Decoding intratumoral heterogeneity

Differential diagnosis and therapy of heterogeneous breast tumors poses a major clinical challenge. To address the need for a comprehensive, non-invasive strategy to define the molecular and functional profiles of tumors in vivo, we investigated a novel combination of metabolic positron emission tomography (PET) and diffusion-weighted (DW) magnetic resonance imaging (MRI) in the polyoma virus middle T transgenic mouse model of breast cancer. The implementation of a voxelwise analysis for the clustering of intra- and intertumoral heterogeneity in this model resulted in a multiparametric profile based on [18F]FDG-PET and DW-MRI which identified 3 distinct tumor phenotypes in vivo, including solid acinar and solid nodular malignancies as well as cystic hyperplasia. To evaluate the feasibility of this approach for clinical use, we examined estrogen receptor-positive (ER+) and progesterone receptor-positive (PR+) breast tumors from 5 patient cases using DW-MRI and [18F]FDG-PET in a simultaneous PET/MRI system. The post-surgical in vivo PET/MRI data was correlated to whole-slide histology using the latter traditional diagnostic standard to define phenotype. By this approach, we showed how molecular, structural (microscopic, anatomic) and functional information could be simultaneously obtained non-invasively to identify precancerous and malignant subtypes within heterogeneous tumors. Combined with an automatized analysis, our results suggest that multiparametric molecular and functional imaging may be capable of providing comprehensive tumor profiling for non-invasive cancer diagnostics.

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