Small-animal PET of steroid hormone receptors predicts tumor response to endocrine therapy using a preclinical model of breast cancer.
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 (18)F-fluoroestradiol ((18)F-FES) for ER, (18)F-fluoro furanyl norprogesterone ((18)F-FFNP) for PR, and (18)F-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 (18)F-FES and (18)F-FFNP uptake and were confirmed to be ERα(+)/PR(+). Classic estrogen-induced regulation of the progesterone receptor gene was demonstrated by increased (18)F-FFNP uptake of estradiol-treated SSM3 tumors. Treatment with fulvestrant decreased (18)F-FFNP, (18)F-FES, and (18)F-FDG uptake and inhibited growth of SSM3 tumors but decreased only (18)F-FES uptake in SSM2 tumors, with no effect on growth, despite both tumors being ERα(+)/PR(+). Decreased (18)F-FFNP uptake by SSM3 tumors occurred early after initiation of treatment, before measurable tumor growth inhibition.


CONCLUSIONS
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 (18)F-FES uptake and initial changes in (18)F-FFNP uptake in a noninvasive manner is a potentially useful strategy to identify responders and nonresponders to endocrine therapy at an early stage.
Division of Radiological Sciences, Edward Mallinckrodt Institute of Radiology, St. Louis, MO, USA. fowlera@mir.wustl.edu
Amy M
AM
Fowler
Szeman Ruby
SR
Chan
Terry L
TL
Sharp
Nicole M
NM
Fettig
Dong
D
Zhou
Carmen S
CS
Dence
Kathryn E
KE
Carlson
M
M
Jeyakumar
John A
JA
Katzenellenbogen
Robert D
RD
Schreiber
Michael J
MJ
Welch
D000230:Adenocarcinoma / Q000000981:diagnostic imaging* / Q000188:drug therapy*; D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D004958:Estradiol / Q000031:analogs & derivatives / Q000494:pharmacology; D047628:Estrogen Receptor alpha / Q000037:antagonists & inhibitors; D005260:Female; D019788:Fluorodeoxyglucose F18; D000077267:Fulvestrant; D008325:Mammary Neoplasms, Experimental / Q000000981:diagnostic imaging* / Q000188:drug therapy*; D051379:Mice; D018345:Mice, Knockout; D009368:Neoplasm Transplantation; D009652:Norpregnenes; D049268:Positron-Emission Tomography; D011237:Predictive Value of Tests; D011817:Rabbits; D019275:Radiopharmaceuticals; D011987:Receptors, Steroid / Q000378:metabolism*; D050794:STAT1 Transcription Factor / Q000235:genetics / Q000502:physiology
C470081:16,17-((1'-furylmethylidene)dioxy)-21(fluoro)-oxy-19-norpregn-4-ene-3,20-dione; D018931:Antineoplastic Agents, Hormonal; D047628:Estrogen Receptor alpha; D009652:Norpregnenes; D019275:Radiopharmaceuticals; D011987:Receptors, Steroid; D050794:STAT1 Transcription Factor; D019788:Fluorodeoxyglucose F18; D000077267:Fulvestrant; D004958:Estradiol; C043436:16-fluoroestradiol