Multicenter clinical study of 18 FAlF-HER2-BCH PET/CT as a molecular pathology tool for linear quantification of HER2 expression levels in breast cancer.

3071 Background: Determining the human epidermal growth factor receptor 2 (HER2) status is essential in metastatic breast cancer (MBC) management. To establish the clinical validity of 18 FAlF-HER2-BCH PET/CT (HER2-PET), we assessed the diagnostic accuracy of qualitative and quantitative HER2-PET assessment to predict HER2 expression by immunohistochemistry (IHC), including HER2-negative and -low breast cancer. Methods: This prospective multicenter trial enrolled treatment-naïve patients with newly diagnosed, non-rapidly progressive breast cancer across all molecular subtypes. Paired HER2 PET and 18 FFDG PET/CT (FDG-PET) scans were acquired within a standardized 7-day. Tumor uptake was quantified using maximum standardized uptake value (SUVmax) and target-to-background ratios (TBR), and analyzed via general linear mixed models. Results: Between 2020 to June 2025, 240 patients were analyzed. Comparative analysis revealed superior diagnostic performance of whole-body HER2-PET versus FDG-PET for malignant lesion detection: sensitivity (97. 6% vs 89. 9%), specificity (83. 9% vs 77. 4%%), and overall accuracy (96. 4% vs 88. 9%). Quantitative HER2-PET analysis revealed significantly different SUVmax values across HER2 expression categories (median IQR: HER2-positive 13. 1 9. 2-20. 7 vs HER2-low 7. 3 5. 1-8. 9 vs HER2-negative 3. 2 2. 7-4. 5; P<0. 001), demonstrating strong correlation with IHC/FISH-defined HER2 status. In contrast, FDG-PET uptake showed no association with HER2 status (P=0. 5). Among 10 discordant cases between HER2-PET and standard IHC/FISH: eight (80%) represented confirmed biological heterogeneity, with differing HER2 status across metastatic sites; two (20%) IHC 1+ cases exhibited PET-positive/FISH-amplified patterns, suggesting potential IHC false-negative results. Conclusions: 18 FAlF-HER2-BCH PET/CT provides comprehensive HER2 profiling beyond single-biopsy IHC, offering new therapeutic insights for HER2-low/negative metastatic breast cancer through whole-body molecular visualization. Clinical trial information: NCT04547309. Diagnostic performance of Al 18 F-HER2-BCH PET/CT and 18 F-FDG PET/CT, in the detection of primary and metastatic lesions in the evaluable imaging core population (N participant=240, N Biopsy-proven lesion=359). HER2 PET FDG PET Difference^ P Value* Participants True positive 207 199 -- -- True negative 26 22 -- -- False positive 2 4 -- -- False negative 5 15 -- -- Sensitivity 97. 6% (94. 7 to 99. 1) 93. 0% (88. 6 to 95. 9) 4. 65% (0. 32 to 8. 98) 0. 036* Specificity 92. 8% (77. 9 to 99. 0) 84. 6% (66. 4 to 94. 7) 8. 24% (-6. 8 to 23. 3) 0. 342 Positive predictive value 99. 0% (96. 6 to 99. 9) 98. 0% (95. 2 to 99. 4) 1. 0 (-1. 1 to 3. 1) 0. 398 Negative predictive value 83. 9% (67. 2 to 93. 7) 59. 5% (43. 3 to 74. 1) 24. 4 (6. 8 to 42) 0. 009** Accuracy 97. 1% (94. 2 to 98. 7) 92. 1% (87. 8 to 95. 2) 5. 0 (1. 3 to 8. 7) 0. 008**