title: The value of genetic polymorphisms to predict toxicity in metastatic colorectal patients with irinotecan-based regimens.
abstract: OBJECTIVE
  We are trying to identify predictive factors of high risk of toxicity by analyzing candidate genes in the irinotecan pathways in order to identify useful tools to improve mCRC patient management under real practice conditions.
  
  
  METHODS
  Genomic DNA was genotyped for UGT1A1 (*28, *60 and *93) from all 101 patients, and irinotecan dose was 180 mg/m(2) every second week. Clinical data were obtained by retrospective chart review. The primary endpoint is to find out whether the pharmacogenetic test in the clinical practice may predict toxicity.
  
  
  RESULTS
  Grade 3/4 diarrhea occurred in twelve patients and required dose reduction in six patients, and neutropenia reached grade 3/4 in 19 patients (only one patient with *28/*28 genotype). The UGT1A1*93 seemed to relate with grade 3/4 neutropenia but only in the heterozygote state (G/A), p = 0.071, and UGT1A*60 showed no association with neutropenia. Twenty-eight percentage of patients required the use of G-CSF; 64.3% of them harbored *1/*28 or *28/*28 genotypes, p = 0.003. Thirty-seven (36.6%) patients required dose reduction of irinotecan and/or 5-FU owing to toxicity, mainly neutropenia and diarrhea. No significant association was detected between *28, *60 and *93 UGT1A variants and severe irinotecan-associated hematologic or GI toxicity.
  
  
  CONCLUSIONS
  The impact of increased risk of toxicity attributed to the UGT1A variants may be offset by irinotecan in clinical practice by dose reduction or the use of colony-stimulating factor.
authors.affiliation: Oncology Pharmacy Unit, Complejo Hospitalario Universitario of Santiago, Choupana S/N, 15706, Santiago de Compostela, Spain. mlamasd@yahoo.es
authors.forename: M J
authors.initials: MJ
authors.lastname: Lamas
authors.forename: G
authors.initials: G
authors.lastname: Duran
authors.forename: E
authors.initials: E
authors.lastname: Balboa
authors.forename: B
authors.initials: B
authors.lastname: Bernardez
authors.forename: S
authors.initials: S
authors.lastname: Candamio
authors.forename: Y
authors.initials: Y
authors.lastname: Vidal
authors.forename: A
authors.initials: A
authors.lastname: Mosquera
authors.forename: J M
authors.initials: JM
authors.lastname: Giraldez
authors.forename: R
authors.initials: R
authors.lastname: Lopez
authors.forename: A
authors.initials: A
authors.lastname: Carracedo
authors.forename: F
authors.initials: F
authors.lastname: Barros
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000972:Antineoplastic Agents, Phytogenic / Q000009:adverse effects*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002166:Camptothecin / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality / Q000473:pathology; D005260:Female; D005838:Genotype; D014453:Glucuronosyltransferase / Q000235:genetics*; D016179:Granulocyte Colony-Stimulating Factor / Q000627:therapeutic use; D006801:Humans; D000077146:Irinotecan; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D011110:Polymorphism, Genetic; D000099148:UGT1A1 Enzyme
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D002166:Camptothecin; D014453:Glucuronosyltransferase; D016179:Granulocyte Colony-Stimulating Factor; D000077146:Irinotecan; D000099148:UGT1A1 Enzyme