Herceptin (Trastuzumab) in Treating Women With Human Epidermal Growth Factor Receptor (HER) 2-Positive Primary Breast Cancer (HERA)

• ClinicalTrials.gov Identifier: NCT00045032
• Recruitment Status: Completed
• First Posted: January 27, 2003
• Results First Posted: April 27, 2017
• Last Update Posted: April 27, 2017
• Sponsor: Hoffmann-La Roche
• Collaborators: Breast International Group; European Organisation for Research and Treatment of Cancer - EORTC; NCIC Clinical Trials Group; ETOP IBCSG Partners Foundation
• Information provided by (Responsible Party): Hoffmann-La Roche

• Study Type: Interventional
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Breast Cancer
• Intervention: Drug: Herceptin
• Enrollment: 5099

Participant Flow

Recruitment Details
Pre-assignment Details	After the release of initial study results, participants in the Observation Arm without disease recurrence were given the opportunity to cross over to receive 1 or 2 years of adjuvant Herceptin. Efficacy analyses were still performed according to original randomization.

Arm/Group Title	Observation Arm	Herceptin 1-Year Arm	Herceptin 2-Year Arm
Arm/Group Description	Participants who completed definitive surgery and systemic adjuvant chemotherapy were observed for efficacy and safety until 10 years from individual randomization and for survival until 10 years after enrollment of the last participant. No Herceptin was provided.	Participants who completed definitive surgery and systemic adjuvant chemotherapy received a loading dose of Herceptin as 8 milligrams per kilogram (mg/kg) via intravenous (IV) infusion on Day 1, followed by a maintenance dose of 6 mg/kg via IV infusion 3 weeks later and thereafter every 3 weeks for 1 year or until disease recurrence, whichever occurred first. Participants were observed for efficacy and safety until 10 years from individual randomization and for survival until 10 years after enrollment of the last participant.	Participants who completed definitive surgery and systemic adjuvant chemotherapy received a loading dose of Herceptin as 8 mg/kg via IV infusion on Day 1, followed by a maintenance dose of 6 mg/kg via IV infusion 3 weeks later and thereafter every 3 weeks for 2 years or until disease recurrence, whichever occurred first. Participants were observed for efficacy and safety until 10 years from individual randomization and for survival until 10 years after enrollment of the last participant.
Period Title: Overall Study
Started	1697 [1]	1702 [1]	1700 [1]
Crossover to Adjuvant Herceptin	888	0 [2]	0 [2]
Completed	834	994	974
Not Completed	863	708	726
Reason Not Completed
Adverse Event/Intercurrent Illness	2	2	7
Death	22	24	17
Insufficient Therapeutic Response	542	437	445
Violation of Selection Criteria at Entry	3	6	6
Other Protocol Violation	2	0	1
Refused/Did Not Cooperate/Withdrew	142	93	84
Failure to Return	57	62	61
Other	93	84	105
[1] Included all participants with available signed Informed Consent Form.; [2] This milestone is not applicable to participants who were already randomized to Herceptin.

Baseline Characteristics

Arm/Group Title		Observation Arm	Herceptin 1-Year Arm	Herceptin 2-Year Arm	Total
Arm/Group Description		Participants who completed definitive surgery and systemic adjuvant chemotherapy were observed for efficacy and safety until 10 years from individual randomization and for survival until 10 years after enrollment of the last participant. No Herceptin was provided.	Participants who completed definitive surgery and systemic adjuvant chemotherapy received a loading dose of Herceptin as 8 mg/kg via IV infusion on Day 1, followed by a maintenance dose of 6 mg/kg via IV infusion 3 weeks later and thereafter every 3 weeks for 1 year or until disease recurrence, whichever occurred first. Participants were observed for efficacy and safety until 10 years from individual randomization and for survival until 10 years after enrollment of the last participant.	Participants who completed definitive surgery and systemic adjuvant chemotherapy received a loading dose of Herceptin as 8 mg/kg via IV infusion on Day 1, followed by a maintenance dose of 6 mg/kg via IV infusion 3 weeks later and thereafter every 3 weeks for 2 years or until disease recurrence, whichever occurred first. Participants were observed for efficacy and safety until 10 years from individual randomization and for survival until 10 years after enrollment of the last participant.	Total of all reporting groups
Overall Number of Baseline Participants		1697	1702	1700	5099
Baseline Analysis Population Description		Full Analysis Set (FAS) Population: All enrolled/randomized participants who had an available signed Informed Consent Form.
Age, Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	1697 participants	1702 participants	1700 participants	5099 participants
		49.2 (10.08)	49.0 (10.06)	49.2 (10.09)	49.1 (10.08)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	1697 participants	1702 participants	1700 participants	5099 participants
	Female	1697 100.0%	1702 100.0%	1700 100.0%	5099 100.0%
	Male	0 0.0%	0 0.0%	0 0.0%	0 0.0%

Outcome Measures

1. Primary Outcome

Title	Percentage of Participants With Disease-Free Survival (DFS) Events in Herceptin 1-Year Arm Compared to Observation: 1-Year Median Follow-Up
Description	DFS events included loco-regional or distant recurrence of breast cancer, development of contralateral breast cancer or second non-breast malignancy other than basal or squamous carcinoma of the skin and carcinoma in situ of the cervix, or death from any cause. The percentage of participants with at least one DFS event was reported. The analysis of the Herceptin 1-Year Arm against the Observation Arm after 1-year median follow-up, as reported below, was performed by the Sponsor in 2006 following database cleaning. The analysis of the Herceptin 2-Year Arm against the Observation Arm was performed for an Independent Data Monitoring Committee (IDMC) in 2005 at a time the Sponsor was blinded. Therefore, these data are reported under a separate Outcome Measure.
Time Frame	From Baseline until time of event (median of 1 year)

Outcome Measure Data

Analysis Population Description

FAS Population. The "Number of Participants Analyzed" reflects the number with data for the endpoint.

Arm/Group Title	Observation Arm	Herceptin 1-Year Arm
Arm/Group Description:	Participants who completed definitive surgery and systemic adjuvant chemotherapy were observed for efficacy and safety until 10 years from individual randomization and for survival until 10 years after enrollment of the last participant. No Herceptin was provided.	Participants who completed definitive surgery and systemic adjuvant chemotherapy received a loading dose of Herceptin as 8 mg/kg via IV infusion on Day 1, followed by a maintenance dose of 6 mg/kg via IV infusion 3 weeks later and thereafter every 3 weeks for 1 year or until disease recurrence, whichever occurred first. Participants were observed for efficacy and safety until 10 years from individual randomization and for survival until 10 years after enrollment of the last participant.
Overall Number of Participants Analyzed	1693	1693
Measure Type: Number; Unit of Measure: percentage of participants
	12.9	7.5

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Observation Arm, Herceptin 1-Year Arm
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	[Not Specified]
	Method	Log Rank
	Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Observation Arm, Herceptin 1-Year Arm
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.54
	Confidence Interval	(2-Sided) 95%; 0.44 to 0.67
	Estimation Comments	HR for Herceptin 1-Year Arm versus Observation Arm.

2. Primary Outcome

Title	Percentage of Participants With DFS Events in Herceptin 2-Year Arm Compared to Observation: 1-Year Median Follow-Up
Description	DFS events included loco-regional or distant recurrence of breast cancer, development of contralateral breast cancer or second non-breast malignancy other than basal or squamous carcinoma of the skin and carcinoma in situ of the cervix, or death from any cause. The percentage of participants with at least one DFS event was reported. The analysis of the Herceptin 2-Year Arm against the Observation Arm after 1-year median follow-up, as reported below, was performed for an IDMC in 2005 at a time the Sponsor was blinded. The analysis of the Herceptin 1-Year Arm against the Observation Arm was performed by the Sponsor in 2006 following database cleaning. Therefore, these data are reported under a separate Outcome Measure.
Time Frame	From Baseline until time of event (median of 1 year)

Outcome Measure Data

Analysis Population Description

FAS Population. The "Number of Participants Analyzed" reflects the number with data for the endpoint.

Arm/Group Title	Observation Arm	Herceptin 2-Year Arm
Arm/Group Description:	Participants who completed definitive surgery and systemic adjuvant chemotherapy were observed for efficacy and safety until 10 years from individual randomization and for survival until 10 years after enrollment of the last participant. No Herceptin was provided.	Participants who completed definitive surgery and systemic adjuvant chemotherapy received a loading dose of Herceptin as 8 mg/kg via IV infusion on Day 1, followed by a maintenance dose of 6 mg/kg via IV infusion 3 weeks later and thereafter every 3 weeks for 2 years or until disease recurrence, whichever occurred first. Participants were observed for efficacy and safety until 10 years from individual randomization and for survival until 10 years after enrollment of the last participant.
Overall Number of Participants Analyzed	1693	1694
Measure Type: Number; Unit of Measure: percentage of participants
	13.0	7.6

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Observation Arm, Herceptin 2-Year Arm
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.000
	Comments	[Not Specified]
	Method	Log Rank
	Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Observation Arm, Herceptin 2-Year Arm
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.43
	Confidence Interval	(2-Sided) 95%; 0.34 to 0.53
	Estimation Comments	HR for Herceptin 2-Year Arm versus Observation Arm.

3. Primary Outcome

Title	DFS Rate According to Kaplan-Meier Analysis in Herceptin 1-Year Arm Compared to Observation: 1-Year Median Follow-Up
Description	DFS events included loco-regional or distant recurrence of breast cancer, development of contralateral breast cancer or second non-breast malignancy other than basal or squamous carcinoma of the skin and carcinoma in situ of the cervix, or death from any cause. The percentage of participants free of DFS events (i.e., the DFS rate) and corresponding 95 percent (%) confidence interval (CI) were estimated by Kaplan-Meier analysis based on available data at the time of the 1-year median follow-up analysis. The analysis of the Herceptin 1-Year Arm against the Observation Arm after 1-year median follow-up, as reported below, was performed by the Sponsor in 2006 following database cleaning. The analysis of the Herceptin 2-Year Arm against the Observation Arm was performed for an IDMC in 2005 at a time the Sponsor was blinded. Therefore, these data are reported under a separate Outcome Measure.
Time Frame	Year 2

Outcome Measure Data

Analysis Population Description

FAS Population. The "Number of Participants Analyzed" reflects the number with data for the endpoint.

Arm/Group Title	Observation Arm	Herceptin 1-Year Arm
Arm/Group Description:	Participants who completed definitive surgery and systemic adjuvant chemotherapy were observed for efficacy and safety until 10 years from individual randomization and for survival until 10 years after enrollment of the last participant. No Herceptin was provided.	Participants who completed definitive surgery and systemic adjuvant chemotherapy received a loading dose of Herceptin as 8 mg/kg via IV infusion on Day 1, followed by a maintenance dose of 6 mg/kg via IV infusion 3 weeks later and thereafter every 3 weeks for 1 year or until disease recurrence, whichever occurred first. Participants were observed for efficacy and safety until 10 years from individual randomization and for survival until 10 years after enrollment of the last participant.
Overall Number of Participants Analyzed	1693	1693
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
	78.18; (75 to 81)	85.80; (83 to 89)

4. Primary Outcome

Title	DFS Rate According to Kaplan-Meier Analysis in Herceptin 2-Year Arm Compared to Observation: 1-Year Median Follow-Up
Description	DFS events included loco-regional or distant recurrence of breast cancer, development of contralateral breast cancer or second non-breast malignancy other than basal or squamous carcinoma of the skin and carcinoma in situ of the cervix, or death from any cause. The percentage of participants free of DFS events (i.e., the DFS rate) and corresponding 95% CI were estimated by Kaplan-Meier analysis based on available data at the time of the 1-year median follow-up analysis. The analysis of the Herceptin 2-Year Arm against the Observation Arm after 1-year median follow-up, as reported below, was performed for an IDMC in 2005 at a time the Sponsor was blinded. The analysis of the Herceptin 1-Year Arm against the Observation Arm was performed by the Sponsor in 2006 following database cleaning. Therefore, these data are reported under a separate Outcome Measure.
Time Frame	Year 2

Outcome Measure Data

Analysis Population Description

FAS Population. The "Number of Participants Analyzed" reflects the number with data for the endpoint.

Arm/Group Title	Observation Arm	Herceptin 2-Year Arm
Arm/Group Description:	Participants who completed definitive surgery and systemic adjuvant chemotherapy were observed for efficacy and safety until 10 years from individual randomization and for survival until 10 years after enrollment of the last participant. No Herceptin was provided.	Participants who completed definitive surgery and systemic adjuvant chemotherapy received a loading dose of Herceptin as 8 mg/kg via IV infusion on Day 1, followed by a maintenance dose of 6 mg/kg via IV infusion 3 weeks later and thereafter every 3 weeks for 2 years or until disease recurrence, whichever occurred first. Participants were observed for efficacy and safety until 10 years from individual randomization and for survival until 10 years after enrollment of the last participant.
Overall Number of Participants Analyzed	1693	1694
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
	73.60; (70 to 77)	87.50; (85 to 90)

5. Primary Outcome

Title	Percentage of Participants With DFS Events Compared to Observation: 8-Year Median Follow-Up
Description	DFS events included loco-regional or distant recurrence of breast cancer, development of contralateral breast cancer or second non-breast malignancy other than basal or squamous carcinoma of the skin and carcinoma in situ of the cervix, or death from any cause. The percentage of participants with at least one DFS event was reported.
Time Frame	From Baseline until time of event (median of 8 years)

Outcome Measure Data

Analysis Population Description

FAS Population

Arm/Group Title	Observation Arm	Herceptin 1-Year Arm	Herceptin 2-Year Arm
Arm/Group Description:	Participants who completed definitive surgery and systemic adjuvant chemotherapy were observed for efficacy and safety until 10 years from individual randomization and for survival until 10 years after enrollment of the last participant. No Herceptin was provided.	Participants who completed definitive surgery and systemic adjuvant chemotherapy received a loading dose of Herceptin as 8 mg/kg via IV infusion on Day 1, followed by a maintenance dose of 6 mg/kg via IV infusion 3 weeks later and thereafter every 3 weeks for 1 year or until disease recurrence, whichever occurred first. Participants were observed for efficacy and safety until 10 years from individual randomization and for survival until 10 years after enrollment of the last participant.	Participants who completed definitive surgery and systemic adjuvant chemotherapy received a loading dose of Herceptin as 8 mg/kg via IV infusion on Day 1, followed by a maintenance dose of 6 mg/kg via IV infusion 3 weeks later and thereafter every 3 weeks for 2 years or until disease recurrence, whichever occurred first. Participants were observed for efficacy and safety until 10 years from individual randomization and for survival until 10 years after enrollment of the last participant.
Overall Number of Participants Analyzed	1697	1702	1700
Measure Type: Number; Unit of Measure: percentage of participants
	33.6	27.7	27.8

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Observation Arm, Herceptin 1-Year Arm
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	[Not Specified]
	Method	Log Rank
	Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Observation Arm, Herceptin 1-Year Arm
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.76
	Confidence Interval	(2-Sided) 95%; 0.67 to 0.86
	Estimation Comments	HR for Herceptin 1-Year Arm versus Observation Arm.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Observation Arm, Herceptin 2-Year Arm
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	[Not Specified]
	Method	Log Rank
	Comments	[Not Specified]

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Observation Arm, Herceptin 2-Year Arm
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.75
	Confidence Interval	(2-Sided) 95%; 0.67 to 0.85
	Estimation Comments	HR for Herceptin 2-Year Arm versus Observation Arm.

