S0221 Adjuvant Doxorubicin, Cyclophosphamide, and Paclitaxel in Treating Patients With Breast Cancer

• ClinicalTrials.gov Identifier: NCT00070564
• Recruitment Status: Active, not recruiting
• First Posted: October 7, 2003
• Results First Posted: April 17, 2017
• Last Update Posted: April 15, 2024
• Sponsor: SWOG Cancer Research Network
• Collaborator: National Cancer Institute (NCI)
• Information provided by (Responsible Party): SWOG Cancer Research Network

• Study Type: Interventional
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Breast Cancer
• Interventions: Biological: pegfilgrastim; Drug: AC regimen; Drug: cyclophosphamide; Drug: doxorubicin hydrochloride; Drug: paclitaxel
• Enrollment: 3294

Participant Flow

Recruitment Details
Pre-assignment Details

Arm/Group Title	Arm I	Arm II	Arm III	Arm IV	Arm V	Arm VI
Arm/Group Description	(closed 11/10/10) Patients receive doxorubicin IV and cyclophosphamide IV on day 1 and pegfilgrastim subcutaneously (SC) on day 2 or filgrastim (G-CSF) SC on days 3-10. Treatment repeats every 14 days for 6 courses. Beginning 2 weeks after completion of doxorubicin and cyclophosphamide, patients receive paclitaxel IV over 3 hours on day 1 and pegfilgrastim SC on day 2. Treatment repeats every 14 days for 6 courses. pegfilgrastim: Given IV AC regimen: Given IV cyclophosphamide: Given IV doxorubicin hydrochloride: Given IV paclitaxel: Given IV	(closed 11/10/10) Patients receive doxorubicin IV on day 1, oral cyclophosphamide on days 1-7, and G-CSF SC on days 2-7. Treatment repeats every 7 days for 15 courses. Beginning 2 weeks after completion of cyclophosphamide, patients receive paclitaxel and pegfilgrastim as in arm I. pegfilgrastim: Given IV AC regimen: Given IV cyclophosphamide: Given IV doxorubicin hydrochloride: Given IV paclitaxel: Given IV	(closed 11/10/10) Patients receive doxorubicin, cyclophosphamide, and pegfilgrastim or G-CSF as in arm I. Beginning 2 weeks after completion of doxorubicin and cyclophosphamide, patients receive paclitaxel IV over 1 hour on day 1. Treatment repeats every 7 days for 12 courses. pegfilgrastim: Given IV AC regimen: Given IV cyclophosphamide: Given IV doxorubicin hydrochloride: Given IV paclitaxel: Given IV	(closed 11/10/10) Patients receive doxorubicin, cyclophosphamide, and G-CSF as in arm II. Beginning 2 weeks after completion of cyclophosphamide, patients receive paclitaxel as in arm III. pegfilgrastim: Given IV AC regimen: Given IV cyclophosphamide: Given IV doxorubicin hydrochloride: Given IV paclitaxel: Given IV	(reopened in 12/2010) Patients receive doxorubicin IV and cyclophosphamide IV on day 1 and pegfilgrastim SC on day 2. Treatment repeats every 14 days for 4 courses. Patients receive doxorubicin IV and cyclophosphamide IV on day 1 and pegfilgrastim SC on day 2. Treatment repeats every 14 days for 6 courses. Beginning 2 weeks after completion of doxorubicin and cyclophosphamide, patients receive paclitaxel IV over 3 hours on day 1 and pegfilgrastim SC on day 2. Treatment repeats every 14 days for 6 courses.	(reopened in 12/2010) Patients receive doxorubicin IV and cyclophosphamide IV on day 1 and pegfilgrastim SC on day 2. Treatment repeats every 14 days for 4 courses. Patients receive doxorubicin IV and cyclophosphamide IV on day 1 and pegfilgrastim SC on day 2. Treatment repeats every 14 days for 6 courses. Beginning 2 weeks after completion of doxorubicin and cyclophosphamide, patients receive paclitaxel IV over 1 hour on day 1. Treatment repeats every 7 days for 12 courses.
Period Title: Overall Study
Started	678	693	697	648	282	296
Completed	478	490	526	481	203	244
Not Completed	200	203	171	167	79	52
Reason Not Completed
Progression	2	4	7	7	1	0
Delinquent	1	4	2	0	0	0
Adverse Event	150	142	120	108	63	36
Death	4	1	5	3	0	1
Other, not protocol specified	17	15	14	19	6	7
Withdrawal by Subject	26	37	23	30	8	8
Not reported	0	0	0	0	1	0

Baseline Characteristics

Arm/Group Title		Arm I	Arm II	Arm III	Arm IV	Arm V	ARM VI	Total
Arm/Group Description		(closed 11/10/10) Patients receive doxorubicin IV and cyclophosphamide IV on day 1 and pegfilgrastim subcutaneously (SC) on day 2 or filgrastim (G-CSF) SC on days 3-10. Treatment repeats every 14 days for 6 courses. Beginning 2 weeks after completion of doxorubicin and cyclophosphamide, patients receive paclitaxel IV over 3 hours on day 1 and pegfilgrastim SC on day 2. Treatment repeats every 14 days for 6 courses. pegfilgrastim: Given IV AC regimen: Given IV cyclophosphamide: Given IV doxorubicin hydrochloride: Given IV paclitaxel: Given IV	(closed 11/10/10) Patients receive doxorubicin IV on day 1, oral cyclophosphamide on days 1-7, and G-CSF SC on days 2-7. Treatment repeats every 7 days for 15 courses. Beginning 2 weeks after completion of cyclophosphamide, patients receive paclitaxel and pegfilgrastim as in arm I. pegfilgrastim: Given IV AC regimen: Given IV cyclophosphamide: Given IV doxorubicin hydrochloride: Given IV paclitaxel: Given IV	(closed 11/10/10) Patients receive doxorubicin, cyclophosphamide, and pegfilgrastim or G-CSF as in arm I. Beginning 2 weeks after completion of doxorubicin and cyclophosphamide, patients receive paclitaxel IV over 1 hour on day 1. Treatment repeats every 7 days for 12 courses. pegfilgrastim: Given IV AC regimen: Given IV cyclophosphamide: Given IV doxorubicin hydrochloride: Given IV paclitaxel: Given IV	(closed 11/10/10) Patients receive doxorubicin, cyclophosphamide, and G-CSF as in arm II. Beginning 2 weeks after completion of cyclophosphamide, patients receive paclitaxel as in arm III. pegfilgrastim: Given IV AC regimen: Given IV cyclophosphamide: Given IV doxorubicin hydrochloride: Given IV paclitaxel: Given IV	(reopened in 12/2010) Patients receive doxorubicin IV and cyclophosphamide IV on day 1 and pegfilgrastim SC on day 2. Treatment repeats every 14 days for 4 courses. Patients receive doxorubicin IV and cyclophosphamide IV on day 1 and pegfilgrastim SC on day 2. Treatment repeats every 14 days for 6 courses. Beginning 2 weeks after completion of doxorubicin and cyclophosphamide, patients receive paclitaxel IV over 3 hours on day 1 and pegfilgrastim SC on day 2. Treatment repeats every 14 days for 6 courses.	(reopened in 12/2010) Patients receive doxorubicin IV and cyclophosphamide IV on day 1 and pegfilgrastim SC on day 2. Treatment repeats every 14 days for 4 courses. Patients receive doxorubicin IV and cyclophosphamide IV on day 1 and pegfilgrastim SC on day 2. Treatment repeats every 14 days for 6 courses. Beginning 2 weeks after completion of doxorubicin and cyclophosphamide, patients receive paclitaxel IV over 1 hour on day 1. Treatment repeats every 7 days for 12 courses.	Total of all reporting groups
Overall Number of Baseline Participants		664	683	681	639	277	294	3238
Baseline Analysis Population Description		Only eligible and analyzable patients were included in the analysis.
Age, Continuous; Median (Full Range); Unit of measure: Years
	Number Analyzed	664 participants	683 participants	681 participants	639 participants	277 participants	294 participants	3238 participants
		50.5; (25 to 77)	50.9; (23 to 79)	51.8; (23 to 86)	50.7; (21 to 76)	52.7; (31 to 79)	53.2; (23 to 76)	52.7; (21 to 86)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	664 participants	683 participants	681 participants	639 participants	277 participants	294 participants	3238 participants
	Female	658 99.1%	679 99.4%	676 99.3%	636 99.5%	275 99.3%	291 99.0%	3215 99.3%
	Male	6 0.9%	4 0.6%	5 0.7%	3 0.5%	2 0.7%	3 1.0%	23 0.7%
Black Race; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	664 participants	683 participants	681 participants	639 participants	277 participants	294 participants	3238 participants
		73 11.0%	77 11.3%	74 10.9%	78 12.2%	31 11.2%	44 15.0%	377 11.6%
Menopausal status (females) [1]; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	658 participants	679 participants	676 participants	636 participants	275 participants	291 participants	3215 participants
	Premenopausal	326 49.5%	325 47.9%	308 45.6%	299 47.0%	124 45.1%	123 42.3%	1505 46.8%
	Postmenopausal	332 50.5%	354 52.1%	368 54.4%	337 53.0%	148 53.8%	166 57.0%	1705 53.0%
	Unknown	0 0.0%	0 0.0%	0 0.0%	0 0.0%	3 1.1%	2 0.7%	5 0.2%
		[1] Measure Analysis Population Description: Only females of the total eligible and analyzable patients were included in menopausal status measurement.
Nodal status; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	664 participants	683 participants	681 participants	639 participants	277 participants	294 participants	3238 participants
	Negative	161 24.2%	153 22.4%	159 23.3%	146 22.8%	105 37.9%	109 37.1%	833 25.7%
	1-3 positive nodes	260 39.2%	266 38.9%	276 40.5%	245 38.3%	103 37.2%	98 33.3%	1248 38.5%
	>= 4 positive nodes	241 36.3%	264 38.7%	243 35.7%	244 38.2%	68 24.5%	87 29.6%	1147 35.4%
	unknown	2 0.3%	0 0.0%	3 0.4%	4 0.6%	1 0.4%	0 0.0%	10 0.3%
ER/PgR [1]; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	664 participants	683 participants	681 participants	639 participants	277 participants	294 participants	3238 participants
	Negative (both negative)	212 31.9%	226 33.1%	232 34.1%	206 32.2%	99 35.7%	108 36.7%	1083 33.4%
	Positive (either or both positive)	450 67.8%	456 66.8%	446 65.5%	430 67.3%	178 64.3%	185 62.9%	2145 66.2%
	Unknown	2 0.3%	1 0.1%	3 0.4%	3 0.5%	0 0.0%	1 0.3%	10 0.3%
		[1] Measure Description: ER, estrogen receptor; PgR, progesterone receptor
HER2 [1]; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	664 participants	683 participants	681 participants	639 participants	277 participants	294 participants	3238 participants
	Negative	528 79.5%	556 81.4%	554 81.4%	525 82.2%	208 75.1%	235 79.9%	2606 80.5%
	Positive	125 18.8%	123 18.0%	118 17.3%	109 17.1%	69 24.9%	57 19.4%	601 18.6%
	Unknown	11 1.7%	4 0.6%	9 1.3%	5 0.8%	0 0.0%	2 0.7%	31 1.0%
		[1] Measure Description: HER2, human epidermal growth factor receptor 2.

