STEP 1: Registration to Arm A, B, C

1. Patients must have histologically confirmed adenocarcinoma of the breast at

significant risk of distant recurrence based on at least one of the following criteria: Involvement of at least one axillary lymph node on routine histologic

examination. Patients with axillary node involvement only demonstrated

by immunohistochemistry are not eligible unless they meet one of the

other eligibility criteria below. ER negative tumor >1 cm, ER+ tumor > 5 cm regardless of recurrence score, ER+ tumor >1 cm but < 5 cm with a recurrence score > 11. (Patients enrolled in the TAILORx trial are eligible.)

NOTE: Premenopausal patients with ER+ tumor may participate in the

IBCSG SOFT trial. NOTE: Premenopausal patients with ER- tumor may participate in S0230.

2. Patients must have completed definitive breast surgery including total mastectomy and axillary dissection (modified radical mastectomy), total mastectomy and sentinel node biopsy, breast conservation surgery and axillary dissection or breast conservation surgery and sentinel node biopsy.

NOTE: Axillary dissection is strongly encouraged in patients with lymph node

involvement identified on sentinel node biopsy. NOTE: Breast conservation surgery includes lumpectomy, partial mastectomy, and excisional biopsy.

3. Margins of breast conservation surgery or mastectomy must be histologically free of invasive breast cancer and ductal carcinoma in situ (DCIS). Patients with resection margins positive for lobular carcinoma in situ (LCIS) are eligible.

4. Interval between last surgery for breast cancer (breast conservation surgery, mastectomy, sentinel node biopsy, axillary dissection or re-excision of breast conservation surgery margins) and Day 1 of treatment must be > 28 days and < 84 days.

5. ECOG performance status of 0-1

6. Patients must have adequate organ function within < 8 weeks prior to randomization, as measured by:

Absolute neutrophil count > 1000/mm3

Platelet count > 100,000/mm3

Total bilirubin < 1.5 mg/dL

AST < 2 upper limit of normal

Serum creatinine < 1.5 mg/dL

Urine protein: creatinine (UPC) ratio <1.0*

PTT < 1.5 x normal X ULN

LVEF > institutional limits of normal by MUGA or ECHO

* Please see Appendix V for instructions on how to obtain the urine

protein:creatinine ratio

7. Patients who have undergone breast conservation surgery must receive radiation. Prior to randomization, the investigator must specify the planned radiation technique. NOTE: If APBI was completed prior to study entry, day 1 of protocol therapy must be at least 4 weeks after the completion of APBI.

8. Post-mastectomy RT is required for all patients with a primary tumor of > 5 cm or involvement of 4 or more lymph nodes. Post-mastectomy RT may be administered at the investigator?s discretion for all other mastectomy patients.

9. Patients with HER2 + (3+ by IHC or FISH+) breast cancer are not eligible.

10. Patients with synchronous bilateral breast cancer (diagnosed within one month) are eligible if the higher TNM stage tumor meets the eligibility criteria for this trial.

11. Patients must not have clinical evidence of inflammatory disease or fixed axillary nodes at diagnosis.

12. Patients must not have received prior cytotoxic chemotherapy or hormonal therapy for this breast cancer. Prior treatment with an anthracycline, anthracenedione or taxane for any condition is not allowed. NOTE: Prior use of tamoxifen for chemoprevention is allowed but must be discontinued at study entry. Similarly, prior raloxifene use is allowed but must be discontinued at study entry.

13. Patients must not have had any major surgical procedure within 28 days of day 1 treatment. NOTE: Non-operative biopsy or placement of a vascular access device is not considered a major surgery.

14. Patients may not have had placement of a vascular access device within 24 hours of planned Day 1 of treatment.

15. Patients must not have clinically significant cardiovascular or cerebrovascular disease, including:

*** SNAP FROZEN PARTICIPATION PROHIBITED ***
***Both PRO and QOL should be completed prior to rand or just after AND BEFORE you tell the patient their rand arm (document this if done post rando). The Week 1 PRO should be completed at the end of Week 1 (after the patient has started treatment).***



1. Age >= 18 years

2. Eastern Cooperative Oncology Group (ECOG) performance status ¡Ü1;

3. Non-metastatic operable primary invasive adenocarcinoma of the breast fulfilling the following:
a. Histologically confirmed;
b. Adequately excised (exceptions: patients who have 'non-resectable' deep margin invasion are eligible provided they have had or will receive radiotherapy encompassing the region concerned; patients with histologically documented infiltration of the skin (pT4) are eligible provided they have undergone or will receive radiotherapy encompassing the tumour bed);
c. Axilla dissected; sentinel node sampling is allowed provided that axillary dissection follows confirmation of a positive sentinel node; sentinel node sampling alone is NOT acceptable after neoadjuvant chemotherapy (in patients receiving neoadjuvant chemotherapy lymph node status will be considered unknown, regardless of the results of post-chemotherapy axillary dissection);
d. Axillary node positive patient OR node negative patient with a tumour greater than or equal to 1.0 cm in greatest diameter (>= T1c) according to TNM.

