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). 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. 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, 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. Conclusions: 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.

中文翻译：

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在接受曲妥珠单抗 emtansine （T-DM1） 治疗的晚期 HER2 阳性乳腺癌中整合分子成像和转录组学分析：ZEPHIR 临床试验分析


目的： ZEPHIR 临床试验评估了 [89Zr]曲妥珠单抗-PET/CT （HER2-PET/CT） 和 2-[18F]氟-2-脱氧-D-葡萄糖 PET/CT （[18F]FDG-PET/CT） 在预测接受曲妥珠单抗 emtansine （T-DM1） 治疗的晚期 HER2 阳性乳腺癌患者预后中的作用。在这里，我们结合了分子/代谢成像和转录组学数据，以研究与 [89Zr] 曲妥珠单抗和 [18F]FDG 摄取相关的生物学过程，并剖析 T-DM1 耐药的机制。实验设计：从 ZEPHIR 试验中获得的转移活检中提取 RNA。将活检病灶的 HER2-PET/CT 和 [18F]FDG-PET/CT 成像数据与转录组学数据相结合。根据 [89Zr] 曲妥珠单抗摄取水平以及存在/不存在代谢反应来比较病变，定义比较基线和治疗中 [18F]FDG-PET/CT。结果： 我们分析了 24 例转移的匹配转录组学和分子/代谢成像数据。参与细胞外基质 （ECM） 组织和糖基磷脂酰肌醇合成的基因和途径在 [89Zr] 曲妥珠单抗摄取率低的病变中富集。[18楼]基线时 FDG 摄取与增殖和免疫相关过程相关。缺氧和 ECM 相关过程在对 T-DM1 无代谢反应的病灶中富集，而免疫相关过程与高 [89Zr] 曲妥珠单抗摄取和代谢反应相关。基因特征包括根据 [89Zr] 曲妥珠单抗摄取和代谢反应的差异表达基因，在外部队列中显示出预测价值。结论： 据我们所知，这项研究代表了 [89Zr] 曲妥珠单抗肿瘤摄取与人类基因表达谱之间的首次相关分析。 我们的研究结果表明，ECM 在损害晚期 HER2 阳性乳腺癌中 [89Zr] 曲妥珠单抗肿瘤摄取和 T-DM1 代谢反应中的作用，突出了分子成像描绘肿瘤微环境特征的潜力。