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    Computed Tomographic Prediction of Response to Treatment in Breast Cancer Induced Bone Metstasis

    Scientific Abstract:
    Skeletal metastases occur in 47% to 85% of breast cancer patients by the time of their death. Annually, 25-40% of breast cancer patients with skeletal metastases will require radiotherapy for bone pain, 30% will develop hypercalcaemia and 17-50% will sustain a fracture. As a result of new and aggressive treatment, breast cancer patients are living longer but skeletal metastases continue to be a feared complication. These complications manifest themselves as intractable pain, fracture after minimal trauma, paralysis due to spinal cord compression and hypercalcaemia. While much has been learned about the mechanisms of metastatic spread of cancer to bone, there has been little headway in establishing guidelines for estimating fracture risk or monitoring the response of skeletal metastases to treatment. Most clinicians make subjective assessments regarding fracture risk and treatment response based on plain radiographs using methods now known to be inaccurate. Biochemical markers of bone metabolism have been used to assess the extent of metastatic spread to the skeleton and to monitor the efficacy of drugs used to treat skeletal metastases, however these serum assays do not identify whether fracture risk is increasing or decreasing for specific skeletal lesions. MRI has been used to assess changes in tumor volume after treatment, but MRI cannot readily assess the healing response of the host bone or the associated fracture risk. The prevention of fractures due to skeletal metastasis depends on objective criteria for evaluating changes in bone structural properties that reflect the interaction of the tumor with the host bone. Optimizing treatment for a particular patient is complicated, in part because there are no proven objective methods for evaluating a patient’s response to treatment. The objective of the proposed study is to prove that CT based structural analysis will provide clinicians not only with an objective means for monitoring the fracture risk of patients with breast cancer induced skeletal metastases but for monitoring the response of a specific bone lesion to anti-cancer and/or anti-resorptive treatment options. Our hypothesis is that CT based assessment of changes in bone structure as a result of breast cancer induced osteolysis can be used to monitor the progression or regression of skeletal metastases in patients undergoing anti-cancer and anti-resorptive treatment options. We have developed a rat model to study the biomechanics of cancer induced osteolysis. In Aim 1 the effect of cancer induced osteolysis on bone mechanical properties will be evaluated by comparing the changes in bone structural properties calculated from transaxial CT images of the rat femur to the changes in tumor activity as a function of time after inoculating Walker 256 carcinosarcoma cells into the femur. Surrogate markers of tumor burden including tumor volume and serum assays for osteolysis will be used to measure tumor activity. In Aim 2 we will evaluate whether bone structural properties can be used to monitor the effect of therapies currently being used to modulate cancer induced osteolysis in breast cancer patients. We will compare the structural properties of rat femurs inoculated with Walker 256 cells and subsequently treated with either saline, paclitaxel (a cytotoxic chemotherapy with little direct effect on osteoclasts), ibandronate (an anti-osteolytic bisphosphonate with little direct effect on cancer cells) and radiotherapy (inhibits all cells in radiated field). To prove that bone structural properties can monitor the effect of treatment on tumor induced osteolysis, the changes in bone structural properties will be compared to changes in tumor activity for each treatment as a function of time after treatment initiation. Successful completion of these aims should allow us to introduce CT based structural analysis as a clinical tool to monitor the fracture risk associated with skeletal metastases in individual patients, to optimize treatment based on fracture risk and to continuously monitor the response of the metastasis to treatment.

    Lay Abstract:
    Breast cancer is the most common cancer among women in the United States and the skeleton is the most common site for metastatic spread of the cancer beyond the breast. Often a skeletal metastasis weakens the affected bone to such an extent that the bone will fracture even when subjected to forces encountered during activities of daily living (e.g. when bending over to pick up a shopping bag vertebral fractures occur in women with metastases to the spine). These fractures can cause considerable pain and loss of function. With new and aggressive treatments, breast cancer patients with skeletal metastases are continuing to lead productive lives. In order to prevent fractures at bone metastases from occurring and to allow physicians to monitor the response of skeletal metastases to treatment it is imperative to establish reliable guidelines for estimating fracture risk in affected bones. Past and present research has provided significant insight into the biology of breast cancer and the mechanisms of spread of breast cancer to bone. However current radiographic and symptom-based guidelines used by physicians to estimate fracture risk in bones containing metastatic breast cancer are inaccurate. Biochemical markers detected in the blood have been developed to measure the extent of tumor induced bone destruction, but these serum markers fail to provide any information about the relative fracture risk of the affected bones. Magnetic Resonance Imaging (MRI) has been used to detect changes in tumor volume following treatment, but this approach cannot measure the healing response of the bone, which significantly affects the fracture risk of the involved bone. The prevention of fractures due to skeletal metastases depends on objective criteria that can reliably predict the maximum load bearing capacity of the affected bone and can be used to monitor the response of specific metastases to systemic and/or local treatment. Finding the optimal treatment for a patient with skeletal metastases is partly complicated by the absence of an objective and reliable method for evaluating a patient’s response to treatment by measuring the reduction in the fracture risk associated with the bone lesion. Therefore, we propose to evaluate whether a computed tomography (CT) based method for measuring bone structural properties and bone fracture risk previously developed and validated by us in women with metastatic breast cancer to the spine can also be used to monitor whether a patient with skeletal metastases is responding to treatment using bisphosphonates, chemotherapy or radiation therapy. This would provide clinicians with a new tool to determine whether the current treatment is effective or whether different drugs, radiation therapy or surgical stabilization is necessary. Since it is impossible to evaluate fracture risk in breast cancer patients with nearly identical skeletal metastases in a controlled manner we plan to conduct this study using rats injected with a cancer that produces a bone lesion similar to human breast cancer. Cancer cells will be injected into the rat femur (thigh bone) to create a lesion similar to that observed in humans with metastatic breast cancer. We will first prove that our CT-based method of structural analysis can be used to predict the actual fracture force in the rat femurs containing the cancer cells by testing the affected bones mechanically. We will then inject another group of rat femurs with tumor cells but after the bone is partially destroyed by the cancer we will treat the rats with either a bisphosphonate (ibandronate), a chemotherapeutic agent (paclitaxel) or radiation therapy similar to humans with skeletal metastases. This time we will investigate whether our CT-based method of bone structural analysis can be used to monitor the response of the rat femur to cancer treatment by comparing the changing bone structural properties to markers of tumor growth, bone destruction and bone fracture force.