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Olivera et al. Cancer Drug Resist 2019;2:53-68 I http://dx.doi.org/10.20517/cdr.2018.25 Page 59
[25]
such as the observed in a GWAS study that correlated the variant rs116855232 C>T in NUDT15 gene with
myelosuppression in inflammatory bowel disease and acute lymphoblastic leukemia patients treated with
[26]
thiopurines . Different studies correlate the CT or TT genotype with higher toxicity risk and conclude that
[27]
doses should be reduced .
Capecitabine, fluorouracil, tegafur and DPYD
Fluoropyrimidines, capecitabine, fluorouracil and tegafur, are antimetabolite drugs widely employed in
colorectal, aerodigestive tract and breast cancer treatment. Between 10% and 40% of the patients with this
type of treatment develop severe toxicity (neutropenia, nausea, vomit, diarrhea, stomatitis, mucositis, foot
hand syndrome), causing even the death in some cases .
[28]
The most common cause of fluoropyrimidines toxicity is the lack of the key enzyme for fluorouracil
metabolism, dihydropyrimidine dehydrogenase (DPD), which is encoded by DPYD gene. A complete lack
of enzyme activity is only present in very few patients. Most patients have a reduced DPD activity due to the
genetic risk variant, but not a complete lack of activity since most patients are heterozygous carriers of these
variants and thus have one fully functional gene copy. Reduced activity is present in 39%-61% of patients
[29]
with severe toxicity, what highlights its relevance as severe toxicity risk factor .
Nowadays, different DPYD gene variants resulting in reduced enzyme function and toxicity risk are known
and described. Variants rs3918290 (G>A) or *2A and rs55886062 (T> G) or *13 present higher impact in
reducing enzyme activity than variants rs67376798 (A>T) and rs75017182(C>G), which are associated with
moderately reduced enzyme activity.

[20]
According to the CPIC guide , the dosing recommendations for fluoropyrimidines are based on individuals
genotype, which can be divided in three main groups: normal metabolizers (NM), carrying two normal
alleles; IM carrying one normal allele and another one with reduced function, or carrying two alleles with
reduced function; and PM, carrying two alleles without function or one non-functional allele and another
one with reduced function.

In NM the administration and doses indicated in drug label are recommended. In intermediate metabolizers,
it is recommended to reduce the doses by 50%. Finally, the poor metabolizers are recommended to be treated
with therapeutic schemes without 5-fluorouracil.

PharmGKB explains the Drug Agencies information in the drug label indicating that “actionable”, means
that “the label does not discuss genetic or other testing for gene/protein/chromosomal variants, but does
contain information about changes in efficacy, dosage or toxicity due to such variants. The label may
mention contraindication of the drug in a particular subset of patients but does not require or recommend
gene, protein or chromosomal testing”. Labels approved by FDA, EMA, HCSC and PMDA for capecitabine
point that those patients with low or absent DPD activity present higher risk of severe or lethal adverse
reactions. Fluorouracil does not appear within EMA label.

There is still scarce information about the DPYD gene variants in pediatric patients. However, there is no
evidence that these variants could affect the 5-fluorouracil metabolism in children in a different way to
adults.

The DPWG guide for capecitabine and fluorouracil recommend to reduce the dose by 50% or to change the
drug in intermediate metabolizers. For poor metabolizers it is recommended to use an alternative drug too.
Tegafur is not an appropriate alternative since it is also a substrate for DPD.