Trop2-targeted PET/CT with ⁶⁸ Ga-MY6349 for the diagnosis of primary and metastatic breast cancer and evaluation towards patient stratification in Trop2-targeted ADCs.

1113 Background: Trop2-targeted ADCs have demonstrated promising efficacy and have been approved in patients with HR+HER2- and triple-negative breast cancer (TNBC). However, not all patients within these subtypes benefit equally from such treatment, highlighting the urgent need for developing tools for patient selection and stratification. We have previously developed a novel PET/CT imaging agent ( 68 Ga-MY6349) that specifically targets Trop2, which has shown high specificity for Trop2 in preclinical and clinical studies (DOI: 10.1172/JCI185408). Methods: This study enrolled patients with newly diagnosed or previously treated breast cancer at the First Affiliated Hospital of Xiamen University between January 2024 and December 2024. All patients underwent paired 18 F-FDG PET/CT and 68 Ga-MY6349 PET/CT imaging. SUVmax derived from the two PET/CT modalities and pathological results were recorded to evaluate the tumor uptake pattern and lesion detectability of the two imaging modalities. Results: A total of 61 patients were prospectively enrolled, including 7 true-negative and 54 true-positive cases. Among the 562 true-positive lesions, 68 Ga-MY6349 uptake (SUVmax) was significantly associated with breast cancer subtypes (P<0.001, Kruskal-Wallis H=34.9). SUVmax values were highest in HR+/HER2- [7.2 (4.4–9.4)], followed by TNBC [5.2 (3.8–6.4)], HER2+ [4.8 (1.7–7.4)], and HR+/HER2+ [3.3 (2.1–8.1)]. In HR+/HER2- subtypes, 68 Ga-MY6349 demonstrated significantly higher uptake compared to 18 F-FDG [7.2 (4.4–9.4) vs. 3.6 (2.3–5.5), P<0.001]. However, no significant difference regarding tumor uptake was observed in other subtypes. In 27 patients with HR+/HER2- subtypes, 18 F-FDG PET/CT detected 139/208 lesions (missing 2 primary, 40 visceral and bone metastases, and 27 lymph node metastases), while 68 Ga-MY6349 PET/CT detected 202/208 lesions (missing 1 visceral and bone metastasis and 5 lymph node metastases). Interestingly, among 215 lesions in 16 TNBC patients, 18 F-FDG PET/CT detected 206 metastatic lesions (missing 9 lymph node metastases), whereas 68 Ga-MY6349 PET/CT detected all lesions. For HER2+ (7 patients with 74 lesions) and HR+/HER2+ (4 patients with 65 lesions) subtypes, the two tracers exhibited comparable lesion detectability. Conclusions: 68 Ga-MY6349 PET/CT demonstrated superior uptake and greater lesion detectability compared to 18 F-FDG PET/CT in patients with HR+/HER2- breast cancer. The high uptake of 68 Ga-MY6349 in HR+/HER2- and TNBC lesions may partially explain the favorable clinical outcomes observed with Trop2-targeted ADCs in these subtypes, suggesting its potential role for patient selection and stratification for Trop2-targeted therapies. However, the observed heterogeneity in uptake warrants further investigation to clarify its applications across different patient populations. Clinical trial information: NCT06188468 .