4.1.1.1 MD Anderson Protocol Number: 2025-0779 Histologically confirmed invasive breast cancer (nodal involvement from presumed invasive breast cancer in the setting of occult breast cancer is sufficient to meet this criteria)  Regional nodal irradiation recommended by treating radiation oncologist. Negative final surgical margins. No more than 12 weeks have elapsed since final breast/lymph node surgery for patients treated with surgery alone or neoadjuvant chemotherapy. No more than 12 weeks have elapsed since final cytotoxic chemotherapy for patients who received adjuvant chemotherapy. Age ≥18 years. Because breast cancer is exceedingly rare in patients < 18 years of age, children are excluded from this study. Patients with a prior or concurrent malignancy are eligible provided that the natural history and treatment of the prior or concurrent malignancy does not interfere with the safety or efficacy assessment of the investigational radiation regimen used in this trial. Ability to understand and the willingness to sign a written informed consent document. Concurrent enrollment on other observational, translational, or therapeutic studies is allowed provided there is no direct conflict between the other protocol and the radiation regimen proscribed in this trial. 

Eligibility Criteria for the Low-Risk Lumpectomy Cohort:

For patients treated with upfront surgery, pathologic stage pT0-T4b N0-N3a breast cancer without infraclavicular or internal mammary nodal involvement. For patients treated with neoadjuvant chemotherapy, clinical stage cT0-T4b N0-N2a breast cancer. Treated with lumpectomy (or axillary surgery only in the case of occult primary breast cancer) No nodal boost recommended by the treating radiation oncologist.

Eligibility Criteria for the High-Risk Lumpectomy Cohort:

Treated with neoadjuvant chemotherapy Clinical stage cT0-T4b N1-N3a/b/c Treated with lumpectomy (or axillary surgery only in the case of occult primary breast cancer) Nodal boost recommended by the treating radiation oncologist. 

Eligibility Criteria for the Low-Risk Mastectomy Cohort:

For patients treated with neoadjuvant chemotherapy, clinical stage T0-T3 N0- N2a For patients treated with neoadjuvant chemotherapy, residual cellularity of primary tumor ≤ 20%. Treated with mastectomy Negative surgical margins ≥ 2 mm. No or only focal lymphovascular space invasion. Age ≥ 40 years Chest wall boost NOT recommended by treating radiation oncologist. 

Eligibility Criteria for High-Risk Mastectomy Cohort:

For patients treated with upfront surgery, pathologic stage T0-T4d N0-N3c For patients treated with neoadjuvant chemotherapy, clinical stage T0-T4d N0- N3c Treated with mastectomy Chest wall boost and/or nodal boost recommended by treating radiation oncologist 

Exclusion Criteria for All Cohorts:

History of therapeutic radiation overlapping with the index breast or nodal basins that require radiation therapy. History of scleroderma Pregnant women are excluded from this study because ionizing radiation has the potential for teratogenic or abortifacient effects. Patients with psychiatric illness/social situations that would limit compliance with study requirements.