Metastatic breast cancer has traditionally been regarded as an incurable disease requiring long-term systemic treatment, with local therapies generally used for symptom relief or prevention of local complications. This approach has been questioned with the emergence of the concept of oligometastatic disease (OMD), which generally refers to a limited number of metastatic lesions, most commonly one to five, and may represent an intermediate state between localized disease and widespread metastatic dissemination. In some patients, the limited metastatic burden may reflect more favourable tumour biology and could potentially be amenable to aggressive local treatment. If a limited number of deposits can be identified and eradicated, some patients might achieve durable disease control, or even cure. Stereotactic Ablative Body Radiotherapy (SABR), has emerged as the tool best suited to test this hypothesis. Unlike conventional palliative radiotherapy, SABR delivers very high, tumoricidal doses in 1–5 precisely targeted fractions while sparing surrounding normal tissue. In oligometastatic breast cancer (OMBC), the rationale for SABR is primarily local tumour ablation. There is also increasing interest in its potential immunological effects, particularly when combined with immune checkpoint inhibitors (ICIs). This review examines where the evidence for SABR in OMBC currently stands, why the immunotherapy combination is generating fresh optimism despite recent disappointments, and what questions remain open.
“SABR may offer durable local control in selected oligometastatic breast cancer patients, but randomized evidence does not yet support routine use.“
Defining Oligometastatic Breast Cancer
Oligometastatic breast cancer is clinically heterogeneous. Classifications distinguish de novo oligometastatic disease (metastases present at initial diagnosis), oligorecurrent disease (a limited relapse after a disease-free interval), and oligoprogressive disease (a small number of lesions progressing while the rest of disease remains controlled on systemic therapy). This distinction matters clinically: emerging data suggest that oligoprogressive and oligorecurrent disease, arising in the context of relatively indolent biology, may respond differently to metastasis-directed therapy than a patient who presents with widespread disease burden from the outset. Biomarker research including candidate markers such as PIK3CA mutation status and YAP/TAZ expression is beginning to explore whether OMD represents a genuinely distinct molecular subtype rather than a matter of tumor burden alone.
The Randomized Evidence: A Story of Contrasts
The strongest signal for metastasis-directed SABR across cancer types comes from SABR-COMET, a phase II trial that randomized patients with a controlled primary tumor and 1–5 metastases (mixed histologies) to standard-of-care systemic therapy with or without SABR to all sites of disease. The long-term results were striking: 8-year overall survival was 27% in the SABR arm versus 14% with standard of care alone, alongside improved progression-free survival. However, breast cancer patients made up only 18% of the trial population, and toxicity, including treatment-related deaths, was seen in the SABR arm underscoring that the benefit came with real risk that needs careful patient selection.
Because SABR-COMET was not breast-cancer-specific, the cooperative group trial NRG-BR002 was designed to answer the question directly. This phase IIR/III study randomized patients with newly diagnosed OMBC (≤4 extracranial metastases, controlled primary, no progression on ≤12 months of first-line systemic therapy) to standard systemic therapy alone versus systemic therapy plus metastasis-directed therapy (SBRT or surgical resection) to all lesions. Presented at ASCO 2022, the results were negative: total ablation added no detectable progression-free or overall survival benefit over systemic therapy alone, and the trial closed early for futility on the OS question. Treatment was safe, with toxicity comparable between arms, but the efficacy signal simply was not there. A related trial, EA2108, similarly found no survival benefit from adding early local therapy in stage IV breast cancer.
The contradictory results of SABR-COMET and NRG-BR002 have led to a temporary halt to rethink the future direction of management in such patients. It has prompted a shift away from treating “oligometastatic breast cancer” as a monolithic target and toward asking which specific clinical scenarios oligoprogression on a given systemic regimen, bone-only disease, hormone receptor–positive disease, or HER2-positive disease with novel systemic partners might still benefit from ablation. Single-arm data, such as the AVATAR trial presented at ASTRO 2023, suggest SABR directed at oligoprogressive lesions in ER-positive advanced breast cancer can meaningfully delay the need to switch systemic therapy, a clinically relevant endpoint even without a proven survival benefit. Real-world registry data, including a large NHS England prospective cohort of SBRT for 1–3 metachronous oligometastases, are being used to further refine which patients are truly benefiting.
Where Immunotherapy Enters the Picture
Combining SABR with immune checkpoint inhibition aims to explore whether high-dose, ablative radiation is not purely destructive but also immunogenic. Ablative radiation causes immunogenic cell death, releasing tumor antigens that are taken up by dendritic cells and presented to T cells, upregulating MHC class I expression, and in some patients inducing systemic immune activation with increased PD-1 expression on circulating CD4+ and CD8+ T cells. This is the biological basis of the abscopal effect: regression of untreated, distant tumor deposits following irradiation of a single site, historically a rare and unpredictable phenomenon but one that checkpoint blockade may make more reliable by removing the inhibitory brakes that would otherwise blunt the radiation-primed immune response.
Preclinical work in the 4T1 murine triple-negative breast cancer (TNBC) model supports this logic: combining focal radiotherapy with anti-PD-1 antibody produced measurable regression of a second, unirradiated tumor and altered infiltration of myeloid-derived suppressor cells, consistent with a genuine abscopal, immune-mediated effect rather than radiation scatter. TNBC has become the focus of most clinical combination efforts because it is comparatively immunogenic, often with higher tumor mutational burden and PD-L1 expression than luminal disease, and already has an approved role for immunotherapy in the metastatic and early-stage settings.
Clinically, a single-arm phase II study evaluated pembrolizumab combined with radiotherapy in metastatic TNBC, motivated by the modest 13–19% response rates seen with checkpoint inhibitor monotherapy in PD-L1-positive disease, and by case reports (including the well-known Postow abscopal case with ipilimumab) suggesting radiation could unlock systemic responses in patients otherwise progressing on immunotherapy alone. Other early-phase and window-of-opportunity studies, such as trials pairing pembrolizumab with SABR in oligometastatic disease, or intraoperative radiotherapy combined with pembrolizumab in early TNBC, are probing whether the sequencing, dose, and fractionation of radiation can be optimized specifically to prime rather than exhaust the immune response. Dose and fractionation appear genuinely important: excessively high single-fraction doses can damage the very lymphocytes needed to mount a systemic response, so hypofractionated regimens are being explored as a middle ground.
Where This Leaves Practice and Future Directions
At present, SABR should not be offered as standard first-line management for newly diagnosed oligometastatic breast cancer outside of a clinical trial; NRG-BR002 was a well-conducted, adequately powered negative study, and enthusiasm generated by tumor-agnostic data like SABR-COMET does not automatically transfer to breast cancer biology. Where SABR does appear to have a defensible role today is in the oligoprogressive setting treating a small number of resistant lesions to prolong the effectiveness of an otherwise-working systemic regimen and pragmatically, for palliation and local control.
Immunotherapy combination represents the most promising avenue for moving beyond, but remains investigational. Ongoing and future work needs to define optimal SABR dose-fractionation for immune priming, identify which breast cancer subtypes (most plausibly TNBC, and potentially HER2-positive disease given newer HER2-targeted immune-active agents) are most likely to respond, and validate predictive biomarkers so that ablative, immune-augmenting strategies can be directed at patients truly capable of a durable, systemic anti-tumor response rather than applied indiscriminately. Larger randomized trials specifically pairing SABR with checkpoint inhibition in biomarker-selected OMBC populations are the logical next step to determine whether precision radiation can finally convert a subset of metastatic breast cancer into a chronic, or even curable, condition.
