e12673 Background: The role of neoadjuvant chemotherapy (NACT) in stage II-III hormone receptor-positive and HER2-negative (HR+/HER2-) breast cancer remains controversial due to low pathological complete response (pCR) rates. Recent evidence from the NATALEE trial subgroup analysis presented at San Gallen 2025 identified prior NACT as an independent negative prognostic factor for invasive disease-free survival (iDFS) in HR+/HER2- early breast cancer, raising concerns about the optimal sequencing of systemic therapy in this population. Whether NACT or adjuvant chemotherapy (ACT) provides better survival outcomes in HR+/HER2- breast cancer is an ongoing debate with significant clinical implications. Methods: Six hundred fifty-five patients (pts) with HR+/HER2- locally advanced breast cancer at stage II-III undergoing NACT (429 pts) or ACT (226 pts) between 2005 and 2021 were identified from Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome. Propensity score matching (PSM) was employed to create cohorts with balanced baseline characteristics across different categories (age, menopausal status, grading, stage, Ki67, ER, PgR, HER2). The efficacy of NACT and ACT in terms of overall survival (OS) and real-world invasive disease-free survival (rwiDFS) was evaluated using Kaplan-Meier analysis and the Cox proportional hazards model. Results: Using PSM, a total of 432 pts was ultimately included in the study (216 vs 216). OS was significantly longer for ACT versus NACT (NR vs 229 months mOS, 96.8% vs 90.6% survival rate at 5 years, HR 0.58, 95% CI 0.36-0.95, p = 0.03). The rwiDFS was longer for ACT versus NACT (NR vs 135 months, 91.6% vs 74.8% survival rate at 5 years, HR 0.63, 95% CI 0.43-0.92, p = 0.017). Patients who underwent ACT had significantly better OS compared to those who did not achieve pCR after NACT (HR 0.56, 95% CI 0.38-0.82, p = 0.016), while no significant difference was observed compared to patients who achieved pCR after NACT (HR 1.81, 95% CI 0.9-3.6, p = NS). Conclusions: In stage II-III HR+/HER2- breast cancer, NACT was associated with inferior OS and rwiDFS compared to ACT, consistent with NATALEE trial findings identifying NACT as an adverse prognostic factor. NACT should be reserved for selected cases requiring downstaging. While neoadjuvant CDK4/6 inhibitors have shown limited efficacy in replacing chemotherapy, emerging oral SERDs and PROTACs may improve pCR rates and bridge the efficacy gap in this subtype.
Orlandi et al. (Thu,) studied this question.