4. Known hormone receptor status (ER/PgR or ER alone);

5. Must have received at least four cycles of an approved anthracycline-based (neo-) adjuvant chemotherapy regimen (see Table 5).
For design 1: Randomisation must be performed no longer than 12 weeks from day 1 of the last chemotherapy cycle after obtaining a post-chemotherapy LVEF ¡Ý 50.
Study treatment should start no more than 14 days after randomisation.
For design 2: Randomisation must be performed no longer than 6 weeks from day 1
of the last anthracycline-containing chemotherapy cycle after obtaining a postanthracycline chemotherapy LVEF ¡Ý 50. Study treatment should start no more than 14 days after randomization and must be concurrent with paclitaxel.

6. Baseline LVEF ¡Ý50% measured by echocardiography or MUGA scan after
completion of all anthracycline-based (neo-) adjuvant chemotherapy and prior to the targeted therapy(ies).

7. Over expression and/or amplification of HER2 in the invasive component of the primary tumour (in case of neoadjuvant treatment, tissue sample used for HER2 testing should be collected before neoadjuvant treatment starts), according to one of the following definitions [Wolff et al 2007] and confirmed by central laboratory prior to randomisation:
¨C 3+ over expression by IHC (> 30% of invasive tumour cells);
¨C 2+ or 3+ (in 30% or less neoplastic cells) over expression by IHC AND in situ
hybridization (FISH/CISH) test demonstrating HER2 gene amplification;
¨C HER2 gene amplification by FISH/CISH ( > 6 HER2 gene copies per nucleus, or a
FISH ratio [HER2 gene copies to chromosome 17 signals] of > than 2.2.)
Patients with a negative or equivocal overall result (FISH test ratio of < 2.2, < 6.0 HER2 gene copies per nucleus) and staining scores of 0,1+, 2+ or 3+ (in 30% or less neoplastic cells) by IHC are not eligible for participation in the trial. Equivocal local results may be submitted for a final determination by the central laboratory.

8. Completion of all necessary baseline laboratory and radiological investigations (see section 6.1);

9. Signed written informed consent (approved by an Independent Ethics Committee

(IEC) and obtained prior to any study specific screening procedures).



Exclusion criteria

Patients meeting any ONE of the following criteria are not eligible for this study:

1. History of any prior (ipsi- and/or contralateral) invasive breast carcinoma;

2. Past or current history of malignant neoplasms, except for curatively treated:

¨C Basal and squamous cell carcinoma of the skin;

