Exploration of Optimal Synergistic Treatment Strategies of Postoperative Radiotherapy and Immunotherapy in Early-Stage Breast Cancer

Background: The optimal sequencing of radiotherapy and immunotherapy in early-stage breast cancer remains uncertain. Although synergistic interactions between radiotherapy and immunotherapy have been widely reported, most available evidence derives from advanced disease with high tumor burden. Whether treatment sequencing influences outcomes in postoperative adjuvant therapy has not been well defined. Methods: Patients with stage I–III human epidermal growth factor receptor 2 (HER2)-negative breast cancer who underwent surgery followed by both adjuvant radiotherapy and immunotherapy were identified from the National Cancer Database. According to treatment initiation dates, patients were classified into immunotherapy-first and radiotherapy-first groups. Overall survival was compared using Kaplan–Meier analysis and weighted Cox regression. Baseline imbalances were adjusted using inverse probability of treatment weighting. Prespecified subgroup analyses were conducted based on adjuvant chemotherapy status and radiotherapy fractionation regimen. A sensitivity analysis was performed in an independent cohort of stage IV inoperable patients. Results: A total of 3813 patients were included. Immunotherapy-first sequencing was associated with improved overall survival compared with radiotherapy-first sequencing after weighted (HR 0.71; 95% CI 0.56–0.89). The survival benefit was most evident among patients receiving adjuvant chemotherapy (HR 0.63; 95% CI 0.48–0.84), whereas no significant difference was observed in patients without chemotherapy (HR 1.01; 95% CI 0.71–1.44). Subgroup analysis according to radiotherapy fractionation demonstrated a significant advantage of immunotherapy-first sequencing in patients treated with conventional fractionation radiotherapy (HR 0.58; 95% CI 0.36–0.92), but not in those receiving hypofractionated radiotherapy (HR 0.44; 95% CI 0.17–1.13). In stage IV inoperable patients, no survival difference was detected between sequencing strategies (HR 1.04; 95% CI 0.88–1.23). Conclusions: For postoperative patients with low residual tumor burden, particularly those receiving adjuvant chemotherapy, immunotherapy-first strategy may provide stronger synergistic effects and lead to improved survival. In addition, conventional fractionation radiotherapy with lower doses per fraction appears to facilitate more effective interaction with immunotherapy compared with hypofractionated regimens. Prospective trials are needed for further validation.