Abstract
Purpose:
Metastasis-directed therapy is increasingly used for oligometastatic breast cancer, despite its uncertain benefit during first-line systemic therapy. We evaluated whether metastasis-directed ablation improves progression-free survival (PFS) compared with first-line systemic therapy alone in patients with oligometastatic breast cancer.
Patients and Methods:
NRG-BR002 is a randomized phase II/III trial across US/Canadian institutions. Participants had ≤4 metastases, controlled primary disease, ≤12 months of first-line systemic therapy without progression with all visible metastases amenable to stereotactic body radiation therapy(SBRT) or surgical resection and were randomized 1:1 to systemic therapy alone(No-Ablation) or with metastasis-directed ablation(Ablation). The primary endpoint was PFS, defined as time to progression or death. Secondary endpoints included overall survival(OS) and toxicity. Circulating tumor cells(CTCs) were evaluated as exploratory biomarkers.
Results:
From December 2014-September 2019, 129 patients were enrolled; 125 eligible for analysis. Median age was 54 years; 79% hormone receptor–positive, HER2-negative disease, 60% solitary metastasis, 50% had bone involvement, 37% bone only. Ablation was delivered via SBRT for 93%. With 72 PFS events and median follow-up of 29.9 months, median PFS was 23.0 months(No-Ablation) vs 19.5 months(Ablation) (hazard ratio [HR] 0.92; 70% CI, 0.71–1.17; 95% CI, 0.57–1.47); 1-sided p=0.36; stratified p=0.42). Thus, the trial did not proceed to Phase III. OS did not differ significantly between arms (HR 1.07; 95% CI, 0.60–1.89; 1-sided p=0.41; stratified p=0.52). No grade 5 toxicities occurred. Exploratory analysis suggested improved PFS with ablation in patients with low or absent pretreatment CTCs.
Conclusions:
The addition of metastasis-directed ablation added to first-line systemic therapy did not improve PFS or OS in patients with oligometastatic breast cancer. Ablation should not be routinely used outside of clinical trials, except for palliation.
Trial Registration:
ClinicalTrials.gov Identifier: NCT02364557
INTRODUCTION
Metastatic breast cancer has traditionally been managed with systemic therapy to delay disease progression and extend survival, with metastasis-directed therapy with radiotherapy or surgery reserved for symptom relief. However, recent advancements suggest that elimination of all metastases when there is a limited number, i.e. oligometastatic, could offer curative potential1. Improved imaging, radiation, and surgical techniques enable focused ablative treatment of limited metastases in most anatomical locations2. Phase II trials across various cancer types have demonstrated improved progression-free survival (PFS) adding metastasis ablation to standard systemic therapy3, yet the benefit of this approach in oligometastatic breast cancer remains unclear4.
The integration of metastasis ablation into standard regimens for patients with limited metastases is appealing to clinicians to intensify treatment of known metastases, and potentially to prolong disease control with minimal acute side effects by preventing seeding of new metastases5. An international survey of 1007 radiation oncologists from 43 countries demonstrated that by 2010 83% were using stereotactic body radiation (SBRT) for ablation of oligometastases largely due to perceived treatment response/durability despite lack of randomized evidence6. However, this contrasts Fisher’s hypothesis of breast cancer as a systemic disease at time of diagnosis requiring systemic treatment rather than simply eliminating gross disease7. Additionally, rapid advances in systemic therapies for metastatic breast cancer have allowed prolonged freedom from progression and challenged the concept of metastasis ablation providing additional benefit.
We hypothesized that by ablating all oligometastases, in addition to standard first-line systemic therapy, new metastatic occurrences would be reduced, improving PFS and ultimately overall survival (OS). Therefore, we conducted the National Cancer Institute (NCI), National Clinical Trial Network (NCTN) NRG Oncology-BR002 randomized phase II/III study evaluating metastasis-directed ablation in patients receiving first-line systemic therapy for oligometastatic breast cancer.
METHODS
Patients:
Eligible patients were diagnosed up to 12 months prior to enrollment with biopsy-proven oligometastatic breast cancer (either relapsed or de novo), defined as ≤4 metastases (maximum diameter ≤5 cm) seen on standard imaging, that were intending to or already on first-line standard systemic therapy (chemotherapy, anti-endocrine therapy, anti-HER2, or other biologic therapy), without progression on imaging. Known breast cancer estrogen and progesterone receptor (hormone receptor), HER2 status, patient age ≥18 years, Zubrod Performance status ≤2, and a controlled primary tumor were required. All metastases were required to be amenable to ablation with either SBRT or resection. Patients with brain metastases or malignant pleural effusion were excluded.
