Hypofractionated Versus Conventionally Fractionated Postmastectomy Radiotherapy With Internal Mammary Node Irradiation for High-Risk Breast Cancer (HypoMast-IMNI): A Randomized Phase III Trial

Purpose When coverage of internal mammary nodes (IMN) is required, the efficacy and safety of hypofractionated regimens within postmastectomy radiotherapy (PMRT) remain to be established. This study evaluated hypofractionated radiotherapy (HypoRT) in patients with high-risk, operable breast cancer undergoing PMRT with IMN irradiation (IMNI). Methods In this phase III noninferiority trial, eligible patients with high-risk disease after mastectomy (including pT1-4N2-3, pT3-4N1, or pT1-2N1 disease with additional high-risk factors) were randomly assigned (1:1) to HypoRT (42.56 Gy in 16 fractions) or conventionally fractionated radiotherapy (ConvRT; 50 Gy in 25 fractions), both targeting the chest wall and regional lymph nodes, including the IMN. The primary end point was locoregional recurrence (LRR). Secondary end points were distant metastasis-free survival (DMFS), breast cancer recurrence-free survival (BCRFS), disease-free survival (DFS), overall survival (OS), and treatment-related toxicity. The trial is registered with ClinicalTrial.gov (identifier: NCT03856372 ). Results Between September 2018 and July 2022, 1,494 patients were randomly assigned. After a median follow-up of 58.1 months in the modified intention-to-treat population (n = 1,429), the 5-year cumulative incidence of LRR was 1.7% (95% CI, 0.9 to 2.9) with HypoRT and 2.2% (95% CI, 1.3 to 3.5) with ConvRT (hazard ratio, 0.69 [95% CI, 0.32 to 1.51]), meeting the noninferiority criterion ( P = .017). No significant differences were observed in 5-year DMFS, BCRFS, DFS, or OS. Grade 3 acute skin toxicity was significantly lower with HypoRT (1.7% v 12.2%, P < .001). The incidence of grade ≥2 radiation pneumonitis and pulmonary fibrosis was low and comparable between arms, with no ischemic cardiac events recorded. Conclusion For patients with high-risk, operable breast cancer requiring PMRT with IMNI, the 16-fraction HypoRT regimen is noninferior to ConvRT for locoregional control, offers a superior acute toxicity profile, and demonstrates excellent cardiopulmonary safety.