Comparison of postprocessing metrics in multimetabolic APT-weighted CEST and 2-deoxy-D-glucose-CEST-MRI for differentiating breast cancer subtypes in a murine model

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Abstract Background Chemical exchange saturation transfer (CEST)-magnetic resonance imaging (MRI), particularly amide proton transfer-weighted (APTw)-CEST and 2-deoxy-D-glucose-CEST, holds promise for noninvasive molecular breast cancer (BC) characterization. However, quantification remains challenging due to field inhomogeneities, overlapping exchange pools, and the limited robustness of conventional metrics such as the magnetization transfer ratio asymmetry (MTR asym ). This study evaluates four CEST postprocessing metrics—MTR asym , Lorentzian amplitudes, MTR relaxation exchange (MTR REX ), and apparent exchange-dependent relaxation (AREX)—for their diagnostic performance in differentiating BC subtypes using endogenous APTw-CEST and exogenous 2-deoxy-D-glucose-CEST in a murine BC xenograft model of Luminal A, human epidermal growth factor receptor 2 (HER2)+, and triple-negative tumors. Materials and methods Metabolic CEST-MRI was performed in vitro on protein and 2-deoxy-D-glucose phantoms and in vivo in a murine BC model. Imaging was conducted at 9.4 T with 120 frequency offsets from +6 to -6 ppm. MTR REX and AREX were derived via Lorentzian fitting using tailored five-pool models. Statistical comparisons across subtypes were performed per metric. Results In APTw-CEST, MTR REX and AREX significantly distinguished Luminal A from HER2+ ( p ≤ 0.027) and Luminal A from triple-negative ( p ≤ 0.006) tumors. Lorentzian amplitudes differentiated Luminal A from triple-negative ( p = 0.019), while MTR asym showed no separation. In 2-deoxy-D-glucose-CEST, only AREX distinguished Luminal A from HER2+ tumors ( p = 0.017). Conclusion Advanced metrics, particularly MTR REX and AREX, improve metabolic CEST-MRI for BC subtyping in a murine preclinical model, while MTR asym is inadequate for this purpose. Relevance statement Our findings underscore the importance of applying advanced postprocessing metrics to metabolic CEST-MRI for improved noninvasive BC characterization in a murine preclinical model. Key Points Advanced multimetabolic APTw-CEST and 2-deoxy-D-glucose-CEST postprocessing metrics allowed adequate preclinical murine BC subtyping. AREX showed potential for 2-deoxy-D-glucose-CEST in tumor characterization; however, APTw-CEST remains superior. MTR asym failed to distinguish between tumor subtypes in CEST-MRI. Graphical Abstract

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