Development of positron emission tomography imaging methods for predicting and monitoring response to breast cancer therapy

Abstract

In clinical breast cancer, endocrine therapy and cytotoxic chemotherapy are the mainstay of treatment. Progesterone receptor (PR) analogues can be radiolabelled by Positron Emission Tomography (PET) to assess response to endocrine therapy while molecular imaging of apoptosis biomarkers can be utilised to monitor early response to chemotherapy. To develop a pre-clinical PR PET imaging agent, LA036 (a PR analogue), based on non-steroidal tanaproget core, was selected due to high affinity to PR with a relative binding affinity of 140%, compared to progesterone. Cell uptake studies in various PR cell lines and blocking studies with progesterone demonstrated specificity of [18F]LA036 for PR. PET imaging of T47D xenografts with [18F]LA036 revealed uptake in the tumour: AUC0-60(%ID/ml)(area under the curve from 0-60min) 498.79±29.7%, muscle: (AUC0-60 423.62±26.3). The tracer was unstable in vivo, with high uptake due to metabolism noted in various organs with deflourination observed in bone. [18F]ICMT-11, an isatin analogue is a novel PET radiotracer for detection of apoptosis. Treatment of a breast cancer xenograft MDA-MB-231 with combination chemotherapy resulted in increased uptake of [18F]ICMT-11 in tumour within 24 hours of treatment and sustained up to 96 hours. The corresponding NUV60(%ID/ml) of time-points was 0.203 (Control), 0.789 (24h), 0.832 (48h), 0.903 (72h) and 0.757 (96h). PET based voxel intensity histograms revealed an increase in voxel intensity maintained between 24 and 96h post-chemotherapy. TUNEL and caspase immunofluorescence of tumours correlated with PET data of increased apoptosis with chemotherapy while Ki67 index correlated with reduced proliferation of the tumour. In clinical breast cancer, [18F]ICMT-11 was utilised to study the optimum time point of apoptosis following chemotherapy. Patients were imaged at baseline and 24-48h post chemotherapy, exhibited an increase in standardised uptake value (SUV) in the lymph nodes; SUVav 0.39±0.02 (pre), SUVav 0.45±0.03 (post), and SUVmax 0.87± 0.02(pre),1.22±0.12 (post). In patients imaged at baseline and 2 weeks post chemotherapy, tumour to breast ratio (TBR) and tumour to muscle ratio (TMR) were increased. Immunohistochemistry with caspase and TUNEL labelling from breast biopsies was related to apoptosis observed in the PET data. Endocrine therapy and chemotherapy in breast cancer treatment can therefore be monitored by utilisation of molecular imaging using PET.