This is a prospective, phase 2, single arm trial to evaluate whether Axillary Lymph Node Dissection (ALND) can be safely omitted for patients with cN2 and cN3 breast cancer who achieve a complete clinical response on exam with a complete or partial response by end-of-treatment (EOT) imaging and have either a partial or complete pathologic nodal response after neoadjuvant chemotherapy (NAC) by performing nodal assessment of sentinel lymph node surgery (with or without targeted axillary dissection (TAD) followed by Regional Nodal Irradiation (RNI).

This study aims to demonstrate that performing only a sentinel node dissection, which includes the removal of palpably gross disease followed by radiation, will not impact distant disease and thus survival.

Inclusion Criteria:

1. Ability of participant to understand this study, and participant willingness to sign a written informed consent. NOTE Remote consenting allowed per IRB policy and approval.
2. Stated willingness to comply with all study procedures and lifestyle considerations and availability for the duration of the study
3. Males and/or females age ≥ 18 to 80 years
4. Clinical stage T1-3 N2-3 M0 breast cancer at diagnosis (prior to the start of neoadjuvant chemotherapy).
5. Patients stage T1-3 cN1 (prior to start of neoadjuvant chemotherapy) and pN2-3 breast cancer based on number of positive nodes on final surgical pathology.
6. All patients must have had an axillary ultrasound with FNA or core needle biopsy of axillary lymph nodes documenting axillary metastasis at the time of diagnosis, prior to or at most 14 days after starting neoadjuvant chemotherapy.
7. Patients must have had estrogen receptor, progesterone receptor and HER2 status (by IHC and/or ISH) evaluated on diagnostic core biopsy prior to start of neoadjuvant chemotherapy. Note: If HER2 status has not been clearly determined (i.e. equivocal/indeterminate), then patients should not be enrolled (see exclusion criteria).
8. Patients must have completed planned chemotherapy (neoadjuvant chemotherapy [NAC]) prior to surgery. Sandwich chemotherapy is not allowed (i.e. chemotherapy planned to be given after surgery). Adjuvant systemic therapy based on final surgical pathology is allowed and at the discretion of the treating medical oncologist. Note: Delays/dose modifications due to toxicities/adverse events are allowed per the treating medical oncologist.
9. Patients with HER-2 positive tumors must have received neoadjuvant trastuzumab, or trastuzumab + pertuzumab, or other approved anti-HER-2 therapy (either with all or with a portion of the neoadjuvant chemotherapy regimen). Therapy must be FDA-approved targeted anti-HER2 therapy, but additional therapies are allowed as are non-trastuzumab regimens if administered in the context of an IRB-approved clinical trial.
10. Benign breast disease, LCIS or DCIS of contralateral breast is allowed
11. All patients must have a clinically negative axilla (no bulky adenopathy) on physical examination documented at the completion of neoadjuvant chemotherapy. Note: A partial or complete imaging response that includes all lymph nodes measuring ≤ 1cm clinically is required for eligibility.
12. ECOG (Zubrod) Performance Status 0-1 (Appendix A)
13. A minimum of 1 sentinel node must be identified and excised by the surgeon. Patients who do not have an identifiable sentinel lymph node will not proceed to omission of ALND.
14. Patients that have a pathologic complete response (pCR) in the breast and axilla can be considered for discussion at the Breast Multidisciplinary Tumor Conference for omission of radiation. Note: Isolated tumor cells (metastases less than or equal to 0.2 mm) will be treated as node negative disease (N0i+).
15. Breast surgery (lumpectomy or mastectomy) and sentinel lymph node surgery must be completed within 56 days of the completion of the last dose of neoadjuvant chemotherapy. Negative margin (by either breast conservation or mastectomy) on final pathology where negative margin is defined as no tumor on ink.
16. Females of childbearing potential must have a negative serum pregnancy at day of surgery in pre-operative holding prior to initiating treatment.
17. Females of child-bearing potential and males with partners of child-bearing potential must agree not to donate sperm, to practice sexual abstinence or to use the forms of contraception listed in Child-Bearing Potential/Pregnancy section for the duration of study participation and, following the last administration of therapy , for as long as directed per standard or care chemotherapy (investigational regimen allowed) and radiation therapy, whichever is longer. Note: Peri-menopausal women must be amenorrheic for ≥ 12 months to be considered not of childbearing potential.

Definition of medically fit for surgery:

• ECOG status of 0-1
• NOTE - participants are eligible for surgery if they have nicotine in the blood or high A1c. These values will be monitored per SOC.

Exclusion Criteria:

1. Diagnosed with a psychiatric illness or is in a social situation that would limit compliance with study requirements and / or giving informed consent.
2. Medical condition such as uncontrolled infection (including HIV), uncontrolled diabetes mellitus or cardiac disease which, in the opinion of the treating physician, would make this study unreasonably hazardous for the patient.
3. Inflammatory breast cancer.
4. Any other malignancy within 5 years of enrollment with the exception of basal cell or squamous cell carcinoma of the skin treated with local resection only or carcinoma in situ of the cervix.
5. HER2 status has not been clearly determined (i.e. equivocal/indeterminate)
6. Patient has had neoadjuvant endocrine therapy > than 8 weeks prior to the start of neoadjuvant chemotherapy.
7. Neoadjuvant radiation therapy.
8. SLN surgery/excisional biopsy for pathological confirmation of axillary status prior to or during neoadjuvant chemotherapy.
9. Prior history of ipsilateral breast cancer (invasive disease or DCIS). NOTE LCIS and benign breast disease is allowed.
10. Prior ipsilateral axillary surgery, such as excisional biopsy of lymph node(s) or treatment of hidradenitis.
11. History of prior or concurrent contralateral invasive breast cancer. .
12. Patient pregnant or nursing.