Trial Design and Treatment:
Patients were randomly assigned 1:1 to receive first line systemic therapy (No-Ablation) or the same plus ablative treatment with either SBRT or surgical resection (Ablation) to all metastases (Figure S1), using a permuted block randomization centrally generated at the NRG Oncology Statistics and Data Management Center (Philadelphia, PA) and provided to the institution following randomization. Treatment assignment was not masked and block size was not known by enrolling sites. Stratification was by number of metastases [1 vs. >1], estrogen, progesterone hormone receptor status [positive vs. negative], HER2 status [positive vs. negative], and first-line systemic chemotherapy initiated prior to study entry [yes vs. no]. Patients were seen every 3 months after randomization for 2 years, and every 6 months thereafter, with regular imaging for progression surveillance. The phase II results for this prospective, randomized, phase II/III trial are reported according to CONSORT requirements for randomized clinical trials. The protocol was reviewed by NRG’s Patient Advocate Committee and has IRB approval. All participation was voluntary with written informed consent.
Metastasis Directed Therapy
Radiation Therapy: Metastasis-directed ablative SBRT was delivered within 6 weeks of study entry in one, three, or five fractions depending on metastatic site and avoidance of adjacent normal tissue consistent with previously described methods on NRG Oncology BR001 trial5. Protocol-specified radiation doses (Supplement eTables 1,2) were derived from phase II data for single metastases or by expert consensus. Modern radiotherapy techniques that had been established by NRG-BR001 were required8. All patients underwent computed tomography (CT)-based radiation treatment planning using customized immobilization devices. Metastases with a potential for respiratory-induced tumor motion were required to be evaluated with 4-dimensional CT, implanted fiducial marker, or fluoroscopy during radiation simulation. Tumors with respiratory motion greater than 1 cm were required to have respiratory motion management. Radiation was completed within 21 days. All institutions were required to be credentialed for the protocol and underwent real time review of the first patient at each anatomic location. Subsequent cases were reviewed after treatment completion (Supplement eMethods 1).
Surgery: Surgical resection to negative margins (R0) was deemed appropriate for liver, lung, adrenal, bone, bowel, ovarian, and nodal metastases with techniques at the discretion of the treating surgeon and central surgical review (Supplement eMethods 1).
Systemic therapy: Systemic therapy choice for both arms was per treating physician and recommended to adhere to standard guidelines for first-line therapy for metastatic breast cancer. In the Ablation arm, antiestrogen, antiandrogen, and anti-HER2 therapies were allowed concurrently during SBRT. Bevacizumab, cetuximab, and systemic cytotoxic chemotherapies were held and could resume 14 days after ablation.
Translational Methods:
Among patients consenting to optional procedures, circulating tumor cells (CTCs) were analyzed prospectively using two methods: CellSearch (CSCTCs) kit and assay, and High-Definition Single Cell Assay (HDSCA) workflow (Supplement eMethods 2)9,10. The total cytokeratin+ counts/ml variable was used per the pre-specified analysis. Additional method details and variables acquired during the HDSCA workflow are described in supplemental documents (Supplement eMethods 2).
OUTCOMES and STATISTICAL ANALYSES
Metastases response and progression were evaluated using the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1)11. The randomized phase 2 (phaseIIR) study was designed with 92% power to test the primary endpoint hypothesis that ablative therapy would reduce PFS failure (progression or death) by a relative 45% for an effect size hazard ratio (HR) of 0.55 (experimental/control), corresponding to an improved median PFS from 10.5 to 19 months; warranting continuation to an integrated phase III trial to test OS improvement. With these assumptions, 116 patients would provide the required 69 PFS events using a log-rank test with a 1-sided significance level of 0.15. Allowing for ineligible/lost patients, the sample size was 128. PFS was estimated by the Kaplan-Meier method12 and distributions between treatment arms were compared using the log-rank test13. If the HR (λAblation/λ No-Ablation) was < 1 when the phase II accrual completed, enrollment would continue; otherwise, accrual would be suspended until a decision is made based on the full phase II go/no-go analysis. If the final phase IIR results met targeted PFS improvement, interpreted as a “Go Signal,” then full accrual of the phase III portion of the trial would proceed, and reporting of the phase II PFS results held. If PFS improvement was not met (i.e., a “No-Go Signal”), the trial would permanently close to accrual and PFS results reported. If continued to phase III, a total of 324 evaluable patients would provide the 231 OS events to determine if ablative therapy improves OS at an effect size of HR=0.67, corresponding to an increase in 5-year OS from 28% to 42.5%, with 85% power using a log-rank test at a 1-sided significance level of 0.025.