Outcome Measures

1. Primary Outcome

Title	Disease-free Survival
Description	Disease-free survival (DFS) defined as time from registration (randomization assignment) to first instance of disease recurrence (local, regional, or distant), new breast primary tumor, or death as a result of any cause. The results are entered as disease free survival at year 5.
Time Frame	every 6 months (annually for mammograms) for 5 years

Outcome Measure Data

Analysis Population Description

Only eligible and analyzable patients were included in this analysis. Two patients in Arm II and one patient in Arm IV with no follow-up were excluded.

Arm/Group Title	Arm I	Arm II	Arm III	Arm IV	Arm V	Arm VI
Arm/Group Description:	(closed 11/10/10) Patients receive doxorubicin IV and cyclophosphamide IV on day 1 and pegfilgrastim subcutaneously (SC) on day 2 or filgrastim (G-CSF) SC on days 3-10. Treatment repeats every 14 days for 6 courses. Beginning 2 weeks after completion of doxorubicin and cyclophosphamide, patients receive paclitaxel IV over 3 hours on day 1 and pegfilgrastim SC on day 2. Treatment repeats every 14 days for 6 courses. pegfilgrastim: Given IV AC regimen: Given IV cyclophosphamide: Given IV doxorubicin hydrochloride: Given IV paclitaxel: Given IV	(closed 11/10/10) Patients receive doxorubicin IV on day 1, oral cyclophosphamide on days 1-7, and G-CSF SC on days 2-7. Treatment repeats every 7 days for 15 courses. Beginning 2 weeks after completion of cyclophosphamide, patients receive paclitaxel and pegfilgrastim as in arm I. pegfilgrastim: Given IV AC regimen: Given IV cyclophosphamide: Given IV doxorubicin hydrochloride: Given IV paclitaxel: Given IV	(closed 11/10/10) Patients receive doxorubicin, cyclophosphamide, and pegfilgrastim or G-CSF as in arm I. Beginning 2 weeks after completion of doxorubicin and cyclophosphamide, patients receive paclitaxel IV over 1 hour on day 1. Treatment repeats every 7 days for 12 courses. pegfilgrastim: Given IV AC regimen: Given IV cyclophosphamide: Given IV doxorubicin hydrochloride: Given IV paclitaxel: Given IV	(closed 11/10/10) Patients receive doxorubicin, cyclophosphamide, and G-CSF as in arm II. Beginning 2 weeks after completion of cyclophosphamide, patients receive paclitaxel as in arm III. pegfilgrastim: Given IV AC regimen: Given IV cyclophosphamide: Given IV doxorubicin hydrochloride: Given IV paclitaxel: Given IV	(reopened in 12/2010) Patients receive doxorubicin IV and cyclophosphamide IV on day 1 and pegfilgrastim SC on day 2. Treatment repeats every 14 days for 4 courses. Patients receive doxorubicin IV and cyclophosphamide IV on day 1 and pegfilgrastim SC on day 2. Treatment repeats every 14 days for 6 courses. Beginning 2 weeks after completion of doxorubicin and cyclophosphamide, patients receive paclitaxel IV over 3 hours on day 1 and pegfilgrastim SC on day 2. Treatment repeats every 14 days for 6 courses.	(reopened in 12/2010) Patients receive doxorubicin IV and cyclophosphamide IV on day 1 and pegfilgrastim SC on day 2. Treatment repeats every 14 days for 4 courses. Patients receive doxorubicin IV and cyclophosphamide IV on day 1 and pegfilgrastim SC on day 2. Treatment repeats every 14 days for 6 courses. Beginning 2 weeks after completion of doxorubicin and cyclophosphamide, patients receive paclitaxel IV over 1 hour on day 1. Treatment repeats every 7 days for 12 courses.
Overall Number of Participants Analyzed	664	681	681	638	277	294
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
	83; (80 to 86)	79; (76 to 82)	81; (78 to 84)	81; (78 to 84)	84; (79 to 88)	85; (80 to 89)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm I, Arm II
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.022
	Comments	[Not Specified]
	Method	Log Rank
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.32
	Confidence Interval	(2-Sided) 95%; 1.04 to 1.68
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Arm I, Arm III
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.072
	Comments	[Not Specified]
	Method	Log Rank
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.24
	Confidence Interval	(2-Sided) 95%; 0.98 to 1.59
	Estimation Comments	[Not Specified]

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Arm I, Arm IV
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.38
	Comments	[Not Specified]
	Method	Log Rank
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.12
	Confidence Interval	(2-Sided) 95%; 0.87 to 1.44
	Estimation Comments	[Not Specified]

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Arm I, Arm II, Arm III, Arm IV
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.11
	Comments	[Not Specified]
	Method	Log Rank
	Comments	[Not Specified]

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Arm V, Arm VI
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.733
	Comments	[Not Specified]
	Method	Log Rank
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.93
	Confidence Interval	(2-Sided) 95%; 0.61 to 1.41
	Estimation Comments	[Not Specified]

2. Primary Outcome

Title	Overall Survival
Description	Overall survival defined as time from registration to death as result of any cause. Results were entered as overall survival rate at year 5.
Time Frame	Every 6 months for 5 years

Outcome Measure Data

Analysis Population Description

Only eligible and analyzable patients were included in this analysis. Two patients in Arm II and one patient in Arm IV with no follow-up were excluded.

Arm/Group Title	Arm I	Arm II	Arm III	Arm IV	Arm V	Arm VI
Arm/Group Description:	(closed 11/10/10) Patients receive doxorubicin IV and cyclophosphamide IV on day 1 and pegfilgrastim subcutaneously (SC) on day 2 or filgrastim (G-CSF) SC on days 3-10. Treatment repeats every 14 days for 6 courses. Beginning 2 weeks after completion of doxorubicin and cyclophosphamide, patients receive paclitaxel IV over 3 hours on day 1 and pegfilgrastim SC on day 2. Treatment repeats every 14 days for 6 courses. pegfilgrastim: Given IV AC regimen: Given IV cyclophosphamide: Given IV doxorubicin hydrochloride: Given IV paclitaxel: Given IV	(closed 11/10/10) Patients receive doxorubicin IV on day 1, oral cyclophosphamide on days 1-7, and G-CSF SC on days 2-7. Treatment repeats every 7 days for 15 courses. Beginning 2 weeks after completion of cyclophosphamide, patients receive paclitaxel and pegfilgrastim as in arm I. pegfilgrastim: Given IV AC regimen: Given IV cyclophosphamide: Given IV doxorubicin hydrochloride: Given IV paclitaxel: Given IV	(closed 11/10/10) Patients receive doxorubicin, cyclophosphamide, and pegfilgrastim or G-CSF as in arm I. Beginning 2 weeks after completion of doxorubicin and cyclophosphamide, patients receive paclitaxel IV over 1 hour on day 1. Treatment repeats every 7 days for 12 courses. pegfilgrastim: Given IV AC regimen: Given IV cyclophosphamide: Given IV doxorubicin hydrochloride: Given IV paclitaxel: Given IV	(closed 11/10/10) Patients receive doxorubicin, cyclophosphamide, and G-CSF as in arm II. Beginning 2 weeks after completion of cyclophosphamide, patients receive paclitaxel as in arm III. pegfilgrastim: Given IV AC regimen: Given IV cyclophosphamide: Given IV doxorubicin hydrochloride: Given IV paclitaxel: Given IV	(reopened in 12/2010) Patients receive doxorubicin IV and cyclophosphamide IV on day 1 and pegfilgrastim SC on day 2. Treatment repeats every 14 days for 4 courses. Patients receive doxorubicin IV and cyclophosphamide IV on day 1 and pegfilgrastim SC on day 2. Treatment repeats every 14 days for 6 courses. Beginning 2 weeks after completion of doxorubicin and cyclophosphamide, patients receive paclitaxel IV over 3 hours on day 1 and pegfilgrastim SC on day 2. Treatment repeats every 14 days for 6 courses.	(reopened in 12/2010) Patients receive doxorubicin IV and cyclophosphamide IV on day 1 and pegfilgrastim SC on day 2. Treatment repeats every 14 days for 4 courses. Patients receive doxorubicin IV and cyclophosphamide IV on day 1 and pegfilgrastim SC on day 2. Treatment repeats every 14 days for 6 courses. Beginning 2 weeks after completion of doxorubicin and cyclophosphamide, patients receive paclitaxel IV over 1 hour on day 1. Treatment repeats every 7 days for 12 courses.
Overall Number of Participants Analyzed	664	681	681	638	277	294
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
	90; (87 to 92)	87; (84 to 90)	87; (84 to 89)	87; (84 to 90)	90; (86 to 93)	91; (87 to 94)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm I, Arm II
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.013
	Comments	[Not Specified]
	Method	Log Rank
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.44
	Confidence Interval	(2-Sided) 95%; 1.08 to 1.93
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Arm I, Arm III
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.011
	Comments	[Not Specified]
	Method	Log Rank
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.46
	Confidence Interval	(2-Sided) 95%; 1.09 to 1.95
	Estimation Comments	[Not Specified]

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Arm I, Arm IV
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.17
	Comments	[Not Specified]
	Method	Log Rank
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.24
	Confidence Interval	(2-Sided) 95%; 0.91 to 1.68
	Estimation Comments	[Not Specified]

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Arm I, Arm II, Arm III, Arm IV
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.040
	Comments	[Not Specified]
	Method	Log Rank
	Comments	[Not Specified]

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Arm V, Arm VI
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.724
	Comments	[Not Specified]
	Method	Log Rank
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.91
	Confidence Interval	(2-Sided) 95%; 0.54 to 1.53
	Estimation Comments	[Not Specified]

3. Secondary Outcome

Title	Number of Patients With Gr 3 Through 5 Adverse Events That Are Related to Study Drugs
Description	Adverse Events (AEs) are reported by CTCAE Version 3.0. Only adverse events that are possibly, probably or definitely related to study drug are reported.
Time Frame	Toxicity assessment was evaluated every 4 weeks while on protocol therapy.

