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Research

Core Protocols

»The Tissue Protocol
»The Blood Library Protocol

Tissue and Blood Library Establishment for Molecular, Biochemical, and Histologic Study of Breast Disease

COL Craig Shriver, Director and Principal Investigator of the Clinical Breast Care Project outside of the Windber Research Institute.

The Clinical Breast Care Project (CBCP) is a congressionally mandated and funded military-civilian collaboration between Windber Research Institute (WRI) in Windber, Pennsylvania, and Walter Reed Army Medical Center (WRAMC) in Washington, D.C.

BACKGROUND AND SIGNIFICANCE

Breast cancer is the second leading cause of cancer-related deaths in American women and the most common cause of cancer-related deaths between the ages 15 and 54. The National Cancer Institute’s Surveillance, Epidemiology and End Results (SEER) program reported that 32% of all malignancies among women are breast cancer. Over the past forty years or so the incidence rate of breast cancer has been steadily increasing worldwide with a rate of one to two percent per year in the United States.

With this high incidence rate, even small improvements in treatment could represent tens of thousands of lives saved every year. For a systematic study of breast disorders, a large supply of good quality breast tissue specimens is needed.

This realization has led to the development of serum and tissue banks. Knowledge gained from cells at their most primitive level may translate into information relevant to clinical treatment and prevention of disease.

Although a small number of tissues can be obtained from different tissue banks for research purposes, they are often not backed by a comprehensive clinical and / or histopathologic information database, and they often are not good representations of the study population and / or study area. High throughput gene and protein expression profiling by microarray is on the forefront in the battle to understand the mechanisms associated with breast cancer development, progression and severity.

The ability to analyze thousands of genes and proteins simultaneously has many potential impacts. It allows researchers to study the gene’s relationship to breast cancer and to understand the pathways of disease development and progression. These discoveries will enable researches to develop novel drugs targeting disease pathways and disease-specific targets. Additionally, research application of these technologies may yield more specific and clinically relevant classification and sub-typing of breast disease. Expression profiling of tumor tissue therefore is a powerful method to identify novel genes involved in oncogenesis. However, the variability in the quality and quantity of fresh tissue is an obstacle to the application of this powerful technology.

We have created a large library of fresh breast tissue, and analyze it with high-throughput technologies in our CBCP laboratories for expression profiling. This tissue will be collected as part of that obtained during the course of clinically required treatment for breast disorders or other clinically indicated breast surgeries. This provides us with the resources to study the evolution of breast disease from normal epithelium to cancerous tumor at the genetic level. A concomitant blood library is used by our functional genomics and proteomic laboratory to investigate gene and protein marker expressions in patients with various forms of breast disease, and in those patients at above average risk for developing breast cancer (Risk Reduction Clinic patients). The biologically relevant information generated from the laboratory is then linked with our clinical database to identify and/or understand associations between biological properties of the tissue and clinical presentations. This multidisciplinary, linked database enables researchers and clinicians to follow patients longitudinally, and ultimately facilitate the correlation between discoveries made in the lab and patient care.

OBJECTIVES

Although there have been remarkable improvements in breast cancer diagnosis and management, most of the complex molecular mechanisms associated with the onset, progression and/or severity of breast cancer are still not well understood. As part of the CBCP we carry out molecular, biochemical and histologic / immunologic analysis of breast tissue and/or blood to provide more insights on the molecular mechanisms that may be relevant in breast cancer development and breast diseases. In achieving this aim, a large supply and a wide variety of good quality tissue samples are continuously needed. Unfortunately, good quality donor breast tissue is extremely scarce and when available is often not backed by a comprehensive medical history and /or not a good representation of the target population or study area. The non-availability of a steady and consistent supply of good quality tissue limits the systematic analysis of tissues and negatively impacts the generation of biologically useful information at the laboratories and by extension clinical practice. The objectives of this project are therefore:

  1. Acquisition and banking of breast tissue, lymph nodes, and/or blood from informed and consenting donors,
  2. Experimental analysis of DNA, RNA and/or proteins isolated from donor tissues for molecular, biochemical, immunological and/or histopathological analysis,
  3. Establishment of an integrated and relational database for tissue/serum and patient clinical characteristics that will provide the resources necessary to achieve the following future goals:
MEDICAL APPLICATION

Total number of patients participating in our core research protocols as of 25 September 2009.

