Optimizing treatment sequence for inoperable locally advanced breast cancer: Long‐term outcomes of surgery first versus neoadjuvant chemotherapy in a real‐world setting

Abstract Locally advanced breast cancer (LABC) is challenging with limited treatment options. This study investigates the feasibility and long‐term outcomes of upfront surgery compared to neoadjuvant chemotherapy (NAC) in a real‐world cohort. This retrospective study analyzed 243 inoperable LABC patients (excluding T3N1M0) that underwent upfront surgery ( n = 187) or NAC ( n = 56) in matched groups. Disease‐free survival (DFS) and overall survival (OS) are primary outcomes. Secondary outcomes included NAC response rate and subgroup analyses based on age, tumor stage, and treatment response. Survival was estimated using Kaplan–Meier methods with log‐rank tests for comparisons. Cox proportional hazards models were used for subgroup analyses. With a median follow‐up of 60.9 months, no significant difference emerged in 5‐year OS (upfront surgery: 89.6%, NAC: 81.9%, p = .12) or 5‐year DFS rates (73.0% vs. 67.1%, p = .24). Subgroup analyses revealed upfront surgery offered significantly better OS for patients under 60 (HR = 0.32; 95% CI: 0.10–0.96; p = .0429) and stage IIIA disease (HR = 0.22; CI: 0.06–0.86; p = .03). Upfront surgery showed a trend towards improved OS for tumors under 5 cm (HR = 0.37; 95% CI: 0.13–1.03; p = .056). Patients with progressive disease (PD) or stable disease (SD) after NAC had significantly worse DFS (HR = 0.27; 95% CI: 0.09–0.79; p = .017) and OS (HR = 0.09; 95% CI: 0.02–0.48; p = .004) compared to responders. Upfront surgery may be viable for LABC patients, particularly younger patients, those with stage IIIA disease, or smaller tumors. NAC response can inform treatment decisions. These findings highlight the need for personalized LABC treatment considering patient characteristics and NAC response.