6. Primary Outcome

Title	DFS Rate at Year 3 According to Kaplan-Meier Analysis Compared to Observation: 8-Year Median Follow-Up
Description	DFS events included loco-regional or distant recurrence of breast cancer, development of contralateral breast cancer or second non-breast malignancy other than basal or squamous carcinoma of the skin and carcinoma in situ of the cervix, or death from any cause. The percentage of participants free of DFS events (i.e., the DFS rate) and corresponding 95% CI were estimated by Kaplan-Meier analysis based on available data at the time of the 8-year median follow-up analysis.
Time Frame	Year 3

Outcome Measure Data

Analysis Population Description

FAS Population

Arm/Group Title	Observation Arm	Herceptin 1-Year Arm	Herceptin 2-Year Arm
Arm/Group Description:	Participants who completed definitive surgery and systemic adjuvant chemotherapy were observed for efficacy and safety until 10 years from individual randomization and for survival until 10 years after enrollment of the last participant. No Herceptin was provided.	Participants who completed definitive surgery and systemic adjuvant chemotherapy received a loading dose of Herceptin as 8 mg/kg via IV infusion on Day 1, followed by a maintenance dose of 6 mg/kg via IV infusion 3 weeks later and thereafter every 3 weeks for 1 year or until disease recurrence, whichever occurred first. Participants were observed for efficacy and safety until 10 years from individual randomization and for survival until 10 years after enrollment of the last participant.	Participants who completed definitive surgery and systemic adjuvant chemotherapy received a loading dose of Herceptin as 8 mg/kg via IV infusion on Day 1, followed by a maintenance dose of 6 mg/kg via IV infusion 3 weeks later and thereafter every 3 weeks for 2 years or until disease recurrence, whichever occurred first. Participants were observed for efficacy and safety until 10 years from individual randomization and for survival until 10 years after enrollment of the last participant.
Overall Number of Participants Analyzed	1697	1702	1700
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
	75.2; (73.1 to 77.3)	81.3; (79.4 to 83.2)	83.5; (81.7 to 85.3)

7. Primary Outcome

Title	DFS Rate at Year 5 According to Kaplan-Meier Analysis Compared to Observation: 8-Year Median Follow-Up
Description	DFS events included loco-regional or distant recurrence of breast cancer, development of contralateral breast cancer or second non-breast malignancy other than basal or squamous carcinoma of the skin and carcinoma in situ of the cervix, or death from any cause. The percentage of participants free of DFS events (i.e., the DFS rate) and corresponding 95% CI were estimated by Kaplan-Meier analysis based on available data at the time of the 8-year median follow-up analysis.
Time Frame	Year 5

Outcome Measure Data

Analysis Population Description

FAS Population

Arm/Group Title	Observation Arm	Herceptin 1-Year Arm	Herceptin 2-Year Arm
Arm/Group Description:	Participants who completed definitive surgery and systemic adjuvant chemotherapy were observed for efficacy and safety until 10 years from individual randomization and for survival until 10 years after enrollment of the last participant. No Herceptin was provided.	Participants who completed definitive surgery and systemic adjuvant chemotherapy received a loading dose of Herceptin as 8 mg/kg via IV infusion on Day 1, followed by a maintenance dose of 6 mg/kg via IV infusion 3 weeks later and thereafter every 3 weeks for 1 year or until disease recurrence, whichever occurred first. Participants were observed for efficacy and safety until 10 years from individual randomization and for survival until 10 years after enrollment of the last participant.	Participants who completed definitive surgery and systemic adjuvant chemotherapy received a loading dose of Herceptin as 8 mg/kg via IV infusion on Day 1, followed by a maintenance dose of 6 mg/kg via IV infusion 3 weeks later and thereafter every 3 weeks for 2 years or until disease recurrence, whichever occurred first. Participants were observed for efficacy and safety until 10 years from individual randomization and for survival until 10 years after enrollment of the last participant.
Overall Number of Participants Analyzed	1697	1702	1700
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
	70.0; (67.8 to 72.3)	75.9; (73.8 to 78.0)	76.5; (74.4 to 78.5)

8. Primary Outcome

Title	DFS Rate at Year 7 According to Kaplan-Meier Analysis Compared to Observation: 8-Year Median Follow-Up
Description	DFS events included loco-regional or distant recurrence of breast cancer, development of contralateral breast cancer or second non-breast malignancy other than basal or squamous carcinoma of the skin and carcinoma in situ of the cervix, or death from any cause. The percentage of participants free of DFS events (i.e., the DFS rate) and corresponding 95% CI were estimated by Kaplan-Meier analysis based on available data at the time of the 8-year median follow-up analysis.
Time Frame	Year 7

Outcome Measure Data

Analysis Population Description

FAS Population

Arm/Group Title	Observation Arm	Herceptin 1-Year Arm	Herceptin 2-Year Arm
Arm/Group Description:	Participants who completed definitive surgery and systemic adjuvant chemotherapy were observed for efficacy and safety until 10 years from individual randomization and for survival until 10 years after enrollment of the last participant. No Herceptin was provided.	Participants who completed definitive surgery and systemic adjuvant chemotherapy received a loading dose of Herceptin as 8 mg/kg via IV infusion on Day 1, followed by a maintenance dose of 6 mg/kg via IV infusion 3 weeks later and thereafter every 3 weeks for 1 year or until disease recurrence, whichever occurred first. Participants were observed for efficacy and safety until 10 years from individual randomization and for survival until 10 years after enrollment of the last participant.	Participants who completed definitive surgery and systemic adjuvant chemotherapy received a loading dose of Herceptin as 8 mg/kg via IV infusion on Day 1, followed by a maintenance dose of 6 mg/kg via IV infusion 3 weeks later and thereafter every 3 weeks for 2 years or until disease recurrence, whichever occurred first. Participants were observed for efficacy and safety until 10 years from individual randomization and for survival until 10 years after enrollment of the last participant.
Overall Number of Participants Analyzed	1697	1702	1700
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
	66.0; (63.6 to 68.3)	72.4; (70.2 to 74.6)	72.5; (70.4 to 74.7)

9. Primary Outcome

Title	DFS Rate at Year 8 According to Kaplan-Meier Analysis Compared to Observation: 8-Year Median Follow-Up
Description	DFS events included loco-regional or distant recurrence of breast cancer, development of contralateral breast cancer or second non-breast malignancy other than basal or squamous carcinoma of the skin and carcinoma in situ of the cervix, or death from any cause. The percentage of participants free of DFS events (i.e., the DFS rate) and corresponding 95% CI were estimated by Kaplan-Meier analysis based on available data at the time of the 8-year median follow-up analysis.
Time Frame	Year 8

Outcome Measure Data

Analysis Population Description

FAS Population

Arm/Group Title	Observation Arm	Herceptin 1-Year Arm	Herceptin 2-Year Arm
Arm/Group Description:	Participants who completed definitive surgery and systemic adjuvant chemotherapy were observed for efficacy and safety until 10 years from individual randomization and for survival until 10 years after enrollment of the last participant. No Herceptin was provided.	Participants who completed definitive surgery and systemic adjuvant chemotherapy received a loading dose of Herceptin as 8 mg/kg via IV infusion on Day 1, followed by a maintenance dose of 6 mg/kg via IV infusion 3 weeks later and thereafter every 3 weeks for 1 year or until disease recurrence, whichever occurred first. Participants were observed for efficacy and safety until 10 years from individual randomization and for survival until 10 years after enrollment of the last participant.	Participants who completed definitive surgery and systemic adjuvant chemotherapy received a loading dose of Herceptin as 8 mg/kg via IV infusion on Day 1, followed by a maintenance dose of 6 mg/kg via IV infusion 3 weeks later and thereafter every 3 weeks for 2 years or until disease recurrence, whichever occurred first. Participants were observed for efficacy and safety until 10 years from individual randomization and for survival until 10 years after enrollment of the last participant.
Overall Number of Participants Analyzed	1697	1702	1700
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
	64.8; (62.4 to 67.2)	71.2; (69.0 to 73.4)	71.0; (68.7 to 73.2)

10. Primary Outcome

Title	Percentage of Participants With DFS Events Compared to Observation: 10-Year Maximum Follow-Up
Description	DFS events included loco-regional or distant recurrence of breast cancer, development of contralateral breast cancer or second non-breast malignancy other than basal or squamous carcinoma of the skin and carcinoma in situ of the cervix, or death from any cause. The percentage of participants with at least one DFS event was reported.
Time Frame	From Baseline until time of event (maximum of 10 years)

Outcome Measure Data

Analysis Population Description

FAS Population

Arm/Group Title	Observation Arm	Herceptin 1-Year Arm	Herceptin 2-Year Arm
Arm/Group Description:	Participants who completed definitive surgery and systemic adjuvant chemotherapy were observed for efficacy and safety until 10 years from individual randomization and for survival until 10 years after enrollment of the last participant. No Herceptin was provided.	Participants who completed definitive surgery and systemic adjuvant chemotherapy received a loading dose of Herceptin as 8 mg/kg via IV infusion on Day 1, followed by a maintenance dose of 6 mg/kg via IV infusion 3 weeks later and thereafter every 3 weeks for 1 year or until disease recurrence, whichever occurred first. Participants were observed for efficacy and safety until 10 years from individual randomization and for survival until 10 years after enrollment of the last participant.	Participants who completed definitive surgery and systemic adjuvant chemotherapy received a loading dose of Herceptin as 8 mg/kg via IV infusion on Day 1, followed by a maintenance dose of 6 mg/kg via IV infusion 3 weeks later and thereafter every 3 weeks for 2 years or until disease recurrence, whichever occurred first. Participants were observed for efficacy and safety until 10 years from individual randomization and for survival until 10 years after enrollment of the last participant.
Overall Number of Participants Analyzed	1697	1702	1700
Measure Type: Number; Unit of Measure: percentage of participants
	35.8	29.7	30.5

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Observation Arm, Herceptin 1-Year Arm
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.76
	Confidence Interval	(2-Sided) 95%; 0.68 to 0.86
	Estimation Comments	HR for Herceptin 1-Year Arm versus Observation Arm.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Observation Arm, Herceptin 2-Year Arm
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.77
	Confidence Interval	(2-Sided) 95%; 0.69 to 0.87
	Estimation Comments	HR for Herceptin 2-Year Arm versus Observation Arm.

11. Primary Outcome

Title	DFS Rate at Year 3 According to Kaplan-Meier Analysis Compared to Observation: 10-Year Maximum Follow-Up
Description	DFS events included loco-regional or distant recurrence of breast cancer, development of contralateral breast cancer or second non-breast malignancy other than basal or squamous carcinoma of the skin and carcinoma in situ of the cervix, or death from any cause. The percentage of participants free of DFS events (i.e., the DFS rate) and corresponding 95% CI were estimated by Kaplan-Meier analysis based on available data at the time of the final analysis with a 10-year maximum follow-up for DFS events.
Time Frame	Year 3

Outcome Measure Data

Analysis Population Description

FAS Population

Arm/Group Title	Observation Arm	Herceptin 1-Year Arm	Herceptin 2-Year Arm
Arm/Group Description:	Participants who completed definitive surgery and systemic adjuvant chemotherapy were observed for efficacy and safety until 10 years from individual randomization and for survival until 10 years after enrollment of the last participant. No Herceptin was provided.	Participants who completed definitive surgery and systemic adjuvant chemotherapy received a loading dose of Herceptin as 8 mg/kg via IV infusion on Day 1, followed by a maintenance dose of 6 mg/kg via IV infusion 3 weeks later and thereafter every 3 weeks for 1 year or until disease recurrence, whichever occurred first. Participants were observed for efficacy and safety until 10 years from individual randomization and for survival until 10 years after enrollment of the last participant.	Participants who completed definitive surgery and systemic adjuvant chemotherapy received a loading dose of Herceptin as 8 mg/kg via IV infusion on Day 1, followed by a maintenance dose of 6 mg/kg via IV infusion 3 weeks later and thereafter every 3 weeks for 2 years or until disease recurrence, whichever occurred first. Participants were observed for efficacy and safety until 10 years from individual randomization and for survival until 10 years after enrollment of the last participant.
Overall Number of Participants Analyzed	1697	1702	1700
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
	75.2; (73.1 to 77.3)	81.3; (79.4 to 83.2)	83.4; (81.6 to 85.2)

12. Primary Outcome

Title	DFS Rate at Year 5 According to Kaplan-Meier Analysis Compared to Observation: 10-Year Maximum Follow-Up
Description	DFS events included loco-regional or distant recurrence of breast cancer, development of contralateral breast cancer or second non-breast malignancy other than basal or squamous carcinoma of the skin and carcinoma in situ of the cervix, or death from any cause. The percentage of participants free of DFS events (i.e., the DFS rate) and corresponding 95% CI were estimated by Kaplan-Meier analysis based on available data at the time of the final analysis with a 10-year maximum follow-up for DFS events.
Time Frame	Year 5

Outcome Measure Data

Analysis Population Description

FAS Population

Arm/Group Title	Observation Arm	Herceptin 1-Year Arm	Herceptin 2-Year Arm
Arm/Group Description:	Participants who completed definitive surgery and systemic adjuvant chemotherapy were observed for efficacy and safety until 10 years from individual randomization and for survival until 10 years after enrollment of the last participant. No Herceptin was provided.	Participants who completed definitive surgery and systemic adjuvant chemotherapy received a loading dose of Herceptin as 8 mg/kg via IV infusion on Day 1, followed by a maintenance dose of 6 mg/kg via IV infusion 3 weeks later and thereafter every 3 weeks for 1 year or until disease recurrence, whichever occurred first. Participants were observed for efficacy and safety until 10 years from individual randomization and for survival until 10 years after enrollment of the last participant.	Participants who completed definitive surgery and systemic adjuvant chemotherapy received a loading dose of Herceptin as 8 mg/kg via IV infusion on Day 1, followed by a maintenance dose of 6 mg/kg via IV infusion 3 weeks later and thereafter every 3 weeks for 2 years or until disease recurrence, whichever occurred first. Participants were observed for efficacy and safety until 10 years from individual randomization and for survival until 10 years after enrollment of the last participant.
Overall Number of Participants Analyzed	1697	1702	1700
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
	70.0; (67.8 to 72.2)	75.9; (73.8 to 78.0)	76.4; (74.4 to 78.5)

13. Primary Outcome

Title	DFS Rate at Year 7 According to Kaplan-Meier Analysis Compared to Observation: 10-Year Maximum Follow-Up
Description	DFS events included loco-regional or distant recurrence of breast cancer, development of contralateral breast cancer or second non-breast malignancy other than basal or squamous carcinoma of the skin and carcinoma in situ of the cervix, or death from any cause. The percentage of participants free of DFS events (i.e., the DFS rate) and corresponding 95% CI were estimated by Kaplan-Meier analysis based on available data at the time of the final analysis with a 10-year maximum follow-up for DFS events.
Time Frame	Year 7

Outcome Measure Data

Analysis Population Description

FAS Population

Arm/Group Title	Observation Arm	Herceptin 1-Year Arm	Herceptin 2-Year Arm
Arm/Group Description:	Participants who completed definitive surgery and systemic adjuvant chemotherapy were observed for efficacy and safety until 10 years from individual randomization and for survival until 10 years after enrollment of the last participant. No Herceptin was provided.	Participants who completed definitive surgery and systemic adjuvant chemotherapy received a loading dose of Herceptin as 8 mg/kg via IV infusion on Day 1, followed by a maintenance dose of 6 mg/kg via IV infusion 3 weeks later and thereafter every 3 weeks for 1 year or until disease recurrence, whichever occurred first. Participants were observed for efficacy and safety until 10 years from individual randomization and for survival until 10 years after enrollment of the last participant.	Participants who completed definitive surgery and systemic adjuvant chemotherapy received a loading dose of Herceptin as 8 mg/kg via IV infusion on Day 1, followed by a maintenance dose of 6 mg/kg via IV infusion 3 weeks later and thereafter every 3 weeks for 2 years or until disease recurrence, whichever occurred first. Participants were observed for efficacy and safety until 10 years from individual randomization and for survival until 10 years after enrollment of the last participant.
Overall Number of Participants Analyzed	1697	1702	1700
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
	65.8; (63.5 to 68.2)	72.4; (70.2 to 74.5)	72.5; (70.3 to 74.7)

14. Primary Outcome

Title	DFS Rate at Year 8 According to Kaplan-Meier Analysis Compared to Observation: 10-Year Maximum Follow-Up
Description	DFS events included loco-regional or distant recurrence of breast cancer, development of contralateral breast cancer or second non-breast malignancy other than basal or squamous carcinoma of the skin and carcinoma in situ of the cervix, or death from any cause. The percentage of participants free of DFS events (i.e., the DFS rate) and corresponding 95% CI were estimated by Kaplan-Meier analysis based on available data at the time of the final analysis with a 10-year maximum follow-up for DFS events.
Time Frame	Year 8

