Standard or Comprehensive Radiation Therapy in Treating Patients With Early-Stage Breast Cancer Previously Treated With Chemotherapy and Surgery

PRIMARY OBJECTIVES:

To evaluate whether the addition of chest wall + regional nodal radiation therapy (XRT)
after mastectomy or breast + regional nodal XRT after breast conserving surgery will
significantly reduce the rate of events for invasive breast cancer recurrence-free interval
(IBC-RFI) in patients who present with histologically positive axillary nodes but convert to
histologically negative axillary nodes following neoadjuvant chemotherapy.

SECONDARY OBJECTIVES:

I. To evaluate whether the addition of chest wall + regional nodal XRT after mastectomy or
breast + regional nodal XRT after breast conserving surgery will significantly prolong
overall survival (OS) in patients who present with histologically positive axillary nodes
but convert to histologically negative axillary nodes following neoadjuvant chemotherapy.

II. To evaluate whether the addition of chest wall + regional nodal XRT after mastectomy or
breast + regional nodal XRT after breast conserving surgery will significantly reduce the
rates of events for local-regional recurrence-free interval (LRRFI) in patients who present
with histologically positive axillary nodes but convert to histologically negative axillary
nodes following neoadjuvant chemotherapy.

III. To evaluate whether the addition of chest wall + regional nodal XRT after mastectomy or
breast + regional nodal XRT after breast conserving surgery will significantly reduce the
rate of events for distant recurrence-free interval (DRFI) in patients who present with
histologically positive axillary nodes but convert to histologically negative axillary nodes
following neoadjuvant chemotherapy.

IV. To compare the rates of disease-free survival (DFS)-ductal carcinoma in situ (DCIS) by
treatment arm.

V. To compare the rates of second primary cancer (SPC) by treatment arm.

VI. To compare the effect of adding XRT on the cosmetic outcomes in mastectomy patients who
have had reconstruction.

VII. To compare the effect of adding XRT on quality of life including arm problems,
lymphedema, pain, and fatigue.

VIII. To evaluate the toxicity associated with each of the radiation therapy regimens.

IX. To determine whether computed tomography (CT)-based conformal methods
(intensity-modulated radiation therapy [IMRT] and 3-dimensional conformal radiation therapy
[3DCRT]) for chestwall + regional nodal XRT post mastectomy and regional nodal XRT with
breast XRT following breast conserving surgery are feasible in a multi-institutional setting
and whether dose-volume analyses can be established to assess treatment adequacy and to
develop normal tissue complication probabilities (NTCP) for the likelihood of toxicity.

X. To compare the effect of XRT in patients receiving mastectomy and in patients receiving
lumpectomy.

XI. To examine the role of proliferation measures as a prognosticator for patients with
residual disease after neoadjuvant chemotherapy.

XII. To develop predictors of the degree of reduction in local regional recurrence (LRR).

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

ARM 1: Patients are assigned to 1 of 2 treatment groups.

GROUP 1A: Lumpectomy patients undergo whole breast radiation therapy using IMRT or 3DCRT
once daily 5 days a week for 5 weeks followed by a radiation therapy boost to the lumpectomy
cavity once daily 5 days a week for 1-1/2 weeks.

GROUP 1B: Mastectomy patients do not undergo radiation therapy.

ARM 2: Patients are assigned to 1 of 2 treatment groups.

GROUP 2A: Lumpectomy patients undergo regional nodal radiation therapy with whole breast
radiation therapy using IMRT or 3DCRT once daily 5 days a week for 5 weeks followed by a
radiation therapy boost to the lumpectomy cavity once daily 5 days a week for 1-1/2 weeks.

GROUP 2B: Mastectomy patients undergo regional nodal radiation therapy and chestwall XRT
using IMRT or 3DCRT once daily 5 days a week for 5 weeks.

All patients also receive systemic therapy as planned (hormonal therapy for patients with
hormone-receptor positive breast cancer and trastuzumab or other anti-human epidermal growth
factor receptor 2 [HER2] therapy for patients with breast cancer that is HER2-positive).

After completion of study treatment, patients are followed up at 6, 12, 18, and 24 months
and then yearly for 8 years.

Inclusion Criteria:

- The patient must have signed and dated an Institutional Review Board (IRB)-approved
consent form that conforms to federal and institutional guidelines

- The patient must have an Eastern Cooperative Oncology Group (ECOG) performance status
of 0 or 1

- Patient must have clinically T1-3, N1 breast cancer at the time of diagnosis (before
neoadjuvant therapy); clinical axillary nodal involvement can be assessed by
palpation, ultrasound, CT scan, magnetic resonance imaging (MRI), positron emission
tomography (PET) scan, or PET/CT scan

- Patient must have had pathologic confirmation of axillary nodal involvement at
presentation (before neoadjuvant therapy) based on either a positive fine needle
aspirate (FNA) (demonstrating malignant cells) or positive core needle biopsy
(demonstrating invasive adenocarcinoma); the FNA or core needle biopsy can be
performed either by palpation or by image guidance; documentation of axillary nodal
positivity by sentinel node biopsy (before neoadjuvant therapy) is not permitted

