Heidari Pedram, Deng Francis, Esfahani Shadi A, Leece Alicia K, Shoup Timothy M, Vasdev Neil, Mahmood Umar
Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Boston, Massachusetts.
Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Boston, Massachusetts. Washington University School of Medicine, St. Louis, Missouri.
Clin Cancer Res. 2015 Mar 15;21(6):1340-7. doi: 10.1158/1078-0432.CCR-14-1178. Epub 2015 Jan 21.
Estrogen receptor (ER) targeting is key in management of receptor-positive breast cancer. Currently, there are no methods to optimize anti-ER therapy dosing. This study assesses the use of 16α-(18)F-fluoroestradiol ((18)F-FES) PET for fulvestrant dose optimization in a preclinical ER(+) breast cancer model.
In vitro, (18)F-FES retention was compared with ERα protein expression (ELISA) and ESR1 mRNA transcription (qPCR) in MCF7 cells (ER(+)) after treatment with different fulvestrant doses. MCF7 xenografts were grown in ovariectomized nude mice and assigned to vehicle, low- (0.05 mg), medium- (0.5 mg), or high-dose (5 mg) fulvestrant treatment groups (5-7 per group). Two and 3 days after fulvestrant treatment, PET/CT was performed using (18)F-FES and (18)F-FDG, respectively. ER expression was assessed by immunohistochemistry, ELISA, and qPCR on xenografts. Tumor proliferation was assessed using Ki67 immunohistochemistry.
In vitro, we observed a parallel graded reduction in (18)F-FES uptake and ER expression with increased fulvestrant doses, despite enhancement of ER mRNA transcription. In xenografts, ER expression significantly decreased with increased fulvestrant dose, despite similar mRNA expression and Ki67 staining among the treatment groups. We observed a significant dose-dependent reduction of (18)F-FES PET mean standardized uptake value (SUV(mean)) with fulvestrant treatment but no significant difference among the treatment groups in (18)F-FDG PET SUV(mean).
We demonstrated that (18)F-FES uptake mirrors the dose-dependent changes in functional ER expression with fulvestrant resulting in ER degradation and/or blockade; these precede changes in tumor metabolism and proliferation. Quantitative (18)F-FES PET may be useful for tracking early efficacy of ER blockade/degradation and guiding ER-targeted therapy dosing in patients with breast cancer.
雌激素受体（ER）靶向治疗是受体阳性乳腺癌治疗的关键。目前，尚无优化抗ER治疗剂量的方法。本研究评估在临床前ER(+)乳腺癌模型中使用16α-(18)F-氟雌二醇（(18)F-FES）PET进行氟维司群剂量优化。
在体外，用不同剂量氟维司群处理MCF7细胞（ER(+)）后，比较(18)F-FES保留与ERα蛋白表达（ELISA）及ESR1 mRNA转录（qPCR）情况。MCF7异种移植瘤在去卵巢裸鼠体内生长，并分为溶剂对照组、低剂量（0.05 mg）、中剂量（0.5 mg）或高剂量（5 mg）氟维司群治疗组（每组5 - 7只）。氟维司群治疗后第2天和第3天，分别使用(18)F-FES和(18)F-FDG进行PET/CT检查。通过免疫组化、ELISA和qPCR评估异种移植瘤中的ER表达。使用Ki67免疫组化评估肿瘤增殖情况。
在体外，尽管ER mRNA转录增强，但随着氟维司群剂量增加，我们观察到(18)F-FES摄取和ER表达呈平行分级降低。在异种移植瘤中，尽管各治疗组间mRNA表达和Ki67染色相似，但随着氟维司群剂量增加，ER表达显著降低。我们观察到氟维司群治疗后(18)F-FES PET平均标准化摄取值（SUV(mean)）呈显著剂量依赖性降低，但各治疗组间(18)F-FDG PET SUV(mean)无显著差异。
我们证明(18)F-FES摄取反映了氟维司群导致ER降解和/或阻断时功能性ER表达的剂量依赖性变化；这些变化先于肿瘤代谢和增殖的改变。定量(18)F-FES PET可能有助于追踪ER阻断/降解的早期疗效，并指导乳腺癌患者的ER靶向治疗剂量。
