The value of genetic polymorphisms to predict toxicity in metastatic colorectal patients with irinotecan-based regimens.

Long Survival and Severe Toxicity Under 5-Fluorouracil–Based Therapy in a Patient With Colorectal Cancer Who Harbors a Germline Codon-Stop Mutation in TYMS

“…26 This mutation has a low prevalence because we did not find it in 230 patients and another group in 200 patients. 26,29,[36][37][38] Literature reports a 1.7-Mb heterozygous deletion and a 1.9-Mb duplication, comprising several genes besides TYMS, but none of them showed phenotypic alterations. 39 To date, no medical condition has been related with TYMS, aside from its relation with cancer.…”

“…34,35 Also, the patient experienced severe toxicities with all treatments. Less than 8% of the patients in our previously published studies 26,29 had a similar grade of severe toxicity (Table). Meta-analysis studies showed that neither efficacy nor toxicity is explained by the genotype in other polymorphisms (see Supplemental Table available online at http://www.mayoclinic proceedings.org).…”

“…2,3,[19][20][21][22] Only the haplotype *28 in the UGTA1A is associated with toxicity due to irinotecan (dose !150 mg/m 2 ). 23,26 But the analysis in our population 26 showed that only 1 of 9 patients (11.1%) with this genotype suffered severe neutropenia and none of them had severe diarrhea. Neither was associated with the haplotypes *60 and *93.…”

“…We genotyped the following pharmacogenetic markers with the strongest support according to the literature, associated with efficacy and toxicity: regarding the toxicity and efficacy of 5-FU, several polymorphisms in TYMS, a 28-bp repeat (rs34743033), a G->C (rs285 3542) that abolishes a USF-binding site, and an ins/del (rs16430) suspected to affect its expression 2,8 ; in DPYD, the limiting enzyme implicated in 5-FU catabolism, *2A (rs3918290), *13 (rs55886062), and D949V (rs67376798) associated with DPYD deficiency 18 ; and in MTHFR, an enzyme that competes for the methyl donors needed for TYMS activity, C677T (rs1801133) and A1298C (rs1801131) 2,19 ; regarding the efficacy of oxaliplatin, in an enzyme implicated in its detoxification, GSTP1 Ile105Val (rs1695), and in enzymes belonging to DNA repair systems, XRCC1 Arg399Gln (rs25487), ERCC1 Asn11 8Asn (rs11615), and ERCC2 Lys751Gln (rs13181) [20][21][22] ; regarding irinotecan, in UGT 1A1, the principal detoxification enzyme, *28 (rs8175347), *60 (rs4124874), and *93 (rs10929302). [23][24][25][26] An extensive description of the experimental procedures is given in the Supplemental Appendix (available online at http://www. mayoclinicproceedings.org).…”

Uridine diphosphate glucuronide transferase 1A1FNx0128 gene polymorphism and the toxicity of irinotecan in recurrent and refractory small cell lung cancer

“…[18] A number of studies confirm that UGT1A1*28 gene variation, especially homozygous mutant (TA) 7 /(TA) 7 , can increase the risks of severe diarrhea and/or neutropenia. [19][20][21][22] Recently, Innocenti et al [23] reported that the dose of irinotecan can be individualized based on different expressions of UGT1A1*28 genotypes. However, some scholars held the opposite opinion.…”