PURPOSE: The Early Breast Cancer Trialists' Collaborative Group's 2023 meta-analysis of radiotherapy to regional nodes in early breast cancer demonstrated a significant improvement in overall survival (OS) without an associated improvement in locoregional recurrence in the trials comparing internal mammary node (IMN) irradiation versus none. We aimed to study cases with IMN relapse (IMNR) and controls without IMNR to examine the link between IMNR and OS. MATERIALS AND METHODS: Patients treated curatively between 2005 and 2014, who subsequently developed IMNR, were identified in a population-based database. The IMNR cases were matched 1:2 to controls without IMNR using patient and tumor characteristics. The internal mammary vessels in the first three intercostal spaces were outlined on planning CTs as the IMN clinical target volume, and the mean equivalent doses in 2 Gy fractions to the IMNs were calculated. Multivariable Fine and Gray competing-risk regression and Cox regression were used to evaluate the effect of the baseline patient, tumor and treatment variables, including therapeutic IMN irradiation with ≥40 Gy on IMNR and OS. RESULTS: Seventy cases were matched with 140 controls. Median follow-up was 9.1 years, median tumor size was 25 mm, and N-stages were: 37% N0, 33% N1, and 30% N2-3. The medians of the IMN doses were 4.1 Gy for cases and 13.7 Gy for controls (p<
0.001). On multivariable analysis, worse IMNR was associated with mastectomy (HR=2.11, p=0.02), and better IMNR was associated with therapeutic IMN irradiation (HR=0.36, p=0.009)
worse OS was associated with larger tumor size (HR=1.02, p=0.006), ≥10 positive axillary nodes (HR=3.15, p=0.04), and triple-negative subtype (HR=2.92, p=0.03), and better OS was associated with therapeutic IMN irradiation (HR=0.49, p=0.02). CONCLUSIONS: We demonstrated that therapeutic IMN irradiation with ≥40 Gy was associated with a lower risk of internal mammary node relapse and improved overall survival.