Outcome Measure Data

Analysis Population Description

Limited to patients who started treatment, who did not have a major deviation in the treatment protocol, and whose toxicity profile has been completed.

Arm/Group Title	ARM I	ARM II	ARM III	ARM IV	ARM V	ARM VI
Arm/Group Description:	(closed 11/10/10) Patients receive doxorubicin IV and cyclophosphamide IV on day 1 and pegfilgrastim subcutaneously (SC) on day 2 or filgrastim (G-CSF) SC on days 3-10. Treatment repeats every 14 days for 6 courses. Beginning 2 weeks after completion of doxorubicin and cyclophosphamide, patients receive paclitaxel IV over 3 hours on day 1 and pegfilgrastim SC on day 2. Treatment repeats every 14 days for 6 courses.	(closed 11/10/10) Patients receive doxorubicin IV on day 1, oral cyclophosphamide on days 1-7, and G-CSF SC on days 2-7. Treatment repeats every 7 days for 15 courses. Beginning 2 weeks after completion of cyclophosphamide, patients receive paclitaxel and pegfilgrastim as in arm I.	(closed 11/10/10) Patients receive doxorubicin, cyclophosphamide, and pegfilgrastim or G-CSF as in arm I. Beginning 2 weeks after completion of doxorubicin and cyclophosphamide, patients receive paclitaxel IV over 1 hour on day 1. Treatment repeats every 7 days for 12 courses.	(closed 11/10/10) Patients receive doxorubicin, cyclophosphamide, and G-CSF as in arm II. Beginning 2 weeks after completion of cyclophosphamide, patients receive paclitaxel as in arm III.	Patients receive doxorubicin IV and cyclophosphamide IV on day 1 and pegfilgrastim SC on day 2. Treatment repeats every 14 days for 4 courses. Patients receive doxorubicin IV and cyclophosphamide IV on day 1 and pegfilgrastim SC on day 2. Treatment repeats every 14 days for 6 courses. Beginning 2 weeks after completion of doxorubicin and cyclophosphamide, patients receive paclitaxel IV over 3 hours on day 1 and pegfilgrastim SC on day 2. Treatment repeats every 14 days for 6 courses.	(reopened in 12/2010) Patients receive doxorubicin IV and cyclophosphamide IV on day 1 and pegfilgrastim SC on day 2. Treatment repeats every 14 days for 4 courses. Patients receive doxorubicin IV and cyclophosphamide IV on day 1 and pegfilgrastim SC on day 2. Treatment repeats every 14 days for 6 courses. Beginning 2 weeks after completion of doxorubicin and cyclophosphamide, patients receive paclitaxel IV over 1 hour on day 1. Treatment repeats every 7 days for 12 courses.
Overall Number of Participants Analyzed	654	663	674	624	275	291
Measure Type: Number; Unit of Measure: Participants
ALT, SGPT (serum glutamic pyruvic transaminase)	7	4	3	4	3	1
AST, SGOT	5	3	2	2	4	1
Acidosis (metabolic or respiratory)	1	0	0	0	0	0
Adult respiratory distress syndrome (ARDS)	1	0	2	0	0	1
Albumin, serum-low (hypoalbuminemia)	1	2	0	0	0	0
Alkaline phosphatase	0	0	0	1	0	0
Allergic reaction/hypersensitivity	8	12	6	3	5	5
Anorexia	6	5	8	4	0	2
Apnea	0	0	1	0	0	0
Arthritis (non-septic)	0	0	0	0	0	1
Ataxia (incoordination)	2	0	1	0	0	0
Bilirubin (hyperbilirubinemia)	3	0	2	0	0	0
Bladder spasms	0	2	0	0	0	0
Blood/Bone Marrow-Other	1	2	2	0	0	0
Bronchospasm, wheezing	0	1	0	0	1	0
CNS cerebrovascular ischemia	0	0	1	1	0	0
Calcium, serum-high (hypercalcemia)	0	0	0	1	0	0
Calcium, serum-low (hypocalcemia)	2	1	1	0	1	1
Cardiac General-Other	2	1	1	0	0	0
Cardiac troponin I (cTnI)	0	0	1	1	0	0
Cardiac troponin T (cTnT)	3	0	2	0	0	0
Cardiac-ischemia/infarction	3	0	1	0	1	0
Cardiopulmonary arrest, cause unknown (non-fatal)	0	0	1	0	0	0
Cataract	0	1	0	0	0	0
Cholecystitis	1	0	0	0	0	0
Colitis	1	0	2	1	1	0
Colitis, infectious (e.g., Clostridium difficile)	0	0	1	2	0	0
Conduction abnormality - Asystole	0	0	1	0	0	0
Confusion	1	1	0	0	0	1
Constipation	3	3	3	3	1	0
Constitutional Symptoms-Other	1	1	0	0	0	0
Cough	3	5	4	0	1	1
Creatinine	1	0	0	0	0	0
Cystitis	0	3	0	0	0	0
Cytokine release syndrome/acute infusion reaction	0	0	0	2	1	0
DIC (disseminated intravascular coagulation)	1	0	0	0	0	0
Death - Multi-organ failure	1	0	1	0	0	0
Death not associated with CTCAE term - Death NOS	0	0	0	1	0	1
Dehydration	8	7	12	3	4	4
Dermatology/Skin-Other	0	3	0	1	1	0
Diarrhea	27	18	24	23	8	6
Distention/bloating, abdominal	0	0	1	1	0	0
Dizziness	5	2	2	5	0	2
Dysphagia (difficulty swallowing)	2	0	1	3	0	0
Dyspnea (shortness of breath)	21	18	25	16	2	4
Edema: head and neck	0	1	0	0	0	0
Edema: limb	0	2	2	3	1	1
Encephalopathy	1	0	0	0	0	0
Endocrine-Other	0	0	1	0	0	0
Esophagitis	5	4	0	3	0	0
Extrapyramidal/involuntary movement/restlessness	0	0	0	1	0	0
Extremity-upper (function)	0	0	1	0	0	0
Eyelid dysfunction	0	0	0	0	1	0
FEV(1)	0	0	1	0	0	0
Fatigue (asthenia, lethargy, malaise)	77	59	87	65	20	14
Febrile neutropenia	49	9	38	20	16	14
Fever in absence of neutropenia, ANC lt1.0x10e9/L	2	3	3	1	1	1
Fistula, GI - Oral cavity	0	0	0	1	0	0
Flu-like syndrome	0	1	1	1	0	0
Fracture	0	2	0	0	0	2
GGT (gamma-glutamyl transpeptidase)	2	0	0	1	0	0
Gastritis (including bile reflux gastritis)	0	0	0	1	0	0
Gastrointestinal-Other	1	0	0	3	0	0
Glucose, serum-high (hyperglycemia)	13	17	9	13	6	5
Glucose, serum-low (hypoglycemia)	4	2	0	1	0	0
Hair loss/Alopecia (scalp or body)	3	0	0	0	0	0
Heartburn/dyspepsia	1	0	3	5	1	1
Hemoglobin	87	48	101	47	21	19
Hemorrhage, GI - Lower GI NOS	0	1	0	1	1	0
Hemorrhage, GI - Oral cavity	0	0	0	1	0	0
Hemorrhage, GI - Rectum	1	0	0	0	1	0
Hemorrhage, GI - Upper GI NOS	1	0	0	0	0	0
Hemorrhage, GU - Urinary NOS	0	0	0	1	0	0
Hemorrhage, GU - Vagina	0	0	1	0	0	0
Hemorrhage, pulmonary/upper respiratory - Nose	0	0	0	1	0	1
Hemorrhage/Bleeding-Other	1	0	0	1	0	0
Hemorrhoids	1	3	1	0	0	1
Hot flashes/flushes	0	2	1	0	1	1
Hypertension	2	1	1	1	2	2
Hypotension	4	1	4	3	0	3
Hypoxia	2	3	3	2	3	1
INR (of prothrombin time)	2	5	1	3	1	2
Ileus, GI (functional obstruction of bowel)	0	0	1	1	0	0
Inf (clin/microbio) w/Gr 3-4 neuts - Abdomen NOS	0	1	0	0	0	0
Inf (clin/microbio) w/Gr 3-4 neuts - Bladder	0	1	1	0	0	0
Inf (clin/microbio) w/Gr 3-4 neuts - Blood	2	1	2	0	2	3
Inf (clin/microbio) w/Gr 3-4 neuts - Catheter-rel	0	1	0	0	0	0
Inf (clin/microbio) w/Gr 3-4 neuts - Colon	0	0	0	0	0	1
Inf (clin/microbio) w/Gr 3-4 neuts - Eye NOS	0	0	1	0	0	0
Inf (clin/microbio) w/Gr 3-4 neuts - Lung	4	2	2	4	1	0
Inf (clin/microbio) w/Gr 3-4 neuts - Lymphatic	0	0	2	0	0	0
Inf (clin/microbio) w/Gr 3-4 neuts - Meninges	0	0	0	0	0	1
Inf (clin/microbio) w/Gr 3-4 neuts - Middle ear	0	0	1	1	0	0
Inf (clin/microbio) w/Gr 3-4 neuts - Mucosa	1	1	0	0	0	0
Inf (clin/microbio) w/Gr 3-4 neuts - Oral cav-gums	0	0	1	0	0	1
Inf (clin/microbio) w/Gr 3-4 neuts - Paranasal	0	0	0	2	0	0
Inf (clin/microbio) w/Gr 3-4 neuts - Pharynx	0	0	1	0	0	0
Inf (clin/microbio) w/Gr 3-4 neuts - Skin	3	1	2	3	1	2
Inf (clin/microbio) w/Gr 3-4 neuts - Soft tissue	0	0	0	0	1	0
Inf (clin/microbio) w/Gr 3-4 neuts - UTI	1	2	0	1	0	0
Inf (clin/microbio) w/Gr 3-4 neuts - Upper airway	0	0	1	0	0	0
Inf (clin/microbio) w/Gr 3-4 neuts - Wound	0	2	3	0	0	0
Inf w/normal ANC or Gr 1-2 neutrophils - Bil. tree	0	0	0	0	1	0
Inf w/normal ANC or Gr 1-2 neutrophils - Bladder	0	1	1	1	0	0
