Abstract
Single nucleotide polymorphism (SNP) in genes encoding drug-metabolizing enzymes (DME) could have a critical role in individual responses to anastrozole. Frequency of CYP3A4*1B, CYP3A5*3 and UGT1A4*2 SNPs in 126 Croatian breast cancer (BC) patients and possible association with anastrozole-induced undesirable side effects were analyzed. Eighty-two postmenopausal patients with estrogen receptor (ER)-positive BC treated with anastrozole and 44 postmenopausal ER-positive BC patients before hormonal adjuvant therapy were included in the study. Genomic DNA was genotyped by TaqMan Real-Time PCR. Bone mineral density (BMD) was measured by dual-energy X-ray absorptiometry. The homozygotes for the variant G allele of CYP3A5*3 were predominant (88%), and the homozygotes for the reference A allele were not detected. While homozygotes for the variant G allele of CYP3A4*1B were not detected, predominantly wild type homozygotes for A allele (94%) were present. CYP3A4*1B and CYP3A5*3 SNPs were in 84.3% linkage disequilibrium (D’ = 0.843) and 95.1% (D’ = 0.951) in group treated with anastrozole and w/o treatment, respectively. Homozygotes for the A allele of UGT1A4*2 were not detected in our study groups. Although the variant CYP3A5*3 allele, which might result in poor metabolizer phenotype and more pronounced side effects, was predominant, significant association with BMD changes induced by anastrozole were not confirmed.
Highlights
Breast cancer (BC) is the most common cancer site with 26% of all cancer sites in females
single nucleotide polymorphism (SNP) in the genes encoding drug-metabolizing enzymes (DME) could have a critical role in individual responses to anastrozole. Even though these polymorphisms are well characterized in different populations, the frequency of CYP3A4*1B, CYP3A5*3 and UGT1A4*2 allele yet have not been determined in the population of Croatia (CRO), the objectives of this study were to analyze the frequency of these SNPs and its possible association with anastrozole therapy-induced undesirable side effects among Croatian breast cancer (BC) population
There were no significant differences between the two groups regarding lifestyle and eating habits, such as alcohol consumption, smoking, calcium intake and consumption of dairy products
Summary
Breast cancer (BC) is the most common cancer site with 26% of all cancer sites in females. Considerable interindividual variability in its tolerability was identified, which may lead to adverse effects [6,7,8] This variability can potentially be attributed to individual differences in the pharmacokinetics and/or pharmacodynamics of anastrozole, possibly due genetic variations [9]. In comparison with the wild type CYP3A4*1A, CYP3A4*1B shows about a 2-fold increase in enzyme activity [15,16] These data are not uniform, since a decrease in the catalytic activity of the enzyme was determined [17], or unclear clinical effect was described [18], and some even linked this SNP with increased cancer risk [19,20]. The mutated allele CYP3A5*3 results in a splicing defect of the mRNA and produces an unstable and nonfunctional protein with decreased activity, or loss of activity of the encoding enzyme, which according to some studies could play a role in interindividual variations and in interethnic variations in anastrozole metabolism [21]
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