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

Purpose: To investigate whether longitudinal functional PET imaging of mammary tumors using the radiopharmaceuticals [F-18] FDG (to measure glucose uptake), [F-18] FES [to measure estrogen receptor (ER) levels], or [F-18] FFNP [to measure progesterone receptor (PgR) levels] is predictive of response to estrogendeprivation therapy. Experimental Design: [F-18] FDG, [F-18] FES, and [F-18] 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 [F-18] FFNP uptake in ERa_ 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 [F-18] FES and [F-18] FDG tumor uptake remained unchanged in endocrine-sensitive tumors after estro-gen-deprivation therapy compared with those at pretreatment. In contrast, estrogen-deprivation therapy led to a reduction in PgR expression and [F-18] FFNP uptake in endocrine-sensitive tumors, but not in endocrine-resistant tumors, as early as 3 days after treatment; the changes in PgR levels were confirmed by IHC. Unlabeled PgR ligand R5020 but not GR ligand dexamethasone blocked [F-18] FFNP tumor uptake, indicating that [F-18] 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 ERa activity by measuring [F-18] FFNP uptake in mammary tumors predicts tumor response to estrogen-deprivation therapy. Longitudinal noninvasive PET imaging using [F-18] FFNP is a robust and effective approach to predict tumor responsiveness to endocrine treatment.