The investigators proposed approach allows them to deliver a low total dose of radiation to patients with low-risk, early-stage breast cancer which would further minimize the impact of adjuvant therapy. This work has the potential to revolutionize partial breast irradiation by allowing it to take place at many radiation oncology centers with minimal specialized equipment beyond that commonly available. The investigators first step is this proposed single institution phase I/II study designed primarily to evaluate the tolerance of this approach which the investigators are choosing to call Three Fraction APBI (Tri-APBI).

Inclusion Criteria:

• AJCC 7th Edition stage 0 or I (TisN0 ≤ 2 cm or T1N0) histologically confirmed carcinoma of the breast, treated with partial mastectomy. Axillary sampling is required only for cases of invasive cancers. Tumor size is determined by the pathologist. Clinical size may be used if the pathologic size is indeterminate. Patients with invasive cancer must have no positive axillary lymph nodes with at least 6 axillary lymph nodes sampled or a negative sentinel node.
• Negative histologic margins of partial mastectomy or re-excision specimen. Margins generally are positive if there is invasive or noninvasive tumor at the inked resection margin, close but negative if the tumor is within 2 mm of the inked margin and negative if the tumor is at least 2 mm away from the inked edge.
• Invasive ductal, lobular, medullary, papillary, colloid (mucinous), tubular histologies, or mixed histologies (lesions ≤ 2 cm) that are estrogen or progesterone receptor positive and do not exhibit HER2/neu gene amplification OR ductal carcinoma in situ (lesions ≤ 2 cm).
• Neoadjuvant hormone therapy, chemotherapy, or biologic therapy is not allowed prior to TRI-APBI, but adjuvant hormone therapy may have been started after surgery. Planned chemotherapy or biologic therapy must not start for at least 4 weeks after the completion of TRI-APBI.
• Good candidate for treatment per protocol in the judgment of the PI and/or treating physician following simulation.
• Postmenopausal status.
• Age ≥ 50 years at diagnosis.
• Able to understand and willing to sign IRB-approved written informed consent document.
• English speaker.
• All radiation therapy must be planned for delivery at BJH. External beam patients will be treated at BJH on a Viewray Unit, the Varian Edge unit, or the Varian Halcyon unit. Brachytherapy cases will be treated in the BJH brachytherapy center. Pre and post treatment care is allowed at any Siteman center.

Exclusion Criteria:

• Presence of distant metastases.
• Nonepithelial breast malignancies such as sarcoma or lymphoma.
• Proven multicentric carcinoma (tumors in different quadrants of the breast, or tumors separated by at least 4 cm) with other clinically or radiographically suspicious areas in the ipsilateral breast unless confirmed to be negative for malignancy by biopsy.
• Histologically confirmed positive axillary nodes in the ipsilateral axilla. Palpable or radiographically suspicious contralateral axillary, supraclavicular, infraclavicular, or internal mammary nodes, unless there is histologic confirmation that these nodes are negative for tumor.
• Prior non-hormonal therapy for the present breast cancer, including radiation therapy or chemotherapy.
• Diagnosis of systemic lupus erythematosis, scleroderma, or dermatomyositis.
• Diagnosis of a coexisting medical condition which limits life expectancy to < 2 years.
• History of other malignancy ≤ 5 years previous with the exception of basal cell or squamous cell carcinoma of the skin which were treated with local resection only or carcinoma in situ of the cervix.
• Paget's disease of the nipple.
• Skin involvement, regardless of tumor size.
• Unsatisfactory breast for TRI-APBI as determined by the treating physician. For example, if there is little breast tissue remaining between the skin and pectoralis muscle after surgery, treatment with TRI-APBI is technically problematic.
• Partial mastectomy so extensive that the cosmetic result is fair or poor prior to TRI-APBI as determined by the treating physician.
• Surgical margins which cannot be microscopically assessed or are positive at pathological evaluation.
• Time between final definitive breast procedures to TRI-APBI simulation is greater than 8 weeks.