One of the major challenges facing researchers and clinicians today is understanding the mechanisms associated with the evolution of benign breast disease and /or transition of breast disorders to breast cancer. The creation of a good and comprehensive tissue /blood bank is essential to the application of modern molecular and genetic analysis of breast diseases. Amongst other goals, this entire (overall CBCP) project will (1) establish a repository of good quality breast tissue and related (lymph nodal, blood) specimens for research on breast cancer and associated breast diseases, and (2) permit the establishment of a single relational database with accurate and comprehensive biologically and clinically relevant information on breast diseases. Since the standard of care for treating breast diseases and breast cancer is based on a multidisciplinary model that integrates prevention, screening, diagnosis, treatment and management, this CBCP project will provide the necessary framework for such an integrated approach, which will positively impact the future management of breast cancer.

PLAN

The rapid advances in basic research and data mining technologies fuels a growing demand for tissue banks. Tissue banks allow these researchers to test their hypotheses rapidly and in a cost effective manner. By linking such molecular information to clinical data, we propose to translate knowledge from the laboratory to the clinic. These new technologies coupled with the information that can be generated with resources available in a tissue bank, will inspire researchers in the field of breast cancer to ask questions and develop hypotheses that more than 20 years ago were inconceivable.

Subjects

Tissue is obtained from three general subject groups: 1) All consenting adult patients presenting to the Breast Center or the Women’s Imaging Center of the WRAMC with known breast cancer, 2) All consenting adult patients presenting to the Breast Center or the Women’s Imaging Center of the WRAMC with evidence of breast disease requiring clinical need for some form of tissue biopsy, and 3) all consenting adult patients presenting to the WRAMC plastic surgery clinic for elective reductive mammoplasty.

Specimen repository storage – All specimens will be held in CBCP freezers for up to an indefinite period of time into the future.

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Creation of a Blood Library for the Analysis of Blood for Molecular Changes Associated with Breast Disease and Breast Cancer Development

The Clinical Breast Care Project (CBCP) is a congressionally mandated and funded military-civilian collaboration between Windber Research Instiltute (WRI) in Windber, PA and Walter Reed Army Medical Center (WRAMC) in Washington, DC.

BACKGROUND AND SIGNIFICANCE

Breast cancer is one of the most common cancers among women. Like many other cancers, it is complex and involves multiple biological changes, which could be somatic or heritable. These changes characterize the transition of a cell from normal to neoplastic and its final progression into an invasive cancer (Deng et al., 1996, Liotta et al., 1974). Broad generalizations can be made about risk, natural history and clinical pattern, but it is not at present possible to accurately predict the future of an individual classified as being "at high-risk" for the development of breast cancer. This label of "high-risk" is applied generally to women who, upon undergoing screening via the computerized Gail Model (which is a validated NCI tool using a series of patient questions / answers resulting in an individualized computerized risk assessment), have any risk outcome that results in a >1.67% risk of breast cancer development over the next 5 years. Current diagnostic procedures are invasive involving biopsies with a high rate of negative results. To make significant future improvements on early breast cancer diagnosis and management, a more effective and minimally invasive method will be required that will be sensitive, predictive and allow accurate diagnosis at the earliest stage of disease onset. Neoplastic cells can be detected in bodily fluids that drain or bathe affected organs (Sidransky, 2000). The use of peripheral blood as a sample source for clinical research purposes is very attractive since it requires a less invasive procedure for sample collection (i.e. a simple blood stick). Clearly the use of circulating soluble markers that can be easily quantified through sensitive procedures such as the polymerase chain reaction (PCR) would be considerably more accurate than subjective approaches such as immunohistochemical staining which also require more invasive procedures for sample (tissue) collection. The spectrum of genetic and physiological events associated with primary tumors can be potential targets for molecular detection in the blood of patients and circulating soluble molecules in blood have been used as biological markers in cancer providing diagnostic and prognostic value (Posthumous et al., 2000, Yushchenko et al., 2000, Adams et al., 2000). High levels of circulating DNA have been observed in patients with metastatic disease and even patients with early stage cancer may harbor these free circulating DNA (Sidransky, 2000).

