This is a prospective clinical trial designed to evaluate the efficacy and safety of hypofractionated regional nodal irradiation in breast cancer patients. After enrollment, participants will be stratified into 2 Groups based on the extent of axillary surgery. Participants will complete activities and assessments at baseline, and after completion of treatment at 1-2 weeks, 3 months, 6 months, 1 year, 2 year, and 3 years following completion of treatment.

This is a prospective clinical trial designed to evaluate the efficacy and safety of hypofractionated regional nodal irradiation in breast cancer patients. Participants are stratified into 2 Groups based on the extent of axillary surgery after enrollment.

Group 1: sentinel lymph node procedure with or without select removal of clipped (clinically involved) lymph nodes.

Group 2: axillary lymph node dissection (with or without sentinel lymph node procedure) or patients who have more than 5 sentinel lymph nodes removed will be stratified into group 2.

Participants will complete activities and assessments at baseline, and after completion of treatment at 1-2 weeks, 3 months, 6 months, 1 year, 2 year, and 3 years following completion of treatment. At baseline consultations, history and physical, lymphedema assessment, toxicity assessment, photographs (optional), patient-reported outcome questionnaire and radiation simulation will be completed. Hypofractionated radiation therapy will be completed weekly through the end of treatment with toxicity assessments. At the 1-2 week follow up, toxicity assessment, photographs (optional) and the patient-reported outcome questionnaire will be completed. At the 3 month, 6 month, 1 year, 2 year and 3 year follow-ups a lymphedema assessment, toxicity assessment, photographs (optional), patient-reported outcome questionnaire and follow up examination will be completed.

All patients will receive a dose of 42.56 Gy in 16 daily fractions to the whole breast or chest wall and regional lymph nodes. A boost dose of 10 or 12.5 Gy in 4 or 5 daily fractions of 2.5 Gy, respectively, will be administered to either the lumpectomy cavity or mastectomy scar, as appropriate. Critical organs will be contoured into the treatment planning such as the heart, left anterior descending artery, ipsilateral lung.

Patients may receive neoadjuvant or adjuvant systemic treatment on this trial. In general, the patient should receive systemic treatment according to the current standard of care at the time of enrollment, taking into account the discretion of the treating medical oncologist.

Expected radiation-related acute adverse events (i.e., those experienced within the first 6 months following treatment) are similar to those with conventionally fractionated radiotherapy and include fatigue and tenderness, pruritus, hyperpigmentation, hypopigmentation, dry desquamation, and moist desquamation of the skin. Potential late effects of radiation include arm lymphedema, shoulder stiffness, fibrosis of normal tissue, telangiectasia, hyperpigmentation, or hypopigmentation of the skin, brachial plexopathy, myositis, rib fracture, pneumonitis, second malignancy, or cardiomyopathy. The participants will be monitored for adverse events during radiotherapy and following radiotherapy.

Inclusion Criteria:

• Female
• Age ≥ 18 years old
• Life expectancy of >5 years
• ECOG (Zubrod) performance status 0-1
• Histologically confirmed invasive carcinoma of the breast, including ductal, lobular, mammary, medullary, and tubular histologies
• Clinical T stage of cT0, cT1, cT2, or cT3
• Clinical N stage of cN0, cN1, or cN2a
• Clinical M stage of cM0Definitive surgery must be performed (either partial mastectomy or mastectomy without immediate reconstruction) with negative surgical margins (defined as no invasive tumor or DCIS on ink).
• Must have pathologic T stage of pT1, pT2, or pT3, or if receiving neoadjuvant chemotherapy, ypT0, ypTis, ypT1, ypT2, or ypT3
• Pathologic N stage of pN0, pN1, pN2a, or pN3a, or if receiving neoadjuvant chemotherapy, ypN0,ypN1, ypN2, or ypN3a) NOTE: any patient with clinically involved but undissected lymph nodes that would require a radiation boost will not be eligible.
• The radiation oncologist is planning to treat the breast/chest wall and ipsilateral regional lymphatics (including the axillary, supraclavicular, and internal mammary chains)
• Patient is able to understand and willing to sign an IRB approved written informed consent document
• All dosimetric constraints outlined in protocol section 3.5 can be met

Exclusion Criteria:

• Clinical or pathologic T4 disease, including inflammatory breast cancer
• Clinical N stage of cN2b, cN3 disease, pathologic N stage of pN2b, pN3b, or pN3c disease, or if receiving neoadjuvant chemotherapy, ypN2b, ypN3b, or ypN3c disease
• Radiologic evidence of gross residual disease
• History of prior ipsilateral breast cancer (invasive disease or DCIS)
• Active or history of another malignancy within 5 years of registration with the exception of basal cell or squamous cell carcinoma of the skin treated with local resection only or carcinoma in situ of the cervix
• Prior history of radiation therapy to the neck, breast, or thorax. Prior radioactive oral iodine is permitted.
• History of active collagen vascular disease including systemic lupus erythematosis, scleroderoma, or dermatomyositis with an elevated CK level
• Pregnancy, active breast feeding, or refusal or inability to use highly effective means of contraception in participants of child-bearing potential.
• The patient is a prisoner.