Development of novel positron emission tomography pharmacodynamic markers for response assessment in cancer

There is an urgent need to develop sensitive and specific biomarkers of response to treatment in oncology. This thesis explores the utility of three novel positron emission tomography (PET) radiotracers: [18F]-3'deoxy-3'fluorothymidine (FLT), [11C]choline and [18F]-AH111585. All patients in the PET studies had breast cancer. Aims: 1) To quantify the uptake and retention of [18F]FLT, [11C]choiine and [18F]-AH111585 in breast cancer, and evaluate the role of mathematical modelling compared to standard techniques for quantifying tracer uptake. 2) To correlate [18F]FLT and [11C]choiine PET data with immunohistochemical markers of proliferation. 3) To establish if [18F]FLT and [11C]choline PET are reproducible in breast cancer. 4) To determine the effect of anti-cancer treatment on [18F]FLT and [11C]choline PET. 5) To evaluate the diagnostic utility of [18F]-AH111585, a novel avps imaging agent, in breast cancer. Methods: 15 patients with primary and metastatic breast cancer were studied with [18F] FLT-PET at baseline, 2-7 days later, and then 7 days post-chemotherapy. [11C]Choline-PET was evaluated in 21 separate breast cancer patients, 13 for repeatability and 8 for response to trastuzumab. Finally, in 7 further patients [18F]-AH111585-PET was used to monitor angiogenesis in metastatic breast cancer. Findings: All tumour lesions had positive uptake of FLT, which correlated with cell proliferation, FLT uptake was found to have good repeatability,, and patients who clinically responded to chemotherapy also demonstrated significant early changes in FLT uptake. In the choline studies, all tumour lesions demonstrated significant uptake compared to normal tissue, and patients who clinically responded to trastuzumab also had a decrease in choline retention parameters. In seven patients studied with [18F]-AH111585-PET all but one lesion had significant retention of the tracer, suggesting that this agent may be promising for imaging angiogenesis