Hypofractionated vs. Conventional Regional Nodal Radiation Therapy for Patients With Invasive Breast Cancer

Primary Objective: To compare the risk of locoregional recurrence, defined as a cancer recurrence in the ipsilateral breast, chest wall, or regional lymph nodes (axillary levels I-III, supraclavicular, or internal mammary) SECONDARY OBJECTIVES FOR BOTH COHORTS 1. To compare the maximum standardized difference in arm volume between the affected arm and the unaffected arm within 24 months after completion of RNI between the two treatment arms. 2. To compare maximal acute (within 6 weeks of treatment) and late (more than 6 weeks after treatment) skin and soft tissue toxicities using the NCI CTCAE v4.0 scale between patients assigned to short versus standard RNI. 3. To compare patient-reported arm and shoulder function for the two treatment arms using the QuickDASH-9. 4. To compare patient quality of life for the two treatment arms using EQ-5D-3L and PROMIS Fatigue SF 6a. 5. To compare the peripheral blood cytokine profile at the end of radiation between patients assigned to short versus standard RNI. 6. To evaluate the effect of the peripheral blood cytokine profile at the end of radiation on developing lymphedema. (optional blood draw for a subset of patients and not applicable for the participating Cancer Network Site patients, or Orlando Health) 7. To evaluate the effect of homocysteine levels prior to radiation on developing lymphedema. (optional blood draw for a subset of patients and not applicable for the participating Cancer Network Site patients, or Orlando Health) 8. To evaluate time to distant metastasis, disease-free survival and overall survival for patients assigned to short versus standard RNI. 9. To evaluate the effect of lipid profiles prior to radiation on acute toxicity, patient reported outcomes, and the time to locoregional recurrence. (optional blood draw for a subset of patients and not applicable for the participating Cancer Network Site patients, or Orlando Health) 10. To evaluate if DNA repair capacity contributes to the presence of acute radiation related toxicity and patient-reported quality of life decrements including fatigue and arm and shoulder symptoms. (optional blood draw for a subset of patients and not applicable for the participating Cancer Network Site patients, or Orlando Health) 11. To evaluate changes in echocardiography global longitudinal strain measurements and cardiac serum biomarkers, based on measurements performed before and after RT, in patients assigned to short versus standard RNI. (optional procedure for a subset of patients and not applicable for the participating Cancer Network Site patients, or Orlando Health) 12. In a separate cohort of 50 patients who will receive RNI before surgery, to collect information on number of patients developing lymphedema within 24 months of RNI on reconstructive complications, and on patient reported quality of life, in those assigned to short versus standard RNI. Participating Cancer Network Sites, or Orlando Health, are not participating in this cohort. 13. To evaluate patient-reported financial burdens using the Economic Strain and Resilience in Cancer- Financial Well- Being instrument. 14. To determine whether radiation therapy induces de novo detectable clonal hematopoiesis mutations or alters the genetic landscape of existing clonal hematopoiesis mutations (optional blood draw for a subset of patients and not applicable for the participating Cancer Network Site patients, or Orlando Health). 15. To determine whether radiation therapy or chemotherapy among individuals with pre- and/or post-treatment clonal hematopoiesis mutations is associated with adverse treatment effects and worse oncologic outcomes (optional blood draw for a subset of patients and not applicable for the participating Cancer Network Site patients, or Orlando Health). OUTLINE: Patients are randomized to 1 of 2 arms. ARM I: Patients undergo hypofractionated RNI in 15 fractions 5 consecutive days a week for 3 weeks. ARM II: Patients undergo standard RNI in 25 fractions 5 consecutive days a week for 5 weeks. In both arms, patients undergo additional boost dose of radiation therapy in 5 or 7 fractions on consecutive days following completion of RNI. PATIENT EVALUATION: Patients participating in the trial will have their arm measured prior to radiation, during the final week of radiation and when they return for follow up visits. Patients will be checked for any arm swelling that may develop. Patients will also fill out questionnaires before treatment and when they return for follow up visits. Patients return 3 and 6 months after radiation, then every 6 months through two and a half years after radiation and then on a yearly basis until ten and a half years after finishing radiation. At some of the follow up visits, we measure arm volume and ask participants to complete questionnaires.