Ethnicity and Pharmacogenetics of Anticancer Therapy

CN01-02 ETHNICITY AND PHARMACOGENETICS OF ANTICANCER THERAPY The human genome is 99.6-99.8% identical; however, 0.2-0.4% variation gives up to 10 million DNA variants, of which 10% may be found between populations of different geographical groups. When interethnic variation of variant frequencies exist in important genes that determine drug disposition or effects, population differences in drug toxicity or efficacy from standard doses of drug would be apparent. Recently, clinically important differences in warfarin dosing requirements between ethnic groups has been attributed mainly to genetic polymorphisms of its drug metabolising enzyme cytochrome P-450 2C9 (CYP2C9) and its target enzyme of inhibition vitamin K epoxide reductase (VKORC1). For anticancer drugs, activating mutations of the epidermal growth factor receptor tyrosine kinase (EGFR TK) domain are more common in Asian lung cancers, resulting in higher responses to EGFR TK inhibitors gefitinib and erlotinib. Docetaxel may have higher myelosuppression in Chinese than reported in literature when given at 75mg/m 2 q3w. In a phase II study, standard docetaxel/carboplatin for non-small cell lung cancer appears to more toxic but has a higher response rate in Singaporean compared to Australian patients. In a study population of 101 breast cancer patients receiving alternating cycles of single agent docetaxel and doxorubicin, Chinese patients had more myelosuppression from doxorubicin than Indian or Malay patients, and together with Indians had more myelosuppression than Malays. This interethnic variability in toxicity from chemotherapy was not explained by common polymorphisms in CYP3A5 , PXR , CAR or HNF4 α . Doxorubicin is metabolized intracellularly to doxorubicinol, a metabolite with 10-fold less cytotoxicity by short-chain dehydrogenases/reductases carbonyl reductases, CBR1 and CBR3. Therefore, we studied polymorphisms of CBR1 and CBR3 on doxorubicin pharmacokinetics and hematologic toxicity in this group of patients. CBR3 11G>A and 730G>A were common polymorphisms, and CBR3 11G>A (C4Y) was associated with lower conversion of doxorubicin to doxorubicinol, and consequently greater myelosuppression. Concordantly, Chinese had a lower frequency of the more active CBR11G allele than Indians, suggesting that this polymorphism may contribute to the interethnic variability of doxorubicin induced myelosuppression observed. An analysis of CBR3 RNA levels in tumour tissue showed higher expression in patients with CBR311GG genotype, suggesting increased transcriptional efficiency compared to the AA genotype. In summary, ethnogeographic factors may have significant impact on pharmacodynamic variability of anticancer drugs, and warrants more work to elucidate the genetic determinants of this variability.