A Prospective Head-to-Head Comparison of HER2-Targeted and 18F-FDG PET/CT for Detecting Axillary Lymph Node Metastases Among Newly Diagnosed HER2-Positive and HER2-Low Breast Cancer

BACKGROUND: To compare HER2-targeted with ¹⁸F-FDG PET/CT for detecting axillary lymph node metastasis in patients with newly diagnosed HER2-positive or HER2-low breast cancer. METHODS: In this prospective study, HER2-expressed breast cancer participants underwent both 18F-FDG and Al18F-NOTA-HER2-BCH PET/CT within 1 week. On the basis of IHC and/or FISH, participants were categorized as HER2-positive (n=25) or HER2-low (n=26). Histopathology or imaging follow-up served as reference standards. Statistical analyses utilized the paired McNemar test for diagnostic performance, and the Wilcoxon signed-rank and Mann-Whitney U tests for paired and unpaired comparisons of uptake parameters, respectively. RESULTS: Between August 2024 and October 2025, 51 participants with breast cancer were enrolled. Among 40 participants with lymph node metastasis, Al18F-NOTA-HER2-BCH detected metastatic lymph nodes exclusively in one HER2-positive participant and more lesions than 18F-FDG in 11 cases. On a per-lesion analysis, Al18F-NOTA-HER2-BCH demonstrated significantly higher sensitivity, accuracy, and negative predictive value than 18F-FDG for detecting metastatic axillary lymph nodes in the HER2-positive cohort (94%, 94%, 93% vs. 79%, 85%, 84%, all P<0.001). This superiority was particularly pronounced for small lymph nodes (<5 mm), with a detection rate of 90% versus 62% for 18F-FDG (P<0.001). Al18F-NOTA-HER2-BCH PET/CT directly influenced nodal staging and subsequent treatment decisions in 4 of 25 (16.0%) HER2-positive participants. In the HER2-low cohort, however, the diagnostic performance of the 2 tracers did not differ significantly, although 18F-FDG PET/CT led to clinically relevant nodal upstaging in one case. CONCLUSIONS: Al18F-NOTA-HER2-BCH retains developmental potential for detecting axillary lymph node metastasis in HER2-positive breast cancer, complementing 18F-FDG.