Study of 3-Day Partial Breast Radiation Therapy in Women With Breast Cancer

Inclusion Criteria:

• Female

• Age >/= 45 years

• Unicentric pathological stage I (pT1 or T2 pN0_M0) invasive ductal breast cancer orDCIS measuring <3 cm in longest diameter on pathology and/or mammogram that ishistologically confirmed. If T2, the tumor must be less than 3cm in longestdiameter. Note: Women ≥ 70 years or older with T1 invasive ductal carcinoma who areestrogen- receptor positive (ER+) with clinically negative axillary nodes, and donot undergo surgical lymph node mapping or dissection (i.e., if tumor deposit is 0.2mm or less, regardless of whether the deposit is detected by immunohistochemistry orhematoxylin and eosin staining) will also be eligible. Patients age 50 or older whoare clinically node-negative by physical exam and ultrasound and have a primarytumor that is <=2 cm and hormone-receptor positive, are also eligible.

• Histologically negative tumor margin or no tumor in a re-excision specimen on finalshaved specimen.

• ECOG Performance Status of 0 or 1.

• Negative serum pregnancy test within 14 days prior to study treatment if a woman haschild-bearing potential. Subjects of child bearing potential are those who have notbeen surgically sterilized or have not been free from menses for > 1 year

• Written informed consent obtained from subject and ability for subject or complywith the requirements of the study

• Female subjects of childbearing potential should be willing to use 2 methods orbirth control or be surgically sterile or abstain from heterosexual activity for theduration of study participation. Should a woman become pregnant while participatingon study, she should inform the treating physician immediately.

Inclusion Criteria for intermediate risk substudy:

• Post-NAC cohort patients: clinical T1-T2 (less than or equal to 5cm in longestdiameter on available imaging) and clinical N0-N1 (on exam and imaging) withpathological ypT0, ypTis, or ypT1 (<=2cm) and ypN0 (any regimen of neoadjuvantchemotherapy agents is allowed)

OR

• Oncotype RS score of 26 or higher

OR

• PAM50 ROR scored as "HIGH"

OR

• Presence or LVI (focal, limited or "not otherwise specified") in the lumpectomyspecimen

OR

• Age 40-49 years (ALL OF THE FOLLOWING MUST BE TRUE : 1) no history of prior benignbreast biopsies, 2) no concomitant or prior atypia in either breast, 3) noconcomitant or prior LCIS in either breast, 4) no family history of breast cancer infirst degree relatives)

OR

• Invasive lobular carcinoma

OR

• Surgical margins less than 1 mm to invasive or in-situ disease.

Exclusion Criteria:

• Patients with distant metastasis

• Patients who are pregnant or breastfeeding

• Patients with diffuse (>1 quadrant or >5cm) suspicious microcalcifications orpatients with known multicentric OR multifocal disease. (microscopic multifocaldisease that may be unifocal and/or appear multifocal due to sectioning is allowedafter review with PI).

• Prior radiation therapy to the ipsilateral or contralateral breast or thorax.

• Histological evidence of extensive lymphovascular invasion (LVI)

• Histological evidence of extensive intraductal component (EIC), defined as thepresence of intraductal carcinoma both within the primary infiltrating ductal tumor (comprising at least 25% of the tumo area) and intraductal carcinoma present clearlybeyond the edges of the invasive tumor.

• Patients are not required to undergo BRCA1 and BRCA2 or other genetic mutation testsin order to enroll on the study. Note: in the event a patient is tested and is foundto be a mutation carrier, she would be excluded from the study. It would be anextremely rare/unlikely scenario for patients to be discovered BRCA positive afterthe completion of PBI, as all patients with risk factors for BRCA mutations (positive family history, Ashkenazi Jewish descent, ER-/PR-/her2-neu-negativereceptor status) are usually tested prior to radiation. Should such a situationexist, these patients will be given the option of remaining on the breastconservation paradigm or opting for mastectomy (as is done in this rare scenario isstandard of care practice). The patient will be replaced on the trial.

• History of cosmetic or reconstructive breast surgery.

• Medical condition such as uncontrolled infection (including HIV), uncontrolleddiabetes mellitus, or connective tissue diseases (lupus, systemic sclerosis, orother collagen vascular diseases) that, in the opinion of the treating physician,would make this protocol unreasonably hazardous for the patient.

• Patients with a "currently active" second malignancy other than non-melanoma skincancers. Patients are not considered to have "currently active" malignancies if theyhave completed therapy and are considered by their physicians to be at <5% risk ofrelapse within 3 years.

• Patients who are already enrolled in or planning to enroll in other adjuvantsystemic therapy protocols for both non-invasive or invasive breast cancer

• Expecting to conceive within the projected duration of the trials, starting withscreening visit through 180 days after the last dose of trial treatment

• Concomitant anti-neoplastic treatment is not allowed during protocol treatment andshould be completed at least 2 weeks prior to commencement of protocol treatment,with resolution of associated acute toxicities. Bisphosponates are permitted withoutrestriction even during protocol treatment. Note: This does not apply to hormonaltherapies such as tamoxifen or AIs, which are permitted. This does not apply toanti-Her2 therapies such as trastuzumab or TDM-1, which are also permitted.

• Ongoing therapy with other investigational agents. Patients may not be receiving anyother investigational agents.