Overall Survival, the planned phase III primary endpoint, is also reported, estimated by Kaplan-Meier, and compared between arms with log-rank test (1-sided alpha=0.025). The Cox proportional hazard regression model was used for PFS/OS13. For PFS, post-hoc exploratory treatment effect subgroup analyses were performed for the following covariates: number of metastases, hormone receptor status, HER2 status, first-line systemic therapy initiated prior to study entry, age, Zubrod performance status, metastatic timing, and tumor subtype. Post-hoc Cox regression analyses were used to explore interactions between treatment and a given covariate and to estimate subgroup level treatment effect for hypothesis generating purposes. The efficacy analysis population includes all eligible patients. Toxicity was assessed using NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. The toxicity analysis population includes eligible patients that started protocol treatment. All analyses were done with patients grouped by randomized treatment.
To assess potential prognostic and/or predictive effects of pretreatment CTCs on PFS, Cox model analyses were carried out on the lab results from both the CellSearch and HDSCA methodologies for eligible patients with available specimens. Further analysis details are in Supplement eMethods 3.
RESULTS
The trial (Supplement eFigure 1) was activated on December 24, 2014, and the phase II portion finished accrual on September 13, 2019, with 129 patients randomized from 47 institutions across the United States and Canada. Of these, 125 participants met eligibility fully (Supplement eFigure 2).
Patient Entry and Treatment Characteristics:
Patient variables were balanced between treatment arms (Table 1). The median patient age was 54 years (IQR: 46–63). Patients were predominantly White (77%), and Zubrod performance status was 0 in 66%. Most patients had hormone receptor positive and HER2 negative disease (79%), 60% had solitary metastasis, 50% had bone involvement, 37% with bone only. Relapsed metastatic breast cancer accounted for 78%; the other 22% presented initially with stage 4 (de novo) disease.
Table 1.
Baseline Patient and Tumor Characteristics*
| Characteristic | No-Ablation (n=65) |
Ablation (n=60) |
Total (n=125) |
|---|---|---|---|
| Median age (IQR) --- year | 53 (45–63) | 55.5 (46–64.5) | 54 (46–63) |
| Race --- no. (%) | |||
| White | 51 (78) | 45 (75) | 96 (77) |
| Black or African American | 5 (8) | 3 (5) | 8 (6) |
| Asian | 2 (3) | 5 (8) | 7 (6) |
| Other/Unknown | 7 (11) | 7 (12) | 14 (11) |
| Hispanic or Latino --- no. (%) | 10 (15) | 6 (10) | 16 (13) |
| Zubrod Performance Status --- no. (%) | |||
| 0 | 41 (63) | 41 (68) | 82 (66) |
| 1 | 24 (37) | 19 (32) | 43 (34) |
| Metastasis Per Patient --- no. (%) | |||
| 1 | 39 (60) | 36 (60) | 75 (60) |
| >1 | 26 (40) | 24 (40) | 50 (40) |
| 2 | 20 | 16 | 36 |
| 3 | 4 | 5 | 9 |
| 4 | 2 | 3 | 5 |
| First-line standard systemic chemotherapy initiated prior to study entry--- no. (%) | |||
| Yes | 46 (71) | 44 (73) | 90 (72) |
| No | 19 (29) | 16 (27) | 35 (28) |
| First-line standard systemic therapy initiated prior to study entry --- no. (%) | |||
| Yes | 56 (86) | 52 (87) | 108 (86) |
| No | 9 (14) | 8 (13) | 17 (14) |
| Tumor subtype --- no. (%) | |||
| ER and PR-; HER2- | 5 (8) | 5 (8) | 10 (8) |
| ER and/or PR+; HER2- | 52 (80) | 47 (78) | 99 (79) |
| ER and PR-; HER2+ | 2 (3) | 1 (2) | 3 (2) |
| ER and/or PR+; HER2+ | 6 (9) | 7 (12) | 13 (10) |
| Metastatic timing --- no. (%) | |||
| Synchronous | 12 (18) | 15 (25) | 27 (22) |
| Relapsed | 52 (80) | 45 (75) | 97 (78) |
| Unknown | 1 (2) | 0 (0) | 1 (1) |
| Site of MetastasesA | |||
| Bone/Osseous | 27 (42) | 35 (58) | 62 (50) |
| Spinal/Paraspinal | 20 (31) | 19 (32) | 39 (31) |
| Mediastinal/Cervical | 7 (11) | 5 (8) | 12 (10) |
| Peripheral Lung | 5 (8) | 7 (12) | 12 (10) |
| Liver | 5 (8) | 4 (7) | 9 (7) |
| Abdominal-pelvic | 3 (5) | 1 (2) | 4 (3) |
| Central Lung | 4 (6) | 0 | 4 (3) |
| UnknownB | 1 (2) | 1 (2) | 2 (2) |
Percentages may not total to 100 because of rounding. IQR denotes interquartile range.
