Why This Study Matters
Metastatic breast cancer has traditionally been treated with systemic therapy to delay progression and extend survival, with radiotherapy or surgery to metastases largely reserved for symptom relief. Improved imaging, radiation, and surgical techniques now allow focused ablation of a limited number of metastases, and phase II trials in other cancer types have reported improved progression-free survival when ablation is added to standard systemic therapy. Whether that benefit applies to oligometastatic breast cancer has been unclear.
The authors cite an international survey of 1007 radiation oncologists from 43 countries in which 83% were using stereotactic body radiation therapy (SBRT) for ablation of oligometastases by 2010, largely because of perceived response and durability and despite a lack of randomized evidence. The paper contrasts this practice with Fisher’s hypothesis of breast cancer as a systemic disease at diagnosis.
Study Design
NRG-BR002 is a randomized phase II/III trial run through the National Cancer Institute’s National Clinical Trials Network by NRG Oncology. Patients were randomly assigned 1:1, using centrally generated permuted-block randomization, to first-line systemic therapy alone (No-Ablation) or the same therapy plus ablation of all metastases with SBRT or surgical resection (Ablation). Treatment assignment was not masked. Stratification factors were number of metastases (1 vs. more than 1), hormone receptor status, HER2 status, and whether first-line chemotherapy had been started before study entry.
The randomized phase II portion was designed with 92% power to detect a hazard ratio of 0.55 for PFS (an improvement in median PFS from 10.5 to 19 months), using a 1-sided significance level of 0.15 and 69 PFS events. A favorable result would have triggered continuation to a phase III test of overall survival; an unfavorable one closed the trial.
SBRT was delivered in one, three, or five fractions depending on metastatic site and was completed within 21 days. Systemic therapy choice was left to the treating physician in both arms, with chemotherapy, bevacizumab and cetuximab held around ablation and resumed 14 days afterward.
Patient Population
Eligible patients had biopsy-proven oligometastatic breast cancer, either relapsed or de novo, with no more than 4 metastases (maximum diameter 5 cm or less) on standard imaging. They were intending to start or already on first-line systemic therapy for up to 12 months without progression, had a controlled primary tumor, and all metastases had to be amenable to SBRT or resection. Brain metastases and malignant pleural effusion were excluded.
129 patients randomized; 125 eligible for analysis (65 vs 60); 47 US and Canadian institutions; 1:1 open-label randomization; SBRT in 1, 3 or 5 fractions by site; 93% of ablation delivered by SBRT.
Median age was 54 years (IQR 46–63). Seventy-nine percent had hormone receptor–positive, HER2-negative disease, 60% had a solitary metastasis, 50% had bone involvement and 37% had bone-only disease. Relapsed disease accounted for 78% and de novo stage IV disease for 22%. Fifty-six patients (93%) in the Ablation arm received SBRT and one (2%), with a liver metastasis, underwent resection.
Primary Endpoint Results
The primary endpoint was progression-free survival, defined as time to progression or death. At the protocol-specified phase II go/no-go analysis (median follow-up 29.9 months, IQR 20.8–44.1), there were 72 PFS events (66 progressions and 6 deaths): 42 in the No-Ablation arm and 30 in the Ablation arm.
| Analysis | No-Ablation (n=65) | Ablation (n=60) | Hazard ratio, Ablation vs No-Ablation |
|---|---|---|---|
| Phase II primary analysis (72 events): median PFS | 23.0 mo (95% CI 15.1–34.0) | 19.5 mo (95% CI 11.9–36.6) | 0.92 (70% CI 0.71–1.17; 95% CI 0.57–1.47); 1-sided P = .36; stratified P = .42 |
| Phase II primary analysis: 2-year PFS | 45.7% (95% CI 32.8–58.5) | 46.8% (95% CI 32.5–61.1) | — |
| Extended follow-up, cutoff Sept 4, 2025 (81 events): median PFS | 23.0 mo | 29.5 mo | 0.93 (70% CI 0.74–1.18; 95% CI 0.60–1.44); 1-sided P = .38; stratified P = .52 |
| Extended follow-up: 4-year PFS | 26.8% (95% CI 15.4–38.3) | 33.8% (95% CI 20.6–46.9) | — |
The extended-follow-up analysis was not protocol-specified. Median follow-up was 57.5 months (IQR 25.5–77.4); 43 PFS events occurred in the No-Ablation arm and 38 in the Ablation arm.
Because the PFS result showed no signal of improvement, the trial did not continue to phase III and was permanently closed to accrual. In the Ablation arm, 40 of 60 patients (67%) were controlled and 20 of 60 (33%) progressed within the ablated area; 10 of the 40 controlled within the ablated area progressed elsewhere and so were still PFS failures. The extended analysis again showed no difference in the development of new metastases between arms.
