Circulating Tumor Cells Enhance Prognostic Stratification Beyond ER Assessment by Biopsy or FES-PET in Endocrine-Treated Metastatic Breast Cancer

Background/Objectives: Outcome prediction in patients with estrogen (ER)-positive metastatic breast cancer (MBC) remains challenging. We investigated whether circulating tumor cell (CTC) count adds prognostic value in ER-positive MBC using immunohistochemical (IHC) or 16α-[¹⁸F]-fluoro-17β-estradiol (FES)-PET imaging. Methods: Patients with newly diagnosed non-rapidly progressive MBC receiving first-line endocrine monotherapy, with ER-positive IHC (biopsy) or FES-PET and available CTC count, were included. Associations of CTC count and CTC-ER status based on ESR1 mRNA expression with progression-free survival (PFS) and overall survival (OS) were analyzed, and the added prognostic value of CTC count (<5 vs. ≥5/7.5 mL) beyond a positive ER result was assessed. Results: In patients with ER-positive IHC (n = 98) or FES-PET (n = 99) out of 106 endocrine-treated patients, ≥5 CTCs were associated with shorter PFS (HR 1.86; p = 0.0047 and 1.75; p = 0.011) and OS (HR 3.19 and 3.22; both p < 0.01), respectively, compared with <5 CTCs. Adding CTC count to ER-positive IHC or FES-PET improved prognostic accuracy for PFS (p = 0.006 and 0.012) and OS (both p < 0.001). CTC-ER status (ESR1 RNA) was not associated with outcomes. Conclusions: CTC count adds prognostic value to PET- or biopsy-based ER analysis in endocrine-treated MBC.