Originally published as JCO Early Release 10.1200/JCO.2008.19.0314 on April 13 2009

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Predictive Role of the UGT1A1, UGT1A7, and UGT1A9 Genetic Variants and Their Haplotypes on the Outcome of Metastatic Colorectal Cancer Patients Treated With Fluorouracil, Leucovorin, and Irinotecan

From the Experimental and Clinical Pharmacology Unit and Medical Oncology Unit, Centro di Riferimento Oncologico, National Cancer Institute, Aviano; Medical Oncology Unit, San Filippo Neri Hospital, Rome, Italy; and Department of Medicine, Cancer Research Center, University of Chicago, Chicago, IL.

Corresponding author: Giuseppe Toffoli, MD, Experimental and Clinical Pharmacology Unit, Centro di Riferimento Oncologico, National Cancer Institute, via Franco Gallini, 2, 33081, Aviano, Italy; e-mail: gtoffoli{at}cro.it.

Purpose UGT1A128 is considered the main pharmacogenetic predictor of the toxicity outcome of irinotecan-treated patients. We evaluated the effect of other UGT1A variants and haplotypes involved in 7-ethyl-10-hydroxycamptothecin (SN-38) glucuronidation on severe toxicity and efficacy of fluorouracil, leucovorin, and irinotecan (FOLFIRI).

Patients and Methods In addition to UGT1A128, UGT1A160, UGT1A193, UGT1A73, and UGT1A922 were genotyped in 250 metastatic colorectal cancer patients, and associations with severe hematologic and nonhematologic toxicity, objective response, time to progression (TTP), and overall survival were evaluated. In a subset of 71 patients, pharmacokinetic data were also available.

Results UGT1A73 was the only marker of severe hematologic toxicity after the first cycle (odds ratio [OR], 3.94; 95% CI, 1.05 to 14.82; P = .04) in a multivariate analysis. It was also associated with glucuronidation ratio (SN-38G area under the curve [AUC]/SN-38 AUC) and biliary index (irinotecan AUC) x (SN-38 AUC/SN-38G AUC). Haplotype I (all the reference sequence alleles but UGT1A922) was a predictor of severe hematologic toxicity during the entire course of therapy (OR, 0.39; 95% CI, 0.19 to 0.82; P = .01), together with sex (OR, 2.08; 95% CI, 1.01 to 4.28; P = .05). In addition to UGT1A128, haplotype II (all the variant alleles but UGT1A922) was associated with a response rate (OR, 8.61; 95% CI, 1.75 to 42.38; P = .01). UGT1A128 was the only marker associated with TTP.

Conclusion We propose that UGT1A variants additional to UGT1A128 might improve the prediction of the outcome of colorectal cancer patients treated with FOLFIRI. A UGT1A haplotype-based approach might be an efficacious strategy to achieve treatment individualization of FOLFIRI.

Terms in blue are defined in the glossary, found at the end of this article and online at www.jco.org.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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				J. M. Hoskins and H. L. McLeod UGT1A and Irinotecan Toxicity: Keeping It in the Family J. Clin. Oncol., May 20, 2009; 27(15): 2419 - 2421. [Full Text] [PDF]