Patients can count in more than one metastatic site.
Patient withdrew the same day or immediately after randomization.
Fifty-six (93%) patients on the Ablation arm received SBRT and one (2%) patient with liver metastasis underwent resection. When SBRT was delivered, it was to one metastasis for 36 patients (64%), two metastases for 14 (25%), three or four metastases in six (11%) (Supplement eTable 3) and was delivered per protocol/acceptable variation on central radiation QA review in 96% of cases (n=54) (Supplement eTable 4). All protocol treated patients received the intervention to which they were randomized.
Efficacy Analyses:
Per the rules for the protocol-specified PFS futility analysis at phase II accrual completion, as the PFS HR from this analysis was not < 1, accrual was temporarily suspended pending the results of the phase II go/no-go analysis.
At the phase II go/no-go analysis, with a median [IQR] follow up of 29.9 months (20.8–44.1), there were 72 PFS events (66 progression and 6 deaths): 42 in the No-Ablation arm and 30 in the Ablation arm. Median (70% CI; 95% CI) and 2-year (70% CI; 95% CI) PFS estimates were 23.0 months (18.0–29.2; 15.1–34.0) and 45.7% (38.9–52.5; 32.8–58.5) in No-Ablation arm and 19.5 months (17.0–35.6; 11.9–36.6) and 46.8% (39.2–54.3; 32.5–61.1) in the Ablation arm (Table 2, HR 0.92, 70% CI 0.71–1.17, 95% CI 0.57–1.47, 1-sided log-rank test p=0.36; stratified p=0.42). For the Ablation arm, based on these results, 40/60 (67%) were controlled and 20/60 (33%) progressed within the ablated area, respectively. However, 10 of the 40 that were controlled within the ablated area progressed outside of the ablated area and are therefore still PFS failures. Since adding metastasis-directed ablation to first-line systemic therapy did not show a signal for improved PFS for patients with oligometastatic breast cancer, the trial did not continue to the phase III and was therefore permanently closed to accrual. At that time, the 2-year OS estimates (95% CI) were: 88.4% (80.2, 96.5) for the No-Ablation arm and 78.0% (66.9, 89.0) for the Ablation arm.
Table 2:
Progression-free survival of the intention-to-treat population
|
|
No-Ablation | Ablation | Total | |
|---|---|---|---|---|
| Protocol-specified analysis (data cutoff September 9, 2019) - Testing at the completion of phase II accrual for decision on temporary accrual suspension or not | ||||
| (n=65) | (n=59) | (n=124) | ||
| Hazard ratioA (Ablation/No-Ablation) (95% CI) | 1.35 (0.69, 2.62) | |||
| Phase II primary endpoint analysis (data cutoff December 20, 2021) | ||||
| Status, n | (n=65) | (n=60) | (n=125) | |
| Event | 42 | 30 | 72 | |
| Censored | 23 | 30 | 53 | |
| Median PFS (months) | (70% CI) | 23.0 (18.0–29.2) | 19.5 (17.0–35.6) | |
| (95% CI) | (15.1–34.0) | (11.9–36.6) | ||
| 24-Month PFS rate | (70% CI) | 45.7% (38.9%, 52.5%) | 46.8% (39.2%, 54.3%) | |
| (95% CI) | (32.8%−58.5%) | (32.5%−61.1%) | ||
| Log-rank p-value (1-sided) | 0.36 | |||
| Stratified log-rank p-value (1-sided) | 0.42 | |||
| Hazard ratioA (Ablation/No-Ablation) | (70% CI) | 0.92 (0.71, 1.17) | ||
| (95% CI) | (0.57, 1.47) | |||
| Extended follow-up (non-protocol-specified) analysis (data cutoff September 4, 2025) | ||||
| Status, n | (n=65) | (n=60) | (n=125) | |
| Event | 43 | 38 | 81 | |
| Censored | 22 | 22 | 44 | |
| Median PFS (months) | (70% CI) | 23.0 (17.3–26.0) | 29.5 (17.2–36.6) | |
| (95% CI) | (15.1–34.3) | (13.2–45.5) | ||
| 24-Month PFS rate | (70% CI) | 44.7% (38.0%−51.4% | 50.5% (43.5%−57.6%) | |
| (95% CI) | (32.1%−57.4%) | (37.2%−63.9%) | ||
| Log-rank p-value (1-sided) | 0.38 | |||
| Stratified log-rank p-value (1-sided) | 0.52 | |||
| Hazard ratioA (Ablation/No-Ablation) | (70% CI) | 0.93 (0.74–1.18) | ||
| (95% CI) | (0.60–1.44) | |||
CI, confidence interval.