Outcome Measure Data

Analysis Population Description

FAS Population

Arm/Group Title	Observation Arm	Herceptin 1-Year Arm	Herceptin 2-Year Arm
Arm/Group Description:	Participants who completed definitive surgery and systemic adjuvant chemotherapy were observed for efficacy and safety until 10 years from individual randomization and for survival until 10 years after enrollment of the last participant. No Herceptin was provided.	Participants who completed definitive surgery and systemic adjuvant chemotherapy received a loading dose of Herceptin as 8 mg/kg via IV infusion on Day 1, followed by a maintenance dose of 6 mg/kg via IV infusion 3 weeks later and thereafter every 3 weeks for 1 year or until disease recurrence, whichever occurred first. Participants were observed for efficacy and safety until 10 years from individual randomization and for survival until 10 years after enrollment of the last participant.	Participants who completed definitive surgery and systemic adjuvant chemotherapy received a loading dose of Herceptin as 8 mg/kg via IV infusion on Day 1, followed by a maintenance dose of 6 mg/kg via IV infusion 3 weeks later and thereafter every 3 weeks for 2 years or until disease recurrence, whichever occurred first. Participants were observed for efficacy and safety until 10 years from individual randomization and for survival until 10 years after enrollment of the last participant.
Overall Number of Participants Analyzed	1697	1702	1700
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
	64.7; (62.3 to 67.0)	71.2; (69.0 to 73.4)	70.7; (68.5 to 72.9)

15. Primary Outcome

Title	DFS Rate at Year 9 According to Kaplan-Meier Analysis Compared to Observation: 10-Year Maximum Follow-Up
Description	DFS events included loco-regional or distant recurrence of breast cancer, development of contralateral breast cancer or second non-breast malignancy other than basal or squamous carcinoma of the skin and carcinoma in situ of the cervix, or death from any cause. The percentage of participants free of DFS events (i.e., the DFS rate) and corresponding 95% CI were estimated by Kaplan-Meier analysis based on available data at the time of the final analysis with a 10-year maximum follow-up for DFS events.
Time Frame	Year 9

Outcome Measure Data

Analysis Population Description

FAS Population

Arm/Group Title	Observation Arm	Herceptin 1-Year Arm	Herceptin 2-Year Arm
Arm/Group Description:	Participants who completed definitive surgery and systemic adjuvant chemotherapy were observed for efficacy and safety until 10 years from individual randomization and for survival until 10 years after enrollment of the last participant. No Herceptin was provided.	Participants who completed definitive surgery and systemic adjuvant chemotherapy received a loading dose of Herceptin as 8 mg/kg via IV infusion on Day 1, followed by a maintenance dose of 6 mg/kg via IV infusion 3 weeks later and thereafter every 3 weeks for 1 year or until disease recurrence, whichever occurred first. Participants were observed for efficacy and safety until 10 years from individual randomization and for survival until 10 years after enrollment of the last participant.	Participants who completed definitive surgery and systemic adjuvant chemotherapy received a loading dose of Herceptin as 8 mg/kg via IV infusion on Day 1, followed by a maintenance dose of 6 mg/kg via IV infusion 3 weeks later and thereafter every 3 weeks for 2 years or until disease recurrence, whichever occurred first. Participants were observed for efficacy and safety until 10 years from individual randomization and for survival until 10 years after enrollment of the last participant.
Overall Number of Participants Analyzed	1697	1702	1700
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
	63.5; (61.2 to 65.9)	70.3; (68.1 to 72.6)	69.2; (67.0 to 71.5)

16. Primary Outcome

Title	DFS Rate at Year 10 According to Kaplan-Meier Analysis Compared to Observation: 10-Year Maximum Follow-Up
Description	DFS events included loco-regional or distant recurrence of breast cancer, development of contralateral breast cancer or second non-breast malignancy other than basal or squamous carcinoma of the skin and carcinoma in situ of the cervix, or death from any cause. The percentage of participants free of DFS events (i.e., the DFS rate) and corresponding 95% CI were estimated by Kaplan-Meier analysis based on available data at the time of the final analysis with a 10-year maximum follow-up for DFS events.
Time Frame	Year 10

Outcome Measure Data

Analysis Population Description

FAS Population

Arm/Group Title	Observation Arm	Herceptin 1-Year Arm	Herceptin 2-Year Arm
Arm/Group Description:	Participants who completed definitive surgery and systemic adjuvant chemotherapy were observed for efficacy and safety until 10 years from individual randomization and for survival until 10 years after enrollment of the last participant. No Herceptin was provided.	Participants who completed definitive surgery and systemic adjuvant chemotherapy received a loading dose of Herceptin as 8 mg/kg via IV infusion on Day 1, followed by a maintenance dose of 6 mg/kg via IV infusion 3 weeks later and thereafter every 3 weeks for 1 year or until disease recurrence, whichever occurred first. Participants were observed for efficacy and safety until 10 years from individual randomization and for survival until 10 years after enrollment of the last participant.	Participants who completed definitive surgery and systemic adjuvant chemotherapy received a loading dose of Herceptin as 8 mg/kg via IV infusion on Day 1, followed by a maintenance dose of 6 mg/kg via IV infusion 3 weeks later and thereafter every 3 weeks for 2 years or until disease recurrence, whichever occurred first. Participants were observed for efficacy and safety until 10 years from individual randomization and for survival until 10 years after enrollment of the last participant.
Overall Number of Participants Analyzed	1697	1702	1700
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
	62.5; (60.1 to 64.8)	69.3; (67.0 to 71.5)	68.5; (66.2 to 70.7)

17. Secondary Outcome

Title	Percentage of Participants With DFS Events in 1-Year Versus 2-Year Herceptin: 10-Year Maximum Follow-Up
Description	DFS events included loco-regional or distant recurrence of breast cancer, development of contralateral breast cancer or second non-breast malignancy other than basal or squamous carcinoma of the skin and carcinoma in situ of the cervix, or death from any cause. The percentage of participants with at least one DFS event was reported.
Time Frame	From Baseline until time of event (maximum of 10 years)

Outcome Measure Data

Analysis Population Description

FAS Population 1-Year Herceptin Versus 2-Year Herceptin (1Y2Y): Participants without a DFS event and still under follow-up at the pre-defined landmark of 366 days after randomization, analyzed when intent-to-treat principle was applied for comparison of 1 year versus 2 years of Herceptin.

Arm/Group Title	Herceptin 1-Year Arm	Herceptin 2-Year Arm
Arm/Group Description:	Participants who completed definitive surgery and systemic adjuvant chemotherapy received a loading dose of Herceptin as 8 mg/kg via IV infusion on Day 1, followed by a maintenance dose of 6 mg/kg via IV infusion 3 weeks later and thereafter every 3 weeks for 1 year or until disease recurrence, whichever occurred first. Participants were observed for efficacy and safety until 10 years from individual randomization and for survival until 10 years after enrollment of the last participant.	Participants who completed definitive surgery and systemic adjuvant chemotherapy received a loading dose of Herceptin as 8 mg/kg via IV infusion on Day 1, followed by a maintenance dose of 6 mg/kg via IV infusion 3 weeks later and thereafter every 3 weeks for 2 years or until disease recurrence, whichever occurred first. Participants were observed for efficacy and safety until 10 years from individual randomization and for survival until 10 years after enrollment of the last participant.
Overall Number of Participants Analyzed	1552	1553
Measure Type: Number; Unit of Measure: percentage of participants
	25.8	26.6

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Herceptin 1-Year Arm, Herceptin 2-Year Arm
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.7962
	Comments	[Not Specified]
	Method	Log Rank
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.02
	Confidence Interval	(2-Sided) 95%; 0.89 to 1.17
	Estimation Comments	HR for Herceptin 2-Year Arm versus Herceptin 1-Year Arm.

18. Secondary Outcome

Title	DFS Rate According to Kaplan-Meier Analysis in 1-Year Versus 2-Year Herceptin: 10-Year Maximum Follow-Up
Description	DFS events included loco-regional or distant recurrence of breast cancer, development of contralateral breast cancer or second non-breast malignancy other than basal or squamous carcinoma of the skin and carcinoma in situ of the cervix, or death from any cause. The percentage of participants free of DFS events (i.e., the DFS rate) and corresponding 95% CI were estimated by Kaplan-Meier analysis based on available data at the time of the final analysis with a 10-year maximum follow-up for DFS events.
Time Frame	Years 3, 5, 7, 8, 9, 10

Outcome Measure Data

Analysis Population Description

FAS Population 1Y2Y

Arm/Group Title	Herceptin 1-Year Arm	Herceptin 2-Year Arm
Arm/Group Description:	Participants who completed definitive surgery and systemic adjuvant chemotherapy received a loading dose of Herceptin as 8 mg/kg via IV infusion on Day 1, followed by a maintenance dose of 6 mg/kg via IV infusion 3 weeks later and thereafter every 3 weeks for 1 year or until disease recurrence, whichever occurred first. Participants were observed for efficacy and safety until 10 years from individual randomization and for survival until 10 years after enrollment of the last participant.	Participants who completed definitive surgery and systemic adjuvant chemotherapy received a loading dose of Herceptin as 8 mg/kg via IV infusion on Day 1, followed by a maintenance dose of 6 mg/kg via IV infusion 3 weeks later and thereafter every 3 weeks for 2 years or until disease recurrence, whichever occurred first. Participants were observed for efficacy and safety until 10 years from individual randomization and for survival until 10 years after enrollment of the last participant.
Overall Number of Participants Analyzed	1552	1553
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
Year 3	86.7; (85.0 to 88.4)	89.0; (87.4 to 90.6)
Year 5	81.0; (79.0 to 82.9)	81.6; (79.6 to 83.5)
Year 7	77.2; (75.1 to 79.3)	77.4; (75.3 to 79.5)
Year 8	75.9; (73.8 to 78.1)	75.5; (73.3 to 77.7)
Year 9	75.0; (72.8 to 77.2)	73.9; (71.7 to 76.1)
Year 10	73.9; (71.7 to 76.1)	73.1; (70.8 to 75.3)

19. Secondary Outcome

Title	Percentage of Participants With Overall Survival (OS) Events in Herceptin 1-Year Arm Compared to Observation: 1-Year Median Follow-Up
Description	OS events referred to death from any cause. The percentage of participants who died was reported. The analysis of the Herceptin 1-Year Arm against the Observation Arm after 1-year median follow-up, as reported below, was performed by the Sponsor in 2006 following database cleaning. The analysis of the Herceptin 2-Year Arm against the Observation Arm was performed for an IDMC in 2005 at a time the Sponsor was blinded. Therefore, these data are reported under a separate Outcome Measure.
Time Frame	From Baseline until time of event (median of 1 year)

Outcome Measure Data

Analysis Population Description

FAS Population. The "Number of Participants Analyzed" reflects the number with data for the endpoint.

Arm/Group Title	Observation Arm	Herceptin 1-Year Arm
Arm/Group Description:	Participants who completed definitive surgery and systemic adjuvant chemotherapy were observed for efficacy and safety until 10 years from individual randomization and for survival until 10 years after enrollment of the last participant. No Herceptin was provided.	Participants who completed definitive surgery and systemic adjuvant chemotherapy received a loading dose of Herceptin as 8 mg/kg via IV infusion on Day 1, followed by a maintenance dose of 6 mg/kg via IV infusion 3 weeks later and thereafter every 3 weeks for 1 year or until disease recurrence, whichever occurred first. Participants were observed for efficacy and safety until 10 years from individual randomization and for survival until 10 years after enrollment of the last participant.
Overall Number of Participants Analyzed	1693	1693
Measure Type: Number; Unit of Measure: percentage of participants
	2.4	1.8

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Observation Arm, Herceptin 1-Year Arm
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.2379
	Comments	[Not Specified]
	Method	Log Rank
	Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Observation Arm, Herceptin 1-Year Arm
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.75
	Confidence Interval	(2-Sided) 95%; 0.47 to 1.21
	Estimation Comments	HR for Herceptin 1-Year Arm versus Observation Arm.

20. Secondary Outcome

Title	Percentage of Participants With OS Events in Herceptin 2-Year Arm Compared to Observation: 1-Year Median Follow-Up
Description	OS events referred to death from any cause. The percentage of participants who died was reported. The analysis of the Herceptin 2-Year Arm against the Observation Arm after 1-year median follow-up, as reported below, was performed for an IDMC in 2005 at a time the Sponsor was blinded. The analysis of the Herceptin 1-Year Arm against the Observation Arm was performed by the Sponsor in 2006 following database cleaning. Therefore, these data are reported under a separate Outcome Measure.
Time Frame	From Baseline until time of event (median of 1 year)

Outcome Measure Data

Analysis Population Description

FAS Population. The "Number of Participants Analyzed" reflects the number with data for the endpoint.

Arm/Group Title	Observation Arm	Herceptin 2-Year Arm
Arm/Group Description:	Participants who completed definitive surgery and systemic adjuvant chemotherapy were observed for efficacy and safety until 10 years from individual randomization and for survival until 10 years after enrollment of the last participant. No Herceptin was provided.	Participants who completed definitive surgery and systemic adjuvant chemotherapy received a loading dose of Herceptin as 8 mg/kg via IV infusion on Day 1, followed by a maintenance dose of 6 mg/kg via IV infusion 3 weeks later and thereafter every 3 weeks for 2 years or until disease recurrence, whichever occurred first. Participants were observed for efficacy and safety until 10 years from individual randomization and for survival until 10 years after enrollment of the last participant.
Overall Number of Participants Analyzed	1693	1694
Measure Type: Number; Unit of Measure: percentage of participants
	2.2	1.4

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Observation Arm, Herceptin 2-Year Arm
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.003
	Comments	[Not Specified]
	Method	Log Rank
	Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Observation Arm, Herceptin 2-Year Arm
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.47
	Confidence Interval	(2-Sided) 95%; 0.28 to 0.79
	Estimation Comments	HR for Herceptin 2-Year Arm versus Observation Arm.

21. Secondary Outcome

Title	OS Rate According to Kaplan-Meier Analysis in Herceptin 1-Year Arm Compared to Observation: 1-Year Median Follow-Up
Description	OS events referred to death from any cause. The percentage of participants alive (i.e., the OS rate) and corresponding 95% CI were estimated by Kaplan-Meier analysis based on available data at the time of the 1-year median follow-up analysis. The analysis of the Herceptin 1-Year Arm against the Observation Arm after 1-year median follow-up, as reported below, was performed by the Sponsor in 2006 following database cleaning. The analysis of the Herceptin 2-Year Arm against the Observation Arm was performed for an IDMC in 2005 at a time the Sponsor was blinded. Therefore, these data are reported under a separate Outcome Measure.
Time Frame	Year 2

Outcome Measure Data

Analysis Population Description

FAS Population. The "Number of Participants Analyzed" reflects the number with data for the endpoint.

Arm/Group Title	Observation Arm	Herceptin 1-Year Arm
Arm/Group Description:	Participants who completed definitive surgery and systemic adjuvant chemotherapy were observed for efficacy and safety until 10 years from individual randomization and for survival until 10 years after enrollment of the last participant. No Herceptin was provided.	Participants who completed definitive surgery and systemic adjuvant chemotherapy received a loading dose of Herceptin as 8 mg/kg via IV infusion on Day 1, followed by a maintenance dose of 6 mg/kg via IV infusion 3 weeks later and thereafter every 3 weeks for 1 year or until disease recurrence, whichever occurred first. Participants were observed for efficacy and safety until 10 years from individual randomization and for survival until 10 years after enrollment of the last participant.
Overall Number of Participants Analyzed	1693	1693
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
	94.98; (93 to 97)	95.88; (94 to 98)

22. Secondary Outcome

Title	OS Rate According to Kaplan-Meier Analysis in Herceptin 2-Year Arm Compared to Observation: 1-Year Median Follow-Up
Description	OS events referred to death from any cause. The percentage of participants alive (i.e., the OS rate) and corresponding 95% CI were estimated by Kaplan-Meier analysis based on available data at the time of the 1-year median follow-up analysis. The analysis of the Herceptin 2-Year Arm against the Observation Arm after 1-year median follow-up, as reported below, was performed for an IDMC in 2005 at a time the Sponsor was blinded. The analysis of the Herceptin 1-Year Arm against the Observation Arm was performed by the Sponsor in 2006 following database cleaning. Therefore, these data are reported under a separate Outcome Measure.
Time Frame	Year 2

Outcome Measure Data

Analysis Population Description

FAS Population. The "Number of Participants Analyzed" reflects the number with data for the endpoint.

