Cell-proliferation imaging for monitoring response to CDK4/6 inhibition combined with endocrine-therapy in breast cancer: Comparison of [18F]FLT and [18F]ISO-1 PET/CT

Purpose: Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors in combination with endocrine-therapy have emerged as an important regimen of care for estrogen-receptor (ER)-positive metastatic breast cancer (BC), though identifying predictive biomarkers remains a challenge. We assessed the ability of two PET-proliferation tracers, [¹⁸F]FLT and [¹⁸F]ISO-1, for evaluating response to CDK4/6-inhibitor (palbociclib) and ER-antagonist (fulvestrant). Experimental Design: To determine the effect of CDK4/6-inhibition combined with estrogen-blockade we assessed cell-proliferation in 6 BC cell-lines after 1, 3, and 6 days of treatment with palbociclib and/or fulvestrant. These data were correlated to in-vitro radiotracer assays and results were verified by longitudinal [¹⁸F]FLT and [¹⁸F]ISO-1 micro-PET imaging performed in MCF7-tumor bearing-mice. Results: All palbociclib-sensitive cell-lines showed decreased [¹⁸F]FLT-accumulation and S-phase depletion after treatment, with both measures augmented by combination-therapy. In contrast, these cells showed changes in [¹⁸F]ISO-1 analogue-binding and G0 arrest only after prolonged treatment. MicroPET imaging of MCF7 xenografts showed a significant decrease in [¹⁸F]FLT but no changes in [¹⁸F]ISO-1 uptake in all treated mice on day-3. On day-14, however, mice treated with combination-therapy showed a significant decrease in [¹⁸F]ISO-1 corresponding to G0-arrest while maintaining reduced [¹⁸F]FLT uptake, which corresponded to S-phase depletion. Conclusions: Our data suggest complementary roles of [¹⁸F]FLT and [¹⁸F]ISO-1 PET in evaluating tumor-proliferation after combined CDK4/6-inhibitor and endocrine-therapy in BC. [¹⁸F]FLT is more sensitive to immediate changes in S-phase, while [¹⁸F]ISO-1 can assess more delayed changes related to cell-cycle arrest and transition to G0-quiescence from combination-therapy. These data suggest a potential role for early-prediction of long-term response using these imaging biomarkers.

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