Abstract
BACKGROUND: Trastuzumab deruxtecan (T-DXd) is effective in HER2-expressing metastatic breast cancer (mBC), yet inter-patient benefit varies. The current reference biomarker-HER2 immunohistochemistry (IHC) on tumor biopsies-is insufficient as a sole predictor of response. HER2-targeted PET/CT offers non-invasive, whole-body, real-time assessment of target expression. We hypothesize that HER2-targeted PET with [68Ga]Ga-ABY-025 improves prediction of T-DXd outcomes and supports individualized treatment planning. METHODS: HER2-Ex PET is a multicenter, phase II open-label diagnostic trial enrolling patients with HER2-low mBC who are candidates for T-DXd under current approvals (EU CT 2024-512721-89-00; NCT06830382). All participants undergo baseline HER2-PET with [68Ga]Ga-ABY-025 and a tumor biopsy. Patients with biopsy-confirmed HER2 expression (IHC 1-2+; Cohort 1) receive T-DXd and repeat HER2-PET after 3-4 cycles; others receive physician's-choice systemic therapy (Cohort 2). The primary endpoint is the association between baseline HER2-PET signal-defined as the mean SUVmax across the five most avid lesions-and objective response per RECIST v1.1 after 3-4 cycles of T-DXd. A total sample size of 70 provides 80% power (α=0.05), allowing for attrition and technical failures. Secondary endpoints include health-economic outcomes and translational analyses of tumor biology and heterogeneity. The study is open at Karolinska University Hospital (Stockholm, Sweden), with Uppsala and Skåne University Hospitals planned for activation in Q1 2026. DISCUSSION: Demonstrating a robust correlation between HER2-PET signal and early radiologic response would validate imaging-based patient selection for T-DXd, facilitate adaptive treatment decisions, and enhance biological understanding of intra- and inter-patient HER2 heterogeneity. Key considerations include standardization of imaging protocols across sites, potential temporal discordance between biopsy and imaging, and the non-randomized design. Positive results would justify incorporation of HER2-targeted PET into clinical pathways and inform the design of subsequent randomized trials testing PET-guided T-DXd strategies. CLINICAL TRIAL REGISTRATION: https://clinicaltrials.gov/study/NCT06830382, identifier NCT06830382.