Human Epidermal Growth Factor Receptor 2–Targeting [(68)Ga]Ga-ABY-025 PET/CT Predicts Early Metabolic Response in Metastatic Breast Cancer

Imaging using the human epidermal growth factor receptor 2 (HER2)–binding tracer (68)Ga-labeled Z(HER2:2891)-Cys-MMA-DOTA ([(68)Ga]Ga-ABY-025) was shown to reflect HER2 status determined by immunohistochemistry and in situ hybridization in metastatic breast cancer (MBC). This single-center open-label phase II study investigated how [(68)Ga]Ga-ABY-025 uptake corresponds to biopsy results and early treatment response in both primary breast cancer (PBC) planned for neoadjuvant chemotherapy and MBC. Methods: Forty patients with known positive HER2 status were included: 19 with PBC and 21 with MBC (median, 3 previous treatments). [(68)Ga]Ga-ABY-025 PET/CT, [(18)F]F-FDG PET/CT, and core-needle biopsies from targeted lesions were performed at baseline. [(18)F]F-FDG PET/CT was repeated after 2 cycles of therapy to calculate the directional change in tumor lesion glycolysis (Δ-TLG). The largest lesions (up to 5) were evaluated in all 3 scans per patient. SUVs from [(68)Ga]Ga-ABY-025 PET/CT were compared with the biopsied HER2 status and Δ-TLG by receiver operating characteristic analyses. Results: Trial biopsies were HER2-positive in 31 patients, HER2-negative in 6 patients, and borderline HER2-positive in 3 patients. The [(68)Ga]Ga-ABY-025 PET/CT cutoff SUV(max) of 6.0 predicted a Δ-TLG lower than −25% with 86% sensitivity and 67% specificity in soft-tissue lesions (area under the curve, 0.74 [95% CI, 0.67–0.82]; P = 0.01). Compared with the HER2 status, this cutoff resulted in clinically relevant discordant findings in 12 of 40 patients. Metabolic response (Δ-TLG) was more pronounced in PBC (−71% [95% CI, −58% to −83%]; P < 0.0001) than in MBC (−27% [95% CI, −16% to −38%]; P < 0.0001), but [(68)Ga]Ga-ABY-025 SUV(max) was similar in both with a mean SUV(max) of 9.8 (95% CI, 6.3–13.3) and 13.9 (95% CI, 10.5–17.2), respectively (P = 0.10). In multivariate analysis, global Δ-TLG was positively associated with the number of previous treatments (P = 0.0004) and negatively associated with [(68)Ga]Ga-ABY-025 PET/CT SUV(max) (P = 0.018) but not with HER2 status (P = 0.09). Conclusion: [(68)Ga]Ga-ABY-025 PET/CT predicted early metabolic response to HER2-targeted therapy in HER2-positive breast cancer. Metabolic response was attenuated in recurrent disease. [(68)Ga]Ga-ABY-025 PET/CT appears to provide an estimate of the HER2 expression required to induce tumor metabolic remission by targeted therapies and might be useful as an adjunct diagnostic tool.