Relationship between single nucleotide polymorphisms and haplotypes in DPYD and toxicity and efficacy of capecitabine in advanced colorectal cancer.

Abstract

PURPOSE:

To explore the effect of dihydropyrimidine dehydrogenase (DPD) single nucleotide polymorphisms (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 IVS14+1G>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 IVS14+1G>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 IVS14+1G>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) = 0.57 (0.35-0.95)].

CONCLUSIONS:

DPYD IVS14+1G>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.

• Authors: Maarten J Deenen, Jolien Tol, Artur M Burylo, Valerie D Doodeman, Anthonius de Boer, Andrew Vincent, Henk-Jan Guchelaar, Paul H M Smits, Jos H Beijnen, Cornelis J A Punt, Jan H M Schellens, Annemieke Cats
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 17 Issue 10 Pg. 3455-68 (May 15 2011) ISSN: 1557-3265 [Electronic] United States
• PMID: 21498394 (Publication Type: Journal Article, Multicenter Study, Research Support, Non-U.S. Gov't)
• Copyright: ©2011 AACR.

Chemical References

• Antimetabolites, Antineoplastic
• Biomarkers, Pharmacological
• Biomarkers, Tumor
• Deoxycytidine
• Capecitabine
• Dihydrouracil Dehydrogenase (NADP)
• Fluorouracil

Topics

• Adult
• Aged
• Aged, 80 and over
• Antimetabolites, Antineoplastic (administration & dosage, adverse effects, therapeutic use)
• Biomarkers, Pharmacological (metabolism)
• Biomarkers, Tumor (genetics)
• Capecitabine
• Carcinoma (drug therapy, genetics)
• Case-Control Studies
• Clinical Trials, Phase III as Topic
• Cohort Studies
• Colorectal Neoplasms (drug therapy, genetics)
• Deoxycytidine (administration & dosage, adverse effects, analogs & derivatives, therapeutic use)
• Dihydrouracil Dehydrogenase (NADP) (genetics, metabolism)
• Disease Progression
• Dose-Response Relationship, Drug
• Drug-Related Side Effects and Adverse Reactions (genetics)
• Female
• Fluorouracil (administration & dosage, adverse effects, analogs & derivatives, therapeutic use)
• Haplotypes
• Humans
• Male
• Middle Aged
• Polymorphism, Single Nucleotide (physiology)
• Randomized Controlled Trials as Topic
• Retrospective Studies
• Treatment Outcome