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

Abstract

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 F]AlF-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 F]FDG 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 F]AlF-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**