Germline TYMS genotype is highly predictive in patients with metastatic gastrointestinal malignancies receiving capecitabine-based chemotherapy

Abstract

Germline polymorphisms of DPYD, TYMS and GSTP1 have a significant effect on toxicity and clinical outcome in patients receiving capecitabine-based chemotherapy for advanced colorectal or gastroesophageal cancer. These data should further be validated in prospective clinical studies.

Pharmacokinetics and pharmacogenetics of capecitabine and its metabolites following replicate administration of two 500 mg tablet formulations

“…Due to the limited number of 35 patients available for genotyping and without correction for multiplicity, a random correlation cannot be excluded. In a recent study, apparently no significant effect of this MTHFR polymorphism on pharmacokinetics or effects of capecitabine was found when given as a component of an epirubicin/cisplatin/capecitabine regimen to 76 patients with advanced gastroesophageal cancer [29], while the number of samples available for pharmacokinetic analysis and many other details of this analysis have not been provided and thus exclude a detailed assessment of this result. The previous finding for 5-FU [28], however, together with the present result suggests that an indirect relationship or a yet unknown mechanism is possible; this should be investigated in further studies.…”

“…A polymorphism in MTHFR (677 C > T; A222V) reduces enzyme activity and presumably increases the level of 5,10-methylenetetrahydrofolate. This increase may be correlated with an improved response to 5-FU [9], although respective results are equivocal [29].…”

Translating DPYD Genotype into DPD Phenotype: Using the DPYD Gene Activity Score

“…Furthermore, a correlation between the DPYD*2A variant and reduced enzyme activity in peripheral blood mononuclear cells (PBMCs) was found in several ex vivo studies that confirmed decreased function of DPYD*2A [26,[28][29][30] and consequently an association was also found between DPYD*2A and reduction in fluoropyrimidine clearance in patients [31,32]. In numerous studies an association between DPYD*2A allele carriership and the increased risk of toxicity related to fluoropyrimidine treatment was confirmed [4,24,31,[33][34][35][36][37][38][39][40][41][42][43][44][45]. For example, in a meta-analysis by Terrazzino et al a strong correlation between the DPYD*2A allele and overall grade ≥3 toxicity was found (odds ratio 5.42, p < 0.001) [33].…”

“…Simultaneously, our work was [4,8,10,11,19,27,[29][30][31][32][33][34][35][36][37][38][39][40][41][42][43][44][45][46] DPYD*13 (rs55886062) [4,19,30,32,33,46,49,50] 0.5 c.2846A>T (rs67376798) [4,13,24,33,36,41,42,44,47] c.1236G>A/ HapB3 (rs56038477) [14,15,42,44,46,47,49,50,56] 1 DPYD*1 (wild-type)…”

“…Deenen et al described an average 25% dose reduction for c.2846A>T heterozygous patients in response to fluoropyrimidine-related toxicity, compared with 50% for DPYD*2A heterozygous patients [42]. Although there are less publications for c.2846A>T than for DPYD*2A, several studies and two meta-analyses found an association between the c.2846A>T variant and increased risk of severe fluoropyrimidine-associated toxicity, which indicates that a dose reduction is warranted [4,24,33,36,41,42,44,45,47]. In the study by Rosmarin et al an odds ratio of 9.35 (p = 0.0043) was found between c.2846A>T and capecitabine-related severe (≥grade 3) toxicity [47].…”