**Title:** Forecasting patient-specific treatment response to neoadjuvant chemotherapy in triple-negative breast cancer via MRI-based digital twins

**Abstract: **Patients with locally advanced, triple-negative breast cancer (TNBC) typically receive neoadjuvant chemotherapy (NAT) to downstage the tumor and improve the outcome of subsequent breast conservation surgery. In this study, we integrated quantitative magnetic resonance imaging (MRI) data with biology-based mathematical modeling to address the currently unmet need for accurate prediction of TNBC response to NAT on an individual patient basis. Specifically, dynamic contrast-enhanced MRI and diffusion-weighted MRI was acquired in 56 patients before, after two, and after four cycles of Adriamycin/Cytoxan (A/C), and again after Taxol as part of the ARTEMIS (NCT02276443) trial. A biology-based mathematical model was established based on the reaction-diffusion equation to characterize the mobility of tumor cells, tumor proliferation, and treatment-induced cell death. Pre- and mid-treatment images were used for model calibration on a patient-specific basis. Two evaluation Frameworks were built: 1. using images acquired before and after two cycles of A/C for calibration and predicting tumor status after A/C, and 2. using images acquired before, after two cycles, and after four cycles of A/C for calibration and predicting response after NAT. For Framework 1, the Pearson correlation coefficients between the predicted and measured patient-specific, post-A/C changes in tumor cellularity and volume were 0.95 and 0.94, respectively. For Framework 2, the biologically-based model achieved an area under the receiver operator characteristic curve of 0.89 (sensitivity/specificity = 0.72/0.95) for differentiating pathological complete response (pCR) from non-pCR, which is statistically superior (P < 0.05) to the value of 0.78 (sensitivity/specificity = 0.72/0.79) achieved by the tumor volume measured after four cycles of A/C. Overall, our biology-based mathematical model successfully captured the patient-specific, spatiotemporal dynamics of TNBC response to NAT, providing highly accurate predictions of NAT response.