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Journal of Clinical Oncology, Vol 25, No 30 (October 20), 2007: pp. 4855 © 2007 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.13.3918
Genotype-Based Methods for Anticipating Gemcitabine-Related Severe Toxicities May Lead to False-Negative ResultsEA3286, Medical Oncology Unit, La Timone University Hospital, Marseille, France
Toxicology Unit, Carémeau University Hospital, Nîmes, France
EA3286, Pharmacokinetics Laboratory, Université de la Mediterranée, Marseille, France To the Editor: In their recently published clinical study, Sugiyama et al1 investigated the effects of cytidine deaminase (CDA) genetic polymorphisms on gemcitabine toxicities and altered pharmacokinetics. They conclude, from the observation of a single Japanese patient with the nonsynonimous mutation 208G > A (Ala70Thr) and displaying an abnormal gemcitabine pharmacokinetic profile resulting in subsequent neutropenia, that haplotype *3 harboring the 208 G more than A single nucleotide polymorphism (SNP) could be associated with the occurrence of severe toxicities after gemcitabine administration, and possibly, in combination with other chemotherapy regimens. Such a patient with severe toxicities was actually, repeatedly selected out of a group of five,2 and then 2561 carcinoma patients for whom linkage disequilibrium and haplotype analyses were performed in relation to CDA activities, gemcitabine pharmacokinetics analyses, and toxicity monitoring. Little correlation was evidenced 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. Surprisingly, little impact was also reported between CDA activities and gemcitabine exposure levels, an observation contradictory to the pharmacokinetics of this drug,3 and no data on a possible relationship between CDA phenotypic status and gemcitabine-related toxicities was reported. Finally, although Sugiyama et al claimed that plasma CDA activities correlated well with the CDA genotypes, it was not clear by their data whether the difference was statistically significant, apart from the homozygous *3 carrier. At our institute, we have phenotyped CDA activity and performed genetic screening, including of the 208G > A mutation reported by Sugiyama et al, in 80 cancer patients (70 white, nine African, and one Asian patient) treated with gemcitabine alone or as part of combinational therapies with platinum derivatives or capecitabine. Four (5%) of 80 patients displayed severe, hematologic toxicities (eg, higher than grade 3 by the National Cancer Institute Common Toxicity Criteria), including a lethal one.4 We found that all four of these patients with severe toxicities had markedly lower CDA activities (mean deficiency, –75%) than those recorded in the 76 patients showing good gemcitabine tolerance. This observation strongly suggests that CDA downregulation was a culprit for increased toxicities with gemcitabine, including, for the first time, in the toxic-death case we reported. Conversely to what was reported by Sugiyama et al, genotypic screening at our institute failed to identify genetic polymorphisms associated with the occurrence of toxicities, since for instance, none of our four toxic patients exhibited the 208G > A (Ala70Thr) mutation. This observation is fully consistent with other studies describing controversies regarding genotype-to-phenotype associations with CDA,5,6 much likely due to the genetic and epigenetic regulations of the CDA gene that remain to be elucidated, and to the possible influence of ethnical origin in the relevance of particular single nucleotide polymorphisms.7 Taken together, in total contradiction with the Sugiyama study, our own experience strongly suggests that genotypic approaches are probably insufficient to identify patients at risk of gemcitabine toxicity, with an elevated risk of precluding the right diagnostic. Conversely, phenotype-based methods seem to be a safer strategy for ensuring a better outcome in the handling of gemcitabine, a major drug used extensively in clinical oncology. AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest. REFERENCES
1. Sugiyama E, Kaniwa N, Kim SR, et al: Pharmacokinetics of gemcitabine in Japanese cancer patients: The impact of a cytidine deaminase polymorphism. J Clin Oncol 25:32-42, 2007 2. Yonemori K, Ueno H, Okusaka T, et al: Severe drug toxicity associated with a single-nucleotide polymorphism of the cytidine deaminase gene in a Japanese cancer patient treated with gemcitabine plus cisplatin. Clin Cancer Res 11:2620-2624, 2005 3. Abbruzzese JL, Grunewald R, Weeks RA, et al: A phase I clinical, plasma, and cellular pharmacology of gemcitabine. J Clin Oncol 9:491-498, 1991[Abstract] 4. Mercier C, Raynal C, Dahan L, et al: Toxic death case in a patient undergoing gemcitabine-based chemotherapy in relation with cytidine deaminase down regulation. Pharmacogenetics 17:841-844, 2007 5. 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] 6. Schroder JK, Kirch C, Seeber S, et al: Structural and functional analysis of the cytidine deaminase gene in patients with acute myeloid leukaemia. Br J Haematol 103:1096-1103, 1998[CrossRef][Medline] 7. 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
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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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