¨C Carcinoma in situ of the cervix

3. Any clinically staged T4 tumour, including inflam

**Open to Limited Institutions Only**

Inclusion
-The tumor must be unilateral invasive adenocarcinoma of the breast on histologic examination.
-The breast cancer must be HER2-negative based on current ASCO/CAP Guideline
Recommendations for Human Epidermal Growth Factor Receptor 2 Testing in Breast
Cancer. If the result of the in situ hybridization testing (FISH, CISH, or other) is equivocal, the patient is eligible if there is no plan to administer HER2-targeted therapy.
-All of the following staging criteria must be met (see Appendix B):
• By pathologic evaluation, primary tumor must be pT1-3;
• By pathologic evaluation, ipsilateral nodes must be pN0, pN1 (pN1mi, pN1a, pN1b, pN1c), pN2a, pN3a, or pN3b
If pN0, at least one of the following criteria must be met:
- ER negative and PgR negative; or
- Pathologic tumor size > 2.0 cm; or
- T1c (pathologic tumor size > 1.0 cm but = 2.0 cm) and ER positive (PgR status
may be positive or negative) and either grade 3 histology or Oncotype DX®
Recurrence Score of = 25.
-Patients must have undergone either a total mastectomy or breast-conserving surgery
-For patients who undergo lumpectomy, the margins of the resected specimen must be histologically free of invasive tumor and DCIS as determined by the local pathologist. If pathologic examination demonstrates tumor at the line of resection, additional operative procedures must 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, margins must be histologically free of invasive tumor and DCIS.
-Patients must have completed one of the following procedures for evaluation of
pathologic nodal status:
• Sentinel lymphadenectomy alone if pathologic nodal staging based on sentinel
lymphadenectomy is pN0, pN1mi, or pN1b;
• Sentinel lymphadenectomy followed by removal of additional non-sentinel lymph
nodes if the sentinel node (SN) is positive; or
• Axillary lymphadenectomy without SN isolation procedure.
-The interval between the last surgery for breast cancer (treatment or staging) and randomization must be at least 28 days but no more than 84 days. (Also, see Section 7.6.2 regarding the timing of PBI [if applicable] prior to randomization and initiation of bevacizumab.)
-Patients must have ER analysis performed on the primary tumor prior to randomization. If ER analysis is negative, then PgR analysis must also be performed. (Either a core biopsy or surgical resection specimen can be used for ER/PgR testing.)
Exclusion
-T4 tumors including inflammatory breast cancer.
-Definitive clinical or radiologic evidence of metastatic disease. (Chest imaging [mandatory for all patients] and other imaging [if required] must have been performed within 90 days prior to randomization.)
-Synchronous or metachronous contralateral invasive breast cancer. (Patients with synchronous and/or metachronous contralateral DCIS are eligible.)
-Any history of ipsilateral invasive breast cancer or ipsilateral DCIS.
-History of non-breast malignancies within 5 years prior to randomization, except for the following: carcinoma in situ of the cervix, colorectal carcinoma in situ, melanoma in situ,and basal cell and squamous cell carcinomas of the skin.
-Previous therapy with anthracyclines, taxanes, or bevacizumab for any malignancy.
-Chemotherapy administered for the currently diagnosed breast cancer prior to
randomization.
-Continued therapy with any hormonal agent such as raloxifene or tamoxifen (or other SERM) or an aromatase inhibitor. (Patients are eligible if these medications are discontinued prior to randomization.)
-Any sex hormonal therapy, e.g., birth control pills, ovarian hormone replacement therapy
(see Section 7.8.3). Patients are eligible if these medications are discontinued prior to
randomization.

*** SPECIAL REGULATORY REQUIREMENTS NEEDED PRIOR TO PATIENT ENTRY - Credentialing Required***

***NEW ELIGIBILITY CHANGES AT BOTTOM OF PAGE***

1)On histological exam, tumor must be DCIS or invasive adenocarcinoma.
2)Must have Stage 0, I, or II breast cancer. If stage II, the tumor size must be 3 cm or less.
3)Must have had a lumpectomy w/ negative margins.
4)Gross dz. must be unifocal w/ pathologic tumor size 3 cm or less.
5)Invasive breast CA - required to have axillary staging.
6)Must be randomized w/in 42 days following last surgery for breast CA.
7)Must have ER / PR analysis performed.
8)No T2 lesions > 3.0 cm, Stage III or IV breast ca.
9)No more than 3 histologically positive axillary nodes.
10)No axillary nodes w/ definite evidence of microscopic or macroscopic extracapsular extension.
11)No positive non-axillary sentinel nodes.
12)No non-epithelial breast malignancies such as sarcoma or lymphoma.
13)No proven multicentric carcinoma in more than 1 quadrant or separated by 4 or more cm.
14)No paget's dz. of the nipple. No breast implants.
15)No synchronous bilateral invasive or non-invasive breast cancer. No hx. or invasive breast cancer or DCIS.
16)Treatment plan must not include regional nodal irradiation.
17)No prior breast or thoracic RT for any condition.

The following patients are NOT eligible:

1. Women who are at least 50 years of age with DCIS regardless of hormone-receptor status.
2. Women with invasive breast cancer who meet ALL of the following criteria:
a. at least 50 years of age and
b. Node-negative and
c. Hormone-receptor positive

1)Must be women or men w/ hisotologically confirmed invasive breast ca, stage I, II, or III with known ER or PR status.
2)Pts. w/ bilateral synchronous breast ca dx. w/in 1 month of each other are eligible if higer TNM stage meets eligibility criteria.
3)Pts. must be high risk, meeting at least 1 of the following criteria: Tumor at least 2 cm in greatest diameter or one or more positive axillary or intramammary nodes, with a minimum of 6 nodes examined by pathology.
4)Must have had either a modified radical mastectomy or lumpectomy w/ negative margins. Must have had an axillary dissection or sentinel node resection prior to registration.
5)Must be registered w/in 84 days from final surgical procedure.
6)No prior cytotoxic chemotherapy for this malignancy and no prior chemo w/ anthracycline, antracenedione or taxane for any condition.
7)No prior radiation for current malignancy. Prior XRT for DCIS are eligible as long as it was completed at least 2 weeks prior to registration.
8)No clinical dx of CHF or angina pectoris. Pts. w/ HTN or at least 60 y.o. must have a MUGA or Echo.

STUDY DRUGS: Provided drugs: GCSF (Filgrastim)

Women with HER2neu positive tumors may have Herceptin added to their treatment.