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.

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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.

Clin Cancer Res. 2019 Jan 28;:

Authors: Elmi A, Makvandi M, Weng CC, Hou C, Clark AS, Mach RH, Mankoff DA

Abstract
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.

PMID: 30692100 [PubMed - as supplied by publisher]

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