Ethnic diversity is recognized as an important factor accounting for inter-individual variations in anticancer drug responsiveness and toxicity. However, similar doses of anticancer drugs have been prescribed to different ethnic populations without consideration of the potential differences in pharmacokinetics and pharmacodynamics, both of which are essentially influenced by pharmacogenomics. Although pharmacoethnicity is determined by genetic and non-genetic factors, the latter factors have not yet been well identified. The possible determinants of ethnicity could include 1) environmental factors that influence bioavailability and metabolism, such as the frequency of smoking, alcohol drinking, herbal medicine use and local dietary varieties, 2) local medical care preferences, 3) ethnic specific drug-drug interactions influenced by drug lag in a specific region, 4) variability of genetic polymorphisms in drug metabolizing enzymes and transporters, and 5) the prevalence of an ethnically restricted mutations in a drug's receptor/target that may cause a particular sensitivity or resistance to that drug.1
Studies on pharmacoethnicity face many challenging issues. However, preclinical and clinical studies should be carefully designed to account for these problems. 1) Clinical trials on pharmacoethnicity require diverse populations. International collaboration, including global trials, is mandatory and repeated trials using the same treatment strategies should be conducted in multiple countries. 2) Chemotherapy-related effects are likely to be under multi-gene control. Unbiased genome-wide models are needed and such models should include multiple mechanism-related and metabolism-related pathways. 3) Potentially important polymorphisms or mutations are generally uncommon. The sample size of clinical trials should be sufficient to enable an appropriate statistical power. Clinical trials in ethnic populations with a specific phenotype of interest may sometimes be necessary. To discover rare variants, new generation of sequencing methodology should be introduced. 4) The detection of genome-wide associations requires multiple SNP testing, which may generate several false-positive SNPs. Accordingly, test and validation sets are mandatory. In addition, both of preclinical and clinical validations, as well as the application of a rigorous statistical methodology is needed. Furthermore, as 5) anti-cancer drugs cannot be administered to healthy volunteers, in vitro cell based models are needed1 and pharmacogenomical selection of patients is recommended by appropriate biomarkers.
The clinical trials included in the present review were large enough to identify ethnic differences, despite the numerous hidden factors that remain unknown. As shown by common arm trials between USA and Japan, Asian patients experience more frequent and profound neutropenia despite receiving the same treatment doses, schedules and same pharmacokinetics. A difference in sensitivity at receptor site has been suggested to be the main cause of these observations, but a concrete mechanism, thereof has not been clarified. On the other hand, the survival period of NSCLC patients was significantly longer among Asian patients than among Caucasians even before EGFR-TKIs became available. In a common arm trial, the OS and one-year survival were both significantly better in Asian patients although response rates were exactly the same. Differences in sensitivity to EGFR-TKI have been clearly explained by EGFR mutation in both Asians and Caucasians. However, why the frequency of EGFR mutation is higher among Asian patients remains unknown. Some germ line and environmental factors may influence this mutation rate. However, all previous genome-wide and proteome analyses that have been performed in association with prospective clinical trials failed to pick up on relevant factors. There is also no clear explanation as to why EGFR-TKI-induced ILD is observed so frequently in Japanese patients only. To date, only clinical characteristics indicating a susceptibility to ILD have been identified. The data of three trials the FLEX, AVAGAST, and Sorafenib after TACE trials, suggested that disease status and local medical care preference strongly influenced the OS of the included patients.
Recently the Shizuoka Cancer Center reported interesting results on Phase I study of ARQ197, a selective, non-ATP competitive inhibitor of c-MET, a receptor tyrosine kinase involved in tumor migration, invasion and proliferation (). Therein, the ratios of poor metabolizers (PM), who exhibited a single nucleotide polymorphism in CYP2C9, a major metabolizing enzyme for ARQ197, among Caucasians and Asians have been reported to be 3 and 20%, respectively (). Recommended phase II dose of ARQ197 for subjects of western countries has been decided to be a single dose of 360 mg bid. On the other hand, the study in Japan demonstrated that CYP2C19 genotype clearly affected exposures such as AUC and C-max of ARQ, which led to the designation of two different recommended doses for phase II trials, 360 mg bid for extensive metabolizer patients and 240 mg bid for PM patients (). Clear ethnic differences mandates the necessity of different protocols for phase II studies of Asians and Caucasians.58
Ethnic Difference for Metabolism of ARQ 197 (Tivantinib)
Phase I combination study with erlotinib in Japan. EM, extensive metabolizer; PM, poor metabolizer.
In summary basic pharmacogenomic differences could only be identified from the prospective analyses of patients of a homogeneous background. The clarification of pharmacoethnic differences will be crucially important to the future development of new anticancer drugs.