Highlights
• Single‑fraction preoperative stereotactic partial breast irradiation (sPBI) at doses up to 38 Gy was feasible and well tolerated; maximum tolerated dose (MTD) was not reached.
• Pathologic complete response (pCR) rates increased over time with endocrine therapy after sPBI; surgery delayed beyond ~9 months yielded a combined pCR/near‑pCR rate >90% in most dose cohorts.
• Acute and late toxicities were low (one late grade 3 event related to uncontrolled diabetes); cosmesis remained stable through 36 months.
Background
Early‑stage, hormone receptor‑positive (HR+), ERBB2‑negative breast cancer represents a large proportion of newly diagnosed breast cancers and is characterized by generally favorable natural history and high sensitivity to endocrine therapy. Conventional management of operable disease has included breast‑conserving surgery followed by adjuvant radiation or, in selected patients, partial‑breast irradiation. There is growing interest in de‑escalating local therapy for selected low‑risk patients, motivated by reductions in overtreatment, improved quality of life, and health‑care resource considerations.
Preoperative radiation—delivered before surgery—offers biological and practical advantages: it irradiates an intact tumor (potentially improving target delineation), may enhance antitumor immunity, and creates an opportunity to observe tumor response, including pathologic complete response (pCR), which could inform risk‑adapted local management. Single‑fraction ablative stereotactic techniques (sPBI) are an emerging approach that concentrates high biologically effective dose to the tumor bed while sparing surrounding normal tissue.
Study design
Rahimi and colleagues conducted a phase 1, nonrandomized dose escalation trial (ClinicalTrials.gov NCT04040569) enrolling patients with early‑stage HR+, ERBB2‑negative, clinically node‑negative (cN0) invasive breast cancer who did not require chemotherapy. From December 2019 to April 2024 at a single academic center, 44 patients received a single preoperative ablative sPBI fraction of 30 Gy (n=14), 34 Gy (n=15), or 38 Gy (n=15). Treatments were delivered using MR‑LINAC, robotic radiosurgery, or cobalt stereotactic unit platforms. All patients received endocrine therapy and had planned delayed surgery within 12 months of radiation. The primary endpoint was maximum tolerated dose (MTD), with dose‑limiting toxicity (DLT) defined as grade ≥3 adverse events within 90 days. Secondary endpoints included pCR, near pCR (npCR), time to surgery, local control, surgical morbidity, and cosmesis. Proliferation marker Ki‑67 was assessed at baseline and on residual disease when available.
Key findings
Patient and follow‑up characteristics
The cohort had a median age of 64.5 years (range 44–77). Median follow‑up varied by dose cohort: 30 Gy (median 52.0 months), 34 Gy (median 40.0 months), and 38 Gy (median 20.0 months).
Toxicity and MTD
The MTD was not reached. Acute toxic effects included 32 grade 1 events and 3 grade 2 events (breast pain and dermatitis). There was one late grade 3 toxicity consisting of wound dehiscence in a patient with uncontrolled diabetes. Overall surgical morbidity was 2.2% (1/44). Cosmesis scores remained stable at 36 months.
Oncologic response
Pathologic outcomes improved numerically across dose cohorts: pCR rates were 35.7% (5/14) at 30 Gy, 46.7% (7/15) at 34 Gy, and 66.7% (10/15) at 38 Gy. When pCR and near‑pCR were combined, rates were 64.3% (9/14), 93.3% (14/15), and 93.3% (14/15), respectively. Importantly, time from sPBI to surgery strongly associated with tumor eradication.
Effect of time to surgery
Using receiver operating characteristic analysis, a time‑to‑surgery threshold of 277 days (≈9 months) optimally predicted pCR (AUC 0.77, 95% CI 0.62–0.91). For patients undergoing surgery more than 9 months after sPBI, pCR rates by cohort were 100% (5/5) for 30 Gy, 66.7% (4/6) for 34 Gy, and 64.3% (9/14) for 38 Gy (P = .40). Combined pCR+npCR rates in the >9‑month group were 100%, 83.3% (5/6), and 92.9% (13/14) respectively (P = .69). Overall, across all patients who had surgery more than 9 months after sPBI, the pCR rate was 72.0% (18/25). In logistic regression, longer time to surgery was associated with pCR (odds ratio 1.02 per day; 95% CI 1.01–1.03; P = .005), while higher radiation dose was not independently associated with pCR.
Biomarker changes
Baseline mean Ki‑67 was 11.3% (SD 6.4%). In evaluable residual tumors after therapy, mean Ki‑67 fell to 1.9% (SD 2.0%) (P < .001), consistent with major biologic response to combined sPBI and endocrine therapy.
Local control and other outcomes
Local control was 100% during the reported follow‑up, and there were no unexpected perioperative complications attributable to preoperative radiation apart from the single late grade 3 wound event in the context of poorly controlled diabetes.
