This randomized phase III trial studies lymph node dissection and radiation therapy to see how well it works compared to radiation therapy alone in treating patients with breast cancer previously treated with chemotherapy and surgery. Lymph node dissection may remove cancer cells that have spread to nearby lymph nodes in patients with breast cancer. Radiation therapy uses high-energy x rays or protons to kill tumor cells. It is not yet known if radiation therapy works better alone or with lymph node dissection in treating patients with breast cancer previously treated with chemotherapy and surgery.

PRIMARY OBJECTIVE:

I. To evaluate whether radiation to the undissected axilla and regional lymph nodes is not inferior to axillary lymph node dissection with radiation to the regional lymph nodes but not to the dissected axilla in terms of invasive breast cancer recurrence-free interval in patients with positive sentinel lymph node(s) (SLN[s]) after completion of neoadjuvant chemotherapy.

SECONDARY OBJECTIVES:

I. To evaluate whether radiation to the undissected axilla and regional lymph nodes is not inferior to axillary lymph node dissection with radiation to the regional lymph nodes but not to the dissected axilla in terms of the incidence of invasive loco-regional recurrences in patients with a positive SLN(s) after completion of neoadjuvant chemotherapy.

II. To obtain an estimate of the distribution of residual disease burden scores.

III. To estimate the distribution of overall survival.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients undergo axillary lymph node dissection. Beginning 3-12 weeks following surgery, patients undergo nodal radiation therapy comprising 3-dimensional (3D) conformal radiation therapy (3D-CRT), intensity-modulated radiation therapy (IMRT), or proton radiation therapy (PRT) 5 days a week for 5-6 weeks.

ARM II: Patients undergo axillary and nodal radiation therapy comprising 3D-CRT, IMRT, or PRT 5 days a week for 5-6 weeks.

After completion of study treatment, patients are followed up at least every 6 months for 2 years and then annually for 3 years.

Pre-Registration Eligibility Criteria:

• Clinical stage T1-3 N1 M0 breast cancer at diagnosis (prior to the start of neoadjuvant chemotherapy) by American Joint Committee on Cancer (AJCC) staging 7th edition

• No inflammatory breast cancer

• No other malignancy within 5 years of registration 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

• All patients must have had an axillary ultrasound with fine needle aspiration (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

  * Note: Biopsy of intramammary nodes does not fulfill eligibility criteria

• Patients must have had estrogen receptor, progesterone receptor and HER2 status (by immunohistochemistry [IHC] and/or in situ hybridization [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

• Patients must have completed all planned neoadjuvant chemotherapy prior to surgery; sandwich chemotherapy is not allowed (i.e. anthracycline/cytoxan or taxane chemotherapy planned to be given after surgery); patients must have completed at least 4 cycles of neoadjuvant chemotherapy consisting of an anthracycline and/or taxane-based regimen without evidence of disease progression in the breast or the lymph nodes

  * Note: Delays/dose modifications due to toxicities/adverse events are allowed as long as a minimum of 4 cycles of neoadjuvant chemotherapy is administered; more than 4 cycles of neoadjuvant chemotherapy (NAC) may be administered at the discretion of the treating medical oncologist

• 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 Food and Drug Administration (FDA)-approved targeted anti-HER2 therapy, but additional therapies are allowed as are non-trastuzumab regimens if administered in the context of an Institutional Review Board (IRB)-approved clinical trial

• All patients must have a clinically negative axilla (no bulky adenopathy) on physical examination documented at the completion of neoadjuvant chemotherapy

  * Note: an ultrasound of the axilla is not required at completion of neoadjuvant chemotherapy; if performed, its findings do NOT impact eligibility

• No more than 8 weeks of neoadjuvant endocrine therapy prior to the start of neoadjuvant chemotherapy

• No neoadjuvant radiation therapy

• No SLN surgery/excisional biopsy for pathological confirmation of axillary status prior to or during neoadjuvant chemotherapy

• No prior history of ipsilateral breast cancer (invasive disease or ductal carcinoma in situ [DCIS]); lobular carcinoma in situ (LCIS) and benign breast disease is allowed

• No prior ipsilateral axillary surgery, such as excisional biopsy of lymph node(s) or treatment of hidradenitis

• No history of prior or concurrent contralateral invasive breast cancer; benign breast disease; LCIS or DCIS of contralateral breast is allowed

• Patients must not be pregnant or nursing

  * Note: Peri-menopausal women must be amenorrheic for > 12 months to be considered not of childbearing potential

• Eastern Cooperative Oncology Group (ECOG) (Zubrod) performance status 0-1

Intra-Operative Registration/Randomization Criteria:

• 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

• A minimum of 1 sentinel node and a maximum of 8 total nodes (sentinel + non-sentinel) are identified and excised; more than 8 nodes identified by either surgeon or pathologist is NOT allowed Note: Patients who do not have an identifiable sentinel lymph node will not proceed to registration/randomization

• At least one lymph node (sentinel or non-sentinel) excised during sentinel lymph node surgery with a metastasis greater than 0.2 mm in greatest dimension identified on intra-operative pathologic assessment

  • Note: Isolated tumor cells (metastases less than or equal to 0.2 mm) will be treated as node negative disease (N0i+)
  • Note: If on final pathology, more than 8 lymph nodes are seen pathologically, then the patient should discontinue study
  • Axillary lymph node dissection (ALND) is not to be performed prior to registration/randomization
  • Note: Patients for whom no positive lymph nodes (sentinel or non-sentinel) are found during sentinel lymph node surgery will not proceed to registration/randomization and can be considered for discussion of the NRG NSABP B-51/RTOG 1304 study "A Randomized Phase III Clinical Trial Evaluating the Role of Post-mastectomy Chest Wall and Regional Nodal XRT and Post-lumpectomy Regional Nodal XRT in Patients with Documented Positive Axillary Nodes Before Neoadjuvant Chemotherapy Who Convert to Pathologically Negative Axillary Nodes After Neoadjuvant Chemotherapy"

Post-Operative Registration/Randomization Criteria:

• For cases where ALND has not been performed and one of the following is true: 1) intra-operative evaluation of sentinel lymph node could not be/was not performed and final pathology identified a positive lymph node (sentinel or non-sentinel) with metastasis greater than 0.2 mm OR 2) lymph node (sentinel or non-sentinel) considered negative on intra-operative evaluation was found to be positive on final pathology (with metastasis greater than 0.2 mm)
• 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
• At least one lymph node (sentinel or non-sentinel) with a metastasis greater than 0.2 mm in greatest dimension identified on final pathology (for cases where intra-operative evaluation was not performed, or was negative and completion dissection was not performed)
• At least one and no more than 8 lymph nodes (sentinel and non-sentinel) were found by the pathologists to have been actually excised during sentinel lymph node procedure Note: Isolated tumor cells (metastases less than or equal to 0.2 mm) will be treated as node negative disease (N0i+)
• For those patients who also undergo contralateral breast surgery, if invasive disease is found in the contralateral breast, the patient is not eligible for registration /randomization