Hazard ratio was estimated by Cox proportional hazards model; exact method was used to handle ties.
With extended follow-up, September 4, 2025 data cutoff, at a median follow-up of 57.5 months (IQR 25.5–77.4), there were 81 PFS events: 43 in the No-Ablation arm and 38 in the Ablation arm. The 2- and 4-year PFS estimates (70% CI; 95% CI) were 44.7% (38.0–51.4; 32.1, 57.4) and 26.8% (20.8–32.9; 15.4–38.3) for the No-Ablation arm and 50.5% (43.5–57.6; 37.2–63.9) and 33.8% (26.8–40.7; 20.6–46.9) for the Ablation arm (Figure 1). Median PFS was 23.0 months (70% CI 17.3–26.0; 95% CI 15.1–34.3) and 29.5 months (70% CI 17.2–36.6; 95% CI 11.9–42.1), respectively, in the No-Ablation versus Ablation arms (HR 0.93; 70% CI: 0.74–1.18; 95% CI: 0.60–1.44) (Table 2). With the extended follow-up, there remained no statistically significant differences in PFS with the addition of ablation to systemic therapy (1-sided log-rank test p=0.38; stratified p=0.52). A post-hoc analysis of treatment effect on PFS by subgroups that included stratification factors and variables of interest was performed (Figure 2). The effect of ablation by most variables was consistent with the overall ablation effect. OS by treatment arm is shown in Figure 3. There were 56 deaths, 31 and 25 on the No-Ablation and Ablation arms, respectively (HR 0.94, 95% CI 0.56–1.60, 1-sided log-rank test p=0.41; stratified p=0.52). The 2- and 4-year OS estimates (95% CI) were: 88.4% (80.2–96.5) and 63.4% (51.2–75.5) for the No-Ablation arm and 78.5% (67.6–89.3) and 59.7% (46.6–72.7) for the Ablation arm, respectively.
Figure 1: Progression-Free Survival.
Abbreviations: MST, median survival time; HR, hazard ratio; RL, reference level; CI, confidence interval
Figure 2: Subgroup Analysis of Progression-Free Survival.
The reference lines are at 1 (null) and 0.55 (alternative).
For 2-yr estimates = “.”, all patients either failed or were censored prior to 2 years as follows:
a n=6 (5 failed, 1 censored); b n=8 (7 failed, 1 censored); c n=5 (4 failed, 1 censored); d n=1 (0 failed, 1 censored)
Abbreviations: ER, estrogen; PR, progesterone; CTC, circulating tumor cell; Q1, first quartile; yr, year
Figure 3: Overall Survival.
Abbreviations: #, number; RL, reference level; CI, confidence interval
Toxicity:
Treatment was generally well tolerated. There were no study-related deaths (grade 5 toxicity). In the No-Ablation arm, grade 4 toxicity was reported in one patient (2%) and grade 3 toxicities in seven. In the Ablation arm, no grade 4 toxicities were reported, and grade 3 (5%) toxicities were reported in three patients (Supplement eTable 5).
Translational Endpoints with CTCs:
Of the 108 patients who consented to blood collection, 62 (57%) patients had pretreatment CellSearch CTCs and 60 (56%) patients had pretreatment HDSCA CTCs (Supplement eFigure 2). CTCs were not prognostic for PFS in the overall population using either laboratory method (CellSearch: HR 1.07, 95% CI 0.57–1.98, p=0.84; HDSCA: HR 0.83, 95% CI 0.41–1.68, p=0.61). However, the results indicated that absent or very low pretreatment CTC levels were predictive of improved PFS with ablation: patients with pretreatment HDSCA CTC counts below the first quartile (Q1) experienced better PFS when treated with ablation, whereas those with counts at or above Q1 did not (Figure 2, interaction p=0.029). Similarly, patients with no pretreatment CellSearch CTCs showed improved PFS with ablation (Figure 2, interaction p=0.03).
