Exploratory Proteomics and Radiomics Correlates of [68Ga]Ga-ABY-025 PET Uptake in HER2-Low Metastatic Breast Cancer: A Pilot Study

Abstract

Background Human epidermal growth factor receptor 2 (HER2)-low metastatic breast cancer is now an actionable subtype, yet patient selection remains challenging. The aim of this work was to investigate whether multi-omics profiling (proteomics and radiomics) of paired tumor biopsies could explain the observed discordance between PET uptake, IHC score and total HER2 abundance. Methods Ten patients with HER2-low metastatic breast cancer underwent [ 68 Ga]Ga-ABY-025 PET/CT and tumor biopsy in a pilot clinical trial. Discovery proteomics quantified 5,341 proteins in eight patients, and CT radiomics extracted 2,046 features from nine patients (seven with both). Multi-Omics Factor Analysis (MOFA), Spearman correlations, and Enrichr pathway/transcription-factor enrichment were performed. Results Total ERBB2 (HER2) protein abundance did not correlate with SUVmax (Spearman r s = 0.19, P = 0.65). MOFA suggested a separation of the radiomics-linked latent factor (LF1) associated with HER2 (ERBB2) abundance from a proteomics-linked factor (LF3) associated with SUVmax. Top SUVmax-correlated proteins included AGPS (membrane composition), ARHGDIA (cytoskeletal remodeling) and ATAD1 (membrane protein quality control) (Spearman r ≥ 0.95). Enrichment of positive correlates implicated vesicle-mediated transport (adjusted P = 0.0024), endocytic recycling (adjusted P = 0.0087), peroxisomal function (adjusted P = 0.0015) and focal adhesion (adjusted P = 0.0007). Specific radiomics features, such as wavelet-HLL_firstorder_Minimum, correlated well with HER2 levels (r s > 0.95) ; however, none remained statistically significant after correction for multiple comparisons in this small cohort. Conclusion In this hypothesis-generating analysis, PET uptake aligned with membrane-microenvironment proteins, rather than with total HER2 abundance. These findings are consistent with a model in which [ 68 Ga]Ga-ABY-025 uptake reflects cell-surface HER2 availability influenced by membrane trafficking, cytoskeletal organization, and endocytic recycling, and identify candidate biomarkers and radiomic signatures for validation in larger cohorts. Trial registration Clinicaltrials.gov, NCT05619016, https://clinicaltrials.gov/study/NCT05619016. Date of registration Nov 30 th 2022.

Abstract as supplied by the indexing source. © the authors / publisher.