Multicenter Trial for Eliminating Breast Cancer Surgery or Radiotherapy in Exceptional Responders to Neoadjuvant Systemic Therapy

Inclusion Criteria:

• Cohort A1 and A2

• Conditions for patient eligibility: Patients on this portion of the study canreceive radiation treatment at any MD Anderson Cancer Center or any outside hospitaland may be enrolled prior to, during, or following neoadjuvant systemic therapyprovided they meet the following eligibility and ineligibility requirements notedbelow:

1. Pathologically confirmed unicentric invasive breast cancer defined asradiologic clinical stage T1 or T2 (≤ 5 cm), N0 or N1 (≤ 4 abnormal axillarynodes on initial ultrasound), clinical stage M0.

2. 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.

3. Patient desires breast conserving therapy.

4. Age 40 years or older. This age cutoff is justified because breast cancers inwomen under the age of 40 are known to have a significantly higher risk of IBTRpresumably due to underlying biologic differences [124, 125].

5. Female sex.

6. If the patient has a history of a prior non-breast cancer, all treatment forthis cancer must have been completed prior to study registration and thepatient must have no evidence of disease for this prior non-breast cancer.

7. Patient must have an initial nodal ultrasound that does not demonstrate morethan four suspicious lymph nodes, any suspicious lymph nodes should be biopsiedto determine if nodal metastatic disease present.

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

• Cohort B1 and B2

• Conditions for patient eligibility: Patients on this portion of the study will belimited to receive radiation treatment at MD Anderson Cancer Center or otherapproved locations and must be enrolled prior to any neoadjuvant systemic therapyprovided they meet the following eligibility and ineligibility requirements notedbelow:

1. ER and/or PR positive, HER2 negative

2. Clinical stage T1N0M0, unicentric non-lobular breast cancer, no lymphovascularspace invasion,

3. At least 40 years of age.

4. Oncotype ≤ 25 if age ≥ 50 years

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

6. Patient agrees to take anti-estrogen therapy and is interested in breastconservation

7. Female sex.

8. If the patient has a history of a prior non-breast cancer, all treatment forthis cancer must have been completed prior to study registration and thepatient must have no evidence of disease for this prior non-breast cancer.

9. No history of prior radiation to the area of the breast that would requireprotocol-mandated treatment

• Cohort C

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

1. Pathologically confirmed invasive breast cancer defined as radiologic clinicalstage T1 or T2 (≤ 5 cm), N0, clinical stage M0 and HER2 positive (IHC 3+ and orFISH amplified) receiving any standard routine clinical NST regimen containingher-2 directed therapy OR Pathologically confirmed invasive breast cancerdefined as radiologic clinical stage T1 (≤ 2 cm), N0, clinical stage M0 andtriple negative, receiving any standard routine clinical NST regimen.

2. For cohort C patients participating in the optional pretreatment biopsy, thepatient should be able undergo biopsy or surgery of the primary tumor site ofsuspected or proven invasive breast cancer and should be planned to receiveneoadjuvant systemic therapy.

3. Patient desires breast conserving therapy.

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

5. Female sex.

6. If the patient has a history of a prior non-breast cancer, all treatment forthis cancer must have been completed prior to study registration and thepatient must have no evidence of disease for this prior non-breast cancer.

7. Patient must have an initial nodal ultrasound that does not demonstratesuspicious lymph nodes; any suspicious lymph nodes should be biopsied todetermine if nodal metastatic disease present.

8. Patient must have no evidence of residual invasive tumor or DCIS on pathologicreview of the lumpectomy surgical specimen

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

10. Unifocal disease or limited multifocal disease that can be excised in a singlelumpectomy specimen

• Cohort D (MD Anderson Houston patients only)

• Conditions for patient eligibility: Patients on this portion of the study meetall eligibility requirements for cohort C, but have not enrolled onto the studyto omit radiation. Patients in Cohort D can be identified at the time ofdiagnosis or prior to lumpectomy. They are not required to participate in oneof the treatment arms of the study, but can ultimately choose to move to anomission Cohort at a later time point.

3.5.1 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.

3.5.2 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

Exclusion Criteria:

1. Radiologic evidence for a stage T3 or clinical stage T4 breast cancer in CohortA1/A2/C; radiologic evidence for a stage T2-T3 or clinical stage T4 breast cancer inCohort B1/B2.

2. Clinical or pathologic evidence for distant metastases.

3. Prior diagnosis of invasive or ductal carcinoma in situ breast cancer in theipsilateral breast.

4. Clinical evidence of progression of disease >20% in the breast or new evidence ofnodal metastases.

5. Patient is known to be pregnant.

6. Patient is participating in a NST protocol in which surgical excision of the breastand or lymph nodes are required in Cohort A1/A2/B1/B2.