In the proposed project, we will identify genetic variants that influence breast cancer chemotherapy-associated toxicity and response by developing and validating a genome-wide, comprehensive approach to test the hypothesis that genetic polymorphisms significantly influence susceptibility to toxicities and response associated with breast cancer agents. Given that chemotherapy is the mainstay of treatment of ER negative breast cancer, a disease that disproportionately affects African Americans resulting in significant health disparities, a more concerted translational research effort devoted to understanding individual variability in chemosensitivity and toxicity is long overdue within the SPORE program. Although this approach will eventually be applied to a variety of breast cancer agents, we will focus on fluoropyrimidines (capecitabine) and platinating agents (carboplatin). The proposal is highly translational employing two clinical trials and uses state of the art, complementary approaches including heritability analysis, linkage analysis, expression studies, and association studies. This global approach opens up the possibility of identifying genes that were previously unknown or unrecognized and offers an advantage over studies that are focused on a single candidate gene or pathway. To this end, we will employ lymphoblastoid cell lines, derived from large reference pedigrees of European descent and trios of Yoruban descent. Cell lines will be phenotyped for cytotoxicity and apoptosis induced by capecitabine and carboplatin. An important outcome of this research is the identification of candidate variants and frequency of polymorphisms in individuals of European and African descent. Because a subset of these cell lines are part of the HapMap Project in which over 1,000,000 SNPs have been genotyped, this resource provides an extremely rich data set that primarily requires phenotyping. Functional studies will follow concomitant with 2 clinical trials of breast cancer patients treated with capecitabine. The first study we will utilize is a phase II study of capecitabine as neoadjuvant therapy in newly diagnosed locally advanced breast cancer. This trial will be performed in Nigeria. The second study we will utilize is the CALGB pharmacogenetic study of capecitabine as second line therapy of metastatic breast cancer progressing on initial chemotherapy.
Our specific aims are: 1. To determine the heritability of variation in the susceptibility to the cytotoxic and apoptotic effects of capecitabine and carboplatin. 2. To perform association studies on CEPH and Yoruban HapMap trios. 3. To examine the relationship between global gene expression patterns and capecitabine and carboplatin-induced cytotoxicity and perform functional studies on candidate genes. 4. To determine whether polymorphisms in candidate genes identified using our global approach are associated with survival or toxicity in breast cancer patients treated with capecitabine.
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