SPOREs : Organ-Specific SPORE Programs : Breast

OVERALL ABSTRACT

The Dana-Farber/Harvard SPORE in Breast Cancer (Breast SPORE) is an integral component of the DF/HCC Program in Breast Cancer. The Breast SPORE represents a significant collaboration that includes research investigators from all of the major DF/HCC sites, Harvard University and Massachusetts Institute of Technology's Whitehead Institute and Broad Institute.

Projects in the Breast SPORE fall into two broad categories: those that start with a clinical trial, and develop biologic questions designed to improve treatment outcome; and projects that start with a biological question about breast cancer and attempt to answer that question by studying patients, their cells and their tissues. The following table summarizes our projects.

The Breast SPORE's shared resources reflect the changing mandates of the SPORE Programs and takes advantage of new technologies. In addition to project-driven demands, new regulations and standards for the protection of human subjects demand that consent to use biological samples linked to clinical information must be obtained at the beginning of treatment, prior to surgical excision.

Breast SPORE Projects

Project 1: Biology and treatment of BRCA1 mutant and sporadic Basal-like cancers

The cancers that arise in women harboring BRCA1 mutations have a characteristic phenotype, being mostly poorly differentiated, high-grade invasive ductal carcinomas that do not express ER or PR and do not have amplification of erbB2. Gene expression array analysis has shown that these BRCA1-mutant cancers display the same gene expression profile as the basal-like cancers (BLC), a distinct subset of high grade ER(-), PR(-), Her2(-) tumors that account for ~15% of human breast cancers. These observations suggest that the BRCA1-mutant and sporadic BLC share a similar functional molecular phenotype. As BRCA1-mutant tumor cells show clear defects in DNA repair and epigenetic stability of the inactive X chromosome, and are characterized by heightened sensitivity to DNA cross linking agents such as cis-platinum, the BLC may also share these features. The goal of our project is to use our knowledge of BRCA1 biology to gain insight into the biology of BLC and identify specific physiologic vulnerabilities that will guide the development of more effective treatment strategies for this group of aggressive breast cancers. The first two aims are to assay specific aspects of genomic stability, DNA repair and heterochromatin maintenance in BLC and BRCA1-mutant cancer samples to characterize their functional similarities and differences. The third aim is to evaluate the response of a cohort of women with ER(-), PR(-), Her2(-) breast cancers, of which the majority should be BLC, to cis-platinum in a phase II pre-operative treatment trial, correlate the results of any informative biological assays validated in the first two aims with treatment response.

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Project 2: Targeted Combinations for HER2 - Positive Breast Cancer Biology

Over-expression of the receptor tyrosine kinase HER (ErbB2/Neu) plays an important role in breast carcinogenesis and response to therapy. The humanized monoclonal anti-HER2 antibody trastuzumab (Herceptin@), in combination with chemotherapy, extends survival of HER2+ breast cancer patients. Unfortunately, cancer often recurs following such regimens, and current treatment is unlikely to cure most patients. New combination approaches to trastuzmab therapy would be of substantial clinical benefit. HER2+ tumors may resist trastuzumab therapy due to activation of other growth factor or cytokine signaling pathways. The goal of this proposal is to develop a three-tiered "pipeline" approach for delineating new combinations of trastuzumab and other targeted signal transduction inhibitors. In Aim 1, we use microarray and immunohistochemical techniques to delineate biomarkers for the early detection of optimal response to trastuzumab alone in a "brief exposure" setting. A Phase I trial of trastuzumab plus the rapamycin analog CCI-779 will be evaluated in metastatic patients, and if the combination is found to be safe, moved to the brief exposure setting. Knowledge gained from the trastzumab exposure study will be used to assess the value of this and other combinations. In Aim 2, we will test combinations of trastuzumab and novel signal transduction inhibitors in the drug development pipeline (Akt, Mek, PI3K, Jnk). We will also determine whether combination therapy can extend the therapeutic range of trastuzumab to breast tumor cells expressing low levels of HER2. In Aim 3 we will carry out a, high throughput siRNA screen kinase targets that enhance trastuzumab action, and a high throughput mutation screen for ErbB family members in HER2+ disease. We envision this pipeline will produce novel targets (Aim 3) that would progress to pre-clinical testing and prioritization of promising drug candidates (Aim 2) that then move to rapid and efficient clinical testing (Aim 1). With these complementary approaches, the results of our research are likely to have impact on the treatment of HER2+ breast cancer patients.

