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

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, although identifying predictive biomarkers remains a challenge. We assessed the ability of two PET-proliferation tracers, [ 18 F]FLT and [ 18 F]ISO-1, for evaluating response to CDK4/6-inhibitor (palbociclib) and ERantagonist (fulvestrant).Experimental Design: To determine the effect of CDK4/6 inhibition combined with estrogen-blockade, we assessed cell proliferation in six breast cancer 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 [ 18 F]FLT and [ 18 F]ISO-1 micro-PET imaging performed in MCF7 tumor-bearing mice.Results: All palbociclib-sensitive cell lines showed decreased [ 18 F]FLT accumulation and S-phase depletion after treatment, with both measures augmented by combination therapy. In contrast, these cells showed changes in [ 18 F]ISO-1 analogue-binding and G 0 arrest only after prolonged treatment. MicroPET imaging of MCF7 xenografts showed a significant decrease in [ 18 F]FLT but no changes in [ 18 F]ISO-1 uptake in all treated mice on day 3. On day 14, however, mice treated with combination therapy showed a significant decrease in [ 18 F]ISO-1, corresponding to G 0 arrest, while maintaining reduced [ 18 F]FLT uptake, which corresponded to S-phase depletion.Conclusions: Our data suggest complementary roles of [ 18 F]FLT and [ 18 F]ISO-1 PET in evaluating tumor-proliferation after combined CDK4/6 inhibitor and endocrine therapy in breast cancer. [ 18 F]FLT is more sensitive to immediate changes in S-phase, whereas [ 18 F]ISO-1 can assess more delayed changes related to cell-cycle arrest and transition to G 0 quiescence from combination therapy. These data suggest a potential role for early prediction of long-term response using these imaging biomarkers.

18F-fluorodeoxyglucose (FDG) PET or 18F-fluorothymidine (FLT) PET to assess early response to aromatase inhibitors (AI) in women with ER+ operable breast cancer in a window-of-opportunity study

“…FLT, on the other hand, is a validated tracer of cellular proliferation, but is investigational, and while it is well visualized in breast and regional nodal lesions, it has high liver and bone marrow uptake, making its application to metastatic breast cancer more challenging. As other novel tracers are in development, PET imaging can help to evaluate molecularly targeted agents and allow patients to remain on neoadjuvant treatment safely for a longer duration to then achieve a measurable pathologic response at surgery, determine which patients could avoid chemotherapy, and/or which patients will benefit from endocrine therapy alone [ 26 , 43 ].…”

“…FLT-PET is correlated with changes in tumor proliferation early after initiating second-line docetaxel chemotherapy and following completion of variable neoadjuvant chemotherapy regimens in breast cancer [ 19 , 25 ]. Pre-clinical studies suggest that FLT-PET may be useful for indicating the need for combined endocrine therapy and cell-cycle targeted drugs (CDK4/6) [ 26 ].…”

The Biological Function of Sigma-2 Receptor/TMEM97 and Its Utility in PET Imaging Studies in Cancer

“…Biomarkers that can monitor changes in tumor proliferation early in the course of therapy can be used to identify patients most likely to benefit from this combinational therapy versus endocrine therapy alone. Recently, Elmi et al assessed the ability of two PET-proliferation tracers, [ 18 F]ISO-1 and [ 18 F]FLT, for evaluating the response to palbociclib, a CDK4/6i and fulvestrant, an ER-antagonist [ 23 ]. PET imaging of MCF7 xenografts showed a significant decrease in [ 18 F]FLT on day 3 and maintained low uptake on day 14 after treatment in all treatment groups (palbociclib, fulvestrant and the combination of both).…”

Imaging of Preclinical Endometrial Cancer Models for Monitoring Tumor Progression and Response to Targeted Therapy

“…Although not yet tested clinically for EC, we have demonstrated the feasibility of FLT-PET to detect and monitor tumor growth in our EC mouse model [12]. For a number of different tumors including animal models of breast-and ovarian cancers, FLT-PET has been used to evaluate treatment response [54][55][56][57][58][59][60].…”