Overall Survival
Overall survival, the planned phase III primary endpoint, was reported as a secondary analysis. The abstract reports HR 1.07 (95% CI, 0.60–1.89; 1-sided P = .41; stratified P = .52). With extended follow-up there were 56 deaths (31 in the No-Ablation arm and 25 in the Ablation arm), with HR 0.94 (95% CI 0.56–1.60). Two-year OS was 88.4% (95% CI 80.2–96.5) without ablation and 78.5% (95% CI 67.6–89.3) with ablation; four-year OS was 63.4% (95% CI 51.2–75.5) versus 59.7% (95% CI 46.6–72.7).
Ablation should not be routinely used outside of clinical trials, except for palliation.
— Conclusion of the abstract, J Clin Oncol 2026 (NRG-BR002)
Subgroup Analyses
Post hoc exploratory analyses of treatment effect on PFS were performed by number of metastases, hormone receptor status, HER2 status, first-line therapy started before study entry, age, performance status, metastatic timing and tumor subtype. The paper states that the effect of ablation by most variables was consistent with the overall effect. The subgroup-level hazard ratios are displayed in the paper’s Figure 2 and are not given numerically in the text, so they are not reproduced here. The authors note that the number of patients in each subset is small and limits conclusions.
| Exploratory analysis | Result reported in the text |
|---|---|
| CTCs as a prognostic marker for PFS (overall population) | CellSearch: HR 1.07, 95% CI 0.57–1.98, P = .84. HDSCA: HR 0.83, 95% CI 0.41–1.68, P = .61. Not prognostic with either method. |
| HDSCA CTC count below the first quartile (treatment interaction) | Better PFS with ablation; counts at or above the first quartile did not benefit. Interaction P = .029. |
| No pretreatment CellSearch CTCs (treatment interaction) | Improved PFS with ablation. Interaction P = .03. |
| Other prespecified-covariate subgroups (stratification factors, age, performance status, timing, subtype) | Not specified numerically in the text (Figure 2 only) |
Of 108 patients who consented to blood collection, 62 (57%) had pretreatment CellSearch CTCs and 60 (56%) had pretreatment HDSCA CTCs.
Safety Profile
Treatment was reported as generally well tolerated, with no study-related deaths (no grade 5 toxicity).
| Toxicity (CTCAE v4.0) | No-Ablation | Ablation |
|---|---|---|
| Grade 5 | None | None |
| Grade 4 | 1 patient (2%) | None |
| Grade 3 | 7 patients | 3 patients (5%) |
Per-event toxicity breakdowns are in the paper’s Supplement (eTable 5) and are not reproduced here. SBRT radiation plan compliance: 96% (n=54) of cases were delivered per protocol or with acceptable variation on central review.
Interpretation and Broader Context
The authors conclude that metastasis-directed ablation with SBRT or surgery should not be routinely used with first-line systemic therapy for oligometastatic breast cancer, and that its use should be reserved for palliation of symptoms or clinical trials. They observed that ablation did not prevent the emergence of new metastases, which any local therapy would need to do in order to affect PFS or survival.
The results differ from SABR-COMET, a randomized phase II trial of 99 patients with multiple cancer types that showed reduced progression with ablation and improved overall survival; only 17 of its patients had breast cancer. The authors note NRG-BR002 was larger for this question (n=125), studied only breast cancer, required first-line systemic therapy and stratified by subtype. They also cite EXTEND, a smaller trial that reported similar results in its breast cancer subset. Both arms showed longer-than-expected median PFS and OS, which the authors interpret as supporting a more indolent disease course in oligometastatic breast cancer.
Limitations Noted by the Authors
Most patients had hormone receptor–positive, HER2-negative disease, limiting generalization to triple-negative and HER2-positive populations; relapsed cases outnumbered de novo cases (78% vs 22%); subset analyses were small; and systemic therapy before and after enrollment, and time off systemic therapy for ablation, were not controlled. The authors also note that late toxicity of ablation may emerge years after ablation and that cost is a consideration. The extended-follow-up analysis was not protocol-specified, the subgroup and CTC analyses were post hoc and exploratory, and treatment assignment was not masked.
What Comes Next
The authors call for research into the biology of oligometastatic breast cancer and for biomarkers, noting that minimal residual disease assays such as HDSCA-CTCs and ctDNA might improve patient selection in future trials. Trials of metastasis-directed therapy in de novo HER2-positive oligometastatic disease are ongoing: SWOG S2511 (NCT07578116) and TRCBC ARCHER (NCT07053085).