Inf w/normal ANC or Gr 1-2 neutrophils - Blood	2	0	0	2	0	1
Inf w/normal ANC or Gr 1-2 neutrophils - Bronchus	0	2	0	2	1	0
Inf w/normal ANC or Gr 1-2 neutrophils - Catheter	0	2	2	0	0	0
Inf w/normal ANC or Gr 1-2 neutrophils - Colon	0	0	1	1	0	1
Inf w/normal ANC or Gr 1-2 neutrophils - Dental	0	1	0	1	0	0
Inf w/normal ANC or Gr 1-2 neutrophils - Esophagus	0	0	0	1	0	0
Inf w/normal ANC or Gr 1-2 neutrophils - Kidney	1	1	0	0	1	0
Inf w/normal ANC or Gr 1-2 neutrophils - Lung	7	5	10	5	2	4
Inf w/normal ANC or Gr 1-2 neutrophils - Meninges	2	0	0	0	0	0
Inf w/normal ANC or Gr 1-2 neutrophils - Muscle	0	0	0	1	0	0
Inf w/normal ANC or Gr 1-2 neutrophils - Neck NOS	0	1	0	0	0	0
Inf w/normal ANC or Gr 1-2 neutrophils - Oral cav	1	0	0	1	0	0
Inf w/normal ANC or Gr 1-2 neutrophils - Sinus	2	2	2	0	0	0
Inf w/normal ANC or Gr 1-2 neutrophils - Skin	7	6	8	11	4	4
Inf w/normal ANC or Gr 1-2 neutrophils - Soft tiss	1	0	1	0	0	0
Inf w/normal ANC or Gr 1-2 neutrophils - UTI	5	3	0	1	0	0
Inf w/normal ANC or Gr 1-2 neutrophils - Ungual	0	1	1	2	0	1
Inf w/normal ANC or Gr 1-2 neutrophils - Up airway	0	1	2	2	1	1
Inf w/normal ANC or Gr 1-2 neutrophils - Vagina	0	1	0	1	0	0
Inf w/normal ANC or Gr 1-2 neutrophils - Vulva	1	0	0	0	0	0
Inf w/normal ANC or Gr 1-2 neutrophils - Wound	0	1	0	2	1	3
Inf w/normal ANC or Gr 1-2 neutrophils - perioral	0	0	1	0	0	0
Inf w/normal ANC or Gr 1-2 neutrophils -Nerve-cran	0	0	1	0	0	0
Inf w/normal ANC or Gr 1-2 neutrophils-Foreign bod	0	1	0	0	0	1
Infection with normal ANC or Grade 1 or 2 neutroph	1	0	1	1	0	0
Infection with unknown ANC - Appendix	1	0	0	0	0	0
Infection with unknown ANC - Blood	0	0	0	0	0	1
Infection with unknown ANC - Catheter-related	0	1	0	0	0	0
Infection with unknown ANC - Foreign body (e.g., g	0	0	0	0	0	1
Infection with unknown ANC - Kidney	0	0	0	1	0	0
Infection with unknown ANC - Lung (pneumonia)	0	1	0	0	1	0
Infection with unknown ANC - Skin (cellulitis)	1	0	0	0	0	1
Infection with unknown ANC - Wound	0	0	0	0	1	0
Infection-Other	4	3	5	0	2	1
Injection site reaction/extravasation changes	1	0	1	0	0	0
Insomnia	1	1	0	6	1	1
Intra-operative injury - Peripheral sensory NOS	0	0	0	0	0	2
Intra-operative injury - Spinal cord	0	0	0	1	0	0
Irregular menses (change from baseline)	1	1	0	0	0	0
Joint-function	0	1	0	0	0	0
Left ventricular diastolic dysfunction	3	0	3	0	0	0
Left ventricular systolic dysfunction	7	2	8	2	1	1
Leukocytes (total WBC)	128	98	157	128	38	34
Liver dysfunction/failure (clinical)	1	0	1	0	0	0
Lymphopenia	24	31	26	32	15	18
Magnesium, serum-low (hypomagnesemia)	0	0	1	0	0	0
Metabolic/Laboratory-Other	1	0	0	0	0	0
Mood alteration - agitation	1	0	0	0	0	0
Mood alteration - anxiety	1	2	1	0	0	0
Mood alteration - depression	1	6	4	4	1	2
Mucositis/stomatitis (clinical exam) - Anus	0	1	0	1	0	0
Mucositis/stomatitis (clinical exam) - Esophagus	1	0	0	2	0	0
Mucositis/stomatitis (clinical exam) - Oral cavity	17	56	23	57	4	3
Mucositis/stomatitis (clinical exam) - Pharynx	2	5	3	1	0	0
Mucositis/stomatitis (functional/symp) - Anus	0	1	0	0	0	0
Mucositis/stomatitis (functional/symp) - Esophagus	2	3	2	5	1	1
Mucositis/stomatitis (functional/symp) - Oral cav	11	38	28	40	1	6
Mucositis/stomatitis (functional/symp) - Pharynx	4	4	5	4	0	1
Mucositis/stomatitis (functional/symp) - Rectum	1	0	0	0	0	0
Muscle weakness, not d/t neuropathy - Extrem-lower	0	0	0	0	2	1
Muscle weakness, not d/t neuropathy - body/general	0	1	1	2	1	1
Musculoskeletal/Soft Tissue-Other	1	0	0	0	0	0
Myelodysplasia	0	1	1	0	0	0
Myocarditis	0	0	1	0	0	1
Nail changes	4	12	5	9	1	1
Nasal cavity/paranasal sinus reactions	1	0	0	0	0	0
Nausea	50	40	53	33	9	9
Neurology-Other	0	1	0	0	0	0
Neuropathy: CN V Motor-jaw muscles; Sensory-facial	1	0	1	1	0	0
Neuropathy: CN VII Motor-face; Sensory-taste	1	0	0	0	0	1
Neuropathy: cranial - CN VIII Hearing and balance	0	0	0	1	0	0
Neuropathy: cranial - CN XII Motor-tongue	1	0	0	0	0	0
Neuropathy: motor	10	13	8	6	5	8
Neuropathy: sensory	107	101	76	56	45	25
Neutrophils/granulocytes (ANC/AGC)	174	156	218	201	57	65
Obesity	0	0	0	0	1	3
Obstruction, GI - Small bowel NOS	0	1	0	0	0	0
Opportunistic inf associated w/gt=Gr 2 lymphopenia	0	0	1	0	0	0
PTT (Partial thromboplastin time)	0	1	0	0	0	0
Pain - Abdomen NOS	2	3	5	0	5	2
Pain - Anus	1	1	0	0	0	0
Pain - Back	0	5	1	3	2	2
Pain - Bone	10	36	15	9	15	1
Pain - Breast	0	0	0	0	0	2
Pain - Cardiac/heart	1	0	0	1	1	0
Pain - Chest wall	1	0	0	0	1	0
Pain - Chest/thorax NOS	0	1	0	3	0	0
Pain - Dental/teeth/peridontal	0	1	0	0	0	1
Pain - Esophagus	0	0	0	1	0	0
Pain - Extremity-limb	4	9	0	3	4	1
Pain - Head/headache	5	8	10	10	1	0
Pain - Joint	39	40	21	12	11	5
Pain - Kidney	0	0	0	2	0	0
Pain - Middle ear	0	1	0	1	0	0
Pain - Muscle	42	48	21	11	10	5
Pain - Neck	0	1	0	0	0	1
Pain - Neuralgia/peripheral nerve	1	3	2	3	1	0
Pain - Pain NOS	3	0	0	1	0	1
Pain - Pelvis	0	1	0	0	0	0
Pain - Rectum	2	1	0	2	0	0
Pain - Skin	0	1	0	0	0	0
Pain - Stomach	0	0	0	1	0	0
Pain - Uterus	0	0	0	0	1	0
Pain-Other	3	5	2	1	4	0
Pericardial effusion (non-malignant)	0	0	0	0	0	2
Phosphate, serum-low (hypophosphatemia)	0	3	0	2	0	0
Platelets	24	21	20	22	6	2
Pleural effusion (non-malignant)	0	1	1	0	0	1
Pneumonitis/pulmonary infiltrates	8	7	11	5	3	1
Potassium, serum-high (hyperkalemia)	1	1	0	1	0	0
Potassium, serum-low (hypokalemia)	18	12	18	7	8	8
Prolapse of stoma, GI	2	3	2	4	0	0
Proteinuria	0	1	0	0	0	0
Pruritus/itching	2	3	0	1	2	1
Psychosis (hallucinations/delusions)	0	0	1	0	0	0
Pulmonary/Upper Respiratory-Other	1	2	1	0	1	1
Rash/desquamation	4	5	1	4	1	1
Rash: acne/acneiform	0	0	1	0	0	0
Rash: hand-foot skin reaction	19	95	16	94	3	4
Restrictive cardiomyopathy	0	0	1	1	0	0
Right ventricular dysfunction (cor pulmonale)	0	1	0	0	0	0
Rigors/chills	1	0	0	0	0	0
SVT and nodal arrhythmia - Atrial fibrillation	1	1	5	1	0	0
SVT and nodal arrhythmia - SVT tachycardia	0	1	0	0	0	0
SVT and nodal arrhythmia - Sinus tachycardia	0	1	1	0	0	0
Salivary gland changes/saliva	0	1	0	0	0	0
Secondary Malignancy-poss rel to cancer Tx	2	2	4	3	1	0
Seizure	0	1	1	1	0	1
Seroma	0	0	2	0	0	0
Sodium, serum-high (hypernatremia)	1	0	0	0	0	0
Sodium, serum-low (hyponatremia)	7	4	5	4	1	3
Somnolence/depressed level of consciousness	2	1	0	1	0	2
Sudden death	2	0	0	0	0	0
Syncope (fainting)	5	5	7	5	5	7
Syndromes-Other	0	2	1	0	0	0
Taste alteration (dysgeusia)	1	0	2	0	0	0
Thrombosis/embolism (vascular access-related)	9	18	10	6	1	4
Thrombosis/thrombus/embolism	10	7	9	8	3	4
Ulcer, GI - Esophagus	1	0	0	0	0	0
Ulcer, GI - Rectum	0	0	0	0	1	0
Uric acid, serum-high (hyperuricemia)	1	0	0	0	0	0
Urticaria (hives, welts, wheals)	1	0	0	0	0	1
Vaginitis (not due to infection)	0	0	0	1	0	0
Valvular heart disease	1	0	0	0	0	0
Vasovagal episode	0	0	1	0	0	0
Ventricular arrhythmia - PVCs	1	0	0	0	0	0
Ventricular arrhythmia - Ventricular tachycardia	1	1	1	0	0	0
Viral hepatitis	1	0	0	0	0	1
Vision-blurred vision	1	0	1	2	0	0
Voice changes/dysarthria	0	0	0	0	0	1
Vomiting	31	29	38	17	8	6
Watery eye (epiphora, tearing)	0	2	0	0	0	0
Weight loss	2	2	1	1	0	2
Wound complication, non-infectious	0	1	1	0	1	0

