RT Journal Article
SR Electronic
T1 Differential effect of an activating <em>ESR1</em> mutation on endocrine therapy modulation of progesterone receptor expression measured with <sup>18</sup>F-fluorofuranylnorprogesterone in ER+ breast cancer
JF Journal of Nuclear Medicine
JO J Nucl Med
FD Society of Nuclear Medicine
SP 350
OP 350
VO 61
IS supplement 1
A1 Kumar, Manoj
A1 Salem, Kelley
A1 Jeffery, Justin
A1 Fowler, Amy
YR 2020
UL http://jnm.snmjournals.org/content/61/supplement_1/350.abstract
AB 350Objectives: Mutations in the estrogen receptor (ER) alpha gene (ESR1) have been reported in patients with metastatic breast cancer that are associated with endocrine therapy resistance and reduced survival. These gain-of-function mutations in the ligand-binding domain of ER results in constitutive transcriptional activity in the absence of ligand. We have previously shown that quantitative imaging of ER ligand binding with 18F-fluoroestradiol in breast cancer xenograft was unable to distinguish between tumors expressing wild-type (WT) ER and constitutively active mutant ER [1]. Progesterone receptor (PR) is a classic estrogen-induced target gene and a surrogate marker of ER function. Given the ER-regulated expression of PR, we investigated the impact of the most prevalent ESR1 mutation (Y537S) on ER transcriptional function through PR protein expression using 18F-fluorofuranynorprogesterone (18F-FFNP) in response to endocrine therapy. Methods: T47D breast cancer cells either expressing WT-ER or CRISPR knock-in of the ESR1 mutation Y537S were used [2]. ER transcriptional function was measured using an estrogen-response element-luciferase reporter gene assay. Tumor xenografts were generated in ovariectomized female NCr-nu/nu (nude) mice supplemented with 17β-estradiol. Tumor volumes were calculated based on caliper measurements. Mice bearing bilateral tumor xenografts (5 mice, 10 tumors/group) were administered either fulvestrant (4 mg/mouse SQ), a selective ER degrader/antagonist, or vehicle control (ethanol + oil) on days 1 and 4. On day 7, tissue biodistribution assay was performed 1-hr after injection of 3.7 MBq (100 μCi) 18F-FFNP via tail vein. Tumor, muscle, and uterus uptake of 18F-FFNP were measured as %injected-dose-per-gram (%ID/g) using a gamma counter. Uterus was included as an internal positive control for the WT-ER function. Quantitative 18F-FFNP uptake was compared between control and fulvestrant treated groups of mutant Y537S-ER and WT-ER tumor-bearing mice. Statistical significance (p&lt;0.05) was determined using analysis of variance. Results: As previously reported, we confirmed constitutive Y537S-ER transcriptional activity (36-fold increase) compared to WT-ER in the absence of estrogen (p=0.019). Y537S-ER xenografts showed estrogen-independent growth, while WT-ER tumors grew only with estrogen supplementation. The average Y537S-ER tumor volume was 121±13 mm3 at day 37 and was 57±7 mm3 for WT-ER tumors at day 40 in the presence of estrogen (Figure 1A). 18F-FFNP uptake in WT-ER tumor was significantly reduced in fulvestrant treated mice compared to vehicle control (p=0.0003). However, there was no significant difference in 18F-FFNP uptake in Y537S-ER tumors between the fulvestrant treatment and control groups (Figure 1B). In the fulvestrant treatment group, 18F-FFNP uptake was 2.68±0.13 and 1.10±0.47 %ID/g for Y537S-ER and WT-ER xenografts, respectively (p=0.006). In contrast to tumor uptake, 18F-FFNP uptake in the uterus was reduced to a similar level after treatment. Conclusions: Y537S-ER tumors failed to reduce PR protein expression, as shown by higher residual uptake of 18F-FFNP after fulvestrant therapy compared to WT-ER tumors. This imaging phenotype is consistent with the constitutively active transcriptional function of Y537S-ER and the association of this ESR1 mutation with reduced effectiveness of antiestrogen therapy. Persistent 18F-FFNP uptake measured by PET imaging in patients with metastatic breast cancer treated with endocrine therapy could potentially signify the presence of acquired ESR1 tumor mutations and would be expected to correlate with shorter time to disease progression. Future Directions: Further studies are focused on validating these results using patient-derived breast cancer xenografts established from metastatic effusions and circulating tumor cell lines.