Between-patient and within-patient (site-to-site) variability in estrogen receptor binding, measured in vivo by ¹⁸F-fluoroestradiol PET

Heterogeneity of estrogen receptor (ER) expression may be an important predictor of breast cancer therapeutic response. ¹⁸F-fluoroestradiol PET produces in vivo quantitative measurements of regional estrogen binding in breast cancer tumors. We describe within-patient (site-to-site) and between-patient heterogeneity of lesions in patients scheduled to receive endocrine therapy. Methods: In 91 patients with a prior ER-positive biopsy, 505 lesions were analyzed for both ¹⁸F-fluoroestradiol and ¹⁸FFDG uptake and the ¹⁸F-fluoroestradiol/ ¹⁸F-FDG uptake ratio. Standardized uptake values (SUVs) were recorded for up to 16 lesions per patient, of 1.5 cm or more and visible on ¹⁸F-FDG PET or conventional staging. Linear mixed-effects regression models examined associations between PET parameters and patient or lesion characteristics and estimated variance components. A reader study of SUV measurements for 9 scans further examined sources of within-patient variability. Results: Average ¹⁸F-fluoroestradiol uptake and ¹⁸F- fluoroestradiol/ ¹⁸F-FDG ratio varied greatly across these patients, despite a history of ER-positive disease: about 37% had low or absent ¹⁸F-fluoroestradiol uptake even with marked ¹⁸F-FDG uptake. ¹⁸F-fluoroestradiol SUV and ¹⁸F-fluoroestradiol/ ¹⁸F-FDG ratio measurements within patients with multiple lesions were clustered around the patient's average value in most cases. Summarizing these findings, the intraclass correlation coefficient (proportion of total variation that is between-patient) was 0.60 (95% confidence interval, 0.50-0.69) for 18F-fluoroestradiol SUV and 0.65 (95% confidence interval, 0.56-0.73) for the ¹⁸F-fluoroestradiol/ ¹⁸FFDG ratio. Some within-patient variation in PET measures (22%-44%) was attributable to interobserver variability as measured by the reader study. A subset of patients had mixed uptake, with widely disparate ¹⁸F-fluoroestradiol SUV or ¹⁸Ffluoroestradiol/ ¹⁸F-FDG ratio for lesions in the same scan. Conclusion: ¹⁸F-fluoroestradiol uptake and the ¹⁸F-fluoroestradiol/ ¹⁸F-FDG ratio varied greatly between patients but were usually consistent across lesions in the same scan. The average ¹⁸F-fluoroestradiol SUV and ¹⁸F-fluoroestradiol/ ¹⁸F-FDG ratio for a limited sample of lesions appear to provide a reasonable summary of synchronous ER expression for most patients. However, imaging the entire disease burden remains important to identify the subset of patients with mixed uptake, who may be at a critical point in their disease evolution.