16-Fraction PMRT With IMN Irradiation Noninferior in High-Risk Breast Cancer

Hypofractionated postmastectomy radiotherapy (PMRT) that included internal mammary node irradiation (IMNI) was noninferior to conventionally fractionated radiotherapy for locoregional control among patients with high-risk, operable breast cancer, according to findings from the phase 3 HypoMast-IMNI trial (NCT03856372) published in the Journal of Clinical Oncology.

After a median follow-up of 58.1 months in the modified intention-to-treat population (n = 1429), the 5-year cumulative incidence of locoregional recurrence (LRR) was 1.7% (95% CI, 0.9%-2.9%) with hypofractionated radiotherapy (HypoRT) vs 2.2% (95% CI, 1.3%-3.5%) with conventionally fractionated radiotherapy (ConvRT; HR, 0.69; 95% CI, 0.32-1.51; P_{noninferiority} = .017).

The shorter regimen also significantly reduced severe acute skin toxicity, with grade 3 events occurring in 1.7% of patients in the HypoRT arm vs 12.2% of those in the ConvRT arm (P <.001). Rates of grade 2 or higher radiation pneumonitis and pulmonary fibrosis were low and comparable between arms, and no ischemic cardiac events were recorded.

“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,” the study authors wrote.

Although hypofractionation is a well-established standard following breast-conserving surgery, its adoption after mastectomy has remained cautious due to limited high-level evidence, particularly when internal mammary node (IMN) coverage is required. According to the investigators, safety concerns have persisted in this setting given the proximity of the IMN chain to the heart and lungs, and a prior trial reporting noninferior outcomes with hypofractionated PMRT was limited by outdated techniques and the exclusion of IMNI.

In the prospective, randomized, open-label, single-center trial conducted at Fudan University Shanghai Cancer Center, 1494 patients were randomly assigned 1:1 between September 2018 and July 2022 to receive HypoRT at 42.56 Gy in 16 fractions (n = 747) or ConvRT at 50 Gy in 25 fractions (n = 747). Both regimens targeted the chest wall and regional lymph nodes, including the IMNs from the first to third intercostal spaces. Most patients were treated with simplified intensity-modulated radiotherapy (HypoRT, 90.5%; ConvRT, 91.4%), and deep inspiration breath hold was used in 21.2% of patients with left-sided disease.

Eligible patients were women aged 18 to 70 years who had undergone mastectomy with negative margins and axillary lymph node dissection with at least 10 nodes removed. Patients were required to have pathologic T1-4N2-3 or T3-4N1 disease, or T1-2N1 disease with at least 1 high-risk factor, including age younger than 40 years, histologic grade 3 tumor, lymphovascular invasion, hormone receptor–negative disease, or HER2 overexpression. Patients who received neoadjuvant chemotherapy were excluded. Breast reconstruction was permitted.

The primary end point was LRR. Secondary end points included distant metastasis–free survival (DMFS), breast cancer recurrence–free survival (BCRFS), disease-free survival (DFS), overall survival (OS), and treatment-related toxicity.

Baseline characteristics were well balanced between the arms. The median patient age was 49 years (range, 21-70), most patients had pT2 disease (62.8%) and pN1 nodal status (57.1%), and no patients had pT4 disease. Overall, 52.5% of patients had hormone receptor–positive/HER2-negative disease, 17.1% had hormone receptor–positive/HER2-positive disease, 15.7% had hormone receptor–negative/HER2-positive disease, and 14.7% had hormone receptor–negative/HER2-negative disease. Nearly all patients (99.9%) received adjuvant chemotherapy.

No significant differences between the arms were observed for any secondary end point. The 5-year DMFS rates were 92.3% with HypoRT vs 92.7% with ConvRT (HR, 1.00; 95% CI, 0.68-1.47; P = .987), and the 5-year BCRFS rates were 91.8% vs 92.3%, respectively (HR, 0.99; 95% CI, 0.69-1.45; P = .980). The 5-year DFS rates were 88.5% vs 89.4% (HR, 1.05; 95% CI, 0.76-1.44; P = .769), and the 5-year OS rates were 95.1% vs 96.1% (HR, 1.21; 95% CI, 0.72-2.01; P = .476).

The effect of HypoRT on LRR was consistent with the primary analysis across subgroups defined by T and N stage, molecular subtype, age, histology, and grade. The 5-year LRR rates were less than 1% among patients with N1 disease and 4% or lower among those with N2-3 disease.

Regarding safety, no grade 4 toxicities or treatment-related deaths occurred. HypoRT was associated with lower rates of grade 1 to 2 skin pruritus (26.7% vs 35.2%; P = .001) and skin pain (7.7% vs 23.3%; P <.001), as well as late grade 1 to 2 hyperpigmentation (21.8% vs 27.2%; P = .019). Grade 2 radiation pneumonitis occurred in 2.0% and 2.1% of patients in the HypoRT and ConvRT arms, respectively, and grade 2 pulmonary fibrosis occurred in 1.3% of each arm. Rates of lymphedema, rib fracture, shoulder dysfunction, and brachial plexus injury were comparable. In a dedicated analysis of 133 patients with breast reconstruction, HypoRT showed no increased risk of complications.

The investigators acknowledged several limitations, including the exclusion of patients who received neoadjuvant chemotherapy, the use of axillary lymph node dissection in all patients, the single-center design, and the lack of representation of patients with N3b or N3c disease. Event rates were also lower than expected, which prompted the independent data and safety monitoring committee to recommend the final analysis in 2025. The authors noted that longer follow-up is needed to assess late toxicities, particularly cardiac effects.

Reference

Wang X, Zhang X, Chen X, et al. Hypofractionated versus conventionally fractionated postmastectomy radiotherapy with internal mammary node irradiation for high-risk breast cancer (HypoMast-IMNI): a randomized phase III trial. J Clin Oncol. Published online October 19, 2026. doi:10.1200/JCO-25-02843