In the proposed project, we will identify genetic variants that influence breast cancer chemotherapy-associatedtoxicity and response by developing and validating a genome-wide, comprehensive approach totest the hypothesis that genetic polymorphisms significantly influence susceptibility to toxicities and responseassociated with breast cancer agents. Given that chemotherapy is the mainstay of treatment of ER negativebreast cancer, a disease that disproportionately affects African Americans resulting in significant healthdisparities, a more concerted translational research effort devoted to understanding individual variability inchemosensitivity and toxicity is long overdue within the SPORE program. Although this approach willeventually 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 anduses state of the art, complementary approaches including heritability analysis, linkage analysis, expressionstudies, and association studies. This global approach opens up the possibility of identifying genes that werepreviously unknown or unrecognized and offers an advantage over studies that are focused on a singlecandidate gene or pathway. To this end, we will employ lymphoblastoid cell lines, derived from largereference pedigrees of European descent and trios of Yoruban descent. Cell lines will be phenotyped forcytotoxicity and apoptosis induced by capecitabine and carboplatin. An important outcome of this research isthe identification of candidate variants and frequency of polymorphisms in individuals of European andAfrican descent. Because a subset of these cell lines are part of the HapMap Project in which over 1,000,000SNPs have been genotyped, this resource provides an extremely rich data set that primarily requiresphenotyping. Functional studies will follow concomitant with 2 clinical trials of breast cancer patients treatedwith capecitabine. The first study we will utilize is a phase II study of capecitabine as neoadjuvant therapy innewly diagnosed locally advanced breast cancer. This trial will be performed in Nigeria. The second study wewill utilize is the CALGB pharmacogenetic study of capecitabine as second line therapy of metastatic breastcancer progressing on initial chemotherapy.
Our specific aims are: 1. To determine the heritability of variationin the susceptibility to the cytotoxic and apoptotic effects of capecitabine and carboplatin. 2. To performassociation studies on CEPH and Yoruban HapMap trios. 3. To examine the relationship between globalgene expression patterns and capecitabine and carboplatin-induced cytotoxicity and perform functionalstudies on candidate genes. 4. To determine whether polymorphisms in candidate genes identified using ourglobal approach are associated with survival or toxicity in breast cancer patients treated with capecitabine.
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