Abstract PO2-01-01: Biophysical simulation using DCE-MRI to forecast response to NAT in HER2+ patients, with glucose characterization and orthogonal validation using FDG-PET
Authors: Whitman John , Adhikarla Vikram , Rockne Russell , Tumyan Lusine , Mortimer Joanne , Huang Wei , Peterson Joseph , Lopez-Ramos Dorys , Cole John 
Published: May 2024

Background: Metabolic reprogramming and tumor angiogenesis are two tightly linked hallmarks of cancer. Regions of high metabolic activity within a tumor can become hypoxic or nutrient starved, eliciting a cascade of pro-angiogenic signals that can lead to increased tumor perfusion and in turn greater metabolic activity. Dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) and 18Fluorodeoxyglucose (FDG) positron emission tomography (PET) are two imaging methods commonly used in the diagnosis of cancer; the former can be also used to identify the perfusion of the tumor microenvironment (TME) and the latter provides a coarse readout of glucose metabolic activity. Here, we are presented with a unique cohort of patients who underwent DCE-MRI, 18FDG-PET and 64Cu-DOTA-Traztuzumab offering potential to perform a pilot analysis. First, we characterize the performance of our perfusion model SimBioSys- Microvasculature (SBS-MV) through a stability analysis, as well as comparison with two PET modalities. Finally, we use this model in 3D simulations of individual HER2+ breast cancer patients to forecast responses to neoadjuvant chemotherapy (NAT). Methods: SBS-MV is a modified Tofts model for pharmacokinetic modeling of DCE-MRI data, utilizing a tissue segmentation model developed in-house to inform parameter fits and ensure that the derived parameters fall within acceptable values on a tissue-by-tissue level, in addition its function for standard fitting of DCE time-course data. We first evaluated the stability of the SBS-MV model by analyzing a separate cohort of 10 patients who underwent ultrafast DCE-MRI. Temporal undersampling was performed on the original high temporal resolution data to mimic low temporal resolution from standard-of-care (SoC) DCE studies. Both datasets were processed with SBS-MV model. Next, we analyzed data from a cohort of 18 patients, each of whom underwent a pre-NAT SoC DCE-MRI study, a mid-treatment FDG PET/CT study, and a mid-treatment 64Cu-DOTA-Trastuzumab/CT study during treatment. Tissue segmentation and SBS-MV fits were performed on the pre-NAT DCE MRI. Tightly cropped boxes encompassing the tumor in the 3D SBS-MV volumes as well as the PET volumes were created. Using these identified regions, all summary statistics were calculated and cross-correlated between imaging modalities. Results: SBS-MV was stable to SoC-mimicking temporally undersampled ultrafast DCE MRI series, demonstrating relatively little variability in the output parameters (a voxel wise median deviation of approximately 0.005 min-1 ). Further, we demonstrate that SBS-MV parameters (Ktrans, ve) are correlated with FDG SUVSA and 64Cu SUVSA. In addition, the glucose concentrations used in the biophysical simulations were correlated with FDG SUVSA, indicating that downstream applications of the SBS-MV models still carry this information about perfusion.

Finally, using SBS-MV, our biophysical simulations of HER2-targeted therapy accurately predict patient response. In this small cohort, our biophysical simulation platform performed well, yielding predictive accuracy of 0.83, with sensitivity and specificity of 0.83 and 0.83, respectively. These performance metrics are in line with previously published reports. Conclusion: Our MV model is capable of extracting biologically meaningful perfusion parameters from standard clinical DCE MRI time series, providing the same benefits of a comprehensive kinetic analysis, without impacting current clinical workflow. This approach could be used in both the research and clinical settings, offering actionable information on what drives individual patient therapeutic response for a more personalized care.

Citation Format: John Whitman, Vikram Adhikarla, Russell Rockne, Lusine Tumyan, Joanne Mortimer, Wei Huang, Joseph Peterson, Dorys Lopez-Ramos, John Cole. Biophysical simulation using DCE-MRI to forecast response to NAT in HER2+ patients, with glucose characterization and orthogonal validation using FDG-PET [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-01-01.