Genetic Markers of Toxicity From Capecitabine and Other Fluorouracil-Based Regimens: Investigation in the QUASAR2 Study, Systematic Review, and Meta-Analysis

Abstract

A B S T R A C T PurposeFluourouracil (FU) is a mainstay of chemotherapy, although toxicities are common. Genetic biomarkers have been used to predict these adverse events, but their utility is uncertain. Patients and MethodsWe tested candidate polymorphisms identified from a systematic literature search for associations with capecitabine toxicity in 927 patients with colorectal cancer in the Quick and Simple and Reliable trial (QUASAR2). We then performed meta-analysis of QUASAR2 and 16 published studies (n ϭ 4,855 patients) to examine the polymorphisms in various FU monotherapy and combination therapy regimens. ResultsGlobal capecitabine toxicity (grades 0/1/2 v grades 3/4/5) was associated with the rare, functional DPYD alleles 2846TϾA and *2A (combined odds ratio, 5.51; P ϭ .0013) and with the common TYMS polymorphisms 5ЈVNTR2R/3R and 3ЈUTR 6bp ins-del (combined odds ratio, 1.31; P ϭ 9.4 ϫ 10 Ϫ6 ). There was weaker evidence that these polymorphisms predict toxicity from bolus and infusional FU monotherapy. No good evidence of association with toxicity was found for the remaining polymorphisms, including several currently included in predictive kits. No polymorphisms were associated with toxicity in combination regimens. ConclusionA panel of genetic biomarkers for capecitabine monotherapy toxicity would currently comprise only the four DPYD and TYMS variants above. We estimate this test could provide 26% sensitivity, 86% specificity, and 49% positive predictive value-better than most available commercial kits, but suboptimal for clinical use. The test panel might be extended to include additional, rare DPYD variants functionally equivalent to *2A and 2846A, though insufficient evidence supports its use in bolus, infusional, or combination FU. There remains a need to identify further markers of FU toxicity for all regimens.

Association and prediction of severe 5-fluorouracil toxicity with dihydropyrimidine dehydrogenase gene polymorphisms: A meta-analysis

“…This finding appears to be inconsistent with a meta-analysis published in 2014 regarding genetic markers of toxicity in the QUASAR2 study, which reported that the associations were only present in 5-FU monotherapy (22). This may be due to differences in ethnicities as certain DPYD gene polymorphisms identified in Asian populations are different from those in the Western population; for example, DPYD * 2A (also known as DPYD: IVS14+1G>A, c.1905+1G>A) was not identified in the majority of the patients assessed from the Asian population.…”

“…study (22). In addition, other genes, such as MTHFR and DPYD haplotypes, may also influence the responses to 5-FU (1,13).…”

S3-Leitlinie – Kolorektales Karzinom

“…Insbesondere bei Patienten über 65 Jahre besteht ohne ein systematisches Monitoring ein hohes Risiko für endgültige Therapieabbrüche von bis zu 30 % wegen anhaltend hoher Nebenwirkungen, verbunden mit einem reduzierten Gesamtüberleben [1219].…”

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

“…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. A traditional non-genetic strategy (i.e., based on the body surface area, organ function, etc.)…”

“…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.…”