Biomarkers for Clinical Oncology
The concept of biomarker to predict not only drug induced toxicities but also clinical response and prognosis of the patients is extremely important in medical oncology. Among many kinds of biomarkers or candidates of biomarker, both pharmacokinetic dose adjustment by analyzing polymorphism of drug metabolizing enzyme and responder enrichment based on pharmacodynamic biomarkers are essential approach for individualized dosing of anticancer agents. Dose modification strategy based on pharmacogenetic- pharmacokinetic information to minimize life-threatening toxicities is extremely important approach for conventional cytotoxic agents. Recent studies reported polymorphism of drug-metabolizing enzymes in anticancer agents such as tegafur (FT), letrozole, tamoxifen, 6-merucaptopurine, 5-fluorouracil (5-FU) and irinotecan. Especially both irinotecan and S1 (tegafur/CDHP/oxonic acid) are key drugs and widely prescribed in Japan in the treatment of gastrointestinal cancers. Genetic polymorphisms of UGT1A1, a crucial drug-metabolizing enzyme of irinotecan, are essential determinants of individual variation in susceptibility to irinotecan induced toxicities. In addition to UGT1A1*28, both UGT1A1*6 and UGT1Al *27 polymorphism increase the risk of toxicities. Establishment of optimal dose of irinotecan for the patients with these polymorphisms is warranted. On the other hand, to analyze contributions of CYP2A6 genotype, plasma 5-chloro-2,4-dihydroxipyridine (CDHP) levels to the pharmacokinetics of FT and 5 -FU is also important issue not only to optimize S1 administration but also to understand possible ethnic difference of this drug. Our prospective clinical trial concludes that clearance of FT is associated only with CYP2A6 genotype. The clearance of FT seen in patients with one- and two-variant alleles is significantly lower than that seen in wild type, respectively. The AUC0-8 for 5-FU correlated with exposure of CDHP and creatinine clearance. These basic information can apply to clinical practice at bedsides.