Quantitative [⁸⁹Zr]Zr-Trastuzumab PET and Diffusion- Weighted MRI for Characterization of Metastatic HER2-Positive Breast Cancer with PET/MRI

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Current methods for evaluating HER2 expression in breast cancer are invasive and fail to capture spatial and temporal heterogeneity between primary tumors and metastases. Nuclear imaging allows for whole-body, noninvasive assessment of human epidermal growth factor receptor 2 (HER2) and can distinguish between HER2-positive and HER2-negative lesions. MRI offers superior soft-tissue contrast and quantitative metrics, such as the apparent diffusion coefficient (ADC) from diffusion-weighted (DW) imaging, providing prognostic value. The goal of this study was to present quantitative imaging metrics from [⁸⁹Zr]Zr-trastuzumab PET and simultaneous DW-MRI to characterize HER2-positive metastatic breast cancer lesions. The secondary aim was to explore the utility of combining [⁸⁹Zr]Zr-trastuzumab PET with DW-MRI for intratumoral habitat mapping using multiparametric [⁸⁹Zr]Zr-trastuzumab PET/MRI to enhance characterization of lesions and assess the response to HER2-targeted therapy. Methods: Fifteen patients with confirmed HER2-positive breast cancer underwent simultaneous PET/MRI 5–7 d after receiving 77 ± 1.9 MBq of [⁸⁹Zr]Zr-trastuzumab. Whole-body ADC maps were generated from DW-MRI, and regions of interest in normal and malignant tissues were delineated. Imaging metrics included SUV for PET and ADC for DW-MRI. Threshold- and clustering-based methods were applied for intratumoral characterization through multiparametric mapping. Results: Malignant tissues exhibited significantly higher [⁸⁹Zr]Zr-trastuzumab uptake than did normal tissues. High uptake in the kidneys, liver, and blood pool complicated lesion identification near these tissues. ADC mapping improved lesion characterization in the brain, soft tissue, and bone. The diagnostic accuracy of [⁸⁹Zr]Zr-trastuzumab PET alone improved when combined with ADC mapping (area under the curve, 0.59 and 0.75, respectively). Multiparametric analysis revealed intratumoral heterogeneity, identifying distinct subregions with variable tracer uptake and diffusion characteristics. Conclusion: Combining [⁸⁹Zr]Zr-trastuzumab PET with DW-MRI offers a multiparametric imaging approach for characterizing HER2 expression and cellular density in HER2-positive metastatic breast cancer. Increased tracer uptake in malignant lesions and improved lesion characterization through ADC mapping highlight the potential of this combination for evaluating treatment response and tumor heterogeneity. Large-scale validation is needed to confirm these findings and support integrating [⁸⁹Zr]Zr-trastuzumab PET and DW-MRI into clinical management for better patient outcomes.