Introduction: Patients with locally advanced, triple-negative breast cancer (TNBC) typically receive neoadjuvant therapy (NAT) to downstage the tumor and to improve the outcome of subsequent breast conservation surgery. There are currently no methods to accurately predict how a TNBC patient will respond to NAT before surgery. In this work, we applied a digital twin framework to address this unmet clinical need, by integrating quantitative magnetic resonance imaging (MRI) data with mechanism-based mathematical modeling.

Methods: Multiparametric MRI was acquired in patients (N = 50) before, after 2 and 4 cycles of Adriamycin/Cyclophosphamide (A/C), and again after 12 cycles of Paclitaxel as part of the ARTEMIS (NCT02276433) trial. Within each imaging session, dynamic contrast-enhanced (DCE) MRI, diffusion-weighted imaging (DWI), and a pre-contrast T1-map were acquired. The images were processed by a pipeline consisting of motion correction, multiparametric image alignment, inter-visit image registration to align the tumor and surrounding breast tissue, tissue segmentation, and estimation of tumor cellularity from DWI. A mechanism-based mathematical model, a reaction-diffusion equation, is used to characterize the mobility of tumor cells via diffusion damped by mechanical tissue properties, tumor proliferation via logistic growth, and treatment-induced cell death via the delivery and decay of therapies. For each patient, pre-treatment images were used for model initialization. The model calibration and prediction were implemented with two strategies: 1) using images acquired during the A/C for calibration and predicting up to the end of A/C, and 2) using images acquired during and after the A/C for calibration and predicting up to the end of NAT. For strategy 1), we evaluated the model by comparing its predicted tumor volume and total tumor cellularity to the imaging measurements at the end of A/C. For strategy 2), we evaluated the model by comparing its predicted final response to the post-surgical pathological findings.

Results: For strategy 1), our framework predicted the change of tumor volume and total tumor cellularity with Pearson correlation coefficients of 0.91 and 0.89, respectively. Regarding strategy 2), our framework achieved an area under the receiver operator characteristic curve of 0.88 for distinguishing pCR from non-pCR. As a comparison, imaging measurement of tumor volume at the end of A/C achieved an AUC of 0.79.

Conclusion: Our approach successfully captures the patient-specific dynamics of TNBC response to NAT and provides an improved prediction of final response, which demonstrates the potential of a digital twin framework to be a powerful tool for predicting response to NAT. Once validated, the method will provide a unique opportunity for optimizing treatment plans on a patient-specific basis.

Citation Format: Chengyue Wu, Angela M. Jarrett, Zijian Zhou, Nabil Elshafeey, Beatriz E. Adrada, Rosalind P. Candelaria, Rania Mohamed, Medine Boge, Lei Huo, Jason White, Debu Tripathy, Vicente Valero, Jennifer Litton, Clinton Yam, Jong Bum Son, Jingfei Ma, Gaiane M. Rauch, Thomas E. Yankeelov. Forecasting treatment response to neoadjuvant therapy in triple-negative breast cancer via an image-guided digital twin [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2736.