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Battaglin et al. J Cancer Metastasis Treat 2018;4:12  I  http://dx.doi.org/10.20517/2394-4722.2018.04                        Page 9 of 25

               metabolism modulating the available dose of the active drug. A genetic variation in these enzymes can affect
               tolerability and toxicity profile in patients.


               Up to 36% of patients treated with irinotecan-containing regimens experience severe and potentially life-
                                                                 [122]
               threatening adverse events, such as neutropenia and diarrhea . Variations in the UGT1A1 activity have been
               shown to be associated with irinotecan-induced toxicities. The most common gene variants are the UGT1A1 *1
               and *28 alleles, representing 98%-99% of all variants in the Caucasian population. The *28 variant, responsible
               for Gilbert syndrome, is characterized by the presence of an extra TA repeat in the promoter of the UGT1A1
               gene which is associated with a remarkably reduced enzymatic activity and correlates with higher incidence
               of drug-related adverse events due to a slower catabolism of SN-38G . In USA, about 45% of the population
                                                                        [123]
               is heterozygous for the *28 allele (*1/*28) while around 10% carries a homozygous genotype for this variant.
               The frequency increases in the African population and is lower in South-East Asian and Pacific populations.
               The role of UGT1A1 genotyping has been evaluated in several clinical trials, and two large meta-analyses
               including nearly 2000 patients confirmed that carriers of the UGT1A1 *28/*28 genotype were at a higher
                                                                                                 2 [124]
               risk for neutropenia compared to WT *1 patients even at a low irinotecan dosage (80-145 mg/m ) , while
               carriers of the *28 allele were at risk of severe diarrhea at doses above 125 mg/m 2[125] . Consistently, genotyping
               analyses of patients treated with 5-FU and irinotecan within the randomized phase III Nordic IV trial  and
                                                                                                    [126]
               the randomized phase III TRIBE trial , confirmed the association between the UGT1A1*28/*28 genotype
                                               [127]
               and higher risk of neutropenia. Subsequent meta-analyses most recently supported once again the role of
               UGT1A1*28 as predictive of irinotecan-related severe toxicities, as well as the role of additional variants such
               as UGT1A1*6, a missense variant frequent in the Asian population [128,129] . Finally, a recent dose-finding and
               pharmacokinetic study suggests that irinotecan treatment dose should be individualized based on UGT1A1
               genotype. Results from this study, in fact, show that the maximum tolerated dose of irinotecan, administered
               as an intravenous infusion every 3 weeks, was 850, 700, and 400 mg in patients bearing the *1/*1, *1/*/28, and
                                         [130]
               *28/*28 genotypes, respectively .
               Based on available data the latest ESMO guidelines suggest UGT genotyping as an option in patients with a
               suspicion of UGT1A1 deficiency and when the administration of a dose of irinotecan >180 mg/m  is planned .
                                                                                                        [9]
                                                                                               2
               On the other hand, the National Comprehensive Cancer Network guidelines version 2.2017 states that
               irinotecan should be used with caution and at a decreased dose in patients with Gilbert syndrome or elevated
                                                                               [10]
               serum bilirubin, but routine genotyping of UGT SNPs is not recommended . It has to be noted, however,
               that FDA has modified irinotecan label to include a toxicity warning for the UGT1A1*28 polymorphism,
               suggesting an initial dose reduction when treating patients carrying the UGT1A1*28 homozygous allele.


               EMERGING BIOMARKERS OF SPECIAL INTEREST
               HER2
               Although tumor RAS WT status is, as previously described, a crucial prerequisite for anti-EGFRs activity
               in mCRC, several patients with RAS and BRAF WT tumors still do not benefit from anti-EGFR treatment.
               Based on preclinical data and retrospective evaluations, additional mechanisms of primary resistance to
               anti-EGFR agents have been identified over time in RAS WT mCRC, including human epidermal growth
               factor receptor 2 (HER2/neu) amplification. HER2 is a member of the EGRF family which regulates key
               cellular processes such as proliferation and apoptosis through the activation of the RAS/RAF/ERK and the
               PI3K/PTEN/AKT signalling pathways. HER2 role as a driver oncogene in CRC and as potential biomarker
               for targeted treatment in the metastatic setting has recently been the object of great interest.


               First data were reported in 2011 when HER2 amplification (which can be found in approximatively 5% of
               RAS WT mCRCs), was detected in a subset of KRAS/NRAS/BRAF/PIK3CA WT cetuximab-resistant patient-
               derived xenografts. Following this first evidence, a proof-of-concept study in the subgroup of HER2-amplified
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