Arm/Group Title	Observation Arm	Herceptin 2-Year Arm
Arm/Group Description:	Participants who completed definitive surgery and systemic adjuvant chemotherapy were observed for efficacy and safety until 10 years from individual randomization and for survival until 10 years after enrollment of the last participant. No Herceptin was provided.	Participants who completed definitive surgery and systemic adjuvant chemotherapy received a loading dose of Herceptin as 8 mg/kg via IV infusion on Day 1, followed by a maintenance dose of 6 mg/kg via IV infusion 3 weeks later and thereafter every 3 weeks for 2 years or until disease recurrence, whichever occurred first. Participants were observed for efficacy and safety until 10 years from individual randomization and for survival until 10 years after enrollment of the last participant.
Overall Number of Participants Analyzed	1693	1694
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
	94.39; (92 to 97)	97.28; (96 to 98)

23. Secondary Outcome

Title	Percentage of Participants With OS Events Compared to Observation: 8-Year Median Follow-Up
Description	OS events referred to death from any cause. The percentage of participants who died was reported.
Time Frame	From Baseline until time of event (median of 8 years)

Outcome Measure Data

Analysis Population Description

FAS Population

Arm/Group Title	Observation Arm	Herceptin 1-Year Arm	Herceptin 2-Year Arm
Arm/Group Description:	Participants who completed definitive surgery and systemic adjuvant chemotherapy were observed for efficacy and safety until 10 years from individual randomization and for survival until 10 years after enrollment of the last participant. No Herceptin was provided.	Participants who completed definitive surgery and systemic adjuvant chemotherapy received a loading dose of Herceptin as 8 mg/kg via IV infusion on Day 1, followed by a maintenance dose of 6 mg/kg via IV infusion 3 weeks later and thereafter every 3 weeks for 1 year or until disease recurrence, whichever occurred first. Participants were observed for efficacy and safety until 10 years from individual randomization and for survival until 10 years after enrollment of the last participant.	Participants who completed definitive surgery and systemic adjuvant chemotherapy received a loading dose of Herceptin as 8 mg/kg via IV infusion on Day 1, followed by a maintenance dose of 6 mg/kg via IV infusion 3 weeks later and thereafter every 3 weeks for 2 years or until disease recurrence, whichever occurred first. Participants were observed for efficacy and safety until 10 years from individual randomization and for survival until 10 years after enrollment of the last participant.
Overall Number of Participants Analyzed	1697	1702	1700
Measure Type: Number; Unit of Measure: percentage of participants
	20.6	16.3	16.1

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Observation Arm, Herceptin 1-Year Arm
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0005
	Comments	[Not Specified]
	Method	Log Rank
	Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Observation Arm, Herceptin 1-Year Arm
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.76
	Confidence Interval	(2-Sided) 95%; 0.65 to 0.88
	Estimation Comments	HR for Herceptin 1-Year Arm versus Observation Arm.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Observation Arm, Herceptin 2-Year Arm
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0001
	Comments	[Not Specified]
	Method	Log Rank
	Comments	[Not Specified]

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Observation Arm, Herceptin 2-Year Arm
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.74
	Confidence Interval	(2-Sided) 95%; 0.63 to 0.86
	Estimation Comments	HR for Herceptin 2-Year Arm versus Observation Arm.

24. Secondary Outcome

Title	OS Rate According to Kaplan-Meier Analysis Compared to Observation: 8-Year Median Follow-Up
Description	OS events referred to death from any cause. The percentage of participants alive (i.e., the OS rate) and corresponding 95% CI were estimated by Kaplan-Meier analysis based on available data at the time of the 8-year median follow-up analysis.
Time Frame	Years 3, 5, 7, 8

Outcome Measure Data

Analysis Population Description

FAS Population

Arm/Group Title	Observation Arm	Herceptin 1-Year Arm	Herceptin 2-Year Arm
Arm/Group Description:	Participants who completed definitive surgery and systemic adjuvant chemotherapy were observed for efficacy and safety until 10 years from individual randomization and for survival until 10 years after enrollment of the last participant. No Herceptin was provided.	Participants who completed definitive surgery and systemic adjuvant chemotherapy received a loading dose of Herceptin as 8 mg/kg via IV infusion on Day 1, followed by a maintenance dose of 6 mg/kg via IV infusion 3 weeks later and thereafter every 3 weeks for 1 year or until disease recurrence, whichever occurred first. Participants were observed for efficacy and safety until 10 years from individual randomization and for survival until 10 years after enrollment of the last participant.	Participants who completed definitive surgery and systemic adjuvant chemotherapy received a loading dose of Herceptin as 8 mg/kg via IV infusion on Day 1, followed by a maintenance dose of 6 mg/kg via IV infusion 3 weeks later and thereafter every 3 weeks for 2 years or until disease recurrence, whichever occurred first. Participants were observed for efficacy and safety until 10 years from individual randomization and for survival until 10 years after enrollment of the last participant.
Overall Number of Participants Analyzed	1697	1702	1700
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
Year 3	90.7; (89.3 to 92.1)	92.7; (91.5 to 94.0)	94.4; (93.3 to 95.6)
Year 5	84.5; (82.8 to 86.3)	86.9; (85.2 to 88.5)	88.7; (87.2 to 90.3)
Year 7	79.5; (77.5 to 81.5)	83.9; (82.1 to 85.7)	84.6; (82.9 to 86.4)
Year 8	77.4; (75.2 to 79.5)	82.7; (80.8 to 84.6)	82.4; (80.4 to 84.3)

25. Secondary Outcome

Title	Percentage of Participants With OS Events Compared to Observation: 11-Year Median Follow-Up
Description	OS events referred to death from any cause. The percentage of participants who died was reported.
Time Frame	From Baseline until time of event (median of 11 years)

Outcome Measure Data

Analysis Population Description

FAS Population

Arm/Group Title	Observation Arm	Herceptin 1-Year Arm	Herceptin 2-Year Arm
Arm/Group Description:	Participants who completed definitive surgery and systemic adjuvant chemotherapy were observed for efficacy and safety until 10 years from individual randomization and for survival until 10 years after enrollment of the last participant. No Herceptin was provided.	Participants who completed definitive surgery and systemic adjuvant chemotherapy received a loading dose of Herceptin as 8 mg/kg via IV infusion on Day 1, followed by a maintenance dose of 6 mg/kg via IV infusion 3 weeks later and thereafter every 3 weeks for 1 year or until disease recurrence, whichever occurred first. Participants were observed for efficacy and safety until 10 years from individual randomization and for survival until 10 years after enrollment of the last participant.	Participants who completed definitive surgery and systemic adjuvant chemotherapy received a loading dose of Herceptin as 8 mg/kg via IV infusion on Day 1, followed by a maintenance dose of 6 mg/kg via IV infusion 3 weeks later and thereafter every 3 weeks for 2 years or until disease recurrence, whichever occurred first. Participants were observed for efficacy and safety until 10 years from individual randomization and for survival until 10 years after enrollment of the last participant.
Overall Number of Participants Analyzed	1697	1702	1700
Measure Type: Number; Unit of Measure: percentage of participants
	23.9	18.8	18.4

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Observation Arm, Herceptin 1-Year Arm
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.74
	Confidence Interval	(2-Sided) 95%; 0.64 to 0.86
	Estimation Comments	HR for Herceptin 1-Year Arm versus Observation Arm.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Observation Arm, Herceptin 2-Year Arm
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.72
	Confidence Interval	(2-Sided) 95%; 0.62 to 0.83
	Estimation Comments	HR for Herceptin 2-Year Arm versus Observation Arm.

26. Secondary Outcome

Title	OS Rate According to Kaplan-Meier Analysis Compared to Observation: 11-Year Median Follow-Up
Description	OS events referred to death from any cause. The percentage of participants alive (i.e., the OS rate) and corresponding 95% CI were estimated by Kaplan-Meier analysis based on available data at the time of the final analysis with an 11-year median follow-up for OS events.
Time Frame	Years 3, 5, 7, 9, 10, 11, 12

Outcome Measure Data

Analysis Population Description

FAS Population

Arm/Group Title	Observation Arm	Herceptin 1-Year Arm	Herceptin 2-Year Arm
Arm/Group Description:	Participants who completed definitive surgery and systemic adjuvant chemotherapy were observed for efficacy and safety until 10 years from individual randomization and for survival until 10 years after enrollment of the last participant. No Herceptin was provided.	Participants who completed definitive surgery and systemic adjuvant chemotherapy received a loading dose of Herceptin as 8 mg/kg via IV infusion on Day 1, followed by a maintenance dose of 6 mg/kg via IV infusion 3 weeks later and thereafter every 3 weeks for 1 year or until disease recurrence, whichever occurred first. Participants were observed for efficacy and safety until 10 years from individual randomization and for survival until 10 years after enrollment of the last participant.	Participants who completed definitive surgery and systemic adjuvant chemotherapy received a loading dose of Herceptin as 8 mg/kg via IV infusion on Day 1, followed by a maintenance dose of 6 mg/kg via IV infusion 3 weeks later and thereafter every 3 weeks for 2 years or until disease recurrence, whichever occurred first. Participants were observed for efficacy and safety until 10 years from individual randomization and for survival until 10 years after enrollment of the last participant.
Overall Number of Participants Analyzed	1697	1702	1700
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
Year 3	90.7; (89.3 to 92.1)	92.7; (91.5 to 94.0)	94.4; (93.3 to 95.6)
Year 5	84.5; (82.8 to 86.3)	86.9; (85.2 to 88.5)	88.7; (87.2 to 90.3)
Year 7	79.4; (77.4 to 81.4)	83.8; (82.0 to 85.6)	84.7; (82.9 to 86.4)
Year 9	76.5; (74.4 to 78.6)	81.9; (80.0 to 83.8)	81.8; (80.0 to 83.7)
Year 10	75.0; (72.9 to 77.2)	80.7; (78.8 to 82.6)	81.0; (79.0 to 82.9)
Year 11	73.7; (71.5 to 76.0)	80.0; (78.1 to 82.0)	80.3; (78.3 to 82.3)
Year 12	72.9; (70.4 to 75.3)	79.4; (77.3 to 81.5)	79.5; (77.4 to 81.7)

27. Secondary Outcome

Title	Percentage of Participants With OS Events in 1-Year Versus 2-Year Herceptin: 11-Year Median Follow-Up
Description	OS events referred to death from any cause. The percentage of participants who died was reported.
Time Frame	From Baseline until time of event (median of 11 years)

Outcome Measure Data

Analysis Population Description

FAS Population 1Y2Y

Arm/Group Title	Herceptin 1-Year Arm	Herceptin 2-Year Arm
Arm/Group Description:	Participants who completed definitive surgery and systemic adjuvant chemotherapy received a loading dose of Herceptin as 8 mg/kg via IV infusion on Day 1, followed by a maintenance dose of 6 mg/kg via IV infusion 3 weeks later and thereafter every 3 weeks for 1 year or until disease recurrence, whichever occurred first. Participants were observed for efficacy and safety until 10 years from individual randomization and for survival until 10 years after enrollment of the last participant.	Participants who completed definitive surgery and systemic adjuvant chemotherapy received a loading dose of Herceptin as 8 mg/kg via IV infusion on Day 1, followed by a maintenance dose of 6 mg/kg via IV infusion 3 weeks later and thereafter every 3 weeks for 2 years or until disease recurrence, whichever occurred first. Participants were observed for efficacy and safety until 10 years from individual randomization and for survival until 10 years after enrollment of the last participant.
Overall Number of Participants Analyzed	1552	1553
Measure Type: Number; Unit of Measure: percentage of participants
	14.7	14.9

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Herceptin 1-Year Arm, Herceptin 2-Year Arm
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.9156
	Comments	[Not Specified]
	Method	Log Rank
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.01
	Confidence Interval	(2-Sided) 95%; 0.84 to 1.21
	Estimation Comments	HR for Herceptin 2-Year Arm versus Herceptin 1-Year Arm.

28. Secondary Outcome

Title	OS Rate According to Kaplan-Meier Analysis in 1-Year Versus 2-Year Herceptin: 11-Year Median Follow-Up
Description	OS events referred to death from any cause. The percentage of participants alive (i.e., the OS rate) and corresponding 95% CI were estimated by Kaplan-Meier analysis based on available data at the time of the final analysis with an 11-year median follow-up for OS events.
Time Frame	Years 3, 5, 7, 9, 10, 11, 12

Outcome Measure Data

Analysis Population Description

FAS Population 1Y2Y

Arm/Group Title	Herceptin 1-Year Arm	Herceptin 2-Year Arm
Arm/Group Description:	Participants who completed definitive surgery and systemic adjuvant chemotherapy received a loading dose of Herceptin as 8 mg/kg via IV infusion on Day 1, followed by a maintenance dose of 6 mg/kg via IV infusion 3 weeks later and thereafter every 3 weeks for 1 year or until disease recurrence, whichever occurred first. Participants were observed for efficacy and safety until 10 years from individual randomization and for survival until 10 years after enrollment of the last participant.	Participants who completed definitive surgery and systemic adjuvant chemotherapy received a loading dose of Herceptin as 8 mg/kg via IV infusion on Day 1, followed by a maintenance dose of 6 mg/kg via IV infusion 3 weeks later and thereafter every 3 weeks for 2 years or until disease recurrence, whichever occurred first. Participants were observed for efficacy and safety until 10 years from individual randomization and for survival until 10 years after enrollment of the last participant.
Overall Number of Participants Analyzed	1552	1553
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
Year 3	96.5; (95.6 to 97.4)	97.4; (96.6 to 98.2)
Year 5	91.4; (90.0 to 92.8)	92.6; (91.2 to 93.9)
Year 7	88.6; (87.0 to 90.2)	88.7; (87.1 to 90.3)
Year 9	86.7; (85.0 to 88.5)	85.9; (84.2 to 87.7)
Year 10	85.4; (83.6 to 87.2)	85.1; (83.3 to 86.9)
Year 11	84.7; (82.9 to 86.6)	84.4; (82.5 to 86.2)
Year 12	84.1; (82.1 to 86.1)	83.6; (81.5 to 85.6)

29. Secondary Outcome

Title	Percentage of Participants With Recurrence-Free Survival (RFS) Events Compared to Observation: 8-Year Median Follow-Up
Description	RFS events included local, regional, or distant tumor recurrence. The percentage of participants with at least one RFS event was reported.
Time Frame	From Baseline until time of event (median of 8 years)

Outcome Measure Data

Analysis Population Description

FAS Population

Arm/Group Title	Observation Arm	Herceptin 1-Year Arm	Herceptin 2-Year Arm
Arm/Group Description:	Participants who completed definitive surgery and systemic adjuvant chemotherapy were observed for efficacy and safety until 10 years from individual randomization and for survival until 10 years after enrollment of the last participant. No Herceptin was provided.	Participants who completed definitive surgery and systemic adjuvant chemotherapy received a loading dose of Herceptin as 8 mg/kg via IV infusion on Day 1, followed by a maintenance dose of 6 mg/kg via IV infusion 3 weeks later and thereafter every 3 weeks for 1 year or until disease recurrence, whichever occurred first. Participants were observed for efficacy and safety until 10 years from individual randomization and for survival until 10 years after enrollment of the last participant.	Participants who completed definitive surgery and systemic adjuvant chemotherapy received a loading dose of Herceptin as 8 mg/kg via IV infusion on Day 1, followed by a maintenance dose of 6 mg/kg via IV infusion 3 weeks later and thereafter every 3 weeks for 2 years or until disease recurrence, whichever occurred first. Participants were observed for efficacy and safety until 10 years from individual randomization and for survival until 10 years after enrollment of the last participant.
Overall Number of Participants Analyzed	1697	1702	1700
Measure Type: Number; Unit of Measure: percentage of participants
	29.8	23.4	22.6

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Observation Arm, Herceptin 1-Year Arm
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	[Not Specified]
	Method	Log Rank
	Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Observation Arm, Herceptin 1-Year Arm
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.73
	Confidence Interval	(2-Sided) 95%; 0.64 to 0.83
	Estimation Comments	HR for Herceptin 1-Year Arm versus Observation Arm.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Observation Arm, Herceptin 2-Year Arm
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	[Not Specified]
	Method	Log Rank
	Comments	[Not Specified]

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Observation Arm, Herceptin 2-Year Arm
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.69
	Confidence Interval	(2-Sided) 95%; 0.61 to 0.79
	Estimation Comments	HR for Herceptin 2-Year Arm versus Observation Arm.

