Longitudinal Noninvasive Imaging of Progesterone Receptor as a Predictive Biomarker of Tumor Responsiveness to Estrogen Deprivation Therapy

Abstract

Purpose To investigate whether longitudinal functional PET imaging of mammary tumors using the radiopharmaceuticals [18F]FDG (to measure glucose uptake), [18F]FES (to measure estrogen receptor (ER) levels), or [18F]FFNP (to measure progesterone receptor (PgR) levels) is predictive of response to estrogen deprivation therapy. Experimental Design [18F]FDG, [18F]FES and [18F]FFNP uptake in endocrine-sensitive and -resistant mammary tumors was quantified serially by PET before ovariectomy or estrogen withdrawal in mice, and on days 3 and 4 after estrogen deprivation therapy. Specificity of [18F]FFNP uptake in ERα+ mammary tumors was determined by competition assay using unlabeled ligands for PgR or glucocorticoid receptor (GR). PgR expression was also assayed by immunohistochemistry (IHC). Results The levels of [18F]FES and [18F]FDG tumor uptake remained unchanged in endocrine-sensitive tumors after estrogen deprivation therapy compared to those at pre-treatment. In contrast, estrogen deprivation therapy led to a reduction in PgR expression and [18F]FFNP uptake in endocrine-sensitive tumors, but not in endocrine-resistant tumors, as early as 3 days post-treatment; the changes in PgR levels were confirmed by IHC. Unlabeled PgR ligand R5020 but not GR ligand dexamethasone blocked [18F]FFNP tumor uptake, indicating that [18F]FFNP bound specifically to PgR. Therefore, a reduction in FFNP tumor to muscle ratio in mammary tumors predicts sensitivity to estrogen deprivation therapy. Conclusions Monitoring the acute changes in ERα activity by measuring [18F]FFNP uptake in mammary tumors predicts tumor response to estrogen deprivation therapy. Longitudinal noninvasive PET imaging using [18F]FFNP is a robust and effective approach to predict tumor responsiveness to endocrine treatment.

Sensitivity and Isoform Specificity of 18F-Fluorofuranylnorprogesterone for Measuring Progesterone Receptor Protein Response to Estradiol Challenge in Breast Cancer

“…For biodistribution assays, tissues (blood, muscle, tumors, and uterus) were harvested 2 h after tail vein injection of 10 MBq (270 mCi) of 18 F-FFNP in an 80-to 180-mL total volume. Uteri were included as a positive control given their high expression of PR and 18 F-FFNP uptake, as shown previously (15). Harvested tissues were wet-weighed and radioactivity measured with a g-counter.…”

“…This radioligand has high relative binding affinity to PR and low nonspecific binding (13,14). The binding specificity of 18 F-FFNP for PR has been demonstrated using tissue biodistribution assays with blocking treatments (13,15). One study of 20 patients has been published, to date, demonstrating the safety, dosimetry, and ability of 18 F-FFNP PET imaging for identifying PR-positive breast cancer (16).…”

Imaging Diagnostic and Therapeutic Targets: Steroid Receptors in Breast Cancer

“…The hypothesis that imaging changes in PR can be an early response biomarker indicative of treatment-induced changes of upstream ER signaling pathway has been tested in preclinical breast cancer models (38, 39). These studies demonstrate that an early decrease in tumoral FFNP uptake predicts responsiveness to fulvestrant and estrogen-deprivation therapy.…”

“…Decreases in FFNP uptake occurred prior to changes in tumor growth. Further, monitoring ERα function through imaging PR with longitudinal FFNP-PET was more predictive of response to estrogen-deprivation therapy than FES-PET and FDG-PET imaging (39). These preclinical data provide the proof-of-principle to support further translational studies in breast cancer patients.…”

Synthesis and pre-clinical evaluation of a [18F]fluoromethyl-tanaproget derivative for imaging of progesterone receptor expression

“…19 This has prompted investigation into PR targeted radioligands to report on the presence of a functional ]FFNP could report on response to endocrine therapy. [20][21][22] Although studies into […”