4. Secondary Outcome

Title	Disease-free Survival Comparison Between 2 Treatments in HR-positive, HER-2 Negative Group
Description	Disease-free survival (DFS) defined as time from registration (randomization assignment) to first instance of disease recurrence (local, regional, or distant), new breast primary tumor, or death as a result of any cause. The results are entered as disease free survival at year 5.
Time Frame	Biomarkers were measured by gene expression analysis before study entry. DFS were measured every 6 months for 5 years

Outcome Measure Data

Analysis Population Description

Patients with HR-positive, HER-2 negative at baseline in each arm were included in this analysis. Arm V and Arm VI were reopened under a new revised protocol and the data were not mature. And the results for Arm V and Arm VI will be reported in a subsequent publication.

Arm/Group Title	Arm I	Arm II	Arm III	Arm IV
Arm/Group Description:	(closed 11/10/10) Patients receive doxorubicin IV and cyclophosphamide IV on day 1 and pegfilgrastim subcutaneously (SC) on day 2 or filgrastim (G-CSF) SC on days 3-10. Treatment repeats every 14 days for 6 courses. Beginning 2 weeks after completion of doxorubicin and cyclophosphamide, patients receive paclitaxel IV over 3 hours on day 1 and pegfilgrastim SC on day 2. Treatment repeats every 14 days for 6 courses. pegfilgrastim: Given IV AC regimen: Given IV cyclophosphamide: Given IV doxorubicin hydrochloride: Given IV paclitaxel: Given IV	(closed 11/10/10) Patients receive doxorubicin IV on day 1, oral cyclophosphamide on days 1-7, and G-CSF SC on days 2-7. Treatment repeats every 7 days for 15 courses. Beginning 2 weeks after completion of cyclophosphamide, patients receive paclitaxel and pegfilgrastim as in arm I. pegfilgrastim: Given IV AC regimen: Given IV cyclophosphamide: Given IV doxorubicin hydrochloride: Given IV paclitaxel: Given IV	(closed 11/10/10) Patients receive doxorubicin, cyclophosphamide, and pegfilgrastim or G-CSF as in arm I. Beginning 2 weeks after completion of doxorubicin and cyclophosphamide, patients receive paclitaxel IV over 1 hour on day 1. Treatment repeats every 7 days for 12 courses. pegfilgrastim: Given IV AC regimen: Given IV cyclophosphamide: Given IV doxorubicin hydrochloride: Given IV paclitaxel: Given IV	(closed 11/10/10) Patients receive doxorubicin, cyclophosphamide, and G-CSF as in arm II. Beginning 2 weeks after completion of cyclophosphamide, patients receive paclitaxel as in arm III. pegfilgrastim: Given IV AC regimen: Given IV cyclophosphamide: Given IV doxorubicin hydrochloride: Given IV paclitaxel: Given IV
Overall Number of Participants Analyzed	375	370	373	362
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
	82; (78 to 86)	82; (77 to 86)	86; (82 to 89)	85; (80 to 88)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm I, Arm II, Arm III, Arm IV
	Comments	Overall treatment differences.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.67
	Comments	[Not Specified]
	Method	Log Rank
	Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Arm I, Arm II, Arm III, Arm IV
	Comments	Test of interaction of two treatments: AC and paclitaxel.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.42
	Comments	[Not Specified]
	Method	Log Rank
	Comments	[Not Specified]

5. Secondary Outcome

Title	Overall Survival Comparison Between 2 Treatments in HR-positive, HER-2 Negative Group
Description	Overall survival defined as time from registration to death as result of any cause. Results were entered as overall survival rate at year 5.
Time Frame	Biomarkers were measured by gene expression analysis before study entry. OS was measured every 6 months for 5 years

Outcome Measure Data

Analysis Population Description

Patients with HR-positive, HER-negative at baseline in each arm were included in this analysis. Arm V and Arm VI were reopened under a new revised protocol and the data were not mature. And the results for Arm V and Arm VI will be reported in a subsequent publication.

Arm/Group Title	Arm I	Arm II	Arm III	Arm IV
Arm/Group Description:	(closed 11/10/10) Patients receive doxorubicin IV and cyclophosphamide IV on day 1 and pegfilgrastim subcutaneously (SC) on day 2 or filgrastim (G-CSF) SC on days 3-10. Treatment repeats every 14 days for 6 courses. Beginning 2 weeks after completion of doxorubicin and cyclophosphamide, patients receive paclitaxel IV over 3 hours on day 1 and pegfilgrastim SC on day 2. Treatment repeats every 14 days for 6 courses. pegfilgrastim: Given IV AC regimen: Given IV cyclophosphamide: Given IV doxorubicin hydrochloride: Given IV paclitaxel: Given IV	(closed 11/10/10) Patients receive doxorubicin IV on day 1, oral cyclophosphamide on days 1-7, and G-CSF SC on days 2-7. Treatment repeats every 7 days for 15 courses. Beginning 2 weeks after completion of cyclophosphamide, patients receive paclitaxel and pegfilgrastim as in arm I. pegfilgrastim: Given IV AC regimen: Given IV cyclophosphamide: Given IV doxorubicin hydrochloride: Given IV paclitaxel: Given IV	(closed 11/10/10) Patients receive doxorubicin, cyclophosphamide, and pegfilgrastim or G-CSF as in arm I. Beginning 2 weeks after completion of doxorubicin and cyclophosphamide, patients receive paclitaxel IV over 1 hour on day 1. Treatment repeats every 7 days for 12 courses. pegfilgrastim: Given IV AC regimen: Given IV cyclophosphamide: Given IV doxorubicin hydrochloride: Given IV paclitaxel: Given IV	(closed 11/10/10) Patients receive doxorubicin, cyclophosphamide, and G-CSF as in arm II. Beginning 2 weeks after completion of cyclophosphamide, patients receive paclitaxel as in arm III. pegfilgrastim: Given IV AC regimen: Given IV cyclophosphamide: Given IV doxorubicin hydrochloride: Given IV paclitaxel: Given IV
Overall Number of Participants Analyzed	375	370	373	362
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
	91; (87 to 93)	92; (89 to 95)	91; (87 to 94)	90; (86 to 93)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm I, Arm II, Arm III, Arm IV
	Comments	Test of overall treatment differences.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.90
	Comments	[Not Specified]
	Method	Log Rank
	Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Arm I, Arm II, Arm III, Arm IV
	Comments	Test of interaction of two treatments: AC and paclitaxel.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.52
	Comments	[Not Specified]
	Method	Log Rank
	Comments	[Not Specified]

6. Secondary Outcome

Title	Disease-free Survival Comparison Between 2 Treatments in HR-negative, HER-2 Negative Group
Description	Disease-free survival (DFS) defined as time from registration (randomization assignment) to first instance of disease recurrence (local, regional, or distant), new breast primary tumor, or death as a result of any cause. The results are entered as disease free survival at year 5.
Time Frame	Biomarkers were measured by gene expression analysis before study entry. DFS was measured every 6 months for 5 years

Outcome Measure Data

Analysis Population Description

Patients with HR-negative, HER-2 negative at baseline in each arm were included in this analysis. Arm V and Arm VI were reopened under a new revised protocol and the data were not mature. And the results for Arm V and Arm VI will be reported in a subsequent publication.

