Pharmacogenetics of Tamoxifen and Chemotherapies and Risk of Contralateral Breast

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DESCRIPTION (provided by applicant): Adjuvant chemotherapy and tamoxifen have been shown to reduce the risk of contralateral breast cancer (CBC) among women with a previous history of breast cancer. It is well recognized that not all individuals metabolize drugs with the same efficiency or experience the same likelihood of adverse side effects related to treatment. Additional information predicting metabolic capacity and outcomes may optimize an individual's response to drug therapy and improve clinical outcomes. Common genetic polymorphisms in drug metabolizing enzymes, functional targets and drug transporters may be key in this distinction. In this pharmacogenetic study, we intend to genotype a key set of functional polymorphisms in metabolic genes in the Women's Environment, Cancer and Radiation Epidemiology (WECARE) Study, a large, population-based, case-control study of women with unilateral and bilateral breast cancer that has systematically collected treatment and outcome data. We will investigate whether selected functional variants in genes involved in the metabolism of tamoxifen and other chemotherapeutic agents modify the protective effect of these treatments on the risk of CBC in the WECARE Study. We consider functional polymorphisms in the following key genes involved in the metabolism of tamoxifen (i.e., CYP2D6, CYP3A5, SULT1A1, UGT2B15) and drugs commonly used in polychemotherapy regimens for breast cancer including: cyclophosphamide (i.e., CYP3A5, GSTM1, GSTP1, GSTT1); anthracyclines (i.e., CYP3A5, MDR1, GSTM1, GSTP1, GSTT1) and antimetabolites (i.e., DHFR, TS, MTHFR) .We propose to genotype 634 women with bilateral breast cancer and 1,158 unilateral breast cancer controls who received the chemotherapy or tamoxifen as treatment for first primary breast cancer. We propose a study design that maximizes available information regarding genetic variability in these key pathways by examining candidate polymorphisms with known or likely functional effects. We plan several follow-up projects using data from this study including incorporating the genotype data collected on the functional polymorphisms in this study with tagSNPs on the Illumina 650K and additional data collection on 1,600 women from a genome-wide study that is expected to be funded in WECARE Study. This will allow for pooled analyses to pursue subgroup analyses and pathway-based statistical modeling approaches. This study uses an efficient approach to address research questions regarding the pharmacogenetics of commonly used therapies and risk of CBC among women younger than 55 years, which has not previously been addressed. These results will contribute to our knowledge base and help improve upon current clinical strategies to determine the right drug for individualized care that minimizes adverse events and maximizes long-term outcomes.