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 AE 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.

Clinical validity of a DPYD‐based pharmacogenetic test to predict severe toxicity to fluoropyrimidines

“…A set of studies [26][27][28][29][30] highlighted the pivotal role of DPYD gene polymorphisms in the insurgence of severe toxicity and led to the definition of pharmacogenetic guidelines for the diagnostic use of some DPYD SNPs testing (i.e., DPYDrs3918290, DPYD-rs67376798, and DPYD-rs55886062). 1 These results were further validated in successive studies which assessed the role of these SNPs in prospective clinical trials, 3,8,9 in retrospective patients collections 7,10,11 and in meta-analysis studies. 17,18 Despite the efforts of the scientific community to thrust the introduction of the DPYD pharmacogenetic tests in the everyday clinical practice for FL treatment personalization, clinicians only occasionally decide to rely on these clinical tools.…”

“…[8][9][10]33 We internally validated these associations by bootstrapping the samples, and the results were still significant after correction for multiple testing.…”

“…Up to date, 160 single nucleotide polymorphisms (SNPs) that alter the DPD aminoacids sequence have been identified within the gene (DPYD) codifying for this enzyme 5,6 and many clinical studies have been trying to investigate their association with FL-related severe toxicities. 3,[7][8][9][10][11] Recently the discussion in the scientific community about the clinical effectiveness of pharmacogenetics has given rise to the publication of drug dosing guidelines with indications and recommendations about drug-related genetic tests and …”

“…Up to date, 160 single nucleotide polymorphisms (SNPs) that alter the DPD aminoacids sequence have been identified within the gene (DPYD) codifying for this enzyme 5,6 and many clinical studies have been trying to investigate their association with FL-related severe toxicities. 3,[7][8][9][10][11] Recently the discussion in the scientific community about the clinical effectiveness of pharmacogenetics has given rise to the publication of drug dosing guidelines with indications and recommendations about drug-related genetic tests and their integration in the clinical routine. In particular, the Clinical Pharmacogenetics Implementation Consortium (CPIC) 12,13 and the Dutch Pharmacogenetics Working Group of the Royal Dutch Association for the Advancement of Pharmacy (DPWG) 14 have published drug-specific guidelines based on the patient genotype.…”

“…15 Particularly, CPIC guidelines recommend choosing an alternative drug for patients who present two variant alleles (compound heterozygous or homozygous variant genotypes) and a 50% reduction of FL starting dose for patients with only one variant allele (heterozygous genotype) for any of these SNPs (http://www.pharmgkb.org/guideline/PA166122686). 1 Despite a number of studies and meta-analyses assessed the association between the DPYD genotyping test and the occurrence of severe toxicity related to FL, [8][9][10][11][16][17][18] its use is still scarcely widespread among clinicians possibly because the rarity of the considered DPYD SNPs renders the three DPYD-markers test sensitivity rather low. In addition, only scanty information is available about the cost-effectiveness of this analysis.…”