30. Secondary Outcome

Title	RFS Rate According to Kaplan-Meier Analysis Compared to Observation: 8-Year Median Follow-Up
Description	RFS events included local, regional, or distant tumor recurrence. The percentage of participants free of RFS events (i.e., the RFS rate) and corresponding 95% CI were estimated by Kaplan-Meier analysis based on available data at the time of the 8-year median follow-up analysis.
Time Frame	Years 3, 5, 7, 8

Outcome Measure Data

Analysis Population Description

FAS Population

Arm/Group Title	Observation Arm	Herceptin 1-Year Arm	Herceptin 2-Year Arm
Arm/Group Description:	Participants who completed definitive surgery and systemic adjuvant chemotherapy were observed for efficacy and safety until 10 years from individual randomization and for survival until 10 years after enrollment of the last participant. No Herceptin was provided.	Participants who completed definitive surgery and systemic adjuvant chemotherapy received a loading dose of Herceptin as 8 mg/kg via IV infusion on Day 1, followed by a maintenance dose of 6 mg/kg via IV infusion 3 weeks later and thereafter every 3 weeks for 1 year or until disease recurrence, whichever occurred first. Participants were observed for efficacy and safety until 10 years from individual randomization and for survival until 10 years after enrollment of the last participant.	Participants who completed definitive surgery and systemic adjuvant chemotherapy received a loading dose of Herceptin as 8 mg/kg via IV infusion on Day 1, followed by a maintenance dose of 6 mg/kg via IV infusion 3 weeks later and thereafter every 3 weeks for 2 years or until disease recurrence, whichever occurred first. Participants were observed for efficacy and safety until 10 years from individual randomization and for survival until 10 years after enrollment of the last participant.
Overall Number of Participants Analyzed	1697	1702	1700
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
Year 3	76.4; (74.3 to 78.4)	82.7; (80.9 to 84.6)	86.0; (84.3 to 87.6)
Year 5	71.9; (69.7 to 74.1)	78.4; (76.4 to 80.4)	79.9; (77.9 to 81.9)
Year 7	69.0; (66.7 to 71.3)	75.7; (73.6 to 77.8)	76.7; (74.6 to 78.8)
Year 8	68.4; (66.1 to 70.7)	75.1; (72.9 to 77.2)	75.8; (73.6 to 77.9)

31. Secondary Outcome

Title	Percentage of Participants With RFS Events in 1-Year Versus 2-Year Herceptin: 8-Year Median Follow-Up
Description	RFS events included local, regional, or distant tumor recurrence. The percentage of participants with at least one RFS event was reported.
Time Frame	From Baseline until time of event (median of 8 years)

Outcome Measure Data

Analysis Population Description

FAS Population 1Y2Y

Arm/Group Title	Herceptin 1-Year Arm	Herceptin 2-Year Arm
Arm/Group Description:	Participants who completed definitive surgery and systemic adjuvant chemotherapy received a loading dose of Herceptin as 8 mg/kg via IV infusion on Day 1, followed by a maintenance dose of 6 mg/kg via IV infusion 3 weeks later and thereafter every 3 weeks for 1 year or until disease recurrence, whichever occurred first. Participants were observed for efficacy and safety until 10 years from individual randomization and for survival until 10 years after enrollment of the last participant.	Participants who completed definitive surgery and systemic adjuvant chemotherapy received a loading dose of Herceptin as 8 mg/kg via IV infusion on Day 1, followed by a maintenance dose of 6 mg/kg via IV infusion 3 weeks later and thereafter every 3 weeks for 2 years or until disease recurrence, whichever occurred first. Participants were observed for efficacy and safety until 10 years from individual randomization and for survival until 10 years after enrollment of the last participant.
Overall Number of Participants Analyzed	1552	1553
Measure Type: Number; Unit of Measure: percentage of participants
	19.7	18.8

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Herceptin 1-Year Arm, Herceptin 2-Year Arm
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.4755
	Comments	[Not Specified]
	Method	Log Rank
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.94
	Confidence Interval	(2-Sided) 95%; 0.80 to 1.11
	Estimation Comments	HR for Herceptin 2-Year Arm versus Herceptin 1-Year Arm.

32. Secondary Outcome

Title	RFS Rate According to Kaplan-Meier Analysis in 1-Year Versus 2-Year Herceptin: 8-Year Median Follow-Up
Description	RFS events included local, regional, or distant tumor recurrence. The percentage of participants free of RFS events (i.e., the RFS rate) and corresponding 95% CI were estimated by Kaplan-Meier analysis based on available data at the time of the 8-year median follow-up analysis.
Time Frame	Years 3, 5, 7, 8

Outcome Measure Data

Analysis Population Description

FAS Population 1Y2Y

Arm/Group Title	Herceptin 1-Year Arm	Herceptin 2-Year Arm
Arm/Group Description:	Participants who completed definitive surgery and systemic adjuvant chemotherapy received a loading dose of Herceptin as 8 mg/kg via IV infusion on Day 1, followed by a maintenance dose of 6 mg/kg via IV infusion 3 weeks later and thereafter every 3 weeks for 1 year or until disease recurrence, whichever occurred first. Participants were observed for efficacy and safety until 10 years from individual randomization and for survival until 10 years after enrollment of the last participant.	Participants who completed definitive surgery and systemic adjuvant chemotherapy received a loading dose of Herceptin as 8 mg/kg via IV infusion on Day 1, followed by a maintenance dose of 6 mg/kg via IV infusion 3 weeks later and thereafter every 3 weeks for 2 years or until disease recurrence, whichever occurred first. Participants were observed for efficacy and safety until 10 years from individual randomization and for survival until 10 years after enrollment of the last participant.
Overall Number of Participants Analyzed	1552	1553
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
Year 3	87.7; (86.0 to 89.3)	90.9; (89.4 to 92.3)
Year 5	83.1; (81.2 to 85.0)	84.5; (82.7 to 86.4)
Year 7	80.2; (78.2 to 82.3)	81.3; (79.3 to 83.2)
Year 8	79.6; (77.5 to 81.6)	80.3; (78.2 to 82.3)

33. Secondary Outcome

Title	Percentage of Participants With Distant Disease-Free Survival (DDFS) Events Compared to Observation: 8-Year Median Follow-Up
Description	DDFS events included distant tumor recurrence, second primary cancer, or contralateral breast cancer. The percentage of participants with at least one DDFS event was reported.
Time Frame	From Baseline until time of event (median of 8 years)

Outcome Measure Data

Analysis Population Description

FAS Population

Arm/Group Title	Observation Arm	Herceptin 1-Year Arm	Herceptin 2-Year Arm
Arm/Group Description:	Participants who completed definitive surgery and systemic adjuvant chemotherapy were observed for efficacy and safety until 10 years from individual randomization and for survival until 10 years after enrollment of the last participant. No Herceptin was provided.	Participants who completed definitive surgery and systemic adjuvant chemotherapy received a loading dose of Herceptin as 8 mg/kg via IV infusion on Day 1, followed by a maintenance dose of 6 mg/kg via IV infusion 3 weeks later and thereafter every 3 weeks for 1 year or until disease recurrence, whichever occurred first. Participants were observed for efficacy and safety until 10 years from individual randomization and for survival until 10 years after enrollment of the last participant.	Participants who completed definitive surgery and systemic adjuvant chemotherapy received a loading dose of Herceptin as 8 mg/kg via IV infusion on Day 1, followed by a maintenance dose of 6 mg/kg via IV infusion 3 weeks later and thereafter every 3 weeks for 2 years or until disease recurrence, whichever occurred first. Participants were observed for efficacy and safety until 10 years from individual randomization and for survival until 10 years after enrollment of the last participant.
Overall Number of Participants Analyzed	1697	1702	1700
Measure Type: Number; Unit of Measure: percentage of participants
	28.8	23.4	23.2

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Observation Arm, Herceptin 1-Year Arm
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	[Not Specified]
	Method	Log Rank
	Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Observation Arm, Herceptin 1-Year Arm
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.76
	Confidence Interval	(2-Sided) 95%; 0.67 to 0.87
	Estimation Comments	HR for Herceptin 1-Year Arm versus Observation Arm.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Observation Arm, Herceptin 2-Year Arm
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	[Not Specified]
	Method	Log Rank
	Comments	[Not Specified]

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Observation Arm, Herceptin 2-Year Arm
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.75
	Confidence Interval	(2-Sided) 95%; 0.65 to 0.85
	Estimation Comments	HR for Herceptin 2-Year Arm versus Observation Arm.

34. Secondary Outcome

Title	DDFS Rate According to Kaplan-Meier Analysis Compared to Observation: 8-Year Median Follow-Up
Description	DDFS events included distant tumor recurrence, second primary cancer, or contralateral breast cancer. The percentage of participants free of DDFS events (i.e., the DDFS rate) and corresponding 95% CI were estimated by Kaplan-Meier analysis based on available data at the time of the 8-year median follow-up analysis.
Time Frame	Years 3, 5, 7, 8

Outcome Measure Data

Analysis Population Description

FAS Population

Arm/Group Title	Observation Arm	Herceptin 1-Year Arm	Herceptin 2-Year Arm
Arm/Group Description:	Participants who completed definitive surgery and systemic adjuvant chemotherapy were observed for efficacy and safety until 10 years from individual randomization and for survival until 10 years after enrollment of the last participant. No Herceptin was provided.	Participants who completed definitive surgery and systemic adjuvant chemotherapy received a loading dose of Herceptin as 8 mg/kg via IV infusion on Day 1, followed by a maintenance dose of 6 mg/kg via IV infusion 3 weeks later and thereafter every 3 weeks for 1 year or until disease recurrence, whichever occurred first. Participants were observed for efficacy and safety until 10 years from individual randomization and for survival until 10 years after enrollment of the last participant.	Participants who completed definitive surgery and systemic adjuvant chemotherapy received a loading dose of Herceptin as 8 mg/kg via IV infusion on Day 1, followed by a maintenance dose of 6 mg/kg via IV infusion 3 weeks later and thereafter every 3 weeks for 2 years or until disease recurrence, whichever occurred first. Participants were observed for efficacy and safety until 10 years from individual randomization and for survival until 10 years after enrollment of the last participant.
Overall Number of Participants Analyzed	1697	1702	1700
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
Year 3	78.6; (76.6 to 80.6)	84.4; (82.7 to 86.2)	85.9; (84.2 to 87.6)
Year 5	74.2; (72.1 to 76.4)	79.6; (77.6 to 81.6)	80.2; (78.2 to 82.1)
Year 7	70.8; (68.6 to 73.1)	76.7; (74.6 to 78.8)	76.7; (74.6 to 78.8)
Year 8	69.6; (67.3 to 71.9)	75.5; (73.4 to 77.6)	75.6; (73.4 to 77.7)

35. Secondary Outcome

Title	Percentage of Participants With DDFS Events in 1-Year Versus 2-Year Herceptin: 8-Year Median Follow-Up
Description	DDFS events included distant tumor recurrence, second primary cancer, or contralateral breast cancer. The percentage of participants with at least one DDFS event was reported.
Time Frame	From Baseline until time of event (median of 8 years)

Outcome Measure Data

Analysis Population Description

FAS Population 1Y2Y

Arm/Group Title	Herceptin 1-Year Arm	Herceptin 2-Year Arm
Arm/Group Description:	Participants who completed definitive surgery and systemic adjuvant chemotherapy received a loading dose of Herceptin as 8 mg/kg via IV infusion on Day 1, followed by a maintenance dose of 6 mg/kg via IV infusion 3 weeks later and thereafter every 3 weeks for 1 year or until disease recurrence, whichever occurred first. Participants were observed for efficacy and safety until 10 years from individual randomization and for survival until 10 years after enrollment of the last participant.	Participants who completed definitive surgery and systemic adjuvant chemotherapy received a loading dose of Herceptin as 8 mg/kg via IV infusion on Day 1, followed by a maintenance dose of 6 mg/kg via IV infusion 3 weeks later and thereafter every 3 weeks for 2 years or until disease recurrence, whichever occurred first. Participants were observed for efficacy and safety until 10 years from individual randomization and for survival until 10 years after enrollment of the last participant.
Overall Number of Participants Analyzed	1552	1553
Measure Type: Number; Unit of Measure: percentage of participants
	19.5	19.5

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Herceptin 1-Year Arm, Herceptin 2-Year Arm
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.9626
	Comments	[Not Specified]
	Method	Log Rank
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.00
	Confidence Interval	(2-Sided) 95%; 0.85 to 1.17
	Estimation Comments	HR for Herceptin 2-Year Arm versus Herceptin 1-Year Arm.

36. Secondary Outcome

Title	DDFS Rate According to Kaplan-Meier Analysis in 1-Year Versus 2-Year Herceptin: 8-Year Median Follow-Up
Description	DDFS events included distant tumor recurrence, second primary cancer, or contralateral breast cancer. The percentage of participants free of DDFS events (i.e., the DDFS rate) and corresponding 95% CI were estimated by Kaplan-Meier analysis based on available data at the time of the 8-year median follow-up analysis.
Time Frame	Years 3, 5, 7, 8

Outcome Measure Data

Analysis Population Description

FAS Population 1Y2Y

Arm/Group Title	Herceptin 1-Year Arm	Herceptin 2-Year Arm
Arm/Group Description:	Participants who completed definitive surgery and systemic adjuvant chemotherapy received a loading dose of Herceptin as 8 mg/kg via IV infusion on Day 1, followed by a maintenance dose of 6 mg/kg via IV infusion 3 weeks later and thereafter every 3 weeks for 1 year or until disease recurrence, whichever occurred first. Participants were observed for efficacy and safety until 10 years from individual randomization and for survival until 10 years after enrollment of the last participant.	Participants who completed definitive surgery and systemic adjuvant chemotherapy received a loading dose of Herceptin as 8 mg/kg via IV infusion on Day 1, followed by a maintenance dose of 6 mg/kg via IV infusion 3 weeks later and thereafter every 3 weeks for 2 years or until disease recurrence, whichever occurred first. Participants were observed for efficacy and safety until 10 years from individual randomization and for survival until 10 years after enrollment of the last participant.
Overall Number of Participants Analyzed	1552	1553
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
Year 3	89.4; (87.9 to 91.0)	90.8; (89.4 to 92.2)
Year 5	84.5; (82.7 to 86.3)	84.7; (82.9 to 86.5)
Year 7	81.4; (79.5 to 83.4)	81.1; (79.1 to 83.1)
Year 8	80.1; (78.1 to 82.2)	79.9; (77.8 to 81.9)

37. Secondary Outcome

Title	Percentage of Participants With Tumor Recurrence (TR) Compared to Observation: 8-Year Median Follow-Up
Description	The percentage of participants with TR of the present breast cancer was reported. TR included local, regional, or distant tumor ignoring contralateral breast cancer and second non-breast malignancy.
Time Frame	From Baseline until time of event (median of 8 years)

Outcome Measure Data

Analysis Population Description

FAS Population

Arm/Group Title	Observation Arm	Herceptin 1-Year Arm	Herceptin 2-Year Arm
Arm/Group Description:	Participants who completed definitive surgery and systemic adjuvant chemotherapy were observed for efficacy and safety until 10 years from individual randomization and for survival until 10 years after enrollment of the last participant. No Herceptin was provided.	Participants who completed definitive surgery and systemic adjuvant chemotherapy received a loading dose of Herceptin as 8 mg/kg via IV infusion on Day 1, followed by a maintenance dose of 6 mg/kg via IV infusion 3 weeks later and thereafter every 3 weeks for 1 year or until disease recurrence, whichever occurred first. Participants were observed for efficacy and safety until 10 years from individual randomization and for survival until 10 years after enrollment of the last participant.	Participants who completed definitive surgery and systemic adjuvant chemotherapy received a loading dose of Herceptin as 8 mg/kg via IV infusion on Day 1, followed by a maintenance dose of 6 mg/kg via IV infusion 3 weeks later and thereafter every 3 weeks for 2 years or until disease recurrence, whichever occurred first. Participants were observed for efficacy and safety until 10 years from individual randomization and for survival until 10 years after enrollment of the last participant.
Overall Number of Participants Analyzed	1697	1702	1700
Measure Type: Number; Unit of Measure: percentage of participants
	29.8	23.4	22.6

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Observation Arm, Herceptin 1-Year Arm
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	[Not Specified]
	Method	Log Rank
	Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Observation Arm, Herceptin 1-Year Arm
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.73
	Confidence Interval	(2-Sided) 95%; 0.64 to 0.83
	Estimation Comments	HR for Herceptin 1-Year Arm versus Observation Arm.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Observation Arm, Herceptin 2-Year Arm
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	[Not Specified]
	Method	Log Rank
	Comments	[Not Specified]

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Observation Arm, Herceptin 2-Year Arm
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.69
	Confidence Interval	(2-Sided) 95%; 0.61 to 0.79
	Estimation Comments	HR for Herceptin 2-Year Arm versus Observation Arm.

