Abstract Background: Most patients with breast cancer are treated with breast conserving surgery (BCS) followed by adjuvant radiation (RT) to reduce the risk of recurrence in the same breast (local recurrence (LR)) and to maximize long-term breast preservation. Although these treatments are quite effective, a growing number of individuals who receive them are at risk of LR or develop a second primary breast cancer, which is traditionally treated with mastectomy. However, mastectomy has been associated with deleterious effects on quality of life. Advances in screening now allow many LRs to be detected as localized, small tumours amenable to further BCS. BCS followed by reirradiation with partial breast irradiation (rPBI) has recently been found to be a safe treatment option in women with prior breast RT, but the optimal fractionation is unknown. For women with early-stage breast cancer receiving upfront treatment, a shorter 1-week course of breast RT (ultra-hypofractionation) has been found to be equivalent to longer fractionation schedules. However, this data cannot be directly applied to LR due to the higher cumulative RT doses and to tissue changes from previous treatment. The safety and efficacy of ultra-hypofractionated rPBI for LR are the focus of the proposed study. We hypothesize that ultra-hypofractionated rPBI following BCS for LR or new primary breast cancer in the previously irradiated breast will be associated with acceptable toxicity at 1 year (<13% grade >3 toxicity). Methods: This study is a phase II, prospective, multi-center, international trial of ultra-hypofractionated rPBI following repeat BCS for LR or new primary breast cancer in the previously irradiated breast. rPBI will be delivered at a dose of 26 Gy in 5 daily fractions over a period of 1-week (excluding weekends and statutory holidays). Boost RT is not permitted. The primary endpoint is the risk of grade >3 adverse events (AEs) occurring at 1-year from rPBI completion (CTCAE v5.0). Secondary endpoints include local, regional and distant recurrence, invasive breast cancer-free survival, mastectomy-free survival, overall survival, financial toxicity, and patient-reported satisfaction. To achieve 80% power with a Type I error rate of 0.05 and 3% lost to follow up or unevaluable, 171 patients will be accrued. Eligible patients are status post BCS for ductal carcinoma in situ or invasive cancer <3 cm in greatest diameter (invasive and non-invasive components) with negative margins (no tumor on ink) who are clinically node negative and who completed treatment >5 years earlier for breast cancer in the ipsilateral breast treated with BCS and adjuvant whole or partial breast RT. Patients with grade >2 late skin toxicity from prior radiation are excluded, as are those with T4 or multicentric disease or the presence of an extensive intraductal component. Final eligibility is determined at the time of RT planning based on ability to clearly define the surgical cavity. The RT planning target volume must be <50% of the whole breast. The study is open to accrual 7 sites in Canada, the US, and Jordan, with an additional 9 international centers in the process of opening; 17 patients have been enrolled and treated as of 10-07-2024. Patients will be followed for a total of 5 years. Clinical trial information: NCT05592938. Supported by the Canadian Cancer Society and the Princess Margaret Cancer Foundation. Citation Format: Danielle Rodin, Fadwa Abdel Rahman, Michelle Audoin, Aisling Barry, Jean-Marc Bourque, Keelan Byrne, Michelle Chan, Hanbo Chen, Eileen Connolly, Marc David, Jane De Rocchis, Frances Duane, Elizabeth Evans, Naamit Gerber, Guilherme Gondim, Revathy Krishnamurthy, Zhihui Liu, Tom Purdie, Valerie Theberge, Timothy Whelan, Martina Wood, Michael Yassa, Eileen Rakovitch, Anne Koch. Partial breast re-irradiation using ultra hypofractionation: A Phase 2 multi- institutional study [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P3-12-26.