BackgroundGeneralizable population-based studies are unable to account for individual tumor heterogeneity that contributes to variability in a patient’s response to physician-chosen therapy. Although molecular characterization of tumors has advanced precision medicine, in early-stage and locally advanced breast cancer patients, predicting a patient’s response to neoadjuvant therapy (NAT) remains a gap in current clinical practice. Here, we perform a study in an independent cohort of early-stage and locally advanced breast cancer patients to forecast tumor response to NAT and assess the stability of a previously validated biophysical simulation platform.MethodsA single-blinded study was performed using a retrospective database from a single institution (9/2014–12/2020). Patients included: ≥ 18 years with breast cancer who completed NAT, with pre-treatment dynamic contrast enhanced magnetic resonance imaging. Demographics, chemotherapy, baseline (pre-treatment) MRI and pathologic data were input into the TumorScope Predict (TS) biophysical simulation platform to generate predictions. Primary outcomes included predictions of pathological complete response (pCR) versus residual disease (RD) and final volume for each tumor. For validation, post-NAT predicted pCR and tumor volumes were compared to actual pathological assessment and MRI-assessed volumes. Predicted pCR was pre-defined as residual tumor volume ≤ 0.01 cm3(≥ 99.9% reduction).ResultsThe cohort consisted of eighty patients; 36 Caucasian and 40 African American. Most tumors were high-grade (54.4% grade 3) invasive ductal carcinomas (90.0%). Receptor subtypes included hormone receptor positive (HR+)/human epidermal growth factor receptor 2 positive (HER2+, 30%), HR+/HER2− (35%), HR−/HER2+ (12.5%) and triple negative breast cancer (TNBC, 22.5%). Simulated tumor volume was significantly correlated with post-treatment radiographic MRI calculated volumes (r= 0.53,p= 1.3 × 10–7, mean absolute error of 6.57%). TS prediction of pCR compared favorably to pathological assessment (pCR: TSn= 28; Pathn= 27; RD: TSn= 52; Pathn= 53), for an overall accuracy of 91.2% (95% CI: 82.8% – 96.4%; Clopper–Pearson interval). Five-year risk of recurrence demonstrated similar prognostic performance between TS predictions (Hazard ratio (HR): − 1.99; 95% CI [− 3.96, − 0.02];p= 0.043) and clinically assessed pCR (HR: − 1.76; 95% CI [− 3.75, 0.23];p= 0.054).ConclusionWe demonstrated TS ability to simulate and model tumor in vivo conditions in silico and forecast volume response to NAT across breast tumor subtypes.Supplementary InformationThe online version contains supplementary material available at 10.1186/s13058-023-01654-z.