Dihydropyrimidine dehydrogenase pharmacogenetics for predicting fluoropyrimidine-related toxicity in the randomised, phase III adjuvant TOSCA trial in high-risk colon cancer patients

Abstract

Background:Dihydropyrimidine dehydrogenase (DPD) catabolises ∼85% of the administered dose of fluoropyrimidines. Functional DPYD gene variants cause reduced/abrogated DPD activity. DPYD variants analysis may help for defining individual patients’ risk of fluoropyrimidine-related severe toxicity.Methods:The TOSCA Italian randomised trial enrolled colon cancer patients for 3 or 6 months of either FOLFOX-4 or XELOX adjuvant chemotherapy. In an ancillary pharmacogenetic study, 10 DPYD variants (*2A rs3918290 G>A, *13 rs55886062 T>G, rs67376798 A>T, *4 rs1801158 G>A, *5 rs1801159 A>G, *6 rs1801160 G>A, *9A rs1801265 T>C, rs2297595 A>G, rs17376848 T>C, and rs75017182 C>G), were retrospectively tested for associations with ⩾grade 3 fluoropyrimidine-related adverse events (FAEs). An association analysis and a time-to-toxicity (TTT) analysis were planned. To adjust for multiple testing, the Benjamini and Hochberg’s False Discovery Rate (FDR) procedure was used.Results:FAEs occurred in 194 out of 508 assessable patients (38.2%). In the association analysis, FAEs occurred more frequently in *6 rs1801160 A allele carriers (FDR=0.0083). At multivariate TTT analysis, significant associations were found for *6 rs1801160 A allele carriers (FDR<0.0001), *2A rs3918290 A allele carriers (FDR<0.0001), and rs2297595 GG genotype carriers (FDR=0.0014). Neutropenia was the most common FAEs (28.5%). *6 rs1801160 (FDR<0.0001), and *2A rs3918290 (FDR=0.0004) variant alleles were significantly associated with time to neutropenia.Conclusions:This study adds evidence on the role of DPYD pharmacogenetics for safety of patients undergoing fluoropyrimidine-based chemotherapy.

The clinical relevance of multiple DPYD polymorphisms on patients candidate for fluoropyrimidine based-chemotherapy. An Italian case-control study

“…Our data confirmed the association between the c.2194G>A SNP and severe toxicity (Table 3), and resulted in line with both the PETACC8 and TOSCA studies in terms of the significant correlation with haematologic toxicity. 23,24 In particular, we found a statistically significant association between this SNP and severe neutropenia, which was observed in 50% of the patients carrying c.2194G>A (23 out of 46) vs. 21% of the patients with WT genotype (67 out of 320) (p < 0.0001).…”

“…The clinical impact of c.2194G>A SNP is still controversial, although recent studies have shown promising relevance in the correlation with fluoropyrimidine-related toxicity. 5,[23][24][25] In the pharmacogenetics analysis on 927 patients of the QUASAR II trial, 19 c.2194G>A variant was not found to be associated with fluoropyrimidine toxicity although it should be considered that this study was performed in patients treated with capecitabine mono-chemotherapy only.…”

“…The time to toxicity (TTT) analysis, as it was used in the study of Ruzzo et al, 23 has been modified for our purpose. Here, we assessed the temporal occurrence of toxicity in relation to the number of chemotherapy cycles dispensed and not to time from date of randomisation in the clinical trial.…”

“…25 In the PETACC-8 trials, the c.2194G>A SNP was associated with increased fluorouracil-related AEs, including haematologic AEs and neutropenia (OR 1.8, 95% CI 1.3-2.4) in 1545 colorectal cancer (CRC) patients who received standard adjuvant FOLFOX4 or FOLFOX4 in combination with cetuximab. 24 The pharmacogenetics study of the TOSCA trial, 23 in which colon cancer patients were enroled for 3 or 6 months of either FOLFOX or XELOX adjuvant chemotherapy, tested ten DPYP variants in correlation with >grade 3 FAEs. In the association analysis of 508 patients, FAEs occurred more frequently in c.2194G>A carriers, and this DPYD variant showed detrimental effects on the time to neutropenia.…”

“…The objective of our case-control study was to analyse the two other variants, c.2846A>T and c.1679T>G, in subjects who have presented FAEs not DPYD*2A correlated, in order to confirm their clinical relevance and to evaluate their possible improvement of predicting toxicity when introduced in the pre-treatment screening. Furthermore, in consideration of the results of some recent studies, 5,[23][24][25] we evaluated the potential clinical impact of the c.2194G>A SNP, a more frequent variant of DPYD with an interesting correlation with fluoropyrimidine-related toxicity.…”