Abstract Background: Accelerated partial breast irradiation (APBI) delivers adjuvant radiation (RT) to the 1-2 cm of the breast at highest risk for recurrence surrounding the lumpectomy (L) cavity over 5-8 days and is an alternative to standard whole breast irradiation for hormone sensitive (HS) stage 1 (T1, N0) breast cancer (BC) based on 2 randomized controlled trials. External beam methods for APBI are common but have notable inherent drawbacks that include: inter-fraction inaccuracy due to patient setup based on anatomy, intra fraction error related to patient or respiratory motion, and inaccurate geometric targeting by relying on L cavity position instead of the tumor position. Postoperative RT has other limitations including delivery in the setting of disrupted blood or lymphatic supply that may be suboptimal for radio sensitivity and it eliminates observation of radiation-induced tumor response. MRI is an established tool for measuring BC extent and response from neoadjuvant systemic therapy. It's hypothesized that MRI directed pre-operative APBI using intensity modulated radiotherapy (IMRT) with image guidance (IGRT) will improve RT delivery, and that MRI features can be identified to correlate with pathologic radiation response. Trial Design: There are 2 cohorts to this single arm prospective trial. The first cohort is for establishing and verifying patient flow and image fusion between MRI, CT and RT planning. In the second cohort eligible patients will receive preoperative APBI 38.5 Gy in 10 fractions BID with IMRT, IGRT in the prone position using MRI defined targets fused to CT treatment planning. Eligibility: For cohort 1 it is HS Stage 1 BC that has completed CT in prone position for RT planning. Eligibility for cohort 2 requires: age > 60 yo, clinical stage 1 BC, HS, HER2 negative, intending L, clinically negative axilla verified by ultrasound, able to tolerate the prone position, and MRI with contrast. Specific aims: To determine the reproducibility of MRI directed preoperative APBI based on meeting 3 criteria: ability to define RT targets by MRI, quality of RT plans and completion of treatment (APBI and surgery). Additional aims include assessing toxicity, cosmetic outcome, local regional cancer control and collection of tissue for correlative studies. Statistical methods: The optimal two-stage design by Simon is used. Sample size for cohort 2 is based on the first endpoint. 19 eligible patients will be required in the first stage; if 3 or more treatments are scored unacceptable, then early stopping will be recommended. Otherwise, accrual will continue to a total accrual of 30. If > 4 of 30 treatments are scored unacceptable, the technique will be considered not reproducible, and a Phase II study will not be pursued. Under the null hypothesis of an 80% reproducibility rate, this two-stage design has an expected sample size of 24.4. Patient accrual to cohort 1 is 2 and targeted accrual is 3. Patient accrual to Cohort 2 is 0 and targeted accrual is 30. Contact information: Soyhun Mc Elroy ( Sohyun.McElroy@osumc.edu) or Julia White (Julia.White@osumc.edu) Funding source: Susan G Komen Breast Cancer Foundation Grant # GRT00035216. Citation Format: White J, McElroy S, Seykon A, Wei L, Bazan J, Yang X, DiCostanzo D, Gupta N, Knopp M. Feasibility of assessing radiation response with MRI/CT directed preoperative accelerated partial breast irradiation in the prone position for hormone sensitive early stage breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr OT2-03-02.