Prognostic value and diagnostic performance of nectin-4-targeted [68Ga]Ga-FZ-NR-1 PET/CT versus [18F]FDG in recurrent or metastatic triple-negative breast cancer.

PURPOSE: Nectin-4 has emerged as an attractive diagnostic and therapeutic target in a wide range of malignancies. Herein, we aimed to evaluate the clinical utility of a novel Nectin-4-targeted radiotracer, [68Ga]Ga-FZ-NR-1, for non-invasive whole-body mapping, head-to-head diagnostic comparison with [18F]FDG, and survival prediction in recurrent or metastatic triple-negative breast cancer (TNBC). METHODS: 40 patients with recurrent or metastatic TNBC who underwent [68Ga]Ga-FZ-NR-1 and [18F]FDG PET/CT within 1 week were enrolled in this clinical translational study. Diagnostic performance was compared using the McNemar test. The survival analyses were performed using the Kaplan-Meier method. RESULTS: [68Ga]Ga-FZ-NR-1 PET/CT revealed high intra-patient spatial heterogeneity of Nectin-4 expression, yielding a median inter-lesion fold difference of 3.10 and a median coefficient of variation of 31.70%. Although a higher SUVmax was observed with [18F]FDG, [68Ga]Ga-FZ-NR-1 achieved a significantly higher tumor-to-background ratio across various metastatic sites. Therefore, [68Ga]Ga-FZ-NR-1 PET/CT detected more lesions than [18F]FDG PET/CT and showed better sensitivity and specificity (98.13% vs.93.46% and 68.63% vs. 27.45%, respectively). Furthermore, high baseline mean MTV40 ([68Ga]Ga-FZ-NR-1) and HI ([68Ga]Ga-FZ-NR-1) predicted significantly shorter progression-free survival (P = 0.009) and overall survival (P = 0.008), respectively. CONCLUSION: [68Ga]Ga-FZ-NR-1 PET/CT demonstrates improved diagnostic performance and independent prognostic value compared to [18F]FDG in recurrent or metastatic TNBC. These hypothesis-generating findings suggest that it holds potential as a non-invasive imaging biomarker to aid future risk stratification and patient selection for Nectin-4-targeted therapies.