Arm/Group Title	Arm I	Arm II	Arm III	Arm IV
Arm/Group Description:	(closed 11/10/10) Patients receive doxorubicin IV and cyclophosphamide IV on day 1 and pegfilgrastim subcutaneously (SC) on day 2 or filgrastim (G-CSF) SC on days 3-10. Treatment repeats every 14 days for 6 courses. Beginning 2 weeks after completion of doxorubicin and cyclophosphamide, patients receive paclitaxel IV over 3 hours on day 1 and pegfilgrastim SC on day 2. Treatment repeats every 14 days for 6 courses. pegfilgrastim: Given IV AC regimen: Given IV cyclophosphamide: Given IV doxorubicin hydrochloride: Given IV paclitaxel: Given IV	(closed 11/10/10) Patients receive doxorubicin IV on day 1, oral cyclophosphamide on days 1-7, and G-CSF SC on days 2-7. Treatment repeats every 7 days for 15 courses. Beginning 2 weeks after completion of cyclophosphamide, patients receive paclitaxel and pegfilgrastim as in arm I. pegfilgrastim: Given IV AC regimen: Given IV cyclophosphamide: Given IV doxorubicin hydrochloride: Given IV paclitaxel: Given IV	(closed 11/10/10) Patients receive doxorubicin, cyclophosphamide, and pegfilgrastim or G-CSF as in arm I. Beginning 2 weeks after completion of doxorubicin and cyclophosphamide, patients receive paclitaxel IV over 1 hour on day 1. Treatment repeats every 7 days for 12 courses. pegfilgrastim: Given IV AC regimen: Given IV cyclophosphamide: Given IV doxorubicin hydrochloride: Given IV paclitaxel: Given IV	(closed 11/10/10) Patients receive doxorubicin, cyclophosphamide, and G-CSF as in arm II. Beginning 2 weeks after completion of cyclophosphamide, patients receive paclitaxel as in arm III. pegfilgrastim: Given IV AC regimen: Given IV cyclophosphamide: Given IV doxorubicin hydrochloride: Given IV paclitaxel: Given IV
Overall Number of Participants Analyzed	153	185	180	162
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
	83; (75 to 88)	71; (63 to 77)	72; (64 to 78)	75; (68 to 81)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm I, Arm II, Arm III, Arm IV
	Comments	Test of overall treatment differences.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.076
	Comments	[Not Specified]
	Method	Log Rank
	Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Arm I, Arm II, Arm III, Arm IV
	Comments	Test of interaction of two treatments: AC and paclitaxel.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.018
	Comments	[Not Specified]
	Method	Log Rank
	Comments	[Not Specified]

7. Secondary Outcome

Title	Overall Survival Comparison Between 2 Treatments in HR-negative, HER-2 Negative Group
Description	Overall survival defined as time from registration to death as result of any cause. Results were entered as overall survival rate at year 5.
Time Frame	Biomarkers were measured by gene expression analysis before study entry. OS was measured every 6 months for 5 years

Outcome Measure Data

Analysis Population Description

Patients with HR-negative, HER2-negative at baseline in each arm were included in this analysis. Arm V and Arm VI were reopened under a new revised protocol and the data were not mature. And the results for Arm V and Arm VI will be reported in a subsequent publication.

Arm/Group Title	Arm I	Arm II	Arm III	Arm IV
Arm/Group Description:	(closed 11/10/10) Patients receive doxorubicin IV and cyclophosphamide IV on day 1 and pegfilgrastim subcutaneously (SC) on day 2 or filgrastim (G-CSF) SC on days 3-10. Treatment repeats every 14 days for 6 courses. Beginning 2 weeks after completion of doxorubicin and cyclophosphamide, patients receive paclitaxel IV over 3 hours on day 1 and pegfilgrastim SC on day 2. Treatment repeats every 14 days for 6 courses. pegfilgrastim: Given IV AC regimen: Given IV cyclophosphamide: Given IV doxorubicin hydrochloride: Given IV paclitaxel: Given IV	(closed 11/10/10) Patients receive doxorubicin IV on day 1, oral cyclophosphamide on days 1-7, and G-CSF SC on days 2-7. Treatment repeats every 7 days for 15 courses. Beginning 2 weeks after completion of cyclophosphamide, patients receive paclitaxel and pegfilgrastim as in arm I. pegfilgrastim: Given IV AC regimen: Given IV cyclophosphamide: Given IV doxorubicin hydrochloride: Given IV paclitaxel: Given IV	(closed 11/10/10) Patients receive doxorubicin, cyclophosphamide, and pegfilgrastim or G-CSF as in arm I. Beginning 2 weeks after completion of doxorubicin and cyclophosphamide, patients receive paclitaxel IV over 1 hour on day 1. Treatment repeats every 7 days for 12 courses. pegfilgrastim: Given IV AC regimen: Given IV cyclophosphamide: Given IV doxorubicin hydrochloride: Given IV paclitaxel: Given IV	(closed 11/10/10) Patients receive doxorubicin, cyclophosphamide, and G-CSF as in arm II. Beginning 2 weeks after completion of cyclophosphamide, patients receive paclitaxel as in arm III. pegfilgrastim: Given IV AC regimen: Given IV cyclophosphamide: Given IV doxorubicin hydrochloride: Given IV paclitaxel: Given IV
Overall Number of Participants Analyzed	153	185	180	162
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
	85; (78 to 90)	76; (69 to 82)	78; (71 to 84)	82; (75 to 87)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm I, Arm II, Arm III, Arm IV
	Comments	Test of overall treatment differences.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.062
	Comments	[Not Specified]
	Method	Log Rank
	Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Arm I, Arm II, Arm III, Arm IV
	Comments	Test of interaction of two treatments: AC and paclitaxel.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.010
	Comments	[Not Specified]
	Method	Log Rank
	Comments	[Not Specified]

8. Secondary Outcome

Title	Disease-free Survival Comparison Between 2 Treatments in HER2-positive Group
Description	Disease-free survival (DFS) defined as time from registration (randomization assignment) to first instance of disease recurrence (local, regional, or distant), new breast primary tumor, or death as a result of any cause. The results are entered as disease free survival at year 5.
Time Frame	Biomarkers were measured by gene expression analysis before study entry. DFS was measured every 6 months for 5 years

Outcome Measure Data

Analysis Population Description

Patients with HER2-positive at baseline in each arm were included in this analysis. One patient in Arm II with no follow-up was excluded. Arm V and Arm VI were reopened under a new revised protocol and the data were not mature. And the results for Arm V and Arm VI will be reported in a subsequent publication.

Arm/Group Title	Arm I	Arm II	Arm III	Arm IV
Arm/Group Description:	(closed 11/10/10) Patients receive doxorubicin IV and cyclophosphamide IV on day 1 and pegfilgrastim subcutaneously (SC) on day 2 or filgrastim (G-CSF) SC on days 3-10. Treatment repeats every 14 days for 6 courses. Beginning 2 weeks after completion of doxorubicin and cyclophosphamide, patients receive paclitaxel IV over 3 hours on day 1 and pegfilgrastim SC on day 2. Treatment repeats every 14 days for 6 courses. pegfilgrastim: Given IV AC regimen: Given IV cyclophosphamide: Given IV doxorubicin hydrochloride: Given IV paclitaxel: Given IV	(closed 11/10/10) Patients receive doxorubicin IV on day 1, oral cyclophosphamide on days 1-7, and G-CSF SC on days 2-7. Treatment repeats every 7 days for 15 courses. Beginning 2 weeks after completion of cyclophosphamide, patients receive paclitaxel and pegfilgrastim as in arm I. pegfilgrastim: Given IV AC regimen: Given IV cyclophosphamide: Given IV doxorubicin hydrochloride: Given IV paclitaxel: Given IV	(closed 11/10/10) Patients receive doxorubicin, cyclophosphamide, and pegfilgrastim or G-CSF as in arm I. Beginning 2 weeks after completion of doxorubicin and cyclophosphamide, patients receive paclitaxel IV over 1 hour on day 1. Treatment repeats every 7 days for 12 courses. pegfilgrastim: Given IV AC regimen: Given IV cyclophosphamide: Given IV doxorubicin hydrochloride: Given IV paclitaxel: Given IV	(closed 11/10/10) Patients receive doxorubicin, cyclophosphamide, and G-CSF as in arm II. Beginning 2 weeks after completion of cyclophosphamide, patients receive paclitaxel as in arm III. pegfilgrastim: Given IV AC regimen: Given IV cyclophosphamide: Given IV doxorubicin hydrochloride: Given IV paclitaxel: Given IV
Overall Number of Participants Analyzed	125	122	118	109
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
	85; (77 to 90)	83; (74 to 89)	82; (74 to 88)	80; (71 to 87)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm I, Arm II, Arm III, Arm IV
	Comments	Test of overall treatment differences.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.69
	Comments	[Not Specified]
	Method	Log Rank
	Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Arm I, Arm II, Arm III, Arm IV
	Comments	Test of interaction two treatments: AC and paclitaxel.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.66
	Comments	[Not Specified]
	Method	Log Rank
	Comments	[Not Specified]

9. Secondary Outcome

Title	Overall Survival Comparison Between 2 Treatments in HER-2 Positive Group.
Description	Overall survival defined as time from registration to death as result of any cause. Results were entered as overall survival rate at year 5.
Time Frame	Biomarkers were measured by gene expression analysis before study entry. OS was measured every 6 months for 5 years

Outcome Measure Data

Analysis Population Description

Patients with HER2-positive at baseline in each arm were included in this analysis. One patient in Arm II with no follow-up was excluded. Arm V and Arm VI were reopened under a new revised protocol and the data were not mature. And the results for Arm V and Arm VI will be reported in a subsequent publication.

