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Research projects

Estimation of Breast Cancer Risk from Mammography and Breast MRI Specificity of MRI with Optimal Temporal, Spatial, and Spectral Sampling in Early Breast Cancer Variation in Hormone and Xenobiotic Metabolizing Enzyme Genes and Breast Cancer Risk Identifying Population Specific Variants Important in Toxicity to Breast Cancer Chemotherapy

Project 1: Estimation of Breast Cancer Risk from Mammography and Breast MRI

This project focuses on developing multi-modality, image-based markers for assessing breast density and parenchymal structure that may be used alone or together with clinical information and biomarkers to quantify breast cancer risk and monitor response to chemopreventive agents.  The general hypothesis is that inclusion of automated analyses of the parenchyma will improve the assessment of breast cancer risk.  In the future, it is expected that the proposed image-based markers will be useful for improved assessment of patients at high risk for breast cancer and for monitoring the response to preventive treatments.

Specific Aims

1. Perform image-based categorization of patient databases based on breast density, parenchyma morphology, and automatically extracted parenchyma kinetics.
   
2. Yield new image-based markers of risk by correlating and modeling various characteristics of breast density and parenchymal patterns with known surrogate markers of risk, such as BRCA1 and BRCA2 genetic mutations and the presence of cancer in the contralateral breast.
   
3. Develop a better understanding of breast cancer risk by correlating various image-markers with developing biomarkers and candidate genes.
   
4. Use these new models to perform preclinical assessment and translation of the density and parenchymal characteristics of women at high risk. 
   

The clinical translational component of this project will involve a quantitative comparison of the current method of risk assessment using the Gail model and a case control study of databases from other institutions, relating the image-based markers to onset of cancer.  In the future, it is expected that such image-based markers will be useful for improved assessment of patients at high risk for breast cancer and for monitoring the response of preventive treatments.  The proposed research is novel in that other correlative image-based research of breast cancer risk involves only breast density.  However, here we incorporate two additional, potentially complementary, analyses of the breast parenchyma into the correlative and modeling research.  The University of Chicago is extremely well-positioned to perform this correlative research on multi-modality image-based analyses for breast cancer risk because of its 20-year history of developing multi-modality computer-aided diagnostic methods for mammography, sonography, and MRI, and its integration with the University of Chicago Cancer Risk Clinic.             Back to top

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

This project studies new ways to use magnetic resonance imaging (MRI) to detect pre-cancerous lesions in their earliest stages of development.  MRI is excellent in detecting potential malignancies before they become serious; however, this sensitivity leads to many false positives, and physicians hesitate to act for fear of performing unnecessary biopsies, surgery, and other treatments.  Researchers are developing and testing MRI techniques that enable them to better determine whether very small lesions are cancerous.  They hope that eventually they will be able to destroy the ones identified as cancerous with MRI-directed, minimally invasive procedures, such as ultrasound.  The research will have a significant impact on clinical management of breast cancer.  If the results demonstrate that these new techniques will be more effective in identifying early breast cancer, this will support increased clinical use of MRI for screening high risk women and integration of improved sampling techniques into clinical MRI.  In addition, the research provides an unusual opportunity to correlate MRI parameters with biological markers for malignancy in early breast cancers.  This could lead to improved design of MRI protocols and interpretation of MR images.

Specific Aims

1. Use MRI with improved spectral, spatial, and temporal sampling (MRITSS) to acquire images of suspicious incidental lesions found in high risk women.  Determine whether MRITSS increases specificity while maintaining adequate sensitivity.  MRITSS will be compared to conventional MRI, and pathology will be used as the gold standard. 
   
2. Determine whether conventional and/or MRITSS MRI can distinguish between invasive and non-invasive (in situ) cancers.
   
3. Determine whether breast lesions in African American women who are at risk for high grade, estrogen receptor negative breast cancer are significantly different from those of the other women in the study.
   
4. Test whether there are specific biological markers that are strongly correlated with MRI parameters, and explain the appearance of functional and anatomic MR images of early breast cancers.              Back to top
   
   

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

Breast cancer is a very complex disease, which varies dramatically from person to person in the age of the individual at diagnosis, its effects, and its genetic composition.  This variability suggests the presence of multiple genetic and/or environmental factors that alter how the disease affects each individual.  This project will enhance our understanding of the interacting role of genes in causing breast cancer.  This information will help us move toward the goal of tailoring risk assessment and treatment in terms of the unique genetic make-up of each person.  This project aims to test whether sequence variation in genes involved in the metabolism of sex hormones (such as estrogen and androgens) and xenobiotics (such as environmental toxins) increases the risk of breast cancer.    To accomplish this, we will extend our existing studies and determine whether sequence variation in specific clusters of genes and enzymes influence breast cancer risk. Constructing genetic profiles for use in risk assessment may increase understanding of the role of gene environment interactions in breast cancer etiology and treatment. Moreover, by researching the role of these genes and enzymes in the metabolism of anticancer agents, the information obtained through these studies may help in dissecting the genetic basis of individual variability in response to cancer treatment and, ultimately, lead to individualized therapy. This would lead to reduced breast cancer morbidity and mortality and improved clinical outcomes for all women with breast cancer.

Specific Aims

1. Re-sequence the UGT2B gene cluster based on comparative genomics analyses in ethnically diverse population samples to select specific pieces of DNA for association study.
   
2. Examine whether variations in the UGT2B genes are associated with breast cancer risk in women of African descent.
   
3. Examine whether UGT2B genes and environmental factors are associated with age at diagnosis, tumor grade, and estrogen receptor/progesterone receptor staining.             Back to top
   
   

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

This project also focuses on genetic variation and its impact on breast cancer treatment by identifying genetic influences of breast cancer chemotherapy-associated toxicity and response.  We will develop and validate a genome-wide, comprehensive approach to test the hypothesis that genetic variation significantly influences susceptibility to toxicities and response associated with breast cancer chemotherapeutic agents. A cancer therapy that is perfectly safe for one person may be highly toxic to another.  Similarly, some therapies are very effective for some people 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 will focus 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. This global approach opens up the possibility of identifying genes that were previously unknown or unrecognized and offers an advantage over studies that focus on a single gene or pathway. An important outcome of this research is the identification of genetic variations in individuals of European and African descent. Functional studies will follow concomitant with two 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 in Nigeria. The second study we will utilize is the CALGB pharmacogenetic study of capecitabine as second line therapy for metastatic breast cancer progressing on initial chemotherapy.

Specific Aims

• Determine the heritability of variation in the susceptibility to the cytotoxic and apoptotic effects of capecitabine and carboplatin.
  
• Perform association studies on CEPH and Yoruban HapMap trios.
  
• Examine the relationship between global gene expression patterns and capecitabine and carboplatin-induced cytotoxicity and perform functional studies on candidate genes.
  
• 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.             Back to top