerase I inhibitor irinotecan is increasingly being used in combined cytotoxic drug regimens for the treatment of solid cancers.1 One current approach consists of the combination of irinotecan with raltitrexed, a potent thymidylate synthase inhibitor. In an attempt to gain insight into the molecular determinants of the toxicity profile of this folate-based thymidylate synthase inhibitor, Stevenson et al,2 in the October 15, 2001, issue of the Journal of Clinical Oncology, focused on a polymorphic variant of methylenetetrahydrofolate reductase (MTHFR) consisting of a C Several points need to be carefully considered in order to avoid misleading conclusions. Indeed, preliminary evidence has been published indicating that the MTHFR C677T polymorphism might be considered as a pharmacogenetic syndrome. It seems to affect the toxicity profile of the antifolate drug methotrexate in bone marrow transplantation,3 although reservations exist as related to the causal association between MTHFR genotype and drug-induced toxicity.4 Unfortunately, neither the irinotecan/raltitrexed trial2 nor the methotrexate study4 considered the presence of a second polymorphic MTHFR variant (A1298C) known to be associated with reduced enzyme activity.5,6 In addition, the impact of further polymorphic variants in enzymes involved in folate and methionine metabolism, including methionine synthase A2756G,7 has not been explored. The study published by Stevenson et al2 related clinical toxicity data in a combined chemotherapy trial to inherited metabolic features of only one of the chemotherapeutic agents administered (raltitrexed). The potential contribution of irinotecan pharmacogenetics to the toxicity profile has neither been assessed nor discussed. This is surprising given the fact that irinotecan itself has been implicated in a pharmacogenetic syndrome causing substantial drug-induced toxicity.8 Irinotecan’s active compound, SN-38, is detoxified by inactivating metabolic pathways consisting predominantly of glucuronide conjugation catalyzed by liver microsomal uridine diphosphate glucuronosyltransferase UGT1A1. Allelic (TA)n variants in the UGT1A1 promoter region with decreased enzyme activity are associated with impaired SN-38 conjugation and drug toxicity. A recent pharmacogenetic analysis revealed that aberrant UGT1A1 promoter alleles represent a significant risk factor for severe irinotecan toxicity. The presence of either heterozygosity or homozygosity for the UGT1A1 (TA)7 allele confers a high risk (odds ratio, 7.2; 95% confidence interval, 2.5 to 22.3) for severe irinotecan toxicity.9 Considering the widespread occurrence of the UGT1A1 (TA)7 allele, it is tempting to speculate that the toxicity observed in the irinotecan/raltitrexed study was confounded by the coexistence of this pharmacogenetic syndrome. Therefore, the investigation of clinical toxicity in cancer patients undergoing drug therapy consisting of several different chemotherapeutic agents calls for the application of a combined pharmacogenetic approach depending on the metabolism of the drugs under con-sideration. REFERENCES
1.
Vanhoefer U, Harstrick A, Achterrath W, et al: Irinotecan in the treatment of colorectal cancer: clinical overview. J Clin Oncol 19: 1501-1518, 2001
2.
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: 4081-4087, 2001
3.
Ulrich CM, Yasui Y, Storb R, et al: Pharmacogenetics of methotrexate: Toxicity among marrow transplantation patients varies with the methylenetetrahydrofolate reductase C677T polymorphism. Blood 98: 231-234, 2001
4.
Matsuo K, Suzuki R, Morishima Y, et al: Attribution of posttransplantation toxicity to methotrexate regarding genotype of methylenetetrahydrofolate reductase gene (MTHFR) polymorphism needs further clarification. Blood 98: 2283-2284, 2001 5. Van der Put NM, Gabreels F, Stevens EM, et al: A second common mutation in the methylenetetrahydrofolate reductase gene: An additional risk factor for neural-tube defects? Am J Hum Genet 62: 1044-1051, 1998[CrossRef][Medline]
6.
Weisberg IS, Jacques PF, Selhub J, et al: The 1298A 7. Tsai MY, Bignell M, Yang F, et al: Polygenic influence on plasma homocysteine: Association of two prevalent mutations, the 844ins68 of cystathionine beta-synthase and A2756G of methionine synthase, with lowered plasma homocysteine levels. Atherosclerosis 149: 131-137, 2000[CrossRef][Medline]
8.
Innocenti F, Iyer L, Ratain MJ: Pharmacogenetics of anticancer agents: Lessons from amonafide and irinotecan. Drug Metab Dispos 29: 596-600, 2001
9.
Ando Y, Saka H, Ando M, et al: Polymorphisms of UDP-glucuronosyltransferase gene and irinotecan toxicity: A pharmacogenetic analysis. Cancer Res 60: 6921-6926, 2000
ResponseUniversity of Pennsylvania, Philadelphia, PA In 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. REFERENCES 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: 4081-4087, 2001 2. 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)
3.
Barbaux S, Kluijtmans LA, Whitehead AS: Accurate and rapid "multiplex heteroduplexing" method for genotyping key enzymes involved in folate/homocysteine metabolism. Clin Chem 46: 907-912, 2000
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Copyright © 2002 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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T transition at nucleotide 677, which leads to a thermolabile enzyme with impaired activity. On the basis of data from a small number of patients (n = 33), of whom seven tested homozygous for the 677T genotype, the authors concluded that genotyping may be predictive of clinical raltitrexed toxicity. 