DISCUSSION
The NRG-BR002 trial assessed the impact of metastasis-directed ablative therapy on progression-free (PFS) and overall survival (OS) in patients with oligometastatic breast cancer on first-line systemic therapy. Although metastasis ablation was safely administered to up to four metastases, it did not improve PFS or OS. Additionally, metastasis-directed ablative therapy did not prevent the emergence of new metastases, which is necessary for any local therapy to impact PFS or survival.
Our trial findings significantly differ from the previously reported SABR-COMET trial15, a randomized phase II trial of 99 patients with multiple cancer histologies that demonstrated reduced progression with ablation and improved OS at initial analysis (30-month median) and with extended follow up (51 months). In contrast to SABR-COMET, which included only 17 patients with breast cancer, our trial was better poised to address this clinical practice question for oligometastatic breast cancer as it was larger (n=125), exclusively studied breast cancer, required first-line systemic therapy use, and stratified by key variables including biologic breast cancer subtype. Since SABR-COMET reported that the impact of SABR on OS was larger in magnitude with extended follow up14 than in the initial analysis and because the NRG-BR002 population was predominantly ER-positive/HER2-negative with an inherently longer expected time to progression, we added an analysis after an extended follow-up of 57.5 months. This updated analysis again demonstrated no difference in the development of new metastases between treatment arms. Another smaller trial, EXTEND, reported similar results to NRG-BR002; metastasis-directed therapy did not improve PFS in the breast cancer subset15.
These findings support that metastasis-specific ablation with SBRT does not improve PFS or OS for oligometastatic breast cancer on first-line systemic therapy. Our trial revealed longer than expected median PFS and OS in both arms, supporting the hypothesis that patients with oligometastatic breast cancer have a more indolent disease course17. Further research to identify the underlying biology of oligometastatic breast cancer and potential biomarkers is merited. Our prospective evaluation of the presence of CTCs suggests minimal residual disease, such as analyzed with HDSCA-CTCs, is a potential means for improved patient selection for metastasis-directed ablation in oligometastatic breast cancer that could lead to improved PFS and OS outcomes. Assays for minimal residual disease including ctDNA are improving and future trials are warranted for ablation of oligometastatic breast cancer in the absence of CTC/ctDNA.
In the SABR-COMET trial, the metastasis-directed ablation arm was associated with three treatment-related grade 5 (fatal) events (4.5%), whereas in our trial, no grade 4 or 5 ablation-associated toxicities were observed3. However, as new systemic therapies for metastatic breast cancer continue to improve PFS and OS, it remains important for future metastasis-directed ablation trials to rigorously assess late effects, as these may emerge years after ablation and could negatively impact quality of life5.
The findings from NRG-BR002 have broader implications beyond clinical decision-making. The absence of PFS or OS benefit with metastasis-directed ablation underscores the need for judicious use of technologies such as SBRT outside of clinical trials until efficacy can be demonstrated. While the treatment was generally safe, the potential for late toxicity and the substantial costs associated with ablative procedures raise concerns about value-based care. In an era of increasing emphasis on cost-effectiveness, these results suggest that routine use of metastasis-directed therapy in this setting may not be justified. This has direct relevance for payers and insurance providers, who must consider evidence-based criteria for coverage decisions. Future reimbursement policies and clinical guidelines should reflect the importance of high-level evidence in determining which therapies merit widespread adoption.
This study has several limitations. Firstly, most enrolled patients had hormone receptor positive, HER2-negative disease limiting the generalization of findings to triple negative breast cancer and HER2-positive populations. Secondly, our trial had more relapsed (78%) versus de novo (22%) first-line oligometastatic cases, as is seen in practice16.
Although the analysis indicated no differences in outcomes by metastatic presentation, these may represent two distinct states that warrant separate investigation16. Clinical trials for metastases-directed therapy for de novo HER2-positive oligometastatic disease are ongoing SWOG S2511(NCT07578116)17, and TRCBC ARCHER(NCT07053085)18.
