Pharmacogenetics in Breast Cancer Therapy

Abstract

Interindividual and interethnic variability of drug pharmacokinetics and pharmacodynamics may be contributed by commonly occurring genetic polymorphisms of drug-metabolizing enzymes and transporters. Polymorphisms of CYP2D6 in particular have been associated with effects on tamoxifen disposition and clinical efficacy, with interethnic differences in distribution of functional alleles that affect metabolizer phenotype. Other tamoxifen-related genetic variants of CYP3A4, CYP3A5, and sulfotransferase1A1 (SULT1A1) are also briefly reviewed here. Polymorphisms of CYP19A1 (aromatase gene) have been reported to correlate with clinical outcomes from aromatase inhibitors in small studies but require further confirmation. Many studies on chemotherapy are based on hypothesis-generating association studies and need to be validated through larger-scale cooperative group studies. For anthracyclines, polymorphisms in genes such as carbonyl reductase 3 (CBR3), ATP-binding cassette subfamily B, member 1 (ABCB1), glutathione-related transporter genes, and oxidative stress^related genes have been reported to correlate with clinical outcomes. The pharmacogenetics of taxanes has been extensively investigated, but associations of genetic polymorphisms in drug-metabolizing enzymes and transporters reported in earlier small studies have not been validated in a recent large clinical trial. Allelic variants associated with gemcitabine, capecitabine/5-fluorouracil, vinorelbine, and platinum disposition are reviewed. No pharmacogenetic studies have been published for targeted agents thus far, although several potential candidate genes warrant investigation. Future pharmacogenetic studies will need to focus on integration of multiple drug pathways to allow a more comprehensive analysis of genetic factors influencing drug efficacy and toxicity.

Cytochrome P450 genetic polymorphisms influence the serum concentration of calcineurin inhibitors in allogeneic hematopoietic SCT recipients

“…3,14,15 To date, no studies have been On the other hand, we have described a lack of association between the patient's genetic polymorphisms and transplantation-related complications. As we could adjust the drug dosage according to the patient's serum calcineurin inhibitor concentration, the drug monitoring strategy should be effective to reduce the frequency of complications even in the specific genetic backgrounds.…”

Automated Extraction of DNA and RNA from a Single Formalin-Fixed Paraffin-Embedded Tissue Section for Analysis of Both Single-Nucleotide Polymorphisms and mRNA Expression

“…The sample dropout rate in this investigation was Ͻ10% across all assays, which indicates that the automated extraction method provides genomic DNA of a quality comparable to that in similar studies in which archived FFPE tissue samples were used with manual DNA extraction procedures (5 ). We selected 5 genes known to harbor germline polymorphisms that have been reported to be related to breast cancer risk or disease progression (14,15 ), to functionally influence estrogen-receptor activity (NCOA3), or to be predictive for breast cancer tamoxifen outcome (16 ). Although our data showed very high concordance rates of genotypes between tumor and corresponding normal tissue, a few samples (1.1%) showed discordant alleles between paired samples.…”

Triple-Negative Breast Cancer: Risk Factors to Potential Targets

“…The optimal therapeutic approach for triple-negative breast cancer will likely include a mixture of targeting the host via an intimate understanding of pharmacogenetics (62) and targeting the molecular biology of the tumor. Based on attempts to pair the molecular biology of triple-negative breast cancer with drug mechanism, multiple compounds are in testing for triplenegative breast cancer.…”