38. Secondary Outcome

Title	TR-Free Rate According to Kaplan-Meier Analysis Compared to Observation: 8-Year Median Follow-Up
Description	The percentage of participants without TR of the present breast cancer (i.e., the TR-free rate) and corresponding 95% CI were estimated by Kaplan-Meier analysis based on available data at the time of the 8-year median follow-up analysis. TR included local, regional, or distant tumor ignoring contralateral breast cancer and second non-breast malignancy.
Time Frame	Years 3, 5, 7, 8

Outcome Measure Data

Analysis Population Description

FAS Population

Arm/Group Title	Observation Arm	Herceptin 1-Year Arm	Herceptin 2-Year Arm
Arm/Group Description:	Participants who completed definitive surgery and systemic adjuvant chemotherapy were observed for efficacy and safety until 10 years from individual randomization and for survival until 10 years after enrollment of the last participant. No Herceptin was provided.	Participants who completed definitive surgery and systemic adjuvant chemotherapy received a loading dose of Herceptin as 8 mg/kg via IV infusion on Day 1, followed by a maintenance dose of 6 mg/kg via IV infusion 3 weeks later and thereafter every 3 weeks for 1 year or until disease recurrence, whichever occurred first. Participants were observed for efficacy and safety until 10 years from individual randomization and for survival until 10 years after enrollment of the last participant.	Participants who completed definitive surgery and systemic adjuvant chemotherapy received a loading dose of Herceptin as 8 mg/kg via IV infusion on Day 1, followed by a maintenance dose of 6 mg/kg via IV infusion 3 weeks later and thereafter every 3 weeks for 2 years or until disease recurrence, whichever occurred first. Participants were observed for efficacy and safety until 10 years from individual randomization and for survival until 10 years after enrollment of the last participant.
Overall Number of Participants Analyzed	1697	1702	1700
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
Year 3	76.5; (74.4 to 78.5)	82.8; (81.0 to 84.6)	86.1; (84.4 to 87.7)
Year 5	72.1; (69.9 to 74.3)	78.6; (76.6 to 80.6)	80.1; (78.2 to 82.1)
Year 7	69.2; (67.0 to 71.5)	75.9; (73.9 to 78.0)	77.0; (75.0 to 79.1)
Year 8	68.6; (66.4 to 70.9)	75.3; (73.2 to 77.4)	76.2; (74.1 to 78.3)

39. Secondary Outcome

Title	Percentage of Participants With TR in 1-Year Versus 2-Year Herceptin: 8-Year Median Follow-Up
Description	The percentage of participants with TR of the present breast cancer was reported. TR included local, regional, or distant tumor ignoring contralateral breast cancer and second non-breast malignancy.
Time Frame	From Baseline until time of event (median of 8 years)

Outcome Measure Data

Analysis Population Description

FAS Population 1Y2Y

Arm/Group Title	Herceptin 1-Year Arm	Herceptin 2-Year Arm
Arm/Group Description:	Participants who completed definitive surgery and systemic adjuvant chemotherapy received a loading dose of Herceptin as 8 mg/kg via IV infusion on Day 1, followed by a maintenance dose of 6 mg/kg via IV infusion 3 weeks later and thereafter every 3 weeks for 1 year or until disease recurrence, whichever occurred first. Participants were observed for efficacy and safety until 10 years from individual randomization and for survival until 10 years after enrollment of the last participant.	Participants who completed definitive surgery and systemic adjuvant chemotherapy received a loading dose of Herceptin as 8 mg/kg via IV infusion on Day 1, followed by a maintenance dose of 6 mg/kg via IV infusion 3 weeks later and thereafter every 3 weeks for 2 years or until disease recurrence, whichever occurred first. Participants were observed for efficacy and safety until 10 years from individual randomization and for survival until 10 years after enrollment of the last participant.
Overall Number of Participants Analyzed	1552	1553
Measure Type: Number; Unit of Measure: percentage of participants
	19.7	18.8

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Herceptin 1-Year Arm, Herceptin 2-Year Arm
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.4500
	Comments	[Not Specified]
	Method	Log Rank
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.94
	Confidence Interval	(2-Sided) 95%; 0.80 to 1.10
	Estimation Comments	HR for Herceptin 2-Year Arm versus Herceptin 1-Year Arm.

40. Secondary Outcome

Title	TR-Free Rate According to Kaplan-Meier Analysis in 1-Year Versus 2-Year Herceptin: 8-Year Median Follow-Up
Description	The percentage of participants without TR of the present breast cancer (i.e., the TR-free rate) and corresponding 95% CI were estimated by Kaplan-Meier analysis based on available data at the time of the 8-year median follow-up analysis. TR included local, regional, or distant tumor ignoring contralateral breast cancer and second non-breast malignancy.
Time Frame	Years 3, 5, 7, 8

Outcome Measure Data

Analysis Population Description

FAS Population 1Y2Y

Arm/Group Title	Herceptin 1-Year Arm	Herceptin 2-Year Arm
Arm/Group Description:	Participants who completed definitive surgery and systemic adjuvant chemotherapy received a loading dose of Herceptin as 8 mg/kg via IV infusion on Day 1, followed by a maintenance dose of 6 mg/kg via IV infusion 3 weeks later and thereafter every 3 weeks for 1 year or until disease recurrence, whichever occurred first. Participants were observed for efficacy and safety until 10 years from individual randomization and for survival until 10 years after enrollment of the last participant.	Participants who completed definitive surgery and systemic adjuvant chemotherapy received a loading dose of Herceptin as 8 mg/kg via IV infusion on Day 1, followed by a maintenance dose of 6 mg/kg via IV infusion 3 weeks later and thereafter every 3 weeks for 2 years or until disease recurrence, whichever occurred first. Participants were observed for efficacy and safety until 10 years from individual randomization and for survival until 10 years after enrollment of the last participant.
Overall Number of Participants Analyzed	1552	1553
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
Year 3	87.7; (86.1 to 89.4)	90.9; (89.5 to 92.4)
Year 5	83.2; (81.3 to 85.1)	84.7; (82.9 to 86.5)
Year 7	80.4; (78.4 to 82.4)	81.5; (79.6 to 83.5)
Year 8	79.8; (77.7 to 81.8)	80.6; (78.6 to 82.6)

41. Secondary Outcome

Title	Percentage of Participants With Distant Tumor Recurrence (DTR) Compared to Observation: 8-Year Median Follow-Up
Description	The percentage of participants with DTR was reported. DTR included distant tumors ignoring local and regional recurrences, contralateral breast cancer, and second non-breast malignancy.
Time Frame	From Baseline until time of event (median of 8 years)

Outcome Measure Data

Analysis Population Description

FAS Population

Arm/Group Title	Observation Arm	Herceptin 1-Year Arm	Herceptin 2-Year Arm
Arm/Group Description:	Participants who completed definitive surgery and systemic adjuvant chemotherapy were observed for efficacy and safety until 10 years from individual randomization and for survival until 10 years after enrollment of the last participant. No Herceptin was provided.	Participants who completed definitive surgery and systemic adjuvant chemotherapy received a loading dose of Herceptin as 8 mg/kg via IV infusion on Day 1, followed by a maintenance dose of 6 mg/kg via IV infusion 3 weeks later and thereafter every 3 weeks for 1 year or until disease recurrence, whichever occurred first. Participants were observed for efficacy and safety until 10 years from individual randomization and for survival until 10 years after enrollment of the last participant.	Participants who completed definitive surgery and systemic adjuvant chemotherapy received a loading dose of Herceptin as 8 mg/kg via IV infusion on Day 1, followed by a maintenance dose of 6 mg/kg via IV infusion 3 weeks later and thereafter every 3 weeks for 2 years or until disease recurrence, whichever occurred first. Participants were observed for efficacy and safety until 10 years from individual randomization and for survival until 10 years after enrollment of the last participant.
Overall Number of Participants Analyzed	1697	1702	1700
Measure Type: Number; Unit of Measure: percentage of participants
	25.3	19.4	18.8

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Observation Arm, Herceptin 1-Year Arm
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	[Not Specified]
	Method	Log Rank
	Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Observation Arm, Herceptin 1-Year Arm
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.72
	Confidence Interval	(2-Sided) 95%; 0.62 to 0.83
	Estimation Comments	HR for Herceptin 1-Year Arm versus Observation Arm.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Observation Arm, Herceptin 2-Year Arm
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	[Not Specified]
	Method	Log Rank
	Comments	[Not Specified]

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Observation Arm, Herceptin 2-Year Arm
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.69
	Confidence Interval	(2-Sided) 95%; 0.59 to 0.79
	Estimation Comments	HR for Herceptin 2-Year Arm versus Observation Arm.

42. Secondary Outcome

Title	DTR-Free Rate According to Kaplan-Meier Analysis Compared to Observation: 8-Year Median Follow-Up
Description	The percentage of participants without DTR (i.e., the DTR-free rate) and corresponding 95% CI were estimated by Kaplan-Meier analysis based on available data at the time of the 8-year median follow-up analysis. DTR included distant tumors ignoring local and regional recurrences, contralateral breast cancer, and second non-breast malignancy.
Time Frame	Years 3, 5, 7, 8

Outcome Measure Data

Analysis Population Description

FAS Population

Arm/Group Title	Observation Arm	Herceptin 1-Year Arm	Herceptin 2-Year Arm
Arm/Group Description:	Participants who completed definitive surgery and systemic adjuvant chemotherapy were observed for efficacy and safety until 10 years from individual randomization and for survival until 10 years after enrollment of the last participant. No Herceptin was provided.	Participants who completed definitive surgery and systemic adjuvant chemotherapy received a loading dose of Herceptin as 8 mg/kg via IV infusion on Day 1, followed by a maintenance dose of 6 mg/kg via IV infusion 3 weeks later and thereafter every 3 weeks for 1 year or until disease recurrence, whichever occurred first. Participants were observed for efficacy and safety until 10 years from individual randomization and for survival until 10 years after enrollment of the last participant.	Participants who completed definitive surgery and systemic adjuvant chemotherapy received a loading dose of Herceptin as 8 mg/kg via IV infusion on Day 1, followed by a maintenance dose of 6 mg/kg via IV infusion 3 weeks later and thereafter every 3 weeks for 2 years or until disease recurrence, whichever occurred first. Participants were observed for efficacy and safety until 10 years from individual randomization and for survival until 10 years after enrollment of the last participant.
Overall Number of Participants Analyzed	1697	1702	1700
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
Year 3	79.8; (77.8 to 81.7)	85.9; (84.2 to 87.6)	88.1; (86.5 to 89.6)
Year 5	76.5; (74.4 to 78.5)	82.1; (80.2 to 84.0)	83.4; (81.5 to 85.2)
Year 7	74.0; (71.8 to 76.1)	80.1; (78.2 to 82.1)	80.7; (78.8 to 82.6)
Year 8	73.3; (71.1 to 75.5)	79.5; (77.5 to 81.5)	80.3; (78.3 to 82.2)

43. Secondary Outcome

Title	Percentage of Participants With DTR in 1-Year Versus 2-Year Herceptin: 8-Year Median Follow-Up
Description	The percentage of participants with DTR was reported. DTR included distant tumors ignoring local and regional recurrences, contralateral breast cancer, and second non-breast malignancy.
Time Frame	From Baseline until time of event (median of 8 years)

Outcome Measure Data

Analysis Population Description

FAS Population 1Y2Y

Arm/Group Title	Herceptin 1-Year Arm	Herceptin 2-Year Arm
Arm/Group Description:	Participants who completed definitive surgery and systemic adjuvant chemotherapy received a loading dose of Herceptin as 8 mg/kg via IV infusion on Day 1, followed by a maintenance dose of 6 mg/kg via IV infusion 3 weeks later and thereafter every 3 weeks for 1 year or until disease recurrence, whichever occurred first. Participants were observed for efficacy and safety until 10 years from individual randomization and for survival until 10 years after enrollment of the last participant.	Participants who completed definitive surgery and systemic adjuvant chemotherapy received a loading dose of Herceptin as 8 mg/kg via IV infusion on Day 1, followed by a maintenance dose of 6 mg/kg via IV infusion 3 weeks later and thereafter every 3 weeks for 2 years or until disease recurrence, whichever occurred first. Participants were observed for efficacy and safety until 10 years from individual randomization and for survival until 10 years after enrollment of the last participant.
Overall Number of Participants Analyzed	1552	1553
Measure Type: Number; Unit of Measure: percentage of participants
	15.5	15.1

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Herceptin 1-Year Arm, Herceptin 2-Year Arm
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.6823
	Comments	[Not Specified]
	Method	Log Rank
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.96
	Confidence Interval	(2-Sided) 95%; 0.80 to 1.15
	Estimation Comments	HR for Herceptin 2-Year Arm versus Herceptin 1-Year Arm.

44. Secondary Outcome

Title	DTR-Free Rate According to Kaplan-Meier Analysis in 1-Year Versus 2-Year Herceptin: 8-Year Median Follow-Up
Description	The percentage of participants without DTR (i.e., the DTR-free rate) and corresponding 95% CI were estimated by Kaplan-Meier analysis based on available data at the time of the 8-year median follow-up analysis. DTR included distant tumors ignoring local and regional recurrences, contralateral breast cancer, and second non-breast malignancy.
Time Frame	Years 3, 5, 7, 8

Outcome Measure Data

Analysis Population Description

FAS Population 1Y2Y

Arm/Group Title	Herceptin 1-Year Arm	Herceptin 2-Year Arm
Arm/Group Description:	Participants who completed definitive surgery and systemic adjuvant chemotherapy received a loading dose of Herceptin as 8 mg/kg via IV infusion on Day 1, followed by a maintenance dose of 6 mg/kg via IV infusion 3 weeks later and thereafter every 3 weeks for 1 year or until disease recurrence, whichever occurred first. Participants were observed for efficacy and safety until 10 years from individual randomization and for survival until 10 years after enrollment of the last participant.	Participants who completed definitive surgery and systemic adjuvant chemotherapy received a loading dose of Herceptin as 8 mg/kg via IV infusion on Day 1, followed by a maintenance dose of 6 mg/kg via IV infusion 3 weeks later and thereafter every 3 weeks for 2 years or until disease recurrence, whichever occurred first. Participants were observed for efficacy and safety until 10 years from individual randomization and for survival until 10 years after enrollment of the last participant.
Overall Number of Participants Analyzed	1552	1553
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
Year 3	90.5; (89.0 to 91.9)	92.4; (91.1 to 93.8)
Year 5	86.7; (85.0 to 88.4)	87.5; (85.8 to 89.2)
Year 7	84.6; (82.8 to 86.4)	84.9; (83.1 to 86.7)
Year 8	83.9; (82.1 to 85.8)	84.4; (82.6 to 86.3)

45. Secondary Outcome

Title	Percentage of Participants With Restricted Disease-Free Survival (RDFS) Events in 1-Year Versus 2-Year Herceptin: 8-Year Median Follow-Up
Description	RDFS events included loco-regional or distant recurrence of breast cancer, development of contralateral breast cancer, or death from any cause. The percentage of participants with at least one RDFS event was reported.
Time Frame	From Baseline until time of event (median of 8 years)

Outcome Measure Data

Analysis Population Description

FAS Population 1Y2Y. In contrast to other study endpoints, RDFS compared to the Observation Arm was not a planned endpoint according to study protocol. Only RDFS in Herceptin 1-Year Arm versus Herceptin 2-Year Arm was a planned endpoint.