While NRG-BR002 is the largest trial of metastasis directed ablation for first line treatment of oligometastatic breast cancer, the number of patients in subset analysis is small limiting conclusions by specific variables. Finally, neither the systemic therapy administered to patients before or after enrollment, nor time off systemic therapy to complete the ablation, was controlled. While systemic therapy use was balanced between arms, potential interactions between treatment arms with newer agents could exist.
For now, metastasis-directed ablation with SBRT or surgery with its attendant potential for patient toxicity as well increased health care costs should not be routinely used with first-line systemic therapy for treatment of oligometastatic breast cancer. The use of metastases-directed therapy should be reserved for palliation of symptoms when needed or performed on clinical trials.
Supplementary Material
Context Summary.
Key Objective:
To determine whether adding metastasis-directed ablation to first-line systemic therapy improves progression-free or overall survival in patients with oligometastatic breast cancer.
Knowledge Generated:
In this randomized phase II trial of 125 patients, metastasis-directed ablation did not improve progression-free or overall survival. SBRT should not be routinely added to first-line therapy for asymptomatic oligometastatic breast cancer outside clinical trials; and reserved for palliation when warranted.
ACKNOWLEDGEMENTS
Dr. Steven J Chmura and NRG Oncology would like to thank the following accrual institutions who have been part of our mission to improve the lives of patients with cancer by conducting practices changing multi-institutional clinical and translational research.
Allegheny General Hospital
Ascension Via Christi Hospitals Wichita
Carle Cancer Center
Case Western Reserve University
CHUM - Centre Hospitalier de l’Universite de Montreal
Cross Cancer Institute
Emory Saint Joseph’s Hospital
Emory University Hospital/Winship Cancer Institute
Helen F Graham Cancer Center
Inova Fairfax Hospital
Jewish General Hospital
Kaiser Permanente Cancer Treatment Center
King Faisal Specialist Hospital and Research Centre
Lahey Hospital and Medical Center
Legacy Good Samaritan Hospital and Medical Center
Los Angeles County-USC Medical Center
Loyola University Medical Center
M D Anderson Cancer Center
Mayo Clinic
Mayo Clinic in Florida
Medical College of Wisconsin
Memorial Regional Hospital/Joe DiMaggio Children’s Hospital
Northwestern University
Ohio State University Comprehensive Cancer Center
Orlando Health Cancer Institute
Rush University Medical Center
The Permanente Medical Group-Roseville Radiation Oncology
Tom Baker Cancer Centre
UC Irvine Health/Chao Family Comprehensive Cancer Center
UM Upper Chesapeake Medical Center
University of Alabama at Birmingham Cancer Center
University of Chicago Comprehensive Cancer Center
University of Colorado Hospital
University of Maryland/Greenebaum Cancer Center
University of Michigan Comprehensive Cancer Center
University of New Mexico Cancer Center
University of Oklahoma Health Sciences Center
University of Rochester
UPMC Pinnacle Cancer Center/Community Osteopathic Campus
USC / Norris Comprehensive Cancer Center
UT Southwestern/Simmons Cancer Center-Dallas
Wake Forest University Health Sciences
Washington University School of Medicine
Wentworth-Douglass Hospital
West Virginia University Healthcare
William Beaumont Hospital-Royal Oak
Yonsei University Health System-Severance Hospital
FUNDING STATEMENT
Research reported in this publication was supported by the National Cancer Institute of the National Institutes of Health under Award Number U10CA180868 (NRG Oncology Operations), U10CA180822 (NRG Oncology SDMC), UG1CA189867 (NCORP), U24CA180803 (IROC) from the National Cancer Institute (NCI) and the Ludwig Foundation for Cancer Research (WAW). The work was also funded in part by the Breast Cancer Research Foundation, BCRF-24-089. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
ROLE OF THE FUNDER/SPONSOR
The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
DECLARATION OF INTERESTS
Drs Bazan, Borges, Gabos, Jaskowiak, Kahn, Lee, Lucci, Lupinacci, Matuszak, Meas, Mishra, Moughan, Nordal, Razaq, Salama, Vallow, Winter, White, Woodward, Ye, and Zoberi have nothing to disclose.
Dr Al-Hallaq declares in the last 36 months Grants or contracts from Varian Medical systems with Specifications/Comments of payments made to my previous institution (Univ of Chicago); Payment for expert testimony from Baker & Enright with Specifications/Comments of payment to me; Leadership or fiduciary role in other board, society, committee, or advocacy group, paid or Unpaid from American Association of Physicists in Medicine Board Member with Specifications/Comments of unpaid.
