Pharmacogenomics-pharmacoepigenomics of breast cancer therapy: Clinical implications

Abstract

Breast cancer is the most common type of cancer and one of the leading causes of death for women. Therapeutic options for breast cancer include tamoxifen, aromatase inhibitors, fulvestrant, chemotherapy, monoclonal antibodies, tyrosine-kinase inhibitors, mTOR inhibitors, and VEGF inhibitors. Thus, endocrine therapy reduces the risk of recurrence and improves survival among women with hormone receptor-positive breast cancer. However, a significant percentage of women who receive therapy in the adjuvant or metastatic setting do not benefit from this therapy, while a number of women who respond will eventually develop disease progression and relapse while on therapy. For example, 30 % of early breast cancer patients treated with tamoxifen acquire tamoxifen resistance and relapse. The observed variability in treatment response to targeted breast cancer treatment could be partly explained by pharmacogenomics-pharmacoepigenomics, i.e., the study of genetic variation in drug response. At the nucleotide level, genetic variation is due to polymorphisms, large insertions, deletions, and duplications. Polymorphisms represent common variations in the DNA sequence that may lead to reduced activity of the encoded gene but, in some cases, to increased activities. Polymorphisms include single-nucleotide polymorphisms (SNPs), microsatellites, and mini-satellites. Pharmacoepigenetics is a novel field of research, with possible relevance in breast cancer treatment. Epigenomics is another aspect of genetic variation that may affect drug response. The term epigenomics refers to heritable traits in the cells and organisms that do not involve changes to the underlying DNA sequence, i.e., changes in gene expression, caused commonly by environmental factors. These changes may persist through cell division and for the remainder of the organism's life. Epigenetic processes include methylation of DNA, acetylation, phosphorylation, ubiquitylation and sumoylation of histones, histone modifications, and noncoding RNA-mediated regulation of gene expression. This chapter will review data on pharmacogenomics-pharmacoepigenomics of breast cancer treatment, focusing on clinical implications for drug efficacy and drug safety.