Predictive Biomarkers and Personalized Medicine Relationship between Single Nucleotide Polymorphisms and Haplotypes in DPYD and Toxicity and Efficacy of Capecitabine in Advanced Colorectal Cancer Maarten J. Deenen 1,2 , Jolien Tol 7 , Artur M Burylo 2 , Valerie D. Doodeman 2 , Anthonius de Boer 8 , Andrew Vincent 3 , Henk-Jan Guchelaar 10 , Paul H.M. Smits 5 , Jos H. Beijnen 6,9 , Cornelis J.A. Punt 7 , Jan H.M. Schellens 1,2,9 , and Annemieke Cats 4 Abstract Purpose: To explore the effect of dihydropyrimidine dehydrogenase (DPD) single nucleotide poly- morphisms (SNP) and haplotypes on outcome of capecitabine. Experimental Design: Germline DNA was available from 568 previously untreated patients with advanced colorectal cancer participating in the CAIRO2 trial, assigned to capecitabine, oxaliplatin, and bevacizumab  cetuximab. The coding region of dihydropyrimidine dehydrogenase gene (DPYD) was sequenced in 45 cases with grade 3 or more capecitabine-related toxicity and in 100 randomly selected controls (cohort). Most discriminating (P < 0.1) or frequently occurring (>1%) nonsynonymous SNPs were analyzed in all 568 patients. SNPs and haplotypes were associated with toxicity, capecitabine dose modifications, and survival. Results: A total of 29 SNPs were detected in the case–cohort analysis, of which 8 were analyzed in all 568 patients. Of the patients polymorphic for DPYD IVS14þ1G>A, 2846A>T, and 1236G>A, 71% (5 of 7), 63% (5 of 8), and 50% (14 of 28) developed grade 3 to 4 diarrhea, respectively, compared with 24% in the overall population. All patients polymorphic for IVS14þ1G>A developed any grade 3 to 4 toxicity, including one possibly capecitabine-related death. Because of toxicity, a mean capecitabine dose reduction of 50% was applied in IVS14þ1G>A and 25% in 2846A>T variant allele carriers. Patients were categorized into six haplotype groups: one predicted for reduced (10%), and two for increased risks (41% and 33%) for severe diarrhea. Individual SNPs were not associated with overall survival, whereas one haplotype was associated with overall survival [HR (95% CI) ¼ 0.57 (0.35–0.95)]. Conclusions: DPYD IVS14þ1G>A and 2846A>T predict for severe toxicity to capecitabine, for which patients require dose reductions. Haplotypes assist in selecting patients at risk for toxicity to capecitabine. Clin Cancer Res; 17(10); 3455–68. Ó2011 AACR. Introduction Colorectal cancer is the second most frequent cause of cancer-related death in the Western world (1, 2). At early stages, resection with a curative intent is the first choice of therapy, but chemotherapy remains the backbone of treat- ment of irresectable, metastasized colorectal cancer (3). Commonly used chemotherapeutics are oxaliplatin, irino- tecan, and fluoropyrimidines such as capecitabine and 5- fluorouracil (5-FU; refs. 4–9). Recently, the addition of targeted agents against the VEGF or EGFR (epidermal growth factor receptor) has shown to improve survival, and the current first-line standard treatment of metastatic colorectal cancer is fluoropyrimidine-based chemotherapy plus bevacizumab (10–12). Although fluoropyrimidine drugs are generally well tol- erated, approximately 10% of the patients suffer from Authors’ Affiliations: 1 Division of Clinical Pharmacology, Department of Medical Oncology, 2 Department of Experimental Therapy, 3 Bio- metrics Department, and 4 Division of Gastroenterology and Hepatol- ogy, Department of Medical Oncology, The Netherlands Cancer Institute; Departments of 5 Molecular Biology and 6 Pharmacy & Phar- macology, Slotervaart Hospital, Amsterdam; 7 Department of Medical Oncology, Radboud University Nijmegen Medical Centre, Nijmegen; 8 Faculty of Science, Department of Pharmaceutical Sciences, Division of Pharmacoepidemiology and Pharmacotherapy; 9 Faculty of Science, Department of Pharmaceutical Sciences, Division of Biomedical Ana- lysis, Utrecht University, Utrecht; and 10 Department of Clinical Phar- macy and Toxicology, Leiden University Medical Center, Leiden, the Netherlands Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/). Corresponding Author: Annemieke Cats, Division of Gastroenterology and Hepatology, Department of Medical Oncology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands. Phone: 31-20-512-2566; Fax: 31-20-512-2572. E-mail: a.cats@nki.nl doi: 10.1158/1078-0432.CCR-10-2209 Ó2011 American Association for Cancer Research. Clinical Cancer Research www.aacrjournals.org 3455 Research. on May 29, 2020. © 2011 American Association for Cancer clincancerres.aacrjournals.org Downloaded from Published OnlineFirst April 15, 2011; DOI: 10.1158/1078-0432.CCR-10-2209