Abstract Background and aim of the study: A.The ongoing Preoperative Accelerated Partial Breast Irradiation (PAPBI) trial (NCT01024582) is based on the rationale that three-dimensional conformal external-beam radiation (3D-CRT) leads to more dose homogeneity compared with brachy-or intraoperative radiotherapy (RT). By irradiating preoperatively this can lead to more accurate tumor delineation and smaller irradiated volumes. As the tumor remains in situ during irradiation, more precise delivery of the radiation dose is guaranteed with CT cone beam linear accelerators, avoiding the uncertainties of the original tumor position in the operation cavity as is the case in postoperative RT. Tumor excision 6 weeks after RT removes the high dose volume tissue and can lead to better cosmesis. B. By assessing tumor response to radiotherapy, an additional goal of the study is to develop a gene expression profile that predicts breast cancer radiosensitivity. This gene signature of breast radiosensitivity would further design optimal treatment strategies for individual breast cancer patients treated with BCT. Inclusion citeria: Patients 60 years or older with a cT< = 3cm, ductal carcinoma (no in situ component), unifocal on mammogram and MRI, pN0(sn) (sentinel node procedure before RT), will be treated by preoperative RT (CTV = GTV + 2 cm, 10 × 4 Gy IMRT/VMAT over two weeks). Six weeks after pre-operative RT, a wide local excision will be performed. Skin toxicity and fibrosis is scored using EORTC/RTOG criteria. Patients are followed during RT and on a 3-monthly basis. Cosmesis is scored and photographs are taken for analysis (BCCT.core project score). To study radiosensit ivity, gene expression profiling from RNA and DNA isolated from biopsies (mRNA gene expression profiles, the miRNA expression profiles and the DNA copy number changes) taken of the tumor before radiotherapy and at time of surgery will be correlated with response to radiotherapy, defined as pathologic response at the time of the lumpectomy. Response of the tumor will be evaluated by MRI scan and PET (before radiotherapy and before surgery) and classical pathology. Endpoint : The main objective is to investigate the impact of a short fractionated schedule given preoperatively on cosmesis and breast fibrosis. Therefore, it is anticipated that the percentage of moderate or severe fibrosis will decrease from 27% as found in the boost arm of the EORTC boost-no boost trial to 15% (Collette et al EJC 2008). The total sample size of 120 patients will provide in excess of 80% power to detect the difference between the null hypotheses (a rate of fibrosis of 27%) and the alternative hypothesis (a rate of fibrosis of 15%) with an exact binomial test at 0.05 2-sided significance level. In addition, the 2-sided 95% confidence interval for the proportion of patients without local recurrence will extend 0.035 from the observed proportion for an expected proportion of 96%. An additional objective is to build a classifier (genomic or proteomic or any kind of molecular signature) to identify responders and non-responders. A total of 120 patients will be included in the study. The main analysis will include 60 patients in the training set and 60 in the validation set. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr OT2-1-03.