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    Awarded Grants
    Clinical Imaging of Breast Cancer Hypoxia and Response to Therapy

    Scientific Abstract:
    Clinical Imaging of Breast Cancer Hypoxia and Response to Therapy Background: Numerous factors influence cancer behavior and response to therapy. In many types of cancer, tumor hypoxia develops as a consequence of limitations in perfusion and metabolic alterations. Tumor hypoxia is known to be associated with a worse clinical outcome and a poorer response to chemotherapy and radiation therapy in several types of cancer, including breast cancer. However, it is not clear whether the primary cause of this relationship is hypoxia itself, or the functional consequences of hypoxia, such as enhanced angiogenesis or anti-apoptotic effects. Furthermore, the optimal way to clinically assess hypoxia and its downstream effects has not been established. Hypothesis and Objective: We hypothesize that non-invasive imaging of tumor hypoxia can provide early indication of therapeutic outcome, allowing therapy to be individualized and optimized for breast cancers. We propose to use specialized magnetic resonance imaging and spectroscopy (MRI and MRS) techniques to measure tumor hypoxia in patients with locally advanced breast cancer and to determine the relationship of these measures to clinical response to therapy and tissue-based markers of hypoxia. Specific Aims: 1. To obtain MRI and MRS measures of breast tumor hypoxia, cellularity and perfusion before and after chemotherapy. 2. To correlate MRI and MRS measures of tumor hypoxia with clinical, radiographic and pathological breast tumor response to chemotherapy. 3. To correlate MRI and MRS measures of tumor hypoxia to immunohistochemical and gene expression markers of hypoxia and hypoxia response. Study Design: Twenty patients with locally advanced breast cancer for whom treatment with chemotherapy is indicated will be consented to undergo pre-chemotherapy core needle biopsy and imaging of the breast with standard, dynamic contrast and water diffusion MRI and additional MRI sequences capitalizing on the blood oxygen level dependent (BOLD) effect. MRS for choline and lactate using 3-dimensional chemical shift imaging spectroscopy (3D-CSI) refined for small volume imaging will also be done. Short term effects after 1 cycle of chemotherapy and after all chemotherapy (immediately before surgery), will be assessed using the imaging techniques. Baseline, and changes in imaging indices will be correlated to clinical, MRI-based and pathological responses using standard response criteria. Imaging indices will also be correlated to tissue markers of hypoxia, vascularity, proliferation, and apoptosis assessed by immunohistochemical means and by global gene expression patterns, focusing on known hypoxia-inducible and angiogenesis-related genes. Potential Outcomes and Benefits of the Research: Refinements and validation of non-invasive imaging methodologies to characterize and measure the hypoxic tumor phenotype could optimally distinguish patients who may most benefit from conventional treatments such as chemotherapy and may also serve to identify the most appropriate subjects for enrollment into clinical trials of novel vascular-targeting agents. Additionally, the identification of key predictive hypoxia-related genes may lead to newer therapeutic or drug resistance-reversal strategies through the targeting of these gene products. Conducting this project in the context of a human trial with clinically relevant outcome measures and corroborating tissue studies maximizes the potential applicability of these findings for diagnostic and therapeutic goals.

    Lay Abstract:
    Clinical Imaging of Breast Cancer Hypoxia and Response to Therapy Background: The behavior of breast cancer is highly variable among individuals. Many factors determine the aggressiveness of cancer and responsiveness to conventional therapies. Among these factors is the development of low oxygen levels, also known as hypoxia, which occurs as a tumor outgrows its blood supply. Hypoxia can lead to resistance to both chemotherapy and radiation therapy, both of which are used in the treatment of breast cancer. Hypoxia leads to other effects on cells, including the production of several proteins, some of which lead to the formation of blood vessels as a response to low oxygen levels. The formation of blood vessels may further promote tumor growth. Very little is known about tumor hypoxia and its effects in individuals with breast cancer. New imaging techniques that are based on magnetic effects can measure hypoxia in laboratory models, and therefore may be promising in assessing biological characteristics in patient which in turn may help choose the most appropriate therapy for that individual. Purpose and Aims: The purpose of this study is to use magnetic resonance imaging and spectroscopy (MRI and MRS) to measure tumor oxygen levels and tissue effects of hypoxia in patients undergoing chemotherapy for breast cancer. This will be correlated with the amount of tumor shrinkage and also with proteins and gene changes in the tumor tissue that are known to occur with hypoxia. The overall goal of this project is to refine these imaging techniques and then to confirm that these can non-invasively measure hypoxia in order to predict who might best respond to chemotherapy and other therapies. Study Design: Patients with operable breast cancer who are to be treated with pre-operative chemotherapy as part of their standard treatment will be enrolled on this study and will undergo MRI and MRS imaging before chemotherapy, after the first cycle of therapy and right before surgery. Additionally, tumor biopsies using a core needle will be obtained at the same time points as the imaging studies, except that the last tissue sample will be obtained at the time of surgery. Statistical correlations of MRI and MRS measurements to tumor response will be made in order to determine whether hypoxia correlates with chemotherapy responsiveness. Tumor response will be determined by breast tumor measurements on physical exam, also by conventional MRI size measurements as well as by residual tumor measured by microscopic examination after surgery. MRI and MRS will also be correlated with tumor tissue assessments of proteins and genes that are known to be induced by hypoxia in order to validate the accuracy of the imaging studies. Potential Outcomes and Benefits of the Research: Refinements and validation of non-invasive imaging methods to characterize and measure tumor hypoxia could optimally distinguish patients who may most benefit from conventional treatments such as chemotherapy. These imaging techniques may also serve to identify the most appropriate subjects for enrollment into clinical trials of newer investigational drugs that block tumor blood vessel formation. Furthermore, the identification of hypoxia-related genes and proteins that correlate to drug response may lead to newer therapeutic or drug resistance-reversal strategies. Conducting this project in the context of a human trial with clinically relevant outcome measures and corroborating tissue studies maximizes the potential applicability of these findings for diagnostic and therapeutic goals.