- Patients must have had estrogen receptor (ER) analysis performed on the primary
breast tumor before neoadjuvant therapy according to current American Society of
Clinical Oncology (ASCO)/College of American Pathologists (CAP) guideline
recommendations for hormone receptor testing; if negative for ER, assessment of
progesterone receptor (PgR) must also be performed according to current ASCO/CAP
guideline recommendations for hormone receptor testing (http://www.asco.org)

- Patients must have had HER2 testing performed on the primary breast tumor before
neoadjuvant chemotherapy according to the current ASCO/CAP guideline recommendations
for human epidermal growth factor receptor 2 testing in Breast Cancer
(http://www.asco.org); patients who have a primary tumor that is either HER2-positive
or HER2-negative are eligible

- Patient must have completed a minimum of 12 weeks of standard neoadjuvant
chemotherapy consisting of an anthracycline and/or taxane-based regimen

- For patients who receive adjuvant chemotherapy after surgery, a maximum of 12 weeks
of intended chemotherapy may be administered but must be completed before
randomization; (if treatment delays occur, chemotherapy must be completed within 14
weeks); the dose and schedule of the adjuvant chemotherapy are at the investigator's
discretion; Note: It is preferred that all intended chemotherapy be administered in
the neoadjuvant setting

- Patients with HER2-positive tumors must have received neoadjuvant trastuzumab or
other anti-HER2 therapy (either with all or with a portion of the neoadjuvant
chemotherapy regimen), unless medically contraindicated

- At the time of definitive surgery, all removed axillary nodes must be histologically
free from cancer; acceptable procedures for assessment of axillary nodal status at
the time of surgery include:

- Axillary node dissection

- Sentinel node biopsy alone or

- Sentinel node biopsy followed by axillary node dissection

- Note: Patients are eligible whether there is residual invasive carcinoma in the
surgical breast specimen or whether there is evidence of pathologic complete
response; patients who are found to be pathologically node-positive at the time
of surgery, based on sentinel node biopsy alone, are candidates for A011202, a
study developed by the Alliance in Oncology, an NCI Cooperative Group; if
A011202 is open at the investigator's institution, patients should be approached
about participating in the A011202 study

- Patients with pathologic staging of ypN0(i+) or ypN0(mol+) are eligible (Note:
Postneoadjuvant therapy is designated with a "yp" prefix.)

- Patient who have undergone either a total mastectomy or a lumpectomy are eligible

- For patients who undergo lumpectomy, the margins of the resected specimen or
re-excision must be histologically free of invasive tumor and DCIS as determined by
the local pathologist; additional operative procedures may be performed to obtain
clear margins; if tumor is still present at the resected margin after re-excision(s),
the patient must undergo total mastectomy to be eligible; (patients with margins
positive for lobular carcinoma in situ [LCIS] are eligible without additional
resection)

- For patients who undergo mastectomy, the margins must be histologically free of
residual (microscopic or gross) tumor

- The interval between the last surgery for breast cancer (including re-excision of
margins) and randomization must be no more than 56 days; also, if adjuvant
chemotherapy was administered, the interval between the last chemotherapy treatment
and randomization must be no more than 56 days

- The patient must have recovered from surgery with the incision completely healed and
no signs of infection

- If adjuvant chemotherapy was administered, chemotherapy-related toxicity that may
interfere with delivery of radiation therapy should have resolved

Exclusion Criteria:

- Definitive clinical or radiologic evidence of metastatic disease

- T4 tumors including inflammatory breast cancer

- Documentation of axillary nodal positivity before neoadjuvant therapy by sentinel
node biopsy alone

- N2 or N3 disease detected clinically or by imaging

- Patients with histologically positive axillary nodes post neoadjuvant therapy

- Patients with microscopic positive margins after definitive surgery

- Synchronous or previous contralateral invasive breast cancer or DCIS; (patients with
synchronous and/or previous contralateral LCIS are eligible)

- Any prior history, not including the index cancer, of ipsilateral invasive breast
cancer or ipsilateral DCIS treated with radiation therapy; (patients with synchronous
or previous ipsilateral LCIS are eligible)

- History of non-breast malignancies (except for in situ cancers treated only by local
excision and basal cell and squamous cell carcinomas of the skin) within 5 years
prior to randomization

- Any radiation therapy for the currently diagnosed breast cancer prior to
randomization

- Any continued use of sex hormonal therapy, e.g., birth control pills, ovarian hormone
replacement therapy; patients are eligible if these medications are discontinued
prior to randomization

- Prior breast or thoracic radiation therapy (RT) for any condition

- Active collagen vascular disease, specifically dermatomyositis with a creatinine
phosphokinase (CPK) level above normal or with an active skin rash, systemic lupus
erythematosus, or scleroderma

- Pregnancy or lactation at the time of study entry; (Note: Pregnancy testing must be
performed within 2 weeks prior to randomization according to institutional standards
for women of childbearing potential)

- Other non-malignant systemic disease that would preclude the patient from receiving
study treatment or would prevent required follow-up

- Psychiatric or addictive disorders or other conditions that, in the opinion of the
investigator, would preclude the patient from meeting the study requirements