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Project 3: Role of Coregulators in Response to Aromatase Inhibitors

Estrogen receptor (ER) regulates transcription in conjunction with the action of coregulatory molecules that interact with the receptor in a ligand-dependent fashion. The gene for one of these ER coregulators, AIB1, is amplified in a subset of human breast cancers and functions as an oncogene. Work from several labs including our own have implicated AIB1 and other coregulators in determining the tissue and tumor-specific activities of selective estrogen receptor modulators (SERMs) such as tamoxifen and as playing a role in tamoxifen resistance. Aromatase inhibitors (AI) have replaced tamoxifen as first-line endocrine therapy for post-menopausal women with advanced ER+ breast cancer and are rapidly replacing tamoxifen in early stage ER+ breast cancer as well. However, little is known concerning the mechanism underlying de novo resistance to AI therapy. We hypothesize that the levels and activity of AIB1 and other ER coregulators play a role in determining a tumor's response to AI therapy. We will test this hypothesis in cell-based models of estrogen deprivation, a transgenic mouse model of AIB1-dependent breast cancer, and in the pre-surgical setting in postmenopausal women with newly diagnosed ER+ breast cancer. These studies will facilitate the translation of progress in our basic understanding of the importance of coregulators in ER action to improvements in endocrine therapy.

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Project 4: Biology of Metastasis in Breast Cancer Patients

Metastasis is the major cause of death in breast cancer patients, but the molecular nature of metastatic breast cancer is poorly understood. This limited understanding is likely due to the genetic complexity of the metastatic phenotype, which is not easily studied using traditional methods. Little is known at the genome-wide level about the degree of heterogeneity that may exist within primary tumors or the relationship of this heterogeneity to eventual metastasis. Few studies have compared paired metastatic lesions and primary tumors; furthermore, most of these studies have been limited to the analysis of single or few molecular markers. Thus, the debate over whether a stochastic versus deterministic model of cancer metastasis is most relevant in breast cancer remains largely unresolved. A comprehensive understanding of the mechanisms of metastasis would greatly accelerate progress in the development of new diagnostic and therapeutic approaches to advanced breast cancer. Our long-term goal is to develop a more accurate understanding of the genetic alterations associated with progression of human breast cancer, through a systematic, genome-wide analysis of primary and metastatic lesions in patients with breast cancer. In addition, we will assess whether patterns of genetic alteration encoded in the primary tumor predispose to site-specific metastasis. To achieve these goals, we propose the following Aims:
Specific Aim 1. To determine the degree and nature of genetic relatedness between paired primary and metastatic lesions in human breast cancer patients using SNP microarrays.
Specific Aim 2. To develop predictive models for site of eventual metastasis using DNA microarray-based gene expression profiling of primary breast tumors.

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Project 5: The Role of Stromal Cells and Stromal-Epithelial Interaction in the Early Stages of Breast Tumor Progression: Implications for Risk, Prevention and Treatment

The importance of stromal-epithelial interactions in established breast cancers has long been recognized, but the role of stromal cells in the early stages of breast cancer initiation and progression are much less well defined. It is possible that biological attributes of the normal stroma in many women may create conditions that favor the inception and progression of mammary carcinomas and/or that stromal cells may have distinct effects on the subsequent behavior of the epithelial cells that comprise pre-invasive lesions, such as epithelial hyperplasias and carcinomas in situ. A better understanding of the role of stromal cells in normal breast tissue from patients with and without breast cancer and a more complete appreciation of their role in precancerous breast lesions would not only help us understand the part these cells play in the early stages of breast tumorigenesis, but would also likely provide new molecular targets both for breast cancer treatment and prevention. The goals of this project, therefore, are to obtain a more complete understanding of the role of stromal cells and of stromal-epithelial interactions in the early stages of breast tumor initiation and progression. This project has three specific aims:
Aim 1. To determine in human breast tissue samples if there is an association between expression of stromal markers that appear to have a role in established breast cancers with the presence of epithelial lesions known to be associated with increased breast cancer risk, and to determine if there are stromal markers that can be used as independent risk indicators in women with benign and pre-invasive breast lesions.
Aim 2. To determine if stromal cells from uninvolved breast tissue from patients with breast cancer are more conducive to cancer development than stromal cells of women. without cancer and to determine the gene expression signatures of such stromal cells
Aim 3. To determine if targeting of genes and proteins involved in stromal-epithelial interactions could potentially be of therapeutic value.

