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    Awarded Grants
    Development of PET Methodology for Monitoring Early Responses to Chemotherapy in Breast Cancer Patients

    Scientific Abstract:
    Early assessment of response to chemotherapy in breast cancer using PET Background and Objective: A non-invasive, in vivo method for distinguishing responders from non-responders early during chemotherapy is essential both for optimizing therapy and for improving quality of life. Treatment can then be tailored to the individual patient, thus avoiding toxicity of ineffective treatment and achieving optimal anti-tumor effects. Monitoring response using anatomical imaging techniques is restricted by limited accuracy, reproducibility in determining tumor size, specificity and the delay between initiation of therapy and clear visible effects. Early information will more likely be obtained at a functional rather than anatomical level. The most common functional measurement is that of glucose metabolism using PET and [F-18] fluorodeoxyglucose (18FDG). In breast cancer, a limited number of prognostic18FDG studies have been reported. As a variety of qualitative and semi-quantitative analytical techniques were used, the actual value of 18FDG-PET in clinical practice is still unclear. To date, an accurate comparative study with full kinetic analysis of 18FDG is lacking. Theoretically, for response monitoring a tracer that more closely correlates with cell proliferation than 18FDG might even perform better. Such a tracer is fluorodeoxythymidine (18FLT), a marker for thymidine kinase activity. Another important parameter with regard to chemotherapy is perfusion (i.e. drug delivery), which can be measured with H215O. Specific Aims: The ultimate aim of the study is to develop PET methodology for monitoring early response to chemotherapy in patients with (locally) advanced breast cancer. For this purpose, the tracers H215O, 18FDG and 18FLT will be investigated and compared with conventional imaging modalities. Since 18FLT is a new tracer, a quantitative kinetic model will be developed and validated. Study Design: In 20 patients with locally advanced and 20 stage IV breast cancer patients, blood flow, glucose metabolism and tumor cell proliferation will be investigated using H215O, 18FDG, and 18FLT PET before and after one cycle of chemotherapy. For response monitoring, PET data will be correlated with clinical response parameters, pathological response status (macroscopic / microscopic residual disease / complete remission), and time to progression. The prognostic value of tracer studies will be tested and compared with known prognostic parameters. Possible outcomes: This study will provide conclusive data on the potential of various PET techniques to monitor the effect of chemotherapy in patients with (locally) advanced breast cancer early during treatment. In addition, a kinetic model for quantification of 18FLT data will be developed and validated.

    Lay Abstract:
    Early assessment of response to chemotherapy in breast cancer using PET For women, breast cancer is the second cause of death, after cardio-vascular disease. Worldwide over 1 million women suffer from breast cancer. In most of these women the disease is limited to the breast itself (stage I-II). In approximately 30% of these patients, however, distant metastases occur at a later stage. About 10% of patients primarily present with locally advanced breast cancer (LABC, stage III), whilst in another 10% of patients the disease has already spread to other organs (stage IV). Treatment of stage III disease usually consists of 4 to 6 courses of neo-adjuvant chemotherapy followed by surgery of the breast and the axilla. The majority subsequently receives radiotherapy. With neo-adjuvant chemotherapy, a clear clinical response is observed in the vast majority of patients (65-85%). At pathologic examination of the removed breast and axilla, however, a pathologic complete remission is observed in only 10-15% of patients. In addition, it is known that the outcome of patients with LABC is determined by the absence of tumor as determined by the pathologist. In view of the undeniable toxicity of neo-adjuvant chemotherapy it would be very helpful and have justified clinical relevance to be able to predict, as early in the treatment as possible, which patients are most likely to respond with a pathological complete remission. In this way, non-responders could be spared from additional, unnecessary toxicities. With present techniques, such as CT-scanning and ultrasound, in general the earliest time point to predict a change in tumor volume is after 2 to 3 courses of chemotherapy. It should be noted that this not necessarily indicates effectiveness of the chemotherapy given that volume changes are not very precise in predicting response. Changes in the function of tumor cells, such as metabolism of glucose, can be observed much earlier and might be a far better method to measure early response to therapy. Preliminary data suggest that PET might already be able to predict response after one course of chemotherapy. In 10% of stage IV breast cancer patients, a prolonged disease-free interval can be achieved using an aggressive chemotherapeutic regimen. Therefore, in 90% of metastasized patients a more aggressive and thus more toxic regimen is not justified and should be avoided. Again, also in stage IV disease, PET-scanning might aid in the selection of the small group of patients that will respond. The present study aims to analyze the predictive value of PET in stage III and stage IV breast cancer patients. Three important biological functions will be investigated: tumor perfusion, glucose metabolism and proliferation of tumor cells.