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Quantification of Cellular Proliferation in Tumor and Normal Tissues of Patients with Breast Cancer by [¹⁸F]Fluorothymidine-Positron Emission Tomography Imaging: Evaluation of Analytical Methods

¹ Molecular Therapy and PET Oncology Research Group, ² Cancer Cell Biology, Faculty of Medicine, Imperial College London at the Clinical Sciences Centre, Hammersmith Hospital, ³ Hammersmith Imanet, Hammersmith Hospital, and ⁴ Department of Nuclear Medicine, Hammersmith Hospital; and ⁵ Department of Pathology, Charing Cross Hospital, Hammersmith Hospitals NHS Trust, London, United Kingdom

Requests for reprints: Eric O. Aboagye, Molecular Therapy and PET Oncology Research Group, Faculty of Medicine, Imperial College London, Clinical Sciences Centre, Medical Research Council Cyclotron Building, Hammersmith Hospital, Du Cane Road, London W12 0NN, United Kingdom. Phone: 44-208-383-3759; Fax: 44-208-383-2029; E-mail: eric.aboagye{at}imperial.ac.uk.

There is an unmet need to develop imaging methods for the early and objective assessment of breast tumors to therapy. 3'-Deoxy-3'-[¹⁸F]fluorothymidine ([¹⁸F]FLT)–positron emission tomography represents a new approach to imaging thymidine kinase activity, and hence, cellular proliferation. We compared graphical, spectral, and semiquantitative analytic methodologies for quantifying [¹⁸F]FLT kinetics in tumor and normal tissue of patients with locally advanced and metastatic breast cancer. The resultant kinetic parameters were correlated with the Ki-67 labeling index from tumor biopsies. [¹⁸F]FLT accumulation was detected in primary tumor, nodal disease, and lung metastasis. In large tumors, there was substantial heterogeneity in regional radiotracer uptake, reflecting heterogeneity in cellular proliferation; radiotracer uptake in primary tumors also differed from that of metastases. [¹⁸F]FLT was metabolized in patients to a single metabolite [¹⁸F]FLT-glucuronide. Unmetabolized [¹⁸F]FLT accounted for 71.54 ± 1.50% of plasma radioactivity by 90 minutes. The rate constant for the metabolite-corrected net irreversible uptake of [¹⁸F]FLT (K_i) ranged from 0.6 to 10.4 x 10^–4 and from 0 to 0.6 x 10^–4 mL plasma cleared/s/mL tissue in tumor (29 regions, 15 patients) and normal tissues, respectively. Tumor K_i and fractional retention of radiotracer determined by spectral analysis correlated with Ki-67 labeling index (r = 0.92, P < 0.0001 and r = 0.92, P < 0.0001, respectively). These correlations were superior to those determined by semiquantitative methods. We conclude that [¹⁸F]FLT-positron emission tomography is a promising clinical tool for imaging cellular proliferation in breast cancer, and is most predictive when analyzed by graphical and spectral methods.

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