Can population differences in chemotherapy outcomes be inferred from differences in pharmacogenetic frequencies?

Abstract

Inter-ethnic differences in drug handling and frequencies of pharmacogenetic variants are increasingly being characterized. In this study, we systematically assessed the feasibility of inferring ethnic trends in chemotherapy outcomes from inter-ethnic differences in pharmacogenetic variant frequencies. Frequencies of 51 variants and chemotherapy outcomes of East Asian and Caucasian colorectal cancer patients on standard chemotherapy regimens were summarized by meta-analyses, and variant frequencies were validated by MassARRAY analysis. Inferences of relative chemotherapy outcomes were made by considering minor allele function and population differences in their frequency. Significant population differences in genotype distributions were observed for 13/23 (60%) and 27/35 (77%) variants in the meta-analyses and validation series, respectively. Across chemotherapy regimens, East Asians had lower rates of grade 3/4 toxicity for diarrhea and stomatitis/mucositis than Caucasians, which was correctly inferred from 13/18 (72%, P=0.018) informative genetic variants. With appropriate variant selection, inferring relative population toxicity rates from population genotype differences may be relevant.

Phosphatidylinositol‐3‐kinase pathway aberrations in gastric and colorectal cancer: Meta‐analysis, co‐occurrence and ethnic variation

“…Caution should also be taken in interpreting ethnic differences observed in our study, as ethnicity was inferred from the country of origin of study populations. In a prior meta‐analysis of sufficient study numbers, we found exclusion of US and multinational trials did not affect observations of ethnic differences in patient outcomes . Nonetheless, the ethnic heterogeneity of modern populations should be acknowledged and considered in interpreting observations of ethnic differences.…”

“…In a prior meta-analysis of sufficient study numbers, we found exclusion of US and multinational trials did not affect observations of ethnic differences in patient outcomes. 37 Nonetheless, the ethnic heterogeneity of modern populations should be acknowledged and considered in interpreting observations of ethnic differences. Clarity in the field awaits further standardized and combined assessment of candidate PI3K response predictors in large, independent sample series and clinical trials.…”

Pharmacogenomic diversity in Singaporean populations and Europeans

“…Singapore is a multi-ethnic city-state comprising three major population groups, the Chinese, Malays and Indians, with a shared environment. Previous studies have documented important differences among Singaporean populations in the frequency of specific drug-response alleles, for example, variants in CYP3A4, PXR, CAR, HNF4a, CBR3, AKR1C3, SLC28A1 and other genes associated with response and toxicity to chemotherapeutic agents, [9][10][11][12][13][14][15] SLCO1B1 variants associated with statin exposure, 16 and CYP2C19 variants associated with clopidogrel response. 17 These studies suggested that, despite the overall similarities between these population groups, they may harbor clinically important differences in the frequencies of specific drug-response alleles that contribute to inter-population differences in the risk of ADRs and drug efficacy.…”

Ethnic Differences in Susceptibility to the Effects of Platinum- Based Chemotherapy

“…Another, but not exclusive, explanation of the findings could be a limitation of the number of polymorphisms tested and a possible omission of other potentially important markers. The latest may be mainly due to the misunderstanding of molecular phenotype(s) of the particular drug(s) [68]. The more relevant is the molecular phenotype, the higher is the potential to optimize the use of a particular drug.…”

“…The more relevant is the molecular phenotype, the higher is the potential to optimize the use of a particular drug. For some drugs, such as fluorouracil, irinotecan, and mercaptopurine, some relevant variants (i.e., DPYD*2A, DPYD 2846T/A, and TYMS 2R/3R; UGT1A1*28 and UGT1A1*6; TPMT *2, TPMT *3A, and TPMT*3C) have been established but for other ones, including platinum-containing agents, they are less apparent [68,69].…”