Comparison of Axillary Lymph Node Dissection With Axillary Radiation for Patients With Node-Positive Breast Cancer Treated With Chemotherapy

Study Outline:

- All patients will undergo surgery to identify sentinel lymph node(s). If a lymph node
(sentinel or non-sentinel) is determined to be positive on intra-operative pathology the
patient will be registered/randomized intra-operatively.

- Patients who do not have a sentinel lymph node identified will not be
registered/randomized to the study.

- Patients whose sentinel lymph node status is cannot be/is not determined intra-
operatively, and have not undergone ALND, but had at least one lymph node (sentinel or
non-sentinel) found to be positive on final pathology review will be
registered/randomized post-operatively.

- Patients whose sentinel lymph node status is found to be negative intra-operatively and
have not undergone ALND, but had at least one lymph node (sentinel or non-sentinel)
found to be positive on final pathology review will be registered/randomized
post-operatively.

- ALND is not to be performed prior to registration/randomization.

- Patients who are determined to have negative lymph nodes on final pathology will not be
registered/randomized, but can be offered participation in another cooperative group
trial.

The primary and secondary objectives of the study are described below. Please see the "Arms"
section for a detailed description of the treatment regimens.

Primary Objective:

- 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 SLN(s) after completion of neoadjuvant chemotherapy

Secondary Objectives:

- 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

- To obtain an estimate of the distribution of residual disease burden scores for each
treatment arm

- To estimate the distribution of overall survival for each treatment arm

Patients may receive adjuvant and ancillary therapy as appropriate per the protocol.

Adjuvant Therapy:

- Adjuvant endocrine therapy: Patients with hormone receptor (ER and/or PR) positive
disease should receive a minimum of 5 years of standard endocrine therapy (experimental
agents/regimens are not permitted). Endocrine therapy should begin following completion
of neoadjuvant chemotherapy and surgery, either before, during or after radiation
therapy at the discretion of the oncologist. Selection of the agents is at the treating
physician's discretion.

- Patients with HER 2 positive disease should complete a total of one year of trastuzumab
therapy (over the neoadjuvant and adjuvant period).

- Chemotherapy, biologic therapy or vaccine therapy in the adjuvant setting is not
allowed.

Patients who wish to receive any of these therapies after surgery must go off study at the
time of their initiation.

Ancillary Therapy:

- Patients should receive full supportive care, including transfusions of blood and blood
products, erythropoetin (unless otherwise specified in the protocol), antibiotics,
antiemetics, etc. when appropriate.

Patients are followed up for 5 years after completion of radiation therapy.

Pre-Registration Eligibility Criteria:

1. Patients ≥ 18 years of age

2. 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

3. No inflammatory breast cancer

4. 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

5. 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.

6. Patients must have had estrogen receptor, progesterone receptor and human epidermal
growth factor receptor 2 (HER2) status by immunohistochemistry [IHC] and/or
fluorescence in situ hybridization [FISH] evaluated on diagnostic core biopsy prior to
start of neoadjuvant chemotherapy. Note: If HER2 status has not been clearly
determined (ie equivocal/indeterminate), then patients should not be enrolled.

7. Patients must have completed all planned chemotherapy prior to surgery. Sandwich
chemotherapy is not allowed (i.e. 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 NAC may be administered at the
discretion of the treating medical oncologist.

8. 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.

9. All patients must have a clinically negative axilla (no palpable lymph nodes or 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.

10. No neoadjuvant endocrine therapy

11. No neoadjuvant radiation therapy

12. No sentinel lymph node (SLN) surgery/excisional biopsy for pathological confirmation
of axillary status prior to or during neoadjuvant chemotherapy

13. 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.

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

15. No history of prior or concurrent contralateral invasive breast cancer. Benign breast
disease, LCIS or DCIS of contralateral breast is allowed.

16. Patients must not be pregnant or nursing. A negative pregnancy test is required prior
to registration for women of childbearing potential. Note: Peri-menopausal women must
be amenorrheic for > 12 months to be considered not of childbearing potential.

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

18. Required Pre-Registration Laboratory Values:

- Serum or urine beta-human chorionic gonadotropin (ß-HCG)

- Negative in women of child-bearing potential

Intra-Operative Registration/Randomization Criteria:

1. Breast surgery (lumpectomy or mastectomy) and sentinel lymph node surgery must be
completed within 56 days of the completion of neoadjuvant chemotherapy.

2. A minimum of 1 sentinel node and a maximum of 6 total nodes (sentinel + non-sentinel)
are identified and excised by the surgeon. Patients who do not have an identifiable
sentinel lymph node will not proceed to Registration/Randomization.

3. At least one lymph node (sentinel or non-sentinel) 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+). Axillary lymph node dissection [ALND] is not to be performed
prior to Registration/Randomization.

Post-Operative Registration/Randomization Criteria:

1. For cases where ALND has not been performed and one of the following is true:

- 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 on hematoxylin and eosin stain (H & E) OR

- 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 on H & E)

- Breast surgery (lumpectomy or mastectomy) and sentinel lymph node surgery must be
completed within 56 days of the completion of neoadjuvant chemotherapy.

- At least one lymph node (sentinel or non-sentinel) with a metastasis greater than
0.2 mm in greatest dimension identified by H&E staining on final pathology (for
cases where intra-operative evaluation was not performed, or was negative and
completion dissection was not performed).

- Among the minimum of 1 and the maximum of 6 nodes (sentinel or non-sentinel)
identified and excised by the surgeon, no more than 8 lymph nodes (sentinel and
non-sentinel) were found by the pathologists to have been actually excised. 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.