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    Research Grants Awarded

    Immunologic Gene Expression in Sentinel Lymph Nodes

    Study Section:
    Detection, Diagnosis and Prognosis

    Scientific Abstract:
    Background. In addition to its importance in the detection of metastatic disease, the sentinel node (SN) is the site where the immune system first comes into contact with a primary tumor. A few reports in the literature have provided snapshots of immunologic events that occur in the SN, suggesting a pivotal role of the SN in the initial activation of the immune response. The clinical availability of axillary SN specimens presents a unique opportunity to study early events in immunological activation in breast cancer patients. Objective/Hypothesis. The overall goal of this study is to determine patterns of gene expression that are relevant to the success of immunologic reactivity and patient prognosis. We hypothesize that the expression of immunologic genes in SNs will be predictive of whether a patient mounts a successful immune response or becomes tolerant to the breast cancer cells. Specific Aims. The specific aims of this project are to: 1) determine whether whole human genome oligonucleotide microarrays can be used to detect qualitative differences in gene expression patterns between SN and NSN, even before metastasis has occurred; 2) define specific gene expression signatures in SNs that relate to the success or failure of the immune system to react to the primary tumor and/or nodal metastases; 3) use microfluidic real-time quantitative PCR to verify gene expression patterns defined by microarray analysis; and 4) determine whether the observed gene expression patterns are related to common prognostic factors and/or survival of breast cancer patients. Study Design. We propose to study gene expression in the SNs of breast cancer patients using whole human genome microarrays to look at qualitative changes in gene expression and real-time PCR to quantitatively examine a more focused array of immunologically relevant genes. Potential Outcomes and Benefits of the Research. We expect to find at least two distinct gene expression patterns in SNs from patients with early stage breast cancer: favorable (immuno-reactive) or unfavorable (immuno-tolerant). We expect to find differences in gene expression patterns among patients who are negative for nodal disease at the time of their SN biopsy vs. those patients with metastases. A better understanding of early events in gene expression in the SN might have important implications for future patients with respect to staging, prognosis and determining which patients are the best candidates for immunotherapy.

    Lay Abstract:
    Background. The sentinel node (SN) is defined as any lymph node that has a direct connection through lymphatic vessels to the area of a primary tumor. In addition to its importance in detection of metastatic disease, the SN is also the site where the immune system first comes into contact with a primary tumor. A few reports in the medical literature have provided snapshots of immunologic events that occur in the SN, suggesting a pivotal role of the SN as the site where activation of the immune response occurs. Objective/Hypothesis. The overall objective of this study is to define patterns of gene expression in SNs that have relevance to the success of immunologic reactivity in patients with breast cancer. We hypothesize that early events in the expression of immune system genes can be detected in SNs compared to nearby non-sentinel nodes (NSN). These changes in gene expression might be predictive of whether a patient mounts a successful immune response or becomes tolerant to the cancer cells. Specific Aims. The specific aims of this project are to: 1) determine whether whole human genome microarrays can be used to detect qualitative differences in gene expression between SN and NSN; 2) define specific gene expression signatures in SN that might relate to the success or failure of the immune system to react to the primary tumor and/or metastases; and 3) determine whether the observed gene expression patterns are related to patient survival. Study Design. We propose to study gene expression in SNs of breast cancer patients compared to nearby NSN. We will use whole human genome microarrays to look at qualitative changes in gene expression and real-time PCR to quantitatively examine a more focused array of immunologically relevant genes. Potential Outcomes and Benefits of the Research. We expect to find at least two distinct gene expression patterns in the SNs from patients with early stage breast cancer: favorable (immuno-reactive) and unfavorable (immuno-tolerant). We believe that a better understanding of events at the level of gene expression in the SN will have important implications for future patients, especially with respect to determining a) whether metastasis has occurred or is likely to occur, b) whether a patient’s immune system is capable of fighting metastatic disease, and c) which patients are the best candidates for immunotherapy. In addition, we hope to identify gene pathways that might be ideal targets for future immunotherapeutic strategies.