Arm/Group Title	Herceptin 1-Year Arm	Herceptin 2-Year Arm
Arm/Group Description:	Participants who completed definitive surgery and systemic adjuvant chemotherapy received a loading dose of Herceptin as 8 mg/kg via IV infusion on Day 1, followed by a maintenance dose of 6 mg/kg via IV infusion 3 weeks later and thereafter every 3 weeks for 1 year or until disease recurrence, whichever occurred first. Participants were observed for efficacy and safety until 10 years from individual randomization and for survival until 10 years after enrollment of the last participant.	Participants who completed definitive surgery and systemic adjuvant chemotherapy received a loading dose of Herceptin as 8 mg/kg via IV infusion on Day 1, followed by a maintenance dose of 6 mg/kg via IV infusion 3 weeks later and thereafter every 3 weeks for 2 years or until disease recurrence, whichever occurred first. Participants were observed for efficacy and safety until 10 years from individual randomization and for survival until 10 years after enrollment of the last participant.
Overall Number of Participants Analyzed	1552	1553
Measure Type: Number; Unit of Measure: percentage of participants
	22.2	21.9

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Herceptin 1-Year Arm, Herceptin 2-Year Arm
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.7251
	Comments	[Not Specified]
	Method	Log Rank
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.97
	Confidence Interval	(2-Sided) 95%; 0.84 to 1.13
	Estimation Comments	HR for Herceptin 2-Year Arm versus Herceptin 1-Year Arm.

46. Secondary Outcome

Title	RDFS Rate According to Kaplan-Meier Analysis in 1-Year Versus 2-Year Herceptin: 8-Year Median Follow-Up
Description	RDFS events included loco-regional or distant recurrence of breast cancer, development of contralateral breast cancer, or death from any cause. The percentage of participants free of RDFS events (i.e., the RDFS rate) and corresponding 95% CI were estimated by Kaplan-Meier analysis based on available data at the time of the 8-year median follow-up analysis.
Time Frame	Years 3, 5, 7, 8

Outcome Measure Data

Analysis Population Description

FAS Population 1Y2Y. In contrast to other study endpoints, RDFS compared to the Observation Arm was not a planned endpoint according to study protocol. Only RDFS in Herceptin 1-Year Arm versus Herceptin 2-Year Arm was a planned endpoint.

Arm/Group Title	Herceptin 1-Year Arm	Herceptin 2-Year Arm
Arm/Group Description:	Participants who completed definitive surgery and systemic adjuvant chemotherapy received a loading dose of Herceptin as 8 mg/kg via IV infusion on Day 1, followed by a maintenance dose of 6 mg/kg via IV infusion 3 weeks later and thereafter every 3 weeks for 1 year or until disease recurrence, whichever occurred first. Participants were observed for efficacy and safety until 10 years from individual randomization and for survival until 10 years after enrollment of the last participant.	Participants who completed definitive surgery and systemic adjuvant chemotherapy received a loading dose of Herceptin as 8 mg/kg via IV infusion on Day 1, followed by a maintenance dose of 6 mg/kg via IV infusion 3 weeks later and thereafter every 3 weeks for 2 years or until disease recurrence, whichever occurred first. Participants were observed for efficacy and safety until 10 years from individual randomization and for survival until 10 years after enrollment of the last participant.
Overall Number of Participants Analyzed	1552	1553
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
Year 3	87.3; (85.6 to 89.0)	89.9; (88.4 to 91.4)
Year 5	81.9; (79.9 to 83.8)	83.0; (81.1 to 84.9)
Year 7	78.5; (76.4 to 80.6)	78.9; (76.9 to 81.0)
Year 8	77.2; (75.1 to 79.3)	77.7; (75.5 to 79.8)

47. Secondary Outcome

Title	Percentage of Participants With Primary Cardiac Endpoint Events Compared to Observation: 10-Year Maximum Follow-Up
Description	Primary cardiac endpoint events included the occurrence of any of the following between randomization and new therapy for recurrent disease: symptomatic New York Heart Association (NYHA) Class III or IV congestive heart failure (CHF) confirmed by a cardiologist with a drop in left ventricular ejection fraction (LVEF) at least 10 percentage points from Baseline and to a value less than (<) 50%, and documentation of definite or probable cardiac death. Definite cardiac death included CHF, myocardial infarction, or primary arrhythmia. Probable cardiac death included unexpected sudden death within 24 hours of a cardiac event (syncope, cardiac arrest, chest pain, infarction, arrhythmia) without documented etiology. The percentage of participants with at least one primary cardiac endpoint event was reported. The 95% CI was calculated by the Pearson-Clopper method for a one-sample binomial.
Time Frame	From Baseline until time of event (maximum up to 10 years)

Outcome Measure Data

Analysis Population Description

Safety Population: All participants randomized/enrolled in the study according to actual treatment received. Hence, participants assigned to Herceptin who received no study treatment were analyzed in the Observation Arm.

Arm/Group Title	Observation Arm	Herceptin 1-Year Arm	Herceptin 2-Year Arm
Arm/Group Description:	Participants who completed definitive surgery and systemic adjuvant chemotherapy were observed for efficacy and safety until 10 years from individual randomization and for survival until 10 years after enrollment of the last participant. No Herceptin was provided.	Participants who completed definitive surgery and systemic adjuvant chemotherapy received a loading dose of Herceptin as 8 mg/kg via IV infusion on Day 1, followed by a maintenance dose of 6 mg/kg via IV infusion 3 weeks later and thereafter every 3 weeks for 1 year or until disease recurrence, whichever occurred first. Participants were observed for efficacy and safety until 10 years from individual randomization and for survival until 10 years after enrollment of the last participant.	Participants who completed definitive surgery and systemic adjuvant chemotherapy received a loading dose of Herceptin as 8 mg/kg via IV infusion on Day 1, followed by a maintenance dose of 6 mg/kg via IV infusion 3 weeks later and thereafter every 3 weeks for 2 years or until disease recurrence, whichever occurred first. Participants were observed for efficacy and safety until 10 years from individual randomization and for survival until 10 years after enrollment of the last participant.
Overall Number of Participants Analyzed	1744	1682	1673
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
	0.11; (0.01 to 0.41)	1.07; (0.64 to 1.69)	1.02; (0.59 to 1.62)

48. Secondary Outcome

Title	Percentage of Participants With Secondary Cardiac Endpoint Events Compared to Observation: 10-Year Maximum Follow-Up
Description	Secondary cardiac endpoint events included NYHA Class I or II CHF with a drop in LVEF measured by multiple-gated acquisition or electrocardiogram, unless the subsequent assessment of LVEF indicated a return to levels that did not meet the definition of a significant LVEF drop. A significant LVEF drop was defined as an absolute reduction of at least 10 percentage points from Baseline and to a value <50%. The percentage of participants with at least one secondary cardiac endpoint event was reported, excluding those with both a primary and secondary cardiac endpoint event. The 95% CI was calculated by the Pearson-Clopper method for a one-sample binomial.
Time Frame	From Baseline until time of event (maximum up to 10 years)

Outcome Measure Data

Analysis Population Description

Safety Population

Arm/Group Title	Observation Arm	Herceptin 1-Year Arm	Herceptin 2-Year Arm
Arm/Group Description:	Participants who completed definitive surgery and systemic adjuvant chemotherapy were observed for efficacy and safety until 10 years from individual randomization and for survival until 10 years after enrollment of the last participant. No Herceptin was provided.	Participants who completed definitive surgery and systemic adjuvant chemotherapy received a loading dose of Herceptin as 8 mg/kg via IV infusion on Day 1, followed by a maintenance dose of 6 mg/kg via IV infusion 3 weeks later and thereafter every 3 weeks for 1 year or until disease recurrence, whichever occurred first. Participants were observed for efficacy and safety until 10 years from individual randomization and for survival until 10 years after enrollment of the last participant.	Participants who completed definitive surgery and systemic adjuvant chemotherapy received a loading dose of Herceptin as 8 mg/kg via IV infusion on Day 1, followed by a maintenance dose of 6 mg/kg via IV infusion 3 weeks later and thereafter every 3 weeks for 2 years or until disease recurrence, whichever occurred first. Participants were observed for efficacy and safety until 10 years from individual randomization and for survival until 10 years after enrollment of the last participant.
Overall Number of Participants Analyzed	1744	1682	1673
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: percentage of participants
	0.86; (0.48 to 1.41)	4.40; (3.47 to 5.49)	7.29; (6.09 to 8.64)