Expert commentary and interpretation
Clinical implications
This phase 1 experience shows that a single high‑dose preoperative sPBI fraction can be delivered safely to selected patients with early HR+ breast cancer when combined with endocrine therapy and delayed surgery, with encouraging pCR and pCR+npCR rates—particularly when surgery was deferred beyond approximately 9 months. The observed marked reduction in proliferation (Ki‑67) supports substantial biologic effect of the combined modality.
Why might delayed surgery increase pCR? HR+ tumors are typically endocrine‑sensitive and often regress gradually over months with aromatase inhibitors or tamoxifen. When focal tumor ablation with accelerated high‑dose radiation is paired with continuous endocrine suppression, radiobiologic killing and endocrine cytostasis may act synergistically over time to eliminate residual viable tumor cells. The finding that higher radiation dose did not independently predict pCR suggests that in this population, biologic time under endocrine therapy is a key determinant of response; ablative radiation likely provides a large initial debulking stimulus, with sustained endocrine suppression consolidating response.
Strengths
Key strengths include prospective design, use of modern stereotactic platforms (including MR‑LINAC), predefined toxicity and response endpoints, objective biomarker measurement (Ki‑67), and detailed timing analysis showing the importance of delayed surgery.
Limitations
Important limitations temper immediate clinical translation. This was a single‑center, nonrandomized phase 1 study with a small sample size and variable follow‑up (notably shorter for the 38 Gy cohort). Selection bias toward older, lower‑risk HR+ cancers likely enriched for tumors predisposed to endocrine response. The trial did not include a randomized comparison to standard‑of‑care surgery followed by adjuvant radiotherapy or an upfront surgery arm, so it cannot establish equivalence in local control or survival. Longer follow‑up is required to exclude late local recurrences or late toxicity. Finally, pCR is a surrogate endpoint; its prognostic significance in HR+ breast cancer is less well established than in triple‑negative or HER2+ subtypes.
Operational and practical considerations
Implementing a preoperative single‑fraction program requires access to stereotactic technology and multidisciplinary coordination among radiation oncology, breast surgery, radiology, and pathology. Rigorous imaging and biopsy‑based surveillance would be necessary in any strategy that intends to avoid surgery for apparently pCR cases. Patient selection needs to be cautious—older age, strongly ER+ disease, low baseline proliferation, small tumor size, and comorbidity profiles that favor nonoperative management are plausible selection factors but require validation.
Comparison to existing paradigms
Prior efforts to de‑escalate local therapy include accelerated partial‑breast irradiation (APBI) and intraoperative radiotherapy (IORT). Randomized data (e.g., TARGIT‑A and ELIOT trials for IORT) have shown mixed results with respect to local recurrence, and large APBI trials (e.g., NSABP B‑39/RTOG 0413, IMPORT LOW) have informed patient selection and dose‑fractionation choices. The present study differs by using a preoperative ablative approach combined with endocrine therapy and intentional delay of surgery, a paradigm that—if validated—could open a pathway toward nonoperative management for a highly selected subset of patients.
Conclusion and next steps
In this phase 1 nonrandomized trial, single‑fraction preoperative stereotactic partial‑breast irradiation up to 38 Gy was feasible, safe, and associated with high rates of pathologic response when combined with endocrine therapy and delayed surgery. The duration of preoperative endocrine therapy (i.e., longer time to surgery) emerged as a stronger predictor of pCR than radiation dose, suggesting that a combined radiation plus prolonged endocrine suppression strategy may maximize tumor eradication in HR+ disease.
These results justify further investigation in larger, multicenter randomized phase II/III trials to evaluate long‑term local control, survival, patient‑reported outcomes, and the feasibility of nonoperative management for confirmed pCR. Key priorities include standardizing imaging and biopsy criteria for clinical complete response, validating biomarkers (including Ki‑67 dynamics), and defining the minimal radiation dose and optimal duration of endocrine therapy to achieve durable tumor eradication while preserving cosmesis and function.
Funding and trial registration
Trial registration: ClinicalTrials.gov Identifier NCT04040569. Funding and institutional details are reported in the primary publication (Rahimi et al., JAMA Netw Open, 2025).
Selected references
Rahimi A, Leitch M, Dogan B, et al. Ablative Preoperative Single‑Fraction Radiation Dose Escalation Among Patients With Breast Cancer: A Phase 1 Nonrandomized Clinical Trial. JAMA Netw Open. 2025 Nov 3;8(11):e2543689. doi:10.1001/jamanetworkopen.2025.43689.
Vaidya JS, Joseph D, Tobias JS, et al. Targeted intraoperative radiotherapy versus whole breast radiotherapy for breast cancer (TARGIT‑A trial): long‑term results. Lancet. 2010;376(9735):91–102.
Veronesi U, Orecchia R, Maisonneuve P, et al. Intraoperative radiotherapy versus external radiotherapy for early breast cancer (ELIOT): a randomised equivalence trial. Lancet Oncol. 2013;14(13):1269–1277.
National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Breast Cancer. (Accessed 2024).
Author note
This article synthesizes primary trial data and places findings in clinical context for physicians and policy makers; it is not a guideline. Clinicians should refer to local protocols and multidisciplinary review when considering novel preoperative radiotherapy approaches.