In order to diagnose breast cancer at the earliest possible stage and provide appropriate therapy after such detection, we need to understand the global profile of the genes and proteins in the blood. So far approximately 68 genes have been associated with breast cancer. They fall into several groups including DNA repair, cell cycle regulation, tumor suppression, internal/external signaling and transcription/growth factor regulation. However their exact expression pattern, which may impact upon disease onset and progression, are not yet fully understood. The techniques of Microarray Analysis and Single nucleotide polymorphism (SNPs) screening are high throughput gene expression analysis strategies that have been used successfully to characterize gene expression in many medical conditions. Microarray analysis allows the identification of gene expression differences through the simultaneous monitoring of thousands of genes in parallel using complementary DNA (cDNA) which are preloaded onto a small (size of a dime) chip. On the other hand, using the SNPs technique, single base variations in DNA can be identified. These new high-throughput technologies provide the tools for the identification of potential markers for disease detection and monitoring, and insights can be gained into individual differences observed in relation to disease susceptibility, onset of disease and/or response to therapy.

Significant improvement in breast cancer mortality rates will be achieved when we can either prevent the disease, or correctly diagnose it at an early stage and provide treatment that will halt metastasis. Until we find a means of preventing cancer, we can reduce mortality rates through early and accurate diagnosis followed by proper management. Developing a diagnosis / prognostic strategy that will be sensitive and which will require only samples collected through a minimally invasive procedure such as a blood stick, would significantly impact breast cancer management.

OBJECTIVES

Although there have been remarkable improvements in breast cancer diagnosis and management, most of the complex molecular mechanisms associated with the onset, progression and / or severity of breast cancer are still not well understood. As part of the CBCP we propose to carry out molecular, biochemical, and histologic / immunologic analysis of breast tissue and / or blood to provide more insights on the molecular mechanism that may be relevant in breast cancer development and breast diseases. To achieve this aim, a large supply and a wide variety of good quality tissue samples and blood specimens are needed. Unfortunately, a good quality donor breast tissue samples and blood specimens are scarce and, when available, are often not backed by a comprehensive medical history and / or not a good representation of the target population or study area. The non-availability of a steady and consistent supply of good quality tissue samples and blood specimens limits the systematic analysis of tissues and negatively impacts the generation of biologically useful information at the laboratories and by extension clinical practice. The objectives of this protocol are therefore:

  1. Acquisition and banking of blood and serum from informed and consenting donors.
  2. To characterize gene and protein expression profiles and single nucleotide polymorphisms associated with breast disease and breast cancer
  3. Identify factors within patient serum and/or blood-derived cellular components that correlate with patient risk factors or clinical status as defined in the corresponding clinical patient database.
MEDICAL APPLICATION

One of the major challenges facing researchers and clinicians today is understanding the mechanisms associated with the evolution of benign breast disease and / or transition of breast disorders to breast cancer. The creation of a good and comprehensive tissue / blood bank is essential to the application of modern molecular and genetic analysis of breast disease. Amongst other goals, this entire (overall CBCP) project has (1) established a repository of good quality breast tissue and related (lymph nodal, blood) specimens for research on breast cancer and associated breast diseases, and (2) has established a single relational database with accurate and comprehensive biologically and clinically relevant information on breast diseases. Since the standard of care for treating breast diseases and breast cancer is based on a multidisciplinary model that integrates prevention, screening, diagnosis, treatment and management, this CBCP project provides the necessary framework for such an integrated approach, which will positively impacts the future management of breast cancer.

This proposed study will identify differences in gene marker and protein expression patterns observed amongst a variety of patients attending the CBCP breast clinics at the WRAMC, WRI, and other sites. The patients will be grouped either as (1) high-risk for breast cancer development; (2) those diagnosed with breast cancer; or (3) other breast diseases (e.g. benign, or non/pre-invasive). Information obtained from the blood analysis will be linked with other clinical data to establish possible relationships between gene expression patterns and specific genetic alteration with disease onset and progression.

The medical implication of this study is the identification of molecular markers that may enable early breast cancer detection, monitoring and prognosis / prediction through a less subjective and less intrusive procedure.

PLAN

Subjects

All participants will be patients attending the CBCP Breast Centers at WRAMC, and Windber, PA, and additional sites participating with the CBCP, and who consent to join in the study. They will include (1) patients seen in the Risk Reduction clinics; (2) patients diagnosed with breast cancer; (3) patients diagnosed with any other type of breast disorder. The far majority of patients will be female, however, 1% of all breast cancers occur in males and these male patients with breast cancer (2 above) would be eligible as well. Patients will be recruited at their next scheduled patient visit.

Additionally, at the time of the initial visit, patients will fill out a questionnaire, assisted by one of the breast clinic nurses. At the time of future follow-up visits, the patients will have an update to their basic information collected annually via abbreviated questionnaire.

Specimen repository storage – All specimens will be held in CBCP freezers for up to an indefinite period of time into the future.

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