<p>This study aimed to verify whether the Down-staging Depth Score (DDS), a novel prognostic indicator, could serve as a robust early predictor of long-term outcomes in patients with locally advanced breast cancer (LABC) after neoadjuvant chemotherapy(NAC). A total of 783 eligible patients with LABC from four tertiary cancer centres were retrospectively enrolled between January 2017 and December 2023. All patients received standard NAC followed by curative surgery. Individualized postoperative radiotherapy, targeted therapy, and endocrine therapy were administered in accordance with clinical guidelines. DDS was calculated as the discrepancy between pre-treatment clinical TNM staging score and post-treatment pathological staging score. The primary endpoint was 5-year disease-free survival (DFS); secondary endpoints included overall survival (OS), local recurrence-free survival (LRFS), and distant metastasis-free survival (DMFS). Survival outcomes were estimated using the Kaplan–Meier method. Univariate analysis and multivariate Cox regression models were applied to identify independent prognostic factors. All patients were randomly assigned to a 70% training cohort and a 30% validation cohort. Receiver operating characteristic (ROC) curve analysis with 1000 bootstrap resamples and decision curve analysis (DCA) were performed to systematically compare the predictive efficacy and net clinical benefit of DDS, pathological complete response (pCR), and Miller–Payne (MP) grading system. The median follow-up duration was 58 months. The overall 5-year DFS, OS, LRFS, and DMFS rates were 73.7%, 92.6%, 85.7%, and 78.7%, respectively. Kaplan–Meier analysis revealed that patients with DDS ≥ 4 exhibited significantly superior 5-year DFS (89.2% vs. 59.7%), LRFS (94.3% vs. 77.9%), DMFS (91.1% vs. 67.6%), and OS (98.1% vs. 87.6%) compared with those with DDS &lt; 4 (all P &lt; 0.001). Multivariate Cox regression confirmed that lymphovascular invasion and DDS were independent prognostic factors for DFS and OS. ROC analysis demonstrated that DDS yielded higher area under the curve (AUC) values than pCR and MP grading in both training (0.733 vs. 0.550 vs. 0.607) and validation cohorts (0.711). Bootstrap validation verified its stable predictive performance. DCA further validated that DDS provided superior net clinical benefit across a broad threshold range compared with conventional prognostic markers. As a novel, objective, and reproducible prognostic indicator and risk-stratification tool, DDS exhibits robust and superior performance in predicting long-term survival outcomes among LABC patients treated with NAC, outperforming conventional pCR and MP grading systems. DDS can reliably stratify prognostic risk and assist clinicians in formulating individualized postoperative adjuvant strategies and surveillance schedules. Further large-sample multicentre external validation is warranted to standardize the optimal DDS cutoff and promote its widespread application in the precise management of breast cancer.</p>