Abstract Background: Postmastectomy radiotherapy (PMRT) is well-established for high-risk breast cancer treatment. However, with the increasing adoption of neoadjuvant chemotherapy (NAC), the necessity of PMRT in patients achieving pathologic complete response (pCR) remains controversial. Recent studies, including the prospective NSABP B-51 trial, suggest minimal or no survival benefit in this population, questioning the routine use of PMRT and opening the door to potential treatment de-escalation. Objective: To evaluate whether PMRT provides an overall survival (OS) benefit in early-stage breast cancer patients who achieve nodal pathologic complete response (pCR) after NAC. Secondary objectives included assessing the impact of PMRT on locoregional control and disease-free survival (DFS). Methods: This systematic review and meta-analysis followed PRISMA guidelines and was registered in PROSPERO (CRD4202460366). A comprehensive search was conducted in PubMed, Embase, Cochrane Library, Scopus, and Web of Science for studies published between January 2005 and June 2024. Eligible studies included retrospective and prospective cohorts of women with breast cancer who received NAC, achieved nodal pCR, and underwent mastectomy with or without PMRT. The primary outcome was OS. Secondary outcomes included LRR and DFS. Pooled risk ratios and hazard ratios were calculated using random-effects models. Heterogeneity was assessed using the I2 statistic and Cochran’s Q test. Publication bias was evaluated through funnel plots and Egger’s test. Methodological quality and risk of bias were assessed using the ROBINS-I tool for non-randomized studies. Results: Twenty studies published between 2007 and 2024 were included, comprising 36,380 patients across North America (45%), Asia (45%), and Europe (10%). Of these, 23,228 (63.8%) received PMRT, and 13,152 (36.2%) did not. Median follow-up ranged from 40 to 91 months. Study populations were heterogeneous, including patients with stages T1-T4, mean ages of 46-55 years, and multiple molecular subtypes. PMRT was associated with a statistically significant reduction in LRR (RR 1.02, 95% CI: 1.01-1.03; p = 0.005), indicating a 2% relative risk reduction. For DFS, HR was 1.05 (95% CI: 1.02-1.09; p = 0.004), favoring PMRT with a 5% improvement. No significant OS benefit was observed (RR 1.02, 95% CI: 0.99-1.05; p = 0.24). Heterogeneity was moderate for OS (I2 = 50%) and DFS (I2 = 54%), and low-to-moderate for LRR (I2 = 32%). Egger’s test indicated possible publication bias for LRR (p = 0.0017) and DFS (p = 0.010), but not for OS (p = 0.188). Conclusion: This meta-analysis found no significant overall survival benefit from PMRT in patients with nodal pCR after NAC. Although PMRT was associated with statistically significant improvements in disease-free survival and locoregional control, the magnitude of these effects was small and likely clinically insignificant. These findings support the hypothesis that many patients may not require PMRT and could safely benefit from treatment de-escalation strategies. A cautious, individualized approach is recommended, and further prospective studies are needed to identify which subgroups may still derive meaningful benefit from PMRT in the era of effective systemic therapy. Citation Format: M. Antonini, F. P. Cavalcante, A. Mattar, F. P. Zerwes, E. C. Millen, F. P. Brenelli, A. L. Frasson, M. D. Teixeira, M. Madeira, H. L. Couto, G. Facina, R. Arakelian, L. R. Soares, A. D. Lima, R. Freitas Júnior, G. N. Garcia, F. Bagnoli, A. G. Amorim, M. F. de Figueiredo, G. T. Tosello, L. H. Gebrim, G. N. Marta. Precise study: postmastectomy radiotherapy evaluated in breast cancer patients achieving complete pathologic response following neoadjuvant chemotherapy and its impact on survival outcomes - a systematic review and meta-analysis abstract. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS1-07-02.
Antonini et al. (Tue,) studied this question.