Hypofractionated Radiotherapy Before or After Breast Surgery for Treatment of Patients With Non-Metastatic Breast Cancer

PRIMARY OBJECTIVE: I. Compare the baseline-adjusted rate of grade (G)3 or higher radiation treatment related adverse events with the use of preoperative and postoperative radiation within the first 2-years for groups A-D. CORRELATIVE AND EXPLORATORY OBJECTIVES: I. To estimate the rate of grade 3 wound complications and seroma infection between preop and postoperative radiation. II. Group A-D: Determine locoregional control with the use of preoperative radiation conformal radiation. III. Group D \& E: Estimate locoregional control among HER 2+ patients with or without surgery at 2-years. IV. Group E: To determine the rates of surgery for locoregional disease after radiation therapy (RT) at 2 and 5 years. V. To evaluate radiographic complete response and near complete response by magnetic resonance imaging (MRI) and positron emission tomography (PET). VI. Group A-D: To determine true radiographic complete response based on post treatment PET standardized uptake value (SUV) \< 2.5 or uptake \< mediastinum. VII. Group A-D: To determine the pathologic complete response (pCR) rate and near pathologic rate with cellularity \< 10% after neoadjuvant chemotherapy and hypofractionated radiotherapy to the whole breast with nodal irradiation if indicated, based on the postsurgical specimen. VIII. To estimate the 5-year locoregional control, distant recurrence, invasive disease-free survival, cause-specific survival, and overall survival. IX. To evaluate patient-reported outcomes. X. To evaluate clinical features, treatment technique, dose-volume parameters, histologic and genetic variants associated with adverse events, and fair and poor cosmetic outcomes or unplanned surgical intervention. XI. Evaluate tumor mutation signatures before and after chemotherapy, radiation, and surgery, correlate tumor mutation signatures before and after radiation with pathologic information at the time of surgery. XII. Evaluate circulating tumor deoxyribonucleic acid (DNA), tumor infiltrating lymphocytes, neo-epitopes, and peripheral blood mononuclear before and after chemotherapy, radiation, and surgery; correlate tumor mutation signatures before and after radiation with pathologic information at the time of surgery. (Arm 1) XIII. To describe the pathologic changes seen in breast cancer patients with preoperative radiation (Arm 1). XIV. Group A-D: Determine the rate of implant/tissue expander failure after preop and postop radiation. XV. Group E: To determine the rates of persistent disease in the breast or regional lymphatics after RT at 2 and 5-years. OUTLINE: Patients with low risk and high risk estrogen receptor (ER) positive disease, triple negative disease and HER2 positive disease without complete response are randomized to 1 of 2 arms. Patients with HER2 positive, complete response disease are assigned to arm I. ARM I: Patients undergo standard of care (SOC) chemotherapy followed by breast hypofractionated radiotherapy once daily (QD) for a total of 5 fractions. Patients then undergo SOC breast surgery 10 weeks after radiation treatment. Patients also undergo computed tomography (CT), MRI, PET, contrast-enhanced digital mammography (CEDM), and/or breast ultrasound (US) throughout the study. Additionally, patients undergo a biopsy and may undergo optional blood sample collection and tissue collection on study. ARM II: Patients undergo SOC chemotherapy and SOC breast surgery followed by breast hypofractionated radiotherapy QD for a total of 5 fractions. Patients also undergo CT, MRI, PET, CEDM, and/or breast US throughout the study. Additionally, patients undergo a biopsy and may undergo optional blood sample collection and tissue collection on study. After completion of study treatment, patients are followed up at 16 weeks, 6 months, 12 months, 24 months, 36 months, 48 months and at 5 years.