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    Research Grants Awarded

    Detection of Early Stages of Breast Cancer Metastasis

    Study Section:
    Detection/Diagnosis/Prognosis

    Scientific Abstract:
    Background: New approaches are urgently needed for detecting early stages of breast cancer (BCa) metastasis to tumor-draining lymph nodes. Along the same lines, better approaches for detecting early systemic BCa spreading and monitoring treatment efficacy are also needed. As BCa develops, tumors release cells into the bloodstream that can be used as surrogate biomarkers of subclinical metastatic disease. Similarly, tumor-related DNA integrity determined through assessment of repetitive genomic repeats (ALU) released into the blood can be used as biomarkers. No single biomarker is efficient to assess early stages of BCa; biomarkers of different platforms are needed to improve accuracy in diagnosing early stage BCa progression. We have developed two molecular blood assays to detect circulating tumor cells (CTC) and tumor-related DNA integrity in serum. The synergistic results of the assays should prove to be more accurate in assessing early stages of BCa. Objective/Hypothesis: Our main hypothesis is that identification of early stage breast cancer progression by non-invasive molecular genetic blood assays can be used to improve BCa management. The objective of these studies is to verify our preliminary studies using circulating ALU DNA segments as surrogate genetic indicators of disease status, and CTC biomarkers in blood as indicators of subclinical metastasis. We will address the utility of these biomarkers in identifying disease progression and treatment response through multiple bleeds. Specific Aims: The Aims are: I) Assessment of circulating ALU DNA integrity in BCa patients? sera before and after surgical removal of primary tumor and involved draining lymph nodes. II) Assessment of CTC in BCa patients? blood before and after surgical removal of primary tumor and involved draining lymph nodes. III) Determine the clinical utility of ALU and CTC biomarker assays in assessment of realtime response to neoadjuvant chemotherapy. Study Design: In Aims I and II we will assess patients (n=120) pre- and post-primary tumor and lymph node surgery to determine the sensitivity of the two assays, ALU DNA integrity assay and CTC detection, respectively. The biomarkers will be correlated to disease burden and clinicopathology characteristics. Upon validating the individual assay sensitivity and specificity, we will assess AJCC stage I-III patients (n=125) undergoing neoadjuvant chemotherapy by monitoring response at specific intervals. Potential Outcomes and Benefits of the Research: A potential outcome is the development of a highly-sensitive non-invasive approach to diagnosing metastatic disease and monitoring ongoing therapy. This approach would improve early identification of women with high-risk of disease recurrence. The two assay platforms will be synergistic, providing a more sensitive comprehensive analysis. The success of these findings would clearly shift the cancer care paradigm, particularly in assessment of new and existing treatments.

    Lay Abstract:
    Background: New approaches are urgently needed for more informative analysis of early stages of breast cancer (BCa) progression and risk of recurrence. No single biomarker is efficient for assessing early stages of BCa progression. It is clear that different types of biomarkers are needed to improve accuracy. We have developed two molecular blood assays using two different biomarkers. As BCa progresses, tumor cells and DNA are released into the bloodstream and can be used as signatures of tumor presence and aggressiveness. We have developed an assay to detect circulating tumor DNA in small amounts of BCa patients? blood, allowing us to assess tumor DNA changes without tumor sampling. We have developed a multimarker assay to detect circulating tumor cells (CTC) to assess early stages of BCa spreading in the patient. The combination of both assays will provide a more efficient approach for diagnosing and monitoring BCa progression. In BCa nodal disease treatment, neoadjuvant therapy consisting of surgery and pre- and post-treatment with chemotherapy is given. The goal is monitoring the efficacy of multidrug-based therapies to make early management decisions. Hypothesis: Our approach is to utilize two blood assays to provide a more sensitive analysis of early disease progression and response to therapy. Our first hypothesis is to detect circulating DNA and CTC in blood that can predict disease burden and progression. The second hypothesis is that the DNA and CTC biomarker assays, together, can efficiently monitor patient response to neoadjuvant therapy. Specific Aims: The first aim is to validate the DNA blood assay in early stage BCa patients. Assay sensitivity and specificity will be assessed by examining blood before and after primary tumor and lymph node surgery. Aim II is to assess CTC in blood for the same patients and times as Aim I. In Aim III, the blood assays will be validated for monitoring of disease response at specific therapy intervals. Our large number of BCa surgeries performed per year will allow us to perform these aims rapidly. Study Design: For Aims I and II, our center is uniquely suited to accomplish these tasks, having large BCa surgery and medical oncology practices. Both assays in Aims I and II are established and ready to be validated. The assays are highly quantitative, thus providing meaningful measurements. The studies will involve 120 BCa patients. The success of these aims will allow us to proceed to Aim III to monitor patients receiving neoadjuvant therapy (n=125) at multiple bleeds. Potential Outcomes and Benefits of the Research: A potential outcome is the development of unique approaches to accurately diagnose early stages of BCa lymph node metastasis and distant spreading. The combination of the two blood assays will be synergistic, providing a comprehensive analysis. The success of these findings would clearly shift the cancer care paradigm, particularly in assessment of new and existing treatments.