Page 21 - Read Online

Kaehler et al. Cancer Drug Resist 2019;2:18-30 I http://dx.doi.org/10.20517/cdr.2019.05 Page 21

NUDT15 genotypes should be considered, although the NUDT15 genotype-related dose recommendations
are not yet fully clear.

Irinotecan and UGT1A1
N- or O-glucuronidation by specific UDP-glucoronosyltransferases (UGT) is a crucial step in the
elimination process of a number of drugs and endogenous compounds. Usually such conjugation elevates
the compound’s hydrophilicity thereby facilitating excretion into urine. This is exemplified by UGT1A1 that
catalyzes the transformation of bilirubin to bilirubin-glucuronide in the liver, before this conjugate can be
secreted via the renal ABC transporter ABCC2 into urine.

In this context, UGT1A1*28 (rs8175347), a TA tandem repeat in the UGT1A1 promoter causing Gilbert
syndrome/Morbus Meulengracht is of relevance causing defective heme metabolism. Wild type alleles
harbor six TA repeats, whereas the seven TA repeat variant leads to diminished protein expression.
Although presence of UGT1A1*28 is abundant in Caucasians (minor allele frequency of carriers 40%), this
genetic variant itself does not contribute to development of defective heme metabolism, as frequency of
Gilbert syndrome is only 3%-9% in Europeans [24-27] .

The topoisomerase I-inhibitor irinotecan, widely used for the treatment of colorectal cancer in combination
with 5-FU, is one of the drugs being metabolized by UGT1A1. Carriers of UGT1A1*28 variants bear a higher
risk for drug toxicities as UGT1A1 is required for detoxification of the drug. Low UGT1A1 activity may
[28]
result in diarrhea and neutropenia in a dose-dependent manner [Table 1] . So far, UGT1A1*28 genotyping
is recommended as part of the irinotecan drug label, although no distinct doses are given. Dependent on
the dosage, patients being heterozygous carriers should be closely monitored for any toxicities, while for
homozygous carriers the starting dose should be reduced [15,29] . Recently, a study in Japanese colorectal cancer
patients revealed that reduction of the initial irinotecan dose from 150 mg/m² to 120 mg/m² results in a
[30]
safe and efficient therapy in UGT1A1 homozygote variant allele carriers . It should be noted that among
Asian populations, c.211G>A leading to p.Gly71Arg and allocated to UGT1A1*6 should be considered as
well due the low activity phenotype. A retrospective study from Switzerland however could not confirm
that UGT1A1*28 is the only risk factor for neutropenia and diarrhea. In a multifactorial analysis baseline
neutrophil count, sex, age and performance status were additional items contributing to the complexity of
[31]
adverse events . Studies investigating the question, whether elevated irinotecan doses are tolerable among
wild-type carriers are ongoing. Here, pharmacogenetic testing could contribute not only to the avoidance of
toxicity, but also to a putative better clinical outcome of the disease.

Pyrimidine analogues and dihydropyrimide dehydrogenase
The pyrimidine analogue 5-FU is commonly used for treatment of metastatic colon carcinoma or breast
cancer. Main metabolism of the drug is performed in the liver by dihydropyrimide dehydrogenases (DPD),
which also metabolize other fluoropyrimidines, e.g., capecitabin. Defects in DPD lead to accumulation of
5-FU and systemic toxicity, ranging from myelosuppression, neurotoxicity or diarrhea [Table 1].

[32]
For DPD, several rare variants have been described (also reviewed in ): DPYD*2A (rs3918290) leads to the
formation of an alternate splicing side in intron 14, resulting in expression of a 165 bp-deleted DPYD mRNA
[33]
and protein lacking the amino acid residues 581-635 . The AA variants leads to complete DPD deficiency
[34]
and severe 5-FU toxicities . Especially in African-Americans, DPYD*9A (rs1801265) has been described
[35]
in 13%-39% of the population . The effect of this variant is still controversial, as some studies revealed
association of DPYD*9A genotype and 5-FU side effects in gastrointestinal malignancies , but others did
[36]
[37]
not observe impairment of enzyme activity of the 9A haplotype . Overall, this points to a dependency of
this haplotype to other non-genetic factors.