Small-Animal PET of Steroid Hormone Receptors Predicts Tumor Response to Endocrine Therapy Using a Preclinical Model of Breast Cancer

Abstract

Estrogen receptor-α (ERα) and progesterone receptor (PR) are expressed in most human breast cancers and are important predictive factors for directing therapy. Because of de novo and acquired resistance to endocrine therapy, there remains a need to identify which ERα-positive (ERα+)/PR-positive (PR+) tumors are most likely to respond. The purpose of this study was to use estrogen- and progestin-based radiopharmaceuticals to image ERα and PR in mouse mammary tumors at baseline and after hormonal therapy and to determine whether changes in these imaging biomarkers can serve as an early predictive indicator of therapeutic response. Methods Mammary adenocarcinomas that spontaneously develop in aged female mice deficient in signal transducer and activator of transcription-1 (STAT1) were used. Imaging of ERα and PR in primary tumor–bearing mice and mice implanted with mammary cell lines (SSM1, SSM2, and SSM3) derived from primary STAT1-deficient (STAT1−/−) tumors was performed. Hormonal treatments consisted of estradiol, an ER agonist; letrozole, an aromatase inhibitor; and fulvestrant, a pure ER antagonist. Small-animal PET/CT was performed using 18F-fluoroestradiol (18F-FES) for ER, 18F-fluoro furanyl norprogesterone (18F-FFNP) for PR, and 18F-FDG for glucose uptake. Tracer uptake in the tumor was quantified and compared with receptor concentration determined by in vitro assays of resected tumors. Results Primary STAT1−/− mammary tumors and implanted SSM2 and SSM3 tumors showed high 18F-FES and 18F-FFNP uptake and were confirmed to be ERα+/PR+. Classic estrogen-induced regulation of the progesterone receptor gene was demonstrated by increased 18F-FFNP uptake of estradiol-treated SSM3 tumors. Treatment with fulvestrant decreased 18F-FFNP, 18F-FES, and 18F-FDG uptake and inhibited growth of SSM3 tumors but decreased only 18F-FES uptake in SSM2 tumors, with no effect on growth, despite both tumors being ERα+/PR+. Decreased 18F-FFNP uptake by SSM3 tumors occurred early after initiation of treatment, before measurable tumor growth inhibition. Conclusion Using small-animal PET, a profile was identified that distinguished fulvestrant-sensitive from fulvestrant-resistant ERα+/PR+ tumors before changes in tumor size. This work demonstrates that imaging baseline tumoral 18F-FES uptake and initial changes in 18F-FFNP uptake in a non-invasive manner is a potentially useful strategy to identify responders and nonresponders to endocrine therapy at an early stage.

Estrogen receptors alpha (ERα) and beta (ERβ): Subtype-selective ligands and clinical potential

“…Efforts PET agents for the in vivo imaging of ERα and ERβ are motivated by the prognostic value of the expression level of this receptor in cancer patients [165]. It is known, for example, that levels of the two ER subtypes change during the progression of breast cancer, so the independent measurement of both ERs might be useful in predicting disease outcome and response to endocrine therapies [171–172]. Unfortunately, despite efforts so far to obtain 18 F-labeled compound 54 and 76 Br-labeled compound 55 , little evidence of ERβ-mediated uptake was observed in model systems, underlining the need for improved in vivo models to develop ERβ-selective radiopharmaceuticals for use as PET imaging agents to measure ERβ levels in breast tumors.…”

International Union of Basic and Clinical Pharmacology. XCVII. G Protein–Coupled Estrogen Receptor and Its Pharmacologic Modulators

“…Radionuclide isotopes that decay with emission of energetic gamma rays or positron particles coupled to targeting agents enable the highly sensitive in vivo detection and imaging of targets and metabolic processes using single photon emission computed tomography (SPECT) or positron emission tomography, respectively. The profound clinical significance of E2 in normal and diseased states including cancer has stimulated the development of diagnostic and therapeutic imaging agents targeting the nuclear ER in pursuit of the ultimate goal of effective noninvasive imaging for improved detection and management of therapy (Katzenellenbogen, 1980(Katzenellenbogen, , 1995Kiesewetter et al, 1984;Skaddan et al, 2000;Yoo et al, 2005;Ramesh et al, 2006;Seo et al, 2007;Fowler et al, 2012). This approach typically involves labeling the native steroid hormone, receptor ligand, or drug with a short-lived isotope (e.g., 18 F for positron emission tomography or 99m Tc for SPECT).…”

PET and SPECT Imaging of Steroid Hormone Receptors

“…18 F]FES in ER-positive breast tumors in mice (Fowler et al 2012 ). PET imaging studies in rodents showed a good correlation of [ 18 F]FES tumor uptake with ER density, as determined in vitro (Aliaga et al 2004 ).…”