Ablative Preoperative Single-Fraction Radiation Dose Escalation Among Patients With Breast Cancer: A Phase 1 Nonrandomized Clinical Trial.

Importance: Single-fraction preoperative ablative stereotactic partial breast irradiation (sPBI) can be safely delivered in early-stage hormone receptor-positive (HR+) breast cancer with delayed time to surgery and high pathologic complete response rates. Objectives: To examine the maximum tolerated dose (MTD) of sPBI and to evaluate clinical outcomes, including pathological complete response (pCR), time to surgery, and toxic effects, associated with dose escalation. Design, Setting, and Participants: This phase 1 nonrandomized clinical trial of dose escalation enrolled patients with HR+, ERBB2-negative, cN0 invasive breast cancer not requiring chemotherapy from a single academic center between December 2019 and April 2024. Interventions: Patients were treated with 30, 34, or 38 Gy using MR-guided linear accelerator (MR-LINAC), robotic radiosurgery, or cobalt stereotactic unit. Patients received endocrine therapy and delayed surgery (≤12 months). Main Outcomes and Measures: The MTD was evaluated using dose-limiting toxicity (DLT), defined as grade 3 or higher toxic effects within 90 days. Additionally, pCR, near pCR (npCR), the association of dose escalation with time to surgery, local control, surgical morbidity, and cosmesis were evaluated. Results: A total of 44 patients (median [range] age, 64.5 [44.0-77.0] years) were treated, with 14 (31.8%) receiving 30 Gy (median [IQR] follow-up, 52.0 [28.2-54.5] months), 15 (34.1%) receiving 34 Gy (median [IQR] follow-up, 40.0 [36.5-41.0] months), and 15 (31.4%) receiving 38 Gy (median [IQR] follow-up, 20.0 [17.0-22.0] months). MTD was not reached. pCR rates were 35.7% (5 patients), 46.7% (7 patients), and 66.7% (10 patients), while pCR with npCR rates were 64.3% (9 patients), 93.3% (14 patients), and 93.3% (14 patients), respectively. Local control was 100%, and surgical morbidity was 2.2% (1 of 44 patients). The mean (SD) Ki-67 was 11.3% (6.4%) at diagnosis, and on evaluable residual disease, it was 1.9% (2.0%) (P < .001). A time-to-surgery threshold of 277 days was the optimal cutoff for pCR (area under the receiver operating characteristic curve, 0.77; 95% CI, 0.62-0.91). In patients with surgery more than 9 months after sPBI, pCR rates were 100% (5 of 5 patients), 66.7% (4 of 6 patients), and 64.3% (9 of 14 patients) (P = .40), and combined pCR and npCR rates were 100%, 83.3% (5 patients), and 92.9% (13 patients) (P = .69) for the 30, 34, and 38 Gy groups, respectively. For all patients who received surgery more than 9 months after sPBI, the pCR rate was 72.0% (18 of 25 patients). Longer time to surgery was associated with pCR (odds ratio, 1.02; 95% CI, 1.01-1.03; P = .005), while higher radiation dose was not. Acute toxic effects included 32 grade 1, 3 grade 2 (breast pain and dermatitis), and 1 late grade 3 (wound dehiscence in patient with uncontrolled diabetes) events. Cosmesis remained stable at 36 months. Conclusions and Relevance: In this nonrandomized clinical trial, the rate of toxic effects was low, and treatments were tolerable up to 38 Gy. Delaying surgery more than 9 months after sPBI with endocrine therapy was associated with increased pCR and npCR (>90%), while higher doses were not. These findings support further investigation of sPBI as a potential nonsurgical approach for selected patients with early-stage HR+ breast cancers. Trial Registration: ClinicalTrials.gov Identifier: NCT04040569.