Dr Chmura declares in the last 36 months Since the initial planning of the work all support for the present manuscript (e.g., funding, provision of study materials, medical writing, article processing charges, etc.) from Grants or contracts from Varian Medical Systems, BMS, Servier Pharmaceuticals, Takeda Pharmaceuticals (none are relevant); Payment or honoraria for lectures, presentations, speakers, bureaus, manuscript writing or educational events from dozens of individual academic institutions and professional societies, Servier for Adboard. Payment for expert testimony from not relevant but have been witness for 5 law firms; Support for attending meetings and/or travel from none relevant but ASTRO 2025 from Servier and academic institutions and professional societies.
Dr Jagsi declares in the last 36 months Since the initial planning of the work all support for the present manuscript (e.g., funding, provision of study materials, medical writing, article processing charges, etc.) from Susan G. Komen Foundation Senior Scholar grant with Specifications/Comments of payments to institution; Grants or contracts from none that are relevant, but I will submit the full AAMC Convey form that NEJM requires if accepted (unrelated grants from NIH, ACS, Doris Duke Foundation); Payment or honoraria for lectures, presentations, speakers, bureaus, manuscript writing or educational events from dozens of individual academic institutions and professional societies, PER for organizing Miami Breast symposium, will submit full AAMC Convey report that NEJM requires; Payment for expert testimony from not relevant but have been witness for 3 law firms; Support for attending meetings and/or travel from none relevant and none from industry, just from academic institutions and professional societies and CME course providers; Leadership or fiduciary role in other board, society, committee, or advocacy group, paid or unpaid from none relevant, only nonprofits/government/academic leadership roles.
Dr Kuhn declares in the last 36 months Since the initial planning of the work all support for the present manuscript (e.g., funding, provision of study materials, medical writing, article processing charges, etc.) from This work was funded in whole or in part by the National Institutes of Health NCI U01CA285013, Breast Cancer Research Foundation BCRF-24-089; Patents planned, issued, or pending from Intellectual Property licensed to Epic Sciences and Cansera.
Dr Mason declares in the last 36 months Since the initial planning of the work all support for the present manuscript (e.g., funding, provision of study materials, medical writing, article processing charges, etc.) from This work was funded in whole or in part by the National Institutes of Health NCI U01CA285013, Breast Cancer Research Foundation BCRF-24-089; Patents planned, issued, or pending from Intellectual Property licensed to Epic Sciences and Cansera.
Dr Shishido declares in the last 36 months Since the initial planning of the work all support for the present manuscript (e.g., funding, provision of study materials, medical writing, article processing charges, etc.) from This work was funded in whole or in part by the National Institutes of Health NCI U01CA285013, Breast Cancer Research Foundation BCRF-24-089.
Dr Smith declares in the last 36 months Grants or contracts from Artidis; Leadership or fiduciary role in other board, society, committee, or advocacy group, paid or unpaid from Board Member, ASTRO with Specifications/Comments of This ended in October 2022.
Dr Milano declares in the last 36 months Since the initial planning of the work all support for the present manuscript (e.g., funding, provision of study materials, medical writing, article processing charges, etc.) from supported by NRG (but not specifically relevant to me as co-author).
Dr Mamounas declares in the last 36 months Consulting fees received from Merck, Exact Sciences, Genentech, GE Healthcare, Biotheranostics, Astra Zeneca, Delphi, Diagnostics, Novartis, Lilly, Provepharm with Specifications/Comments of Me; Payment or honoraria for lectures, presentations, speakers, bureaus, manuscript writing or educational events from Exact Sciences, Merck, Novartis, Astra Zeneca, Lilly with Specifications/Comments of Me; Stock or stock options received from Moderna with Specifications/Comments of Me.
Footnotes
NOTICE:
This research was supported by the National Institutes of Health (NIH). In accordance with the NIH Public Access Policy, the final peer-reviewed manuscript will be submitted to PubMed Central upon acceptance for publication and made publicly available immediately upon publication.
Previous Presentation
A version of the abstract was presented at the 2023 American Society of Clinical Oncology (ASCO) Annual Meeting.
DATA ACCESS, RESPONSIBILITY, AND ANALYSIS:
Steven J Chmura, MD, PhD and Kathryn Winter, MS had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
DATA SHARING STATEMENT
Deidentified individual participant data that underlie the results reported in this article are available by request from NRG Oncology 6 months after article publication.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
Deidentified individual participant data that underlie the results reported in this article are available by request from NRG Oncology 6 months after article publication.