Evaluating Predictive Pharmacogenetic Signatures of Adverse Events in Colorectal Cancer Patients Treated with Fluoropyrimidines

Abstract

The potential clinical utility of genetic markers associated with response to fluoropyrimidine treatment in colorectal cancer patients remains controversial despite extensive study. Our aim was to test the clinical validity of both novel and previously identified markers of adverse events in a broad clinical setting. We have conducted an observational pharmacogenetic study of early adverse events in a cohort study of 254 colorectal cancer patients treated with 5-fluorouracil or capecitabine. Sixteen variants of nine key folate (pharmacodynamic) and drug metabolising (pharmacokinetic) enzymes have been analysed as individual markers and/or signatures of markers. We found a significant association between TYMP S471L (rs11479) and early dose modifications and/or severe adverse events (adjusted OR = 2.02 [1.03; 4.00], p = 0.042, adjusted OR = 2.70 [1.23; 5.92], p = 0.01 respectively). There was also a significant association between these phenotypes and a signature of DPYD mutations (Adjusted OR = 3.96 [1.17; 13.33], p = 0.03, adjusted OR = 6.76 [1.99; 22.96], p = 0.002 respectively). We did not identify any significant associations between the individual candidate pharmacodynamic markers and toxicity. If a predictive test for early adverse events analysed the TYMP and DPYD variants as a signature, the sensitivity would be 45.5 %, with a positive predictive value of just 33.9 % and thus poor clinical validity. Most studies to date have been under-powered to consider multiple pharmacokinetic and pharmacodynamic variants simultaneously but this and similar individualised data sets could be pooled in meta-analyses to resolve uncertainties about the potential clinical utility of these markers.

Variants inCDAandABCB1are predictors of capecitabine-related adverse reactions in colorectal cancer

“…CDA 79A>C has been associated with CDA activity and with toxicity to cytarabine, which is also metabolized by CDA [31, 32]. In contrast to our findings, those of other studies did not show a connection between this SNP and toxicity induced by capecitabine [11, 22] and fluoropyrimidines [33]. The variables considered responsible for these discrepant results include differences in study design, sample size, criteria for establishing a cut-off for severe ADRs, as well as variations in concomitant medication [34].…”

“…Afzal et al used polymorphisms in TYMS and MTHFR to predict gastrointestinal toxicity in 5-FU-treated patients [19], while Rosmarin et al developed a test to predict overall toxicity with polymorphisms in TYMS and DPYD in capecitabine-treated patients [11]. Jennings et al suggested a predictive test for early adverse events by analyzing TYMP and DPYD variants as a signature (sensitivity of 45.5% and a positive predictive value of 39.9%) [33]. Our results for predicting overall toxicity using the CDA-ABCB1 score are similar to those obtained in the studies, although they do not take into consideration the main factor contributing to toxicity in fluoropyrimidine-based treatments, namely, DPYD variants.…”

Association between DPYD c.1129-5923 C>G/hapB3 and severe toxicity to 5-fluorouracil-based chemotherapy in stage III colon cancer patients

“…A subsequent study identified a deep intronic variant (c.1129-5923 C>G; rs75017182) in tight linkage with HapB3 that was shown to affect pre-mRNA splicing [12]. Though evidence suggests a correlation between c.1129-5923 C>G / hapB3 and severe 5-FU toxicity [13,14], other studies have shown no significant associations [6, 15-17]. …”

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

“…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.…”