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Project 6: Variation in Receptor Tyrosine Kinases and Breast Cancer Risk

It is clear that part of the risk of developing breast cancer is genetically determined. The genetic contribution to breast cancer risk may arise from either common or rare variants (or both) in the population. In order to systematically assess both common and rare polymorphisms, we propose to apply a structured and highly multidisciplinary two pronged approach designed to initially maximize the power to detect the effect of each class of variants on breast cancer risk. For the common variants, we will focus on cancer association studies using DNA from breast cancer cases and controls in the Nurses' Health Study and breast cancer cases from the SPORE's High Risk Cohort. The rarer missense variants will be subjected to functional cellular and molecular assays, combined with tracking of the variants in cases of familial breast cancer. Any variant that scores positive (for function or association) will be pursued by the complementary approach. In the previous SPORE cycle, we employed a 3-dimensional (3D) culture model of breast acini to identify genes from the 'Breast Cancer 1000' cDNA library that induce phenotypic changes resembling events associated with breast tumor initiation and progression. Building on these results, we will initially focus on four candidate receptor tyrosine kinases, which showed the most dramatic phenotypic effects: EGF-R, CSF-1R, ERBB2, and IGF-1R. This research approach will be extended to other genes in future years. In this proposal, we will specifically:1) test common variants for association with breast cancer across a spectrum of risk classes, 2) test rare variants for distinguishable functional activity and association with familial and early-onset breast cancer, 3) examine the relationship between genetic variation and breast tumor receptor expression status in sporadic breast cancer and 4) when possible evaluate the association of circulating ligands for these receptors and subsequent breast cancer risk. Using this paradigm to investigate the role of genetic variation and breast cancer, we hope to identify modestly penetrant alleles conferring breast cancer risk .

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Breast SPORE Core Resources

Core 1: Tissue and Pathology

The Tissue and Pathology Core Resource will provide tissue to SPORE investigators for translational research projects and limited pathology research services to SPORE projects. The Tissue and Pathology Core maintains several distributed tissue banks: At the MGH, blood from women with breast cancer or who have a high risk for breast cancer is stored. Also at the MGH, tissue from the operating room is stored. The BWH stores a variety of tissues from breast operations conducted in their operating rooms. The DFCI holds blood from women seen in its Breast Oncology Clinic with breast cancer, and from women with an increased risk for breast cancer seen in risk evaluation programs. At the BIDMC, a large collection of archived, paraffin embedded blocks is kept linked to a database containing clinical information without patient identifiers but with detailed pathologic descriptions in searchable data fields. The BIDMC maintains a SPORE research pathology laboratory, which will perform immunohistochemistry, fluorescent in-situ hybridization, and other simple or complex histologic applications. This service is available to SPORE projects, including Developmental Projects and Career Developmental Awardees. The tissues are available to SPORE investigators, DF/HCC members and other collaborating investigators on a case-by-case basis. The Tissue and Pathology Core participates in the Core Coordinating Committee and abides by its policies and procedures.

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Core 2 - Clinical Studies

The Clinical Studies Core will be involved in any SPORE study that requires patient consent, specimen acquisition, and/or protocol-based treatment. The core will provide an over-arching structure within the SPORE and the Dana-Farber/Harvard Cancer Center that will eliminate the need to create individual project-based study teams in each of the clinical institutions. The Core will supply direct support to Projects 1, 2, 3, and 4. In addition, the Clinical Studies Core will obtain consent from all patients who are included in the cohort studies described in Core 3. Finally, the Clinical Studies Core will provide support to investigators to expedite the development, review, and activation of all clinical protocols.

