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Page 8 of 25                         Battaglin et al. J Cancer Metastasis Treat 2018;4:12  I  http://dx.doi.org/10.20517/2394-4722.2018.04

               leading to a decreased enzymatic activity have been found to correlate with the risk of 5-FU and capecitabine
               severe toxicities in several pharmacogenetic studies. Over 30 single nucleotide polymorphisms (SNPs) in
               the DPYD gene have been studied over the last 20 years, although many of these variants did not appear to
               have any functional effect. Among the most well-known, the c.2846 A>T and c.1679 T>G variants, alongside
               the G>A mutation (DPYD*2A) of the invariant splice site in exon 14 (IVS14+1G>A), coding for a truncated
               protein with no enzymatic activity, have been consistently associated with decreased DPD activity and a
                                                                   [114]
               4-fold increase of risk of developing 5-FU related toxicities . DPYD*2A is the most frequent SNPs in
               the Caucasian population, nevertheless its incidence is low (about 1%-2% for the heterozygote genotype)
               and shows substantial ethnic variations. Homozygous for DPYD*2A have been associated with cases of
               lethal toxicities in patients treated with fluoropyrimidine-based chemotherapy [115,116] . More recently a large
                                                [117]
               meta-analysis from Meulendijks et al.  confirmed the predictive role for drug-related toxicities for four
               DPYD variants:  DPYD*2A, c.2846A>T, c.1679 T>G and c.1236G>A/haplotype B3. Data from retrospective
               pharmacogenetic analyses from the Italian adjuvant TOSCA trial confirm the role of DPDY*2A as a risk
               factor for fluoropyrimidine-related toxicities . Additionally, a prospective study enrolling 2,038 patients
                                                     [118]
               candidate to receive a fluoropyrimidine-based chemotherapy demonstrated the feasibility and cost-
               effectiveness of upfront DPYD*2A genotyping before treatment start. DPYD*2A variant allele carriers were
               treated with a reduced dose-intensity leading to a significant reduction of the risk of grade ≥ 3 toxicity
               (28% vs. 73% in historical controls, P < 0.001) and a reduction of drug-induced death from 10% to 0% .
                                                                                                       [119]
               The low frequencies of the aforementioned risk alleles, however, cannot fully explain the estimated risk of
               DPD-linked fluoropyrimidine-related adverse events, underlining the complex multi-level modulation of
               DPD activity, involving both transcriptional and post-transcriptional mediators, and the need to investigate
               additional DPYD risk variants. Nevertheless, available data support the role of DPYD testing as a pre-
               treatment screening in patients undergoing 5-FU and capecitabine treatment in order to improve the safety
               of fluoropyrimidine-based therapies and potentially allow genotype-guided dose adaptations, as recently
               recommended by the clinical pharmacogenetics implementation consortium .
                                                                                [120]
               Evidence on the role of DPD deficiency as a toxicity biomarker led the FDA to include a warning annotation on
               the label of fluorouracil for patients with low or absent DPD activity, recommending to withheld or permanently
               discontinue fluorouracil in patients with evidence of acute early-onset or unusually severe toxicity, which may
               indicate near complete or total absence of DPD activity. On the other hand, latest published ESMO clinical
               practice guidelines on metastatic colorectal cancer management suggest for the first-time pre-treatment DPYD
               testing as an option . This indication, however, is focused on those patients who experience severe 5-FU toxicity
                               [9]
               before 5-FU re-introduction and routine testing is not recommended, despite the authors stating that patients
               with known partial DPD deficiency benefit from dose adaptation of 5-FU/capecitabine therapy to avoid severe
               toxicity, while in patients with complete DPD deficiency fluoropyrimidines should be avoided and an alternative
               treatment offered. The lack of recommended standardized assessment techniques represents an additional issue
               to the introduction of routine DPD testing.


               The predictive role of genetic variants in other key genes involved in the folate pathway, such as TYMS and
               5,10-methylenetetrahydrofolate reductase, has not been validated and their use in clinical practice is not
               recommended.


               UDP-Glucuronosyltrasferase A1
               Irinotecan, a topoisomerase I inhibitor, is another key drug in the chemotherapy treatment of mCRC, which
               can be used as a monotherapy or in combination with 5-FU and/or other agents in different treatment
               lines [9,10] . This agent is administered as a pro-drug which is metabolized to its active form, SN-38, via
               carboxylation. SN-38 catabolism and excretion are subsequently dependent on conversion to its inactive
               form, SN-38G, operated by hepatic UDP-Glucuronosyltrasferases (UGT) such as UGT1A1 . Additionally,
                                                                                           [121]
               the pharmacokinetics of irinotecan involves several other enzymes, such as CYP3A4, which control its
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