• Cohort A1 and A2

• • Conditions for patient eligibility: Patients on this portion of the study can receive radiation treatment at any MD Anderson Cancer Center or any outside hospital and may be enrolled prior to, during, or following neoadjuvant systemic therapy provided they meet the following eligibility and ineligibility requirements noted below:

⁃ Pathologically confirmed unicentric invasive breast cancer defined as radiologic clinical stage T1 or T2 (≤ 5 cm), N0 or N1 (≤ 4 abnormal axillary nodes on initial ultrasound), clinical stage M0.

⁃ HER2 positive (IHC 3+ and or FISH amplified) or triple receptor negative (TN, ER/PR\< 10% HER2 negative (IHC 1+ or 2+ FISH non-amplified) receiving any standard routine clinical NST regimen.

⁃ Patient desires breast conserving therapy.

⁃ Age 40 years or older. This age cutoff is justified because breast cancers in women under the age of 40 are known to have a significantly higher risk of IBTR presumably due to underlying biologic differences \[124, 125\].

⁃ Female sex.

⁃ 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.

⁃ Patient must have an initial nodal ultrasound that does not demonstrate more than four suspicious lymph nodes, any suspicious lymph nodes should be biopsied to determine if nodal metastatic disease present.

⁃ Patient understands that the breast lesion size on final breast imaging must be less than or equal to 2 cm prior to the biopsy procedure being performed on study and if the biopsy shows residual carcinoma the patient will be taken off study.

• Cohort B1 and B2

• • Conditions for patient eligibility: Patients on this portion of the study will be limited to receive radiation treatment at MD Anderson Cancer Center or other approved locations and must be enrolled prior to any neoadjuvant systemic therapy provided they meet the following eligibility and ineligibility requirements noted below:

⁃ ER and/or PR positive, HER2 negative

⁃ Clinical stage T1N0M0, unicentric non-lobular breast cancer, no lymphovascular space invasion,

⁃ At least 40 years of age.

⁃ Oncotype ≤ 25 if age ≥ 50 years

⁃ Oncotype 0-20 and tumor size ≤ 1.5cm if age 40-49 years.

⁃ Patient agrees to take anti-estrogen therapy and is interested in breast conservation

⁃ Female sex.

⁃ 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.

⁃ No history of prior radiation to the area of the breast that would require protocol-mandated treatment

• Cohort C

• • Conditions for patient eligibility: Patients on this portion of the study can receive surgical treatment at any MD Anderson Cancer Center or any outside hospital and may be enrolled prior to or following neoadjuvant systemic therapy provided they meet the following eligibility and ineligibility requirements noted below:

⁃ Pathologically confirmed invasive breast cancer defined as radiologic clinical stage T1 or T2 (≤ 5 cm), N0, clinical stage M0 and HER2 positive (IHC 3+ and or FISH amplified) receiving any standard routine clinical NST regimen containing her-2 directed therapy OR Pathologically confirmed invasive breast cancer defined as radiologic clinical stage T1 (≤ 2 cm), N0, clinical stage M0 and triple negative, receiving any standard routine clinical NST regimen.

⁃ For cohort C patients participating in the optional pretreatment biopsy, the patient should be able undergo biopsy or surgery of the primary tumor site of suspected or proven invasive breast cancer and should be planned to receive neoadjuvant systemic therapy.

⁃ Patient desires breast conserving therapy.

⁃ Age 30 years or older if HER2 positive. Age 50 or older if HER2 negative (triple negative).

⁃ Female sex.

⁃ 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.

⁃ Patient must have an initial nodal ultrasound that does not demonstrate suspicious lymph nodes; any suspicious lymph nodes should be biopsied to determine if nodal metastatic disease present.

⁃ Patient must have no evidence of residual invasive tumor or DCIS on pathologic review of the lumpectomy surgical specimen

⁃ Patient must have no evidence of metastatic disease or isolated tumor cells involving the lymph nodes on pathologic review of the lymph node surgical specimen. If treatment effect in the nodes is noted on the pathology report, the investigators would generally discourage enrollment on this protocol.

‣ Unifocal disease or limited multifocal disease that can be excised in a single lumpectomy specimen

• Cohort D (MD Anderson Houston patients only)

⁃ Conditions for patient eligibility: Patients on this portion of the study meet all eligibility requirements for cohort C, but have not enrolled onto the study to omit radiation. Patients in Cohort D can be identified at the time of diagnosis or prior to lumpectomy. They are not required to participate in one of the treatment arms of the study, but can ultimately choose to move to an omission Cohort at a later time point.

• 5.1 Patients with triple negative or her-2 positive tumor who are amenable to breast conserving treatment and have received or are planned for neoadjuvant systemic therapy prior to surgery are eligible for Cohort D.

• 5.2 Eligible patients in cohort D who have undergone optional ARTIDIS biopsies of the primary breast tumor at the time of diagnosis, prior to starting neoadjuvant therapy, or following completion of systemic therapy, at the time of surgery, may later move to Cohort A or C if they meet all eligibility requirements and ultimately desire surgery or radiation omission