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

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

Research output: Contribution to journalArticleAcademicpeer-review

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.

Original languageEnglish
Pages (from-to)3455-68
Number of pages14
JournalClinical Cancer Research
Volume17
Issue number10
DOIs
Publication statusPublished - 2011

Keywords

  • Adult
  • Aged
  • Aged, 80 and over
  • Antimetabolites, Antineoplastic
  • Biomarkers, Pharmacological
  • Carcinoma
  • Case-Control Studies
  • Clinical Trials, Phase III as Topic
  • Cohort Studies
  • Colorectal Neoplasms
  • Deoxycytidine
  • Dihydrouracil Dehydrogenase (NADP)
  • Disease Progression
  • Dose-Response Relationship, Drug
  • Drug-Related Side Effects and Adverse Reactions
  • Female
  • Fluorouracil
  • Haplotypes
  • Humans
  • Male
  • Middle Aged
  • Polymorphism, Single Nucleotide
  • Randomized Controlled Trials as Topic
  • Retrospective Studies
  • Treatment Outcome
  • Tumor Markers, Biological

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