Ten-year survival after postmastectomy chest-wall irradiation in breast cancer - The SUPREMO Trial

Authors: Kunkler IH, Russell NS, Anderson N, et al.

Journal: New England Journal of Medicine, November 6, 2025

Trial: SUPREMO randomized phase 3

Key takeaways

• In intermediate-risk post-mastectomy patients (pT1–2N1; pT3N0; or pT2N0 with grade 3 and/or lymphovascular invasion), chest-wall RT did not improve 10-year overall survival vs no RT (81.4% vs 81.9%; HR 1.04, 95% CI 0.82–1.30).

• RT halved chest-wall recurrences (HR 0.45, 95% CI 0.20–0.99) but the absolute reduction was <2% over 10 years (1.1% vs 2.5%).

• No differences in disease-free or distant metastasis–free survival (10-yr DFS 76.2% vs 75.5%; DMFS 78.2% vs 79.2%).

• In a triple-negative subgroup, overall survival was worse with RT (HR 1.91, 95% CI 1.06–3.46).

Background

Whether to irradiate the chest wall after mastectomy for intermediate-risk disease (pT1–2N1; pT3N0; or pT2N0 with grade 3 and/or lymphovascular invasion) is controversial in the modern systemic therapy era.

Objective

Test whether omitting chest-wall RT compromises overall survival at 10 years in intermediate-risk patients treated with contemporary multimodality therapy.

Methods

• Design/setting: International, randomized, phase 3 trial; chest-wall RT (40–50 Gy) versus no chest-wall RT. Primary endpoint: overall survival (OS). Secondary: chest-wall/locoregional recurrence, DFS, DMFS, safety. Median follow-up 9.6 years.

• Population: 1607 randomized; ITT: 808 RT, 799 no RT; intermediate-risk post-mastectomy; high uptake of chemotherapy (~85%) and endocrine therapy (~79%); trastuzumab ~20%.

Results

• Overall survival (primary): 10-yr OS 81.4% (RT) vs 81.9% (no RT); HR 1.04 (P=0.80).

• Chest-wall recurrence: 1.1% vs 2.5%; HR 0.45 (95% CI 0.20–0.99). Absolute benefit <2%.

• Locoregional recurrence: 2.7% vs 4.5%; HR 0.61 (95% CI 0.36–1.03).

• Distant metastasis–free survival: 78.2% vs 79.2%; HR 1.06 (95% CI 0.86–1.31). Disease-free survival: 76.2% vs 75.5%; HR 0.97 (95% CI 0.79–1.18).

• Subgroups: No OS interaction by nodal status or age; triple-negative patients had worse OS with RT (HR 1.91, 95% CI 1.06–3.46).

• Safety: Overall toxicities were low; pulmonary events were uncommon but numerically higher with RT (e.g., grade ≥2 lung events 13 vs 5). Cardiac deaths ≤1% in both groups.

Conclusion

In intermediate-risk patients after mastectomy receiving modern systemic therapy, routine chest-wall RT did not improve 10-year OS, while offering a small absolute reduction in chest-wall recurrences.

Strengths & limitations

• Strengths: Large, international RCT with long follow-up and high systemic-therapy adherence; robust RT quality assurance.

• Limitations: Initiated nearly two decades ago; evolving axillary and neoadjuvant practices; event rates lower than anticipated, limiting power for small effects.

Clinical relevance

• For pT1–2N1 or selected pN0 with high-risk features after mastectomy, these data support considering omission of chest-wall RT when regional nodal RT is not otherwise indicated, given no OS/DMFS benefit and very low baseline chest-wall failure.

• Be cautious in triple-negative disease: the signal for worse OS with RT warrants multidisciplinary discussion and alignment with emerging de-escalation trials.

• When nodal irradiation is needed, modern planning can treat nodes while avoiding the chest wall/reconstruction, aligning with reconstructive goals and minimizing late effects.

Commentary

SUPREMO reflects today’s reality: excellent systemic therapy drives very low chest-wall recurrence, shrinking the marginal value of routine chest-wall RT in intermediate-risk patients. The absolute gain (<2%) in local control is unlikely to translate into survival, and late-effect avoidance (cardiac, pulmonary, reconstructive outcomes) is a compelling reason to individualize and, in many cases, omit chest-wall RT.