To compare how often cancer recurs (comes back) after 3 weeks of radiation compared to 5 weeks of radiation in patients who receive radiation therapy delivered to the lymph nodes near the breast. The side effects that can develop during or after radiation treatment, including how often arm swelling (edema) happens, will also be studied.

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.

Inclusion Criteria, if receiving postoperative radiation therapy

• Radiation oncologist recommends radiation treatment to the supraclavicular and infraclavicular fossa (i.e. RNI).
• Pathologically-confirmed invasive breast cancer. If patients undergo upfront surgery, the pathologic stage must be T0-T3, N0-N2a or N3a. If patients receive neoadjuvant chemotherapy prior to surgery, the clinical stage must be T0-T3, N0-N2a or N3a. T4b disease is permitted if the patient undergoes breast conserving surgery.
• Treatment with mastectomy or segmental mastectomy and axillary evaluation (sentinel node evaluation, axillary sampling, or axillary lymph node dissection). If the patient has T0 disease, breast surgery is not required.
• Age 18 years or older.
• If enrolling on in the arm lymphedema assessment cohort, documentation of arm volume measurement by perometer prior to axillary surgery.
• If the patient has a history of a prior non-breast cancer, all treatment for this cancer must have been completed prior to study registration, and the patient must have no evidence of disease for this prior non-breast cancer.
• Patients must be enrolled on the trial within 24 weeks of the later of two dates: the final breast cancer surgical procedure or administration of the last cycle of cytotoxic chemotherapy. If after trial enrollment it is determined the patient requires additional cytotoxic chemotherapy or additional breast cancer surgery prior to radiation therapy the patient may stay on trial but the patient must start radiation therapy within 24 weeks of the final breast cancer surgical procedure or administration of the last cycle of cytotoxic chemotherapy.

Inclusion Criteria, if receiving preoperative radiation therapy

• Surgeon and radiation oncologist recommend preoperative radiation therapy
• Radiation oncologist recommends radiation treatment to the supraclavicular and infraclavicular fossa (i.e. RNI).
• Pathologically-confirmed invasive breast cancer. The clinical stage must be T0-T3, N0-N3b
• Planned treatment with mastectomy and axillary evaluation (sentinel node evaluation, axillary sampling, or axillary lymph node dissection).
• Planned breast reconstruction with autologous reconstruction.
• Age 18 years or older.
• If the patient has a history of a prior non-breast cancer, all treatment for this cancer must have been completed prior to study registration, and the patient must have no evidence of disease for this prior non-breast cancer.

Exclusion Criteria, if receiving postoperative radiation therapy

• Pathologic or clinical evidence for a stage T4 breast cancer. However, T4b disease is permitted if the patient undergoes breast conserving surgery.
• Pathologic or clinical evidence for a stage N2b, N3b, or N3c breast cancer (supraclavicular, or internal mammary lymph node involvement).
• Clinical or pathologic evidence for distant metastases.
• Current diagnosis of invasive breast cancer in the contralateral breast (ductal carcinoma in situ is permitted).
• Prior diagnosis of invasive breast cancer in the contralateral breast.
• If enrolling on in the arm lymphedema assessment cohort, current diagnosis of bilateral breast cancer.
• History of therapeutic irradiation to the breast, lower neck, mediastinum or other area in which there could potentially be overlap with the affected breast. Except those patients enrolled and treated on the PRECISE trial (MD Anderson 2017-0362).
• Patient is pregnant.
• Patients who are cognitively impaired. Subjects will undergo a brief physical exam including a brief exam to determine cognitive review.

Exclusion Criteria, if receiving preoperative radiation therapy

• Pathologic or clinical evidence for a stage T4 breast cancer.
• Pathologic or clinical evidence for a stage N3c breast cancer (supraclavicular lymph node involvement).
• Clinical or pathologic evidence for distant metastases.
• Current diagnosis of invasive breast cancer in the contralateral breast (ductal carcinoma in situ is permitted).
• Prior diagnosis of invasive breast cancer in the contralateral breast.
• History of therapeutic irradiation to the breast, lower neck, mediastinum or other area in which there could potentially be overlap with the affected breast. Except those patients enrolled and treated on the PRECISE trial (MD Anderson 2017-0362).
• Patient is pregnant.
• Patients who are cognitively impaired. Subjects will undergo a brief physical exam including a brief exam to determine cognitive review.