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Journal of Clinical Oncology, Vol 25, No 30 (October 20), 2007: pp. 4855-4856 © 2007 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.13.4577
In ReplyProject Team for Pharmacogenetics, National Institute of Health Sciences; Division of Medicinal Safety Sciences, National Institute of Health Sciences; Division of Biochemistry and Immunochemistry, National Institute of Health Sciences, Setagaya, Tokyo, Japan
Hepatobiliary and Pancreatic Oncology Division, National Cancer Center Hospital East, Kashiwa, Chiba, Japan
Genetics Division, Research Institute, National Cancer Center, Tsukiji, Tokyo, Japan
Hepatobiliary and Pancreatic Oncology Division, National Cancer Center Hospital, Tsukiji, Tokyo, Japan
National Cancer Center Hospital East, Kashiwa, Chiba, Japan We appreciate the comments raised by Mercier et al and the opportunity to respond to them. We agree that the reduced intracellular CDA level is one of the major factors increasing gemcitabine-mediated toxicities. We also recognize that the genotyping based on CDA 208G>A (Ala70Thr) itself gives false-negative results with respect to the prediction of hematological toxicities (Table 7 in our article1), as is often the case with genotyping. Thus, phenotype-based methods are useful for identification of patients at a higher risk toward gemcitabine-mediated toxicities. However, as far as Japanese patients are concerned, the genetic method is fairly useful for predicting severe toxicities of gemcitabine because CDA 208G>A, a tagging SNP of haplotype CDA*3, is one of the factors that reduce CDA activity as clearly demonstrated by us.1 According to the letter by Mercier et al, four patients displayed severe hematologic toxicities (> grade 3) without any associations with CDA genotypes in their study. Their observations are quite reasonable from the following points: CDA 208G>A has not been detected in white people, and its allele frequency is relatively low in other populations (probably variable within African populations2,3; only nine Africans and one Asian were included in their study); all other genetic polymorphisms that we detected, including CDA 79A>C (*2, Lys27Gln),4,5 failed to show any significant associations with altered pharmacokinetics and toxicities of gemcitabine and plasma CDA activity.1 Therefore, we consider that, in white people, no validated genotype is currently available for predicting gemcitabine toxicities.
Mercier et al pointed out that little correlation was evident among the various diplotype groups, the pharmacokinetic parameters of gemcitabine, and the occurrence of severe toxicities, other than the *3/*3 diplotype recorded in the single patient. However, as presented in our article,1 significant differences were observed between *3/*1 and *1/*1 for pharmacokinetic parameters (our Fig 2), and the incidences of grade
In order to reply to the comments by Mercier et al, we re-evaluated the association between grade 4 neutropenia and gemcitabine area under the curve (AUC) or CDA activity (one patient with an extremely high level was excluded) either for the monotherapy or the combined therapy (fluorouracil, carboplatin, or cisplatin) group by the Mann-Whitney test. The median values of AUC were higher in the grade 4 group than in the grade Taken together, both predictive genotype (*3) and phenotype markers, gemcitabine AUC and plasma CDA activity, could predict grade 4 neutropenia, but with some false-negative cases and with increased false-positive cases for AUC and plasma CDA. At least, CDA 208G>A is a useful marker to predict gemcitabine toxicities in Japanese and probably East Asians. AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest. ACKNOWLEDGMENTS Supported in part by the Program for the Promotion of Fundamental Studies in Health Sciences, and the Health and Labour Sciences Research grant (Research on Human Genome, Tissue Engineering) from the Ministry of Health, Labour and Welfare. REFERENCES
1. Sugiyama E, Kaniwa N, Kim S-R, et al: Pharmacokinetics of gemcitabine in Japanese cancer patients: The impact of a cytidine deaminase polymorphism. J Clin Oncol 25:32-42, 2007 2. Gilbert JA, Salavaggione OE, Ji Y, et al: Gemcitabine pharmacogenomics: Cytidine deaminase and deoxycytidylate deaminase gene resequencing and functional genomics. Clin Cancer Res 12:1794-1803, 2006 3. Fukunaga AK, Marsh S, Murry DJ, et al: Identification and analysis of single-nucleotide polymorphisms in the gemcitabine pharmacologic pathway. Pharmacogenomics J 4:307-314, 2004[CrossRef][Medline] 4. Kirch HC, Schroder J, Hoppe H, et al: Recombinant gene products of two natural variants of the human cytidine deaminase gene confer different deamination rates of cytarabine in vitro. Exp Hematol 26:421-425, 1998[Medline] 5. Thompson PW, Jones DD, Currey HLF: Cytidine deaminase activity as a measure of acute inflammation in rheumatoid arthritis. Annals Rheum Dis 45:9-14, 1986
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Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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3 or grade 4 neutropenia in the combined chemotherapies with fluorouracil or platinum-containing drugs were mostly higher in the non-*3/*3 patients than in the non-*3/non-*3 patients (Table 7). Our Figures 3A (gemcitabine as a substrate) and 3B (cytidine as a substrate) show that when plasma CDA activities of the *3/*1 and *3/*2 patients were compared with those of the *1/*1 patients by Dunn's multiple comparison test, statistically significant differences were obtained (P < .001 and <0.05 for *3/*1 and *3/*2 groups, respectively, in Fig 3A; P < .001 for *3/*1 group in Fig 3B; P values were not provided in our report).
3 group (
, +9% for the monotherapy; 