Arm/Group Title	Arm I	Arm II	Arm III	Arm IV
Arm/Group Description:	(closed 11/10/10) Patients receive doxorubicin IV and cyclophosphamide IV on day 1 and pegfilgrastim subcutaneously (SC) on day 2 or filgrastim (G-CSF) SC on days 3-10. Treatment repeats every 14 days for 6 courses. Beginning 2 weeks after completion of doxorubicin and cyclophosphamide, patients receive paclitaxel IV over 3 hours on day 1 and pegfilgrastim SC on day 2. Treatment repeats every 14 days for 6 courses. pegfilgrastim: Given IV AC regimen: Given IV cyclophosphamide: Given IV doxorubicin hydrochloride: Given IV paclitaxel: Given IV	(closed 11/10/10) Patients receive doxorubicin IV on day 1, oral cyclophosphamide on days 1-7, and G-CSF SC on days 2-7. Treatment repeats every 7 days for 15 courses. Beginning 2 weeks after completion of cyclophosphamide, patients receive paclitaxel and pegfilgrastim as in arm I. pegfilgrastim: Given IV AC regimen: Given IV cyclophosphamide: Given IV doxorubicin hydrochloride: Given IV paclitaxel: Given IV	(closed 11/10/10) Patients receive doxorubicin, cyclophosphamide, and pegfilgrastim or G-CSF as in arm I. Beginning 2 weeks after completion of doxorubicin and cyclophosphamide, patients receive paclitaxel IV over 1 hour on day 1. Treatment repeats every 7 days for 12 courses. pegfilgrastim: Given IV AC regimen: Given IV cyclophosphamide: Given IV doxorubicin hydrochloride: Given IV paclitaxel: Given IV	(closed 11/10/10) Patients receive doxorubicin, cyclophosphamide, and G-CSF as in arm II. Beginning 2 weeks after completion of cyclophosphamide, patients receive paclitaxel as in arm III. pegfilgrastim: Given IV AC regimen: Given IV cyclophosphamide: Given IV doxorubicin hydrochloride: Given IV paclitaxel: Given IV
Overall Number of Participants Analyzed	125	122	118	109
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
	94; (88 to 97)	89; (81 to 94)	89; (82 to 94)	88; (80 to 93)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm I, Arm II, Arm III, Arm IV
	Comments	Test of overall treatment differences
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.40
	Comments	[Not Specified]
	Method	Log Rank
	Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Arm I, Arm II, Arm III, Arm IV
	Comments	Test of interaction of two treatments: AC and paclitaxel.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.28
	Comments	[Not Specified]
	Method	Log Rank
	Comments	[Not Specified]

Adverse Events

Time Frame	Toxicity assessment was evaluated every 4 weeks while on protocol therapy.
Adverse Event Reporting Description	[Not Specified]
Arm/Group Title	ARM I	ARM II	ARM III	ARM IV	ARM V	ARM VI
Arm/Group Description	(closed 11/10/10) Patients receive doxorubicin IV and cyclophosphamide IV on day 1 and pegfilgrastim subcutaneously (SC) on day 2 or filgrastim (G-CSF) SC on days 3-10. Treatment repeats every 14 days for 6 courses. Beginning 2 weeks after completion of doxorubicin and cyclophosphamide, patients receive paclitaxel IV over 3 hours on day 1 and pegfilgrastim SC on day 2. Treatment repeats every 14 days for 6 courses.	(closed 11/10/10) Patients receive doxorubicin IV on day 1, oral cyclophosphamide on days 1-7, and G-CSF SC on days 2-7. Treatment repeats every 7 days for 15 courses. Beginning 2 weeks after completion of cyclophosphamide, patients receive paclitaxel and pegfilgrastim as in arm I.	(closed 11/10/10) Patients receive doxorubicin, cyclophosphamide, and pegfilgrastim or G-CSF as in arm I. Beginning 2 weeks after completion of doxorubicin and cyclophosphamide, patients receive paclitaxel IV over 1 hour on day 1. Treatment repeats every 7 days for 12 courses.	(closed 11/10/10) Patients receive doxorubicin, cyclophosphamide, and G-CSF as in arm II. Beginning 2 weeks after completion of cyclophosphamide, patients receive paclitaxel as in arm III.	Patients receive doxorubicin IV and cyclophosphamide IV on day 1 and pegfilgrastim SC on day 2. Treatment repeats every 14 days for 4 courses. Patients receive doxorubicin IV and cyclophosphamide IV on day 1 and pegfilgrastim SC on day 2. Treatment repeats every 14 days for 6 courses. Beginning 2 weeks after completion of doxorubicin and cyclophosphamide, patients receive paclitaxel IV over 3 hours on day 1 and pegfilgrastim SC on day 2. Treatment repeats every 14 days for 6 courses.	(reopened in 12/2010) Patients receive doxorubicin IV and cyclophosphamide IV on day 1 and pegfilgrastim SC on day 2. Treatment repeats every 14 days for 4 courses. Patients receive doxorubicin IV and cyclophosphamide IV on day 1 and pegfilgrastim SC on day 2. Treatment repeats every 14 days for 6 courses. Beginning 2 weeks after completion of doxorubicin and cyclophosphamide, patients receive paclitaxel IV over 1 hour on day 1. Treatment repeats every 7 days for 12 courses.
All-Cause Mortality
	ARM I	ARM II	ARM III	ARM IV	ARM V	ARM VI
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	--/--	--/--	--/--	--/--	--/--	--/--
Serious Adverse Events
	ARM I	ARM II	ARM III	ARM IV	ARM V	ARM VI
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	10/654 (1.53%)	8/663 (1.21%)	17/674 (2.52%)	9/624 (1.44%)	5/275 (1.82%)	8/291 (2.75%)
Blood and lymphatic system disorders
Blood/Bone Marrow-Other † 1	1/654 (0.15%)	0/663 (0.00%)	0/674 (0.00%)	0/624 (0.00%)	0/275 (0.00%)	0/291 (0.00%)
DIC (disseminated intravascular coagulation) † 1	1/654 (0.15%)	0/663 (0.00%)	0/674 (0.00%)	0/624 (0.00%)	0/275 (0.00%)	0/291 (0.00%)
Febrile neutropenia † 1	0/654 (0.00%)	0/663 (0.00%)	0/674 (0.00%)	0/624 (0.00%)	1/275 (0.36%)	2/291 (0.69%)
Cardiac disorders
Cardiac-ischemia/infarction † 1	0/654 (0.00%)	0/663 (0.00%)	1/674 (0.15%)	0/624 (0.00%)	0/275 (0.00%)	0/291 (0.00%)
Conduction abnormality - Asystole † 1	0/654 (0.00%)	0/663 (0.00%)	1/674 (0.15%)	0/624 (0.00%)	0/275 (0.00%)	0/291 (0.00%)
Left ventricular diastolic dysfunction † 1	1/654 (0.15%)	0/663 (0.00%)	1/674 (0.15%)	0/624 (0.00%)	0/275 (0.00%)	0/291 (0.00%)
Left ventricular systolic dysfunction † 1	1/654 (0.15%)	0/663 (0.00%)	0/674 (0.00%)	0/624 (0.00%)	1/275 (0.36%)	0/291 (0.00%)
Myocarditis † 1	0/654 (0.00%)	0/663 (0.00%)	1/674 (0.15%)	0/624 (0.00%)	0/275 (0.00%)	0/291 (0.00%)
Pericardial effusion (non-malignant) † 1	0/654 (0.00%)	0/663 (0.00%)	0/674 (0.00%)	0/624 (0.00%)	0/275 (0.00%)	1/291 (0.34%)
Ventricular arrhythmia - PVCs † 1	1/654 (0.15%)	0/663 (0.00%)	0/674 (0.00%)	0/624 (0.00%)	0/275 (0.00%)	0/291 (0.00%)
General disorders
Constitutional Symptoms-Other † 1	0/654 (0.00%)	1/663 (0.15%)	0/674 (0.00%)	0/624 (0.00%)	0/275 (0.00%)	0/291 (0.00%)
Death - Multi-organ failure † 1	1/654 (0.15%)	0/663 (0.00%)	1/674 (0.15%)	0/624 (0.00%)	0/275 (0.00%)	0/291 (0.00%)
Death not associated with CTCAE term - Death NOS † 1	0/654 (0.00%)	0/663 (0.00%)	0/674 (0.00%)	1/624 (0.16%)	0/275 (0.00%)	1/291 (0.34%)
Hepatobiliary disorders
Liver dysfunction/failure (clinical) † 1	1/654 (0.15%)	0/663 (0.00%)	1/674 (0.15%)	0/624 (0.00%)	0/275 (0.00%)	0/291 (0.00%)
Infections and infestations
Inf (clin/microbio) w/Gr 3-4 neuts - Lung † 1	1/654 (0.15%)	1/663 (0.15%)	0/674 (0.00%)	2/624 (0.32%)	0/275 (0.00%)	0/291 (0.00%)
Inf w/normal ANC or Gr 1-2 neutrophils - Blood † 1	1/654 (0.15%)	0/663 (0.00%)	0/674 (0.00%)	0/624 (0.00%)	0/275 (0.00%)	0/291 (0.00%)
Inf w/normal ANC or Gr 1-2 neutrophils - Lung † 1	0/654 (0.00%)	0/663 (0.00%)	0/674 (0.00%)	1/624 (0.16%)	0/275 (0.00%)	0/291 (0.00%)
Inf w/normal ANC or Gr 1-2 neutrophils - Soft tiss † 1	0/654 (0.00%)	0/663 (0.00%)	1/674 (0.15%)	0/624 (0.00%)	0/275 (0.00%)	0/291 (0.00%)
Infection with unknown ANC - Blood † 1	0/654 (0.00%)	0/663 (0.00%)	0/674 (0.00%)	0/624 (0.00%)	0/275 (0.00%)	1/291 (0.34%)
Infection with unknown ANC - Skin (cellulitis) † 1	0/654 (0.00%)	0/663 (0.00%)	0/674 (0.00%)	0/624 (0.00%)	0/275 (0.00%)	1/291 (0.34%)
Injury, poisoning and procedural complications
Thrombosis/embolism (vascular access-related) † 1	0/654 (0.00%)	1/663 (0.15%)	0/674 (0.00%)	0/624 (0.00%)	0/275 (0.00%)	0/291 (0.00%)
Investigations
ALT, SGPT (serum glutamic pyruvic transaminase) † 1	0/654 (0.00%)	0/663 (0.00%)	2/674 (0.30%)	0/624 (0.00%)	0/275 (0.00%)	0/291 (0.00%)
AST, SGOT † 1	0/654 (0.00%)	0/663 (0.00%)	1/674 (0.15%)	0/624 (0.00%)	0/275 (0.00%)	0/291 (0.00%)
Bilirubin (hyperbilirubinemia) † 1	0/654 (0.00%)	0/663 (0.00%)	1/674 (0.15%)	0/624 (0.00%)	0/275 (0.00%)	0/291 (0.00%)
Cardiac troponin I (cTnI) † 1	0/654 (0.00%)	0/663 (0.00%)	1/674 (0.15%)	0/624 (0.00%)	0/275 (0.00%)	0/291 (0.00%)
Neutrophils/granulocytes (ANC/AGC) † 1	0/654 (0.00%)	0/663 (0.00%)	1/674 (0.15%)	0/624 (0.00%)	3/275 (1.09%)	0/291 (0.00%)
Metabolism and nutrition disorders
Potassium, serum-low (hypokalemia) † 1	0/654 (0.00%)	0/663 (0.00%)	0/674 (0.00%)	0/624 (0.00%)	0/275 (0.00%)	1/291 (0.34%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Myelodysplasia † 1	0/654 (0.00%)	1/663 (0.15%)	1/674 (0.15%)	0/624 (0.00%)	0/275 (0.00%)	0/291 (0.00%)
Secondary Malignancy-poss rel to cancer Tx † 1	2/654 (0.31%)	1/663 (0.15%)	4/674 (0.59%)	3/624 (0.48%)	1/275 (0.36%)	0/291 (0.00%)
Nervous system disorders
CNS cerebrovascular ischemia † 1	0/654 (0.00%)	0/663 (0.00%)	0/674 (0.00%)	1/624 (0.16%)	0/275 (0.00%)	0/291 (0.00%)
Seizure † 1	0/654 (0.00%)	0/663 (0.00%)	0/674 (0.00%)	0/624 (0.00%)	0/275 (0.00%)	1/291 (0.34%)
Somnolence/depressed level of consciousness † 1	0/654 (0.00%)	0/663 (0.00%)	0/674 (0.00%)	0/624 (0.00%)	0/275 (0.00%)	1/291 (0.34%)
Psychiatric disorders
Confusion † 1	0/654 (0.00%)	1/663 (0.15%)	0/674 (0.00%)	0/624 (0.00%)	0/275 (0.00%)	0/291 (0.00%)
Respiratory, thoracic and mediastinal disorders
Adult respiratory distress syndrome (ARDS) † 1	1/654 (0.15%)	0/663 (0.00%)	0/674 (0.00%)	0/624 (0.00%)	0/275 (0.00%)	0/291 (0.00%)
Dyspnea (shortness of breath) † 1	0/654 (0.00%)	0/663 (0.00%)	1/674 (0.15%)	0/624 (0.00%)	0/275 (0.00%)	0/291 (0.00%)
Pleural effusion (non-malignant) † 1	0/654 (0.00%)	1/663 (0.15%)	0/674 (0.00%)	0/624 (0.00%)	0/275 (0.00%)	0/291 (0.00%)
Pneumonitis/pulmonary infiltrates † 1	0/654 (0.00%)	0/663 (0.00%)	1/674 (0.15%)	0/624 (0.00%)	0/275 (0.00%)	0/291 (0.00%)
Pulmonary/Upper Respiratory-Other † 1	1/654 (0.15%)	1/663 (0.15%)	1/674 (0.15%)	0/624 (0.00%)	0/275 (0.00%)	0/291 (0.00%)
Vascular disorders
Hypotension † 1	0/654 (0.00%)	0/663 (0.00%)	1/674 (0.15%)	0/624 (0.00%)	0/275 (0.00%)	0/291 (0.00%)
Thrombosis/thrombus/embolism † 1	1/654 (0.15%)	2/663 (0.30%)	2/674 (0.30%)	1/624 (0.16%)	0/275 (0.00%)	0/291 (0.00%)
† Indicates events were collected by systematic assessment; 1 Term from vocabulary, CTCAE (3.0)
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	ARM I	ARM II	ARM III	ARM IV	ARM V	ARM VI
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	381/654 (58.26%)	412/663 (62.14%)	389/674 (57.72%)	391/624 (62.66%)	131/275 (47.64%)	126/291 (43.30%)
Blood and lymphatic system disorders
Febrile neutropenia † 1	49/654 (7.49%)	9/663 (1.36%)	38/674 (5.64%)	20/624 (3.21%)	15/275 (5.45%)	12/291 (4.12%)
Hemoglobin † 1	87/654 (13.30%)	48/663 (7.24%)	101/674 (14.99%)	47/624 (7.53%)	21/275 (7.64%)	19/291 (6.53%)
Gastrointestinal disorders
Mucositis/stomatitis (clinical exam) - Oral cavity † 1	17/654 (2.60%)	56/663 (8.45%)	23/674 (3.41%)	57/624 (9.13%)	4/275 (1.45%)	3/291 (1.03%)
Mucositis/stomatitis (functional/symp) - Oral cav † 1	11/654 (1.68%)	38/663 (5.73%)	28/674 (4.15%)	40/624 (6.41%)	1/275 (0.36%)	6/291 (2.06%)
Nausea † 1	50/654 (7.65%)	40/663 (6.03%)	53/674 (7.86%)	33/624 (5.29%)	9/275 (3.27%)	9/291 (3.09%)
Vomiting † 1	31/654 (4.74%)	29/663 (4.37%)	38/674 (5.64%)	17/624 (2.72%)	8/275 (2.91%)	6/291 (2.06%)
General disorders
Fatigue (asthenia, lethargy, malaise) † 1	77/654 (11.77%)	59/663 (8.90%)	87/674 (12.91%)	65/624 (10.42%)	20/275 (7.27%)	14/291 (4.81%)
Investigations
Leukocytes (total WBC) † 1	128/654 (19.57%)	98/663 (14.78%)	157/674 (23.29%)	128/624 (20.51%)	38/275 (13.82%)	34/291 (11.68%)
Lymphopenia † 1	24/654 (3.67%)	31/663 (4.68%)	26/674 (3.86%)	32/624 (5.13%)	15/275 (5.45%)	18/291 (6.19%)
Neutrophils/granulocytes (ANC/AGC) † 1	174/654 (26.61%)	156/663 (23.53%)	217/674 (32.20%)	201/624 (32.21%)	54/275 (19.64%)	65/291 (22.34%)
Musculoskeletal and connective tissue disorders
Pain - Bone † 1	10/654 (1.53%)	36/663 (5.43%)	15/674 (2.23%)	9/624 (1.44%)	15/275 (5.45%)	1/291 (0.34%)
Pain - Joint † 1	39/654 (5.96%)	40/663 (6.03%)	21/674 (3.12%)	12/624 (1.92%)	11/275 (4.00%)	5/291 (1.72%)
Pain - Muscle † 1	42/654 (6.42%)	48/663 (7.24%)	21/674 (3.12%)	11/624 (1.76%)	10/275 (3.64%)	5/291 (1.72%)
Nervous system disorders
Neuropathy: sensory † 1	107/654 (16.36%)	101/663 (15.23%)	76/674 (11.28%)	56/624 (8.97%)	45/275 (16.36%)	25/291 (8.59%)
Skin and subcutaneous tissue disorders
Rash: hand-foot skin reaction † 1	19/654 (2.91%)	95/663 (14.33%)	16/674 (2.37%)	94/624 (15.06%)	3/275 (1.09%)	4/291 (1.37%)
† Indicates events were collected by systematic assessment; 1 Term from vocabulary, CTCAE (3.0)

