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The University of Chicago Breast Cancer SPORE
Overall Abstract The University of Chicago Breast Cancer SPORE brings together a multidisciplinary team of basic, clinical, and population science investigators to design innovative research that will reduce the worldwide suffering from breast cancer using a uniquely global strategy. This integrated effort aims at developing genetic and imaging-based approaches to the prevention, detection, and treatment of breast cancer in women who are at increased risk of developing an aggressive form of malignancy at a young age. This is a grave clinical issue because currently there is no defined screening strategy for reducing breast cancer mortality in women less than 40 years of age. This is a particular problem for young women of African ancestry, because this type of breast cancer disproportionately affects them. Thus, a portion of the study tackles the global issue of health disparities between different ethnic and racial groups. The goal of the SPORE is to get to the root of the problem by identifying genetic mutations and altered protein pathways that promote aggressive behavior in breast cancer and limit the effectiveness of treatment for some patients. Understanding these cellular dynamics will help us create more effective and less harmful ways to prevent, screen, diagnose, and treat breast cancer in all women. The Breast Cancer SPORE is composed of four primary research projects, which will be supported by three core resources that will serve the purposes of administration, biospecimen management, and informatics. In addition, a Developmental Research Program and Career Development program will promote new research endeavors and enhance the quality of breast cancer research and investigators at University of Chicago for years to come. The SPORE investigators, core facilities, and development programs are joining and expanding upon the current efforts of the University of Chicago Cancer Research Center with the expectation that together our work will translate into dramatic improvements in breast cancer outcomes. The four main projects of the SPORE are as follows: Project 1 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
The clinical translational component of this project will involve 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. Project 2 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
Project 3 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
Project 4 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 of metastatic breast cancer progressing on initial chemotherapy. Specific Aims
Core 1 The purpose of the Administrative Core is to facilitate translational research in breast cancer by harnessing intellectual capacity and providing a mechanism for cost effective utilization of resources. The Core will provide necessary administrative support structure to components of the SPORE program such that communication, integration, and oversight activities are optimized. The Administrative Core will facilitate communication and effectiveness in the activities among SPORE participants, involvement of other researchers and clinical providers at the University, collaborations with investigators and SPOREs outside of the University, interaction with government agencies, and relations with the outside patient and advocate community. Specific Aims
Core 2 Effective procurement of tissue and other biospecimen, and their optimal utilization is vital for meaningful translational research activities. Thus, the function of the Biospecimen, Pathology, and Genotyping Core is to facilitate acquisition, preservation, analysis, and dispersal of well-annotated clinical samples and to provide histopathologic characterization of tumor tissues for all project investigators. The Core will obtain and maintain a repository of biospecimen including tumor tissue, pre-malignant tissue, adjacent non-malignant tissue, serum, plasma, peripheral blood lymphocytes, and lymphoblastoid cell lines, along with their derivates such as DNA and RNA samples for laboratory use. An effective coding system for all laboratory specimens will ensure patient confidentiality and prevent experimental bias. Continuous communication between the surgeons, research nurses, biostatisticians, and pathologists, as well as standardized operating procedures will provide for optimal biospecimen collection and accurate processing, analysis, and storage of each sample. Samples will be prepared for genotyping in an efficient manner in a CLIA certified laboratory that assures quality control while ensuring that these precious materials are not wasted. The Biospecimen, Pathology, and Genotyping Core of the Breast Cancer SPORE will be integrated with two existing resources of the University of Chicago Cancer Research Center – the Human Tissue Research Core Facility and the DNA Sequencing and Genotyping Core Facility. Currently, these facilities provide tissue and pathology services for cancer research, including microdissection, tissue microarray, immunohistochemistry, and genomics analysis. By collaborating with these facilities in the Cancer Research Center, the Biospecimen Core can provide investigators with a coordinated, efficient service for managing the procurement and analysis of biospecimen and clinical data from breast cancer patients. Core 3 The goal of the Analytic and Informatics Core (AIC) is to work with each SPORE research project and the Biospecimen, Pathology, and Genotyping Core to provide an integrated data management system to facilitate integration among all projects and cores and to serve as a resource for the design of basic science experiments and clinical trials, development of innovative statistical methodology, statistical analysis, and publishing translational research generated through the Breast SPORE program. The AIC will merge all demographic, epidemiology, and specimen data into a single database to meet statistical needs and ensure research quality of all translational projects supported by this SPORE. This effort will be integrated with the Cancer Center Biostatistics Core Facility and the Bioinformatics Core of the University of Chicago for ease of administration, avoiding duplication of existing infrastructure and taking advantage of existing expertise. The Analytic and Informatics Core will incorporate sound experimental design principles within each project to enhance interpretability of study results, will carry out data analyses using appropriate statistical methodology, and will contribute to interpretation of results through written reports and frequent interaction with project investigators. Specific Aims
Developmental Research Program The objective of the University of Chicago Breast Cancer SPORE Developmental Research Program (DRP) is to create a streamlined and transparent mechanism for soliciting and selecting exciting and novel research projects that have significant potential for translational success. Such projects may be collaborative among scientists within our SPORE or outside the SPORE environment. Most importantly, they should be innovative, have the potential for high impact results, and preferably be multi-disciplinary. Criteria for Selection:
The University of Chicago Breast Cancer SPORE DRP will provide $50,000/year ($25,000 of SPORE funds matched with $25,000 of institution support) to each of four projects per year. There will be a possibility of a second year of support based on progress. The University of Chicago SPORE Executive Committee will work with the Internal Advisory Committee to encourage successful investigators to pursue independent funding so that even investigators who may be new to breast cancer research will have a high likelihood of successful application of their ideas to breast cancer prevention, diagnosis, and treatment. Specific Aims:
Career Development Program This program will be used to support early careers of the most promising junior investigators and to recruit new senior investigators into breast cancer translational research. The University of Chicago has long recognized the importance of clinician scientists capable of using clinical observations to inform and shape basic investigations, and in turn, evolving novel therapeutic approaches through laboratory discoveries. The Career Development Program of the Chicago Breast Cancer SPORE is committed to identifying and mentoring investigators interested in translational breast cancer research. The program will primarily provide tightly-structured, multidisciplinary mentoring for junior faculty with the greatest potential of developing independent programs in translational breast cancer research; however, exceptional senior faculty who demonstrate strong interest in developing such programs may also be eligible. Investigators may come from clinical or basic science backgrounds, provided that their research aims are translational in nature. We will use a rigorous review process, working with department Chairs to identify and recruit the most talented and promising candidates to participate in our comprehensive mentoring program. Programmatic leadership and individual mentoring will be provided by a multidisciplinary mentoring committee, which must include the necessary representation from the basic/population sciences, clinical sciences, and biostatistics so that all disciplines are represented for optimal mentoring of the awardees. These mentors are established cancer researchers, and as members of the UCCRC, have access to all the Cancer Center sponsored Cores. |
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