Integrating molecular imaging and transcriptomic profiling in advanced HER2-positive breast cancer receiving trastuzumab emtansine (T-DM1): an analysis of the ZEPHIR clinical trial

• Published in: Clinical cancer research
• Main Authors: Rediti, Mattia, Fimereli, Danai, Mileva, Magdalena, Wimana, Zéna, Venet, David, Flamen, Patrick, Guiot, Thomas, de Vries, Elisabeth G E, Schröder, Carolina P, Menke-van der Houven van Oordt, C Willemien, Maetens, Marion, Majjaj, Samira, Larsimont, Denis, Rothé, Françoise, Sotiriou, Christos, Gebhart, Géraldine
• Format: Journal Article
• Language: English
• Published: United States 29.10.2024
• ISSN: 1078-0432; 1557-3265; 1557-3265
• DOI: 10.1158/1078-0432.CCR-24-1007

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). Here, we combined molecular/metabolic imaging and transcriptomic data to investigate the biological processes associated with [89Zr]trastuzumab and [18F]FDG uptake, and to dissect the mechanisms involved in T-DM1 resistance. 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. 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, while immune-related processes were associated with high [89Zr]trastuzumab 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. To 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 of 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.