Identifying population specific variants important in toxicity to breast cancer C

University Of Chicago, Chicago IL

Investigators

Linked publications & trials

Abstract

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