par Rediti, Mattia
;Fimereli, Danai
;Mileva, Magdalena
;Wimana, Zéna;Venet, David
;Flamen, Patrick
;Guiot, Thomas
;de Vries, Elisabeth E.G.E.;Schröder, Carolien P;Menke-van der Houven van Oordt, Willemien C.W.;Maetens, Marion M.
;Majjaj, Samira
;Larsimont, Denis
;Rothé, Françoise
;Sotiriou, Christos
;Gebhart, Géraldine 
Référence Clinical cancer research, 31, 1, page (110-121)
Publication Publié, 2025-01-01












Référence Clinical cancer research, 31, 1, page (110-121)
Publication Publié, 2025-01-01
Article révisé par les pairs
Résumé : | Purpose: The ZEPHIR clinical trial evaluated the role of [89Zr] trastuzumab-PET/CT (HER2-PET/CT) and 2-[18F]fluoro-2-deoxy-D-glucose PET/CT ([18F]FDG-PET/CT) in predicting outcomes in patients with advanced HER2-positive breast cancer treated with trastuzumab emtansine (T-DM1). In this study, we combined molecular/metabolic imaging and transcriptomic data to investigate the biological processes associated with [89Zr]tras-tuzumab and [18F]FDG uptake and to dissect the mechanisms involved in T-DM1 resistance. Experimental Design: RNA was extracted from metastasis biopsies obtained in the ZEPHIR trial. HER2-PET/CT and [18F] FDG-PET/CT imaging data of biopsied lesions were integrated with transcriptomic data. Lesions were compared based on the level of [89Zr]trastuzumab uptake as well as on the presence/ absence of metabolic response, defined comparing baseline and on-treatment [18F]FDG-PET/CT. Results: We analyzed matched transcriptomic and molecular/ metabolic imaging data for 24 metastases. Genes and pathways involved in extracellular matrix (ECM) organization and glycosylphosphatidylinositol synthesis were enriched in lesions presenting low [89Zr]trastuzumab uptake. [18F]FDG uptake at baseline correlated with proliferation and immune-related processes. Hypoxia and ECM-related processes were enriched in lesions showing no metabolic response to T-DM1, whereas immune-related processes were associated with high [89Zr]tras-tuzumab uptake and metabolic response. Gene signatures including differentially expressed genes according to [89Zr] trastuzumab uptake and metabolic response showed predictive value in an external cohort. Conclusions: To the best of our knowledge, this study represents the first correlative analysis between [89Zr]trastuzumab tumor uptake and gene expression profiling in humans. Our findings suggest a role for ECM in impairing [89Zr]trastuzumab tumor uptake and T-DM1 metabolic response in advanced HER2-positive breast cancer, highlighting the potential of molecular imaging to depict tumor microenvironment features. |