Diagnostic accuracy and safety of 16α-[¹⁸F]fluoro-17β-estradiol positron emission tomography/computed tomography for the assessment of estrogen receptor status of recurrent or metastatic lesions in patients with breast cancer: an open label, non-randomized, phase 3 study

Objectives: The standard diagnostic workup for recurrent or metastatic breast cancer includes biopsy and determination of tumor estrogen receptor (ER) status. However, biopsy procedures are not always feasible, and thus treatment is planned according to the previous pathological findings. We aimed to evaluate the diagnostic accuracy and safety of ¹⁸F-FES positron emission tomography/computed tomography (PET/CT) in assessing ER status in patients with recurrent or metastatic breast cancer.Methods: We conducted a prospective, open-label, non-randomized phase 3 study at Asan Medical Center. Study participants eligible for inclusion were patients who were scheduled to undergo core needle biopsy or surgery of the recurrent or distant metastatic breast cancer lesions within 15 days after ¹⁸F-FES PET/CT, or had already undergone core needle biopsy of those lesions within 30 days before ¹⁸F-FES PET/CT. Whole-body ¹⁸F-FES PET/CT imaging was performed 90 minutes after intravenous injection of 111-222 MBq of ¹⁸F-FES. ¹⁸F-FES uptake in recurrent or metastatic lesions was assessed qualitatively and quantitatively. ¹⁸F-FES uptake above background intensity was interpreted as ¹⁸F-FES PET/CT positive. ER status assessed by immunohistochemical testing was used as the reference standard. We planned to study 47 ER-positive and 38 ER-negative patients assuming 10% dropouts to detect a difference between the null and alternative hypotheses of agreements (H₀: <0.55 vs. H₁: ≥0.75 for positive agreement; H₀: <0.82 vs. H₁: ≥0.97 for negative agreement) with 80% power and a significance level of 2.5% using a one-sided exact binomial test. We consecutively enrolled participants until ER-positive or ER-negative population reached the planned number of patients, and then included only those patients who did not reach the target number.Results: Between November 2013 and November 2016, we recruited 93 women, of whom 90 completed the study. Five patients were excluded from the efficacy analyses for pre-specified reasons. A total of 85 patients were included for accuracy analysis, of whom 47 had ER-positive lesions (median age 55) and 38 had ER-negative lesions (median age 54). Recurrent or metastatic sites for pathological diagnosis were lymph node (n=53), lung (n=18), chest wall (n=13) and pleura (n=1). Positive and negative percent agreements of ¹⁸F-FES PET/CT for diagnosing ER status were 76.6% (95% CI, 62.0-87.7, p=0.0018) and 100% (95% CI, 90.8-100, p=0.0005), respectively. The maximum standardized uptake values of ER-positive and negative lesions were 6.34±7.04 and 1.26±0.39, respectively (p<0.0001). A positive correlation was found between maximum standardized value of ¹⁸F-FES and Allred scores of ER immuhohistochemical testing (all 85 lesions: ρ=0.83, p<0.0001; 47 ER-positive lesions: ρ=0.70, p<0.0001). ¹⁸F-FES PET/CT was well tolerated without serious adverse events.Conclusions: ¹⁸F-FES PET/CT can noninvasively assess ER-status of recurrent or metastatic breast cancer. High specificity of ¹⁸F-FES PET/CT indicates that positive ¹⁸F-FES PET/CT results can reliably rule in the diagnosis of ER-positive recurrent or metastatic breast cancer, and thus can substitute for immunohistochemical assessment of ER-status. Registration: ClinicalTrials.gov: NCT01986569.