Project 4: Identifying Population Specific Variants Important in Toxicity to Breast Cancer Chemotherapy


Leader Eileen Dolan, PhD
Co-Leader Mark Ratain, MD

This project is focused on developing and validating a genome-wide, comprehensive approach to test thehypothesis that genetic variation significantly influences susceptibility to toxicities and response associated with breast cancer chemotherapeutic agents.  Some cancer therapies that are safe and effective for some people may be toxic to and ineffective for others.  Since chemotherapy is one of the mainstays for treatment of breast cancer, this project has great potential for enhancing treatment of the disease.  This 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 are focusing on fluoropyrimidines (capecitabine) and platinating agents (carboplatin).  

The project is highly translational, employing two clinical trials and the use of state of the art, complementary approaches including heritability analysis, linkage analysis, expression studies, and association studies. Our specific aims are to:

Aim 1: Determine the heritability of variation in the susceptibility to the
cytotoxic and apoptotic effects of capecitabine and carboplatin.

Aim 2: Perform association studies on CEPH and Yoruban HapMap trios.

Aim 3: Examine the relationship between global gene expression patterns and
capecitabine and carboplatin-induced cytotoxicity and perform functional studies on candidate genes.

Aim 4: Determine whether polymorphisms in candidate genes identified using our global approach are associated with survival or toxicity in breast cancer patients treated with capecitabine.

Project 4 Publications

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Project 1: Imaging-Based Determination of Breast Cancer Risk

Project 2: Specificity of MRI with Optimal Temporal, Spatial, and Spectral Sampling for Early Breast Cancer

Project 3: Variation in Hormone and Xenobiotic Metabolizing Enzyme Genes and Breast Cancer