The specific aims of the Clinical Studies Core are:

• To coordinate the review, preparation, and activation of all clinical studies in the SPORE
• To support all active SPORE clinical studies through:
  • Recruitment and consent of patients to clinical studies
  • Management and follow-up of patients on clinical studies
  • Monitoring of accrual and toxicity, data management
• To obtain consent for data collection, banking of tissue and blood specimens, and permission to recon tact for cohort studies in women with breast cancer and those women at high risk of developing breast cancer

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Core 3: Cohort Studies and Databases

The Cohorts and Databases Core (CDC) will maintain two cohorts of patients and their associated databases and continually update and add information. In addition, the Core will maintain a database supporting tissue storage and use. The two populations of patients are men and women with breast cancer or women at increased risk because of genetic or histologic risk factors. Tissues are those blood samples and breast specimens kept in repositories at the DFCI, BWH or MGH. The databases are called CRIS (Clinical Research Information System), REACH (Risk Evaluation And Cancer History), and STIP (Specimen Tracking and Inventory Program). Men and women with breast cancer are prospectively entered into CRIS from the Gillette Breast Oncology Clinic at the DFCI and the AVON Breast Evaluation Center at the MGH. Women at high risk for breast cancer are entered into REACH at the risk evaluation clinics at the DFCI and BIDMC. Data managers at the DFCI and MGH prospectively enter data into both registries. Users in the tissue banks at the DFCI, BWH and MGH use STIP for entry and inventory purposes. Reports are issued by specialized software to requesting investigators and down loaded to other registries. All three databases are kept on Partners HealthCare Information Systems' central computer facilities, and available on workstations throughout the Partners System. The Core will provide reports to SPORE investigators who have approved projects and after consultation about data requirements. The Core is also available to collaborators who are members of the DF/HCC or other investigators on a case-by-case basis. The Core will participate in the Core Coordinating Committee and will abide by policies and procedures agreed upon by the Committee.

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Core 4: Biostatistics

The Biostatistics Core provides consultation and collaboration on quantitative methods to investigators on 6 of the SPORE projects and all developmental projects and to Cores 1, 2, and 4. The specific aims are:

1. To provide "open door" (more likely "open phone" or "open email") short term statistical consultation to the entire group of SPORE investigators.
2. To provide biostatistical expertise for the planning, conduct, analysis, and reporting of laboratory, animal, clinical, and epidemiological studies for SPORE projects.
3. To provide consultation on computer databases, statistical computer packages, publicly available statistical programs and moving data between computers and between databases, as well as to provide statistical collaboration in developing statistical programs for specialized problems.
4. To facilitiate sharing of information between SPORE projects and developmental projects on variability of and statistical distributions of various measures, such as new assays, methods of tumor burden measurements in animal studies, and short and long term changes in markers in human studies in order to permit studies in order to permit study designs to be informed by several data sets (rather than just the pilot studies done in that project),

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Core 5: Genomic Data and Bioinformatics

High throughput genomic experiments are becoming commonplace, and are an essential component of many research projects in cancer as well as many other diseases. The research proposed in Projects 1 through 6 in this application will place a substantial reliance on high throughput genomic data. The role of this core is two-fold. First, we will provide a clearinghouse solution for data analysis, primarily through the laboratory of Dr. Liu. The second major role of this core is to create a paradigm for storing data, providing access to the many different investigators (at a variety of resolutions) and providing tools to support meta-analyses of the experimental data, in conjunction with other, publicly available, data.

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Core 6: Communications, Planning and Administration

The Communication, Planning and Administration Core will organize and fund the distributed research that takes place in the SPORE. This includes responsibility for both federally funded research, and the administration of institutional funds made available to us by the Dana-Farber Cancer Institute. This Core will organize the evaluation of SPORE scientific projects and core resources by 1) constituting an External Advisory Board, 2) organizing meetings of the Internal Advisory Board, and 3) reporting to the Steering Committee of the Dana-Farber/Harvard Cancer Center (DF/HCC) Breast Program. We will foster communication by holding regular research-in-progress meetings, annual retreats, attendance at Workshops and Roundtables, and by planning seminars and symposia. The Core will continue to arrange the visits of outside scientists and clinical leaders to Boston for the purpose of meeting with SPORE investigators and providing us with reports of their research. The Core will provide integration of the SPORE into the DF/HCC by reporting to and participating in Cancer Center committees, using Center Core Resources, and providing valuable SPORE resources to DF/HCC members. Planning and policy will be provided by the Core Coordinating Committee for use of shared resources in the SPORE. This Core will facilitate and promote the activities of an Advocacy Committee, involve advocates in planning activities of the SPORE, and report to the Committee at their request. Core 6 provides fiscal oversight for the entire SPORE including subcontracting to participating institutions, reporting to the NCI, and insuring the rapid use of available funds to promote breast cancer research. The Core also will administer privately raised funds that are earmarked to support Core activities. The Core will also publicize our data sharing strategies and policies and continue to promote open sharing of scientific information.

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