A Randomized Phase III Trial Evaluating the Role of Axillary Lymph Node Dissection in Breast Cancer Patients (cT1-3N1) Who Have Positive Sentinel Lymph Node Disease After Neoadjuvant Chemotherapy

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.

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