Limitations and Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

Results Point of Contact

• Name/Title: Breast Committee Statistician
• Organization: SWOG Statistical Center
• Phone: 206-667-4623
• EMail: jmiao@fredhutch.org

Publications of Results:

Budd GT, Barlow WE, Moore HC, Hobday TJ, Stewart JA, Isaacs C, Salim M, Cho JK, Rinn KJ, Albain KS, Chew HK, Burton GV, Moore TD, Srkalovic G, McGregor BA, Flaherty LE, Livingston RB, Lew DL, Gralow JR, Hortobagyi GN. SWOG S0221: a phase III trial comparing chemotherapy schedules in high-risk early-stage breast cancer. J Clin Oncol. 2015 Jan 1;33(1):58-64. doi: 10.1200/JCO.2014.56.3296. Epub 2014 Nov 24.

Sucheston LE, Zhao H, Yao S, Zirpoli G, Liu S, Barlow WE, Moore HC, Thomas Budd G, Hershman DL, Davis W, Ciupak GL, Stewart JA, Isaacs C, Hobday TJ, Salim M, Hortobagyi GN, Gralow JR, Livingston RB, Albain KS, Hayes DF, Ambrosone CB. Genetic predictors of taxane-induced neurotoxicity in a SWOG phase III intergroup adjuvant breast cancer treatment trial (S0221). Breast Cancer Res Treat. 2011 Dec;130(3):993-1002. doi: 10.1007/s10549-011-1671-3. Epub 2011 Jul 16.

Ambrosone CB, Sucheston LE, Zhao H, et al.: Variants in the BRCA1/Fanconi-anemia repair pathway and taxane-induced neuropathy in SWOG S0221. [Abstract] 32nd Annual San Antonio Breast Cancer Symposium, December 9-13, 2009, San Antonio, Texas. A-2001, 2009.

• Responsible Party: SWOG Cancer Research Network
• ClinicalTrials.gov Identifier: NCT00070564
• Other Study ID Numbers: CDR0000334899; S0221 ( Other Identifier: SWOG ); U10CA032102 ( U.S. NIH Grant/Contract )
• First Submitted: October 3, 2003
• First Posted: October 7, 2003
• Results First Submitted: January 9, 2017
• Results First Posted: April 17, 2017
• Last Update Posted: April 15, 2024