Adverse Events

Time Frame	From Baseline until end of treatment (maximum up to 2 years) with the exception of cardiac/cardiovascular events, second primary malignancies, pregnancies, and Herceptin-related adverse events (maximum up to 10 years)
Adverse Event Reporting Description	Analysis Population Description: Safety Population
Arm/Group Title	Observation Arm	Herceptin 1-Year Arm	Herceptin 2-Year Arm
Arm/Group Description	Participants who completed definitive surgery and systemic adjuvant chemotherapy were observed for efficacy and safety until 10 years from individual randomization and for survival until 10 years after enrollment of the last participant. No Herceptin was provided. After the release of initial study results, participants in the Observation Arm were allowed to cross over to receive adjuvant Herceptin prior to disease recurrence. As such, adverse events that occurred after crossover were not included in the safety analyses for this arm.	Participants who completed definitive surgery and systemic adjuvant chemotherapy received a loading dose of Herceptin as 8 mg/kg via IV infusion on Day 1, followed by a maintenance dose of 6 mg/kg via IV infusion 3 weeks later and thereafter every 3 weeks for 1 year or until disease recurrence, whichever occurred first. Participants were observed for efficacy and safety until 10 years from individual randomization and for survival until 10 years after enrollment of the last participant.	Participants who completed definitive surgery and systemic adjuvant chemotherapy received a loading dose of Herceptin as 8 mg/kg via IV infusion on Day 1, followed by a maintenance dose of 6 mg/kg via IV infusion 3 weeks later and thereafter every 3 weeks for 2 years or until disease recurrence, whichever occurred first. Participants were observed for efficacy and safety until 10 years from individual randomization and for survival until 10 years after enrollment of the last participant.
All-Cause Mortality
	Observation Arm	Herceptin 1-Year Arm	Herceptin 2-Year Arm
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	--/--	--/--	--/--
Serious Adverse Events
	Observation Arm	Herceptin 1-Year Arm	Herceptin 2-Year Arm
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	143/1744 (8.20%)	269/1682 (15.99%)	344/1673 (20.56%)
Blood and lymphatic system disorders
Leukopenia * 1	1/1744 (0.06%)	0/1682 (0.00%)	0/1673 (0.00%)
Lymphadenopathy * 1	0/1744 (0.00%)	1/1682 (0.06%)	0/1673 (0.00%)
Thrombocytopenia * 1	0/1744 (0.00%)	0/1682 (0.00%)	1/1673 (0.06%)
Cardiac disorders
Acute coronary syndrome * 1	1/1744 (0.06%)	1/1682 (0.06%)	1/1673 (0.06%)
Acute myocardial infarction * 1	0/1744 (0.00%)	1/1682 (0.06%)	1/1673 (0.06%)
Angina pectoris * 1	2/1744 (0.11%)	2/1682 (0.12%)	1/1673 (0.06%)
Arrhythmia * 1	0/1744 (0.00%)	1/1682 (0.06%)	0/1673 (0.00%)
Atrial fibrillation * 1	1/1744 (0.06%)	1/1682 (0.06%)	2/1673 (0.12%)
Atrial flutter * 1	1/1744 (0.06%)	0/1682 (0.00%)	0/1673 (0.00%)
Atrioventricular block * 1	0/1744 (0.00%)	0/1682 (0.00%)	1/1673 (0.06%)
Atrioventricular block complete * 1	0/1744 (0.00%)	1/1682 (0.06%)	0/1673 (0.00%)
Bradycardia * 1	0/1744 (0.00%)	1/1682 (0.06%)	0/1673 (0.00%)
Cardiac arrest * 1	0/1744 (0.00%)	1/1682 (0.06%)	0/1673 (0.00%)
Cardiac failure * 1	0/1744 (0.00%)	1/1682 (0.06%)	0/1673 (0.00%)
Cardiac failure chronic * 1	0/1744 (0.00%)	2/1682 (0.12%)	0/1673 (0.00%)
Cardiac failure congestive * 1	1/1744 (0.06%)	19/1682 (1.13%)	24/1673 (1.43%)
Cardiomyopathy * 1	0/1744 (0.00%)	0/1682 (0.00%)	1/1673 (0.06%)
Coronary artery disease * 1	0/1744 (0.00%)	1/1682 (0.06%)	2/1673 (0.12%)
Coronary artery stenosis * 1	1/1744 (0.06%)	1/1682 (0.06%)	1/1673 (0.06%)
Extrasystoles * 1	0/1744 (0.00%)	1/1682 (0.06%)	0/1673 (0.00%)
Hypertensive heart disease * 1	0/1744 (0.00%)	1/1682 (0.06%)	0/1673 (0.00%)
Left ventricular dysfunction * 1	0/1744 (0.00%)	0/1682 (0.00%)	1/1673 (0.06%)
Left ventricular failure * 1	1/1744 (0.06%)	0/1682 (0.00%)	0/1673 (0.00%)
Myocardial infarction * 1	2/1744 (0.11%)	4/1682 (0.24%)	4/1673 (0.24%)
Palpitations * 1	0/1744 (0.00%)	1/1682 (0.06%)	0/1673 (0.00%)
Pericarditis lupus * 1	0/1744 (0.00%)	1/1682 (0.06%)	0/1673 (0.00%)
Sinus node dysfunction * 1	1/1744 (0.06%)	0/1682 (0.00%)	0/1673 (0.00%)
Supraventricular tachycardia * 1	0/1744 (0.00%)	1/1682 (0.06%)	1/1673 (0.06%)
Tachyarrhythmia * 1	0/1744 (0.00%)	1/1682 (0.06%)	0/1673 (0.00%)
Tachycardia * 1	0/1744 (0.00%)	1/1682 (0.06%)	1/1673 (0.06%)
Ventricular fibrillation * 1	0/1744 (0.00%)	1/1682 (0.06%)	0/1673 (0.00%)
Congenital, familial and genetic disorders
Dermoid cyst * 1	1/1744 (0.06%)	0/1682 (0.00%)	0/1673 (0.00%)
Odontogenic cyst * 1	0/1744 (0.00%)	0/1682 (0.00%)	1/1673 (0.06%)
Tooth hypoplasia * 1	0/1744 (0.00%)	0/1682 (0.00%)	1/1673 (0.06%)
Ventricular septal defect * 1	0/1744 (0.00%)	1/1682 (0.06%)	0/1673 (0.00%)
Ear and labyrinth disorders
Otosclerosis * 1	0/1744 (0.00%)	0/1682 (0.00%)	1/1673 (0.06%)
Sudden hearing loss * 1	0/1744 (0.00%)	1/1682 (0.06%)	0/1673 (0.00%)
Vertigo * 1	1/1744 (0.06%)	0/1682 (0.00%)	0/1673 (0.00%)
Endocrine disorders
Basedow's disease * 1	1/1744 (0.06%)	0/1682 (0.00%)	0/1673 (0.00%)
Goitre * 1	1/1744 (0.06%)	1/1682 (0.06%)	3/1673 (0.18%)
Eye disorders
Cataract * 1	0/1744 (0.00%)	1/1682 (0.06%)	0/1673 (0.00%)
Eyelid ptosis * 1	1/1744 (0.06%)	0/1682 (0.00%)	0/1673 (0.00%)
Glaucoma * 1	0/1744 (0.00%)	0/1682 (0.00%)	1/1673 (0.06%)
Retinal detachment * 1	1/1744 (0.06%)	0/1682 (0.00%)	0/1673 (0.00%)
Visual impairment * 1	0/1744 (0.00%)	0/1682 (0.00%)	2/1673 (0.12%)
Gastrointestinal disorders
Abdominal hernia * 1	0/1744 (0.00%)	0/1682 (0.00%)	1/1673 (0.06%)
Abdominal pain * 1	1/1744 (0.06%)	1/1682 (0.06%)	2/1673 (0.12%)
Anal fissure * 1	0/1744 (0.00%)	2/1682 (0.12%)	0/1673 (0.00%)
Diarrhoea * 1	1/1744 (0.06%)	1/1682 (0.06%)	3/1673 (0.18%)
Dyspepsia * 1	0/1744 (0.00%)	0/1682 (0.00%)	1/1673 (0.06%)
Gastritis * 1	1/1744 (0.06%)	0/1682 (0.00%)	1/1673 (0.06%)
Gastrointestinal haemorrhage * 1	0/1744 (0.00%)	1/1682 (0.06%)	1/1673 (0.06%)
Haemorrhoidal haemorrhage * 1	0/1744 (0.00%)	0/1682 (0.00%)	1/1673 (0.06%)
Haemorrhoids * 1	0/1744 (0.00%)	0/1682 (0.00%)	1/1673 (0.06%)
Hiatus hernia * 1	0/1744 (0.00%)	0/1682 (0.00%)	1/1673 (0.06%)
Ileus * 1	0/1744 (0.00%)	1/1682 (0.06%)	0/1673 (0.00%)
Inguinal hernia * 1	0/1744 (0.00%)	1/1682 (0.06%)	0/1673 (0.00%)
Intestinal ischaemia * 1	0/1744 (0.00%)	0/1682 (0.00%)	1/1673 (0.06%)
Intestinal obstruction * 1	0/1744 (0.00%)	0/1682 (0.00%)	1/1673 (0.06%)
Large intestine polyp * 1	0/1744 (0.00%)	1/1682 (0.06%)	1/1673 (0.06%)
Nausea * 1	1/1744 (0.06%)	1/1682 (0.06%)	0/1673 (0.00%)
Oesophagitis * 1	0/1744 (0.00%)	0/1682 (0.00%)	1/1673 (0.06%)
Pancreatitis * 1	1/1744 (0.06%)	0/1682 (0.00%)	0/1673 (0.00%)
Pancreatitis acute * 1	0/1744 (0.00%)	0/1682 (0.00%)	1/1673 (0.06%)
Pancreatitis chronic * 1	0/1744 (0.00%)	0/1682 (0.00%)	1/1673 (0.06%)
Paraesthesia oral * 1	0/1744 (0.00%)	0/1682 (0.00%)	1/1673 (0.06%)
Rectal haemorrhage * 1	0/1744 (0.00%)	0/1682 (0.00%)	1/1673 (0.06%)
Upper gastrointestinal haemorrhage * 1	0/1744 (0.00%)	0/1682 (0.00%)	1/1673 (0.06%)
Vomiting * 1	2/1744 (0.11%)	1/1682 (0.06%)	0/1673 (0.00%)
General disorders
Adverse drug reaction * 1	0/1744 (0.00%)	1/1682 (0.06%)	0/1673 (0.00%)
Axillary pain * 1	0/1744 (0.00%)	1/1682 (0.06%)	0/1673 (0.00%)
Breast complication associated with device * 1	0/1744 (0.00%)	0/1682 (0.00%)	1/1673 (0.06%)
Catheter site haemorrhage * 1	0/1744 (0.00%)	0/1682 (0.00%)	1/1673 (0.06%)
Chest pain * 1	1/1744 (0.06%)	3/1682 (0.18%)	0/1673 (0.00%)
Chills * 1	0/1744 (0.00%)	4/1682 (0.24%)	1/1673 (0.06%)
Death * 1	0/1744 (0.00%)	1/1682 (0.06%)	0/1673 (0.00%)
Device breakage * 1	0/1744 (0.00%)	1/1682 (0.06%)	0/1673 (0.00%)
Device dislocation * 1	0/1744 (0.00%)	0/1682 (0.00%)	2/1673 (0.12%)
Device failure * 1	0/1744 (0.00%)	0/1682 (0.00%)	1/1673 (0.06%)
Device leakage * 1	0/1744 (0.00%)	0/1682 (0.00%)	1/1673 (0.06%)
Fat necrosis * 1	0/1744 (0.00%)	0/1682 (0.00%)	1/1673 (0.06%)
Fatigue * 1	0/1744 (0.00%)	1/1682 (0.06%)	0/1673 (0.00%)
Granuloma * 1	1/1744 (0.06%)	0/1682 (0.00%)	0/1673 (0.00%)
Ill-defined disorder * 1	0/1744 (0.00%)	0/1682 (0.00%)	1/1673 (0.06%)
Local swelling * 1	0/1744 (0.00%)	0/1682 (0.00%)	1/1673 (0.06%)
Medical device complication * 1	0/1744 (0.00%)	2/1682 (0.12%)	0/1673 (0.00%)
Medical device pain * 1	0/1744 (0.00%)	1/1682 (0.06%)	0/1673 (0.00%)
Mucosal haemorrhage * 1	0/1744 (0.00%)	0/1682 (0.00%)	1/1673 (0.06%)
Multi-organ disorder * 1	0/1744 (0.00%)	0/1682 (0.00%)	1/1673 (0.06%)
Non-cardiac chest pain * 1	0/1744 (0.00%)	0/1682 (0.00%)	1/1673 (0.06%)
Pain * 1	1/1744 (0.06%)	0/1682 (0.00%)	0/1673 (0.00%)
Peripheral swelling * 1	0/1744 (0.00%)	1/1682 (0.06%)	0/1673 (0.00%)
Pyrexia * 1	0/1744 (0.00%)	3/1682 (0.18%)	6/1673 (0.36%)
Sudden death * 1	0/1744 (0.00%)	1/1682 (0.06%)	1/1673 (0.06%)
Hepatobiliary disorders
Cholecystitis * 1	1/1744 (0.06%)	0/1682 (0.00%)	0/1673 (0.00%)
Cholecystitis chronic * 1	1/1744 (0.06%)	0/1682 (0.00%)	0/1673 (0.00%)
Cholelithiasis * 1	2/1744 (0.11%)	3/1682 (0.18%)	3/1673 (0.18%)
Cholestasis * 1	0/1744 (0.00%)	0/1682 (0.00%)	1/1673 (0.06%)
Hepatitis toxic * 1	0/1744 (0.00%)	1/1682 (0.06%)	0/1673 (0.00%)
Portal vein thrombosis * 1	0/1744 (0.00%)	0/1682 (0.00%)	1/1673 (0.06%)
Immune system disorders
Anaphylactic reaction * 1	0/1744 (0.00%)	0/1682 (0.00%)	1/1673 (0.06%)
Anaphylactic shock * 1	0/1744 (0.00%)	1/1682 (0.06%)	0/1673 (0.00%)
Drug hypersensitivity * 1	1/1744 (0.06%)	0/1682 (0.00%)	0/1673 (0.00%)
Infections and infestations
Abdominal wall abscess * 1	0/1744 (0.00%)	1/1682 (0.06%)	0/1673 (0.00%)
Anal abscess * 1	0/1744 (0.00%)	0/1682 (0.00%)	1/1673 (0.06%)
Appendicitis * 1	0/1744 (0.00%)	2/1682 (0.12%)	4/1673 (0.24%)
Arthritis infective * 1	0/1744 (0.00%)	0/1682 (0.00%)	1/1673 (0.06%)
Atypical pneumonia * 1	0/1744 (0.00%)	0/1682 (0.00%)	1/1673 (0.06%)
Bartholin's abscess * 1	0/1744 (0.00%)	0/1682 (0.00%)	1/1673 (0.06%)
Breast abscess * 1	0/1744 (0.00%)	2/1682 (0.12%)	0/1673 (0.00%)
Breast cellulitis * 1	1/1744 (0.06%)	0/1682 (0.00%)	0/1673 (0.00%)
Bronchitis * 1	0/1744 (0.00%)	0/1682 (0.00%)	1/1673 (0.06%)
Catheter site cellulitis * 1	0/1744 (0.00%)	1/1682 (0.06%)	0/1673 (0.00%)
Catheter site infection * 1	1/1744 (0.06%)	0/1682 (0.00%)	1/1673 (0.06%)
Cellulitis * 1	1/1744 (0.06%)	5/1682 (0.30%)	5/1673 (0.30%)
Device related infection * 1	2/1744 (0.11%)	9/1682 (0.54%)	8/1673 (0.48%)
Device related sepsis * 1	0/1744 (0.00%)	1/1682 (0.06%)	0/1673 (0.00%)
Diverticulitis * 1	1/1744 (0.06%)	0/1682 (0.00%)	0/1673 (0.00%)
Endocarditis * 1	0/1744 (0.00%)	1/1682 (0.06%)	0/1673 (0.00%)
Endometritis * 1	1/1744 (0.06%)	0/1682 (0.00%)	0/1673 (0.00%)
Erysipelas * 1	1/1744 (0.06%)	8/1682 (0.48%)	4/1673 (0.24%)
Extradural abscess * 1	0/1744 (0.00%)	0/1682 (0.00%)	1/1673 (0.06%)
Gastroenteritis * 1	1/1744 (0.06%)	0/1682 (0.00%)	2/1673 (0.12%)
Genital infection female * 1	1/1744 (0.06%)	0/1682 (0.00%)	0/1673 (0.00%)
Hepatitis B * 1	1/1744 (0.06%)	0/1682 (0.00%)	0/1673 (0.00%)
Herpes zoster * 1	0/1744 (0.00%)	1/1682 (0.06%)	1/1673 (0.06%)
Infection * 1	0/1744 (0.00%)	0/1682 (0.00%)	1/1673 (0.06%)
Influenza * 1	0/1744 (0.00%)	2/1682 (0.12%)	0/1673 (0.00%)
Labyrinthitis * 1	1/1744 (0.06%)	0/1682 (0.00%)	0/1673 (0.00%)
Lower respiratory tract infection * 1	0/1744 (0.00%)	0/1682 (0.00%)	2/1673 (0.12%)
Lymphangitis * 1	0/1744 (0.00%)	1/1682 (0.06%)	1/1673 (0.06%)
Mastitis * 1	2/1744 (0.11%)	2/1682 (0.12%)	2/1673 (0.12%)
Muscle abscess * 1	1/1744 (0.06%)	0/1682 (0.00%)	0/1673 (0.00%)
Neutropenic sepsis * 1	1/1744 (0.06%)	0/1682 (0.00%)	0/1673 (0.00%)
Parotitis * 1	1/1744 (0.06%)	0/1682 (0.00%)	0/1673 (0.00%)
Peritonitis * 1	0/1744 (0.00%)	1/1682 (0.06%)	1/1673 (0.06%)
Pneumonia * 1	0/1744 (0.00%)	4/1682 (0.24%)	5/1673 (0.30%)
Pneumonia bacterial * 1	0/1744 (0.00%)	1/1682 (0.06%)	0/1673 (0.00%)
Postoperative wound infection * 1	1/1744 (0.06%)	0/1682 (0.00%)	1/1673 (0.06%)
Pulmonary mycosis * 1	0/1744 (0.00%)	0/1682 (0.00%)	1/1673 (0.06%)
Pulmonary sepsis * 1	1/1744 (0.06%)	0/1682 (0.00%)	0/1673 (0.00%)
Pyelonephritis acute * 1	0/1744 (0.00%)	0/1682 (0.00%)	1/1673 (0.06%)
Rectal abscess * 1	0/1744 (0.00%)	1/1682 (0.06%)	0/1673 (0.00%)
Respiratory tract infection * 1	0/1744 (0.00%)	2/1682 (0.12%)	0/1673 (0.00%)
Salmonellosis * 1	0/1744 (0.00%)	1/1682 (0.06%)	1/1673 (0.06%)
Salpingo-oophoritis * 1	0/1744 (0.00%)	0/1682 (0.00%)	1/1673 (0.06%)
Soft tissue infection * 1	0/1744 (0.00%)	0/1682 (0.00%)	1/1673 (0.06%)
Spinal cord abscess * 1	0/1744 (0.00%)	0/1682 (0.00%)	1/1673 (0.06%)
Staphylococcal sepsis * 1	0/1744 (0.00%)	1/1682 (0.06%)	0/1673 (0.00%)
Streptococcal sepsis * 1	0/1744 (0.00%)	1/1682 (0.06%)	0/1673 (0.00%)
Tonsillitis * 1	0/1744 (0.00%)	0/1682 (0.00%)	1/1673 (0.06%)
Tuberculosis * 1	0/1744 (0.00%)	1/1682 (0.06%)	1/1673 (0.06%)
Upper respiratory tract infection * 1	1/1744 (0.06%)	0/1682 (0.00%)	0/1673 (0.00%)
Urinary tract infection * 1	1/1744 (0.06%)	1/1682 (0.06%)	0/1673 (0.00%)
Wound infection * 1	2/1744 (0.11%)	3/1682 (0.18%)	0/1673 (0.00%)
Injury, poisoning and procedural complications
Acetabulum fracture * 1	0/1744 (0.00%)	0/1682 (0.00%)	1/1673 (0.06%)
Alcohol poisoning * 1	0/1744 (0.00%)	0/1682 (0.00%)	1/1673 (0.06%)
Ankle fracture * 1	2/1744 (0.11%)	0/1682 (0.00%)	4/1673 (0.24%)
Concussion * 1	0/1744 (0.00%)	0/1682 (0.00%)	1/1673 (0.06%)
Femoral neck fracture * 1	0/1744 (0.00%)	0/1682 (0.00%)	1/1673 (0.06%)
Femur fracture * 1	1/1744 (0.06%)	0/1682 (0.00%)	0/1673 (0.00%)
Fibula fracture * 1	1/1744 (0.06%)	0/1682 (0.00%)	0/1673 (0.00%)
Fractured coccyx * 1	0/1744 (0.00%)	0/1682 (0.00%)	1/1673 (0.06%)
Hand fracture * 1	0/1744 (0.00%)	0/1682 (0.00%)	1/1673 (0.06%)
Humerus fracture * 1	0/1744 (0.00%)	0/1682 (0.00%)	1/1673 (0.06%)
Joint dislocation * 1	0/1744 (0.00%)	0/1682 (0.00%)	1/1673 (0.06%)
Laceration * 1	0/1744 (0.00%)	1/1682 (0.06%)	0/1673 (0.00%)
Lower limb fracture * 1	0/1744 (0.00%)	2/1682 (0.12%)	1/1673 (0.06%)
Meniscus injury * 1	0/1744 (0.00%)	0/1682 (0.00%)	1/1673 (0.06%)
Nerve injury * 1	0/1744 (0.00%)	1/1682 (0.06%)	0/1673 (0.00%)
Patella fracture * 1	0/1744 (0.00%)	0/1682 (0.00%)	1/1673 (0.06%)
Pneumothorax traumatic * 1	0/1744 (0.00%)	1/1682 (0.06%)	1/1673 (0.06%)
Post procedural haematoma * 1	1/1744 (0.06%)	0/1682 (0.00%)	0/1673 (0.00%)
Post procedural haemorrhage * 1	0/1744 (0.00%)	0/1682 (0.00%)	1/1673 (0.06%)
Post-traumatic neck syndrome * 1	1/1744 (0.06%)	0/1682 (0.00%)	0/1673 (0.00%)
Postoperative hernia * 1	0/1744 (0.00%)	0/1682 (0.00%)	1/1673 (0.06%)
Procedural pain * 1	0/1744 (0.00%)	0/1682 (0.00%)	1/1673 (0.06%)
Pubis fracture * 1	0/1744 (0.00%)	1/1682 (0.06%)	0/1673 (0.00%)
Pulmonary contusion * 1	0/1744 (0.00%)	0/1682 (0.00%)	1/1673 (0.06%)
Radiation pneumonitis * 1	0/1744 (0.00%)	0/1682 (0.00%)	1/1673 (0.06%)
Radius fracture * 1	0/1744 (0.00%)	1/1682 (0.06%)	0/1673 (0.00%)
Rib fracture * 1	1/1744 (0.06%)	0/1682 (0.00%)	0/1673 (0.00%)
Road traffic accident * 1	0/1744 (0.00%)	2/1682 (0.12%)	0/1673 (0.00%)
Scar * 1	0/1744 (0.00%)	1/1682 (0.06%)	0/1673 (0.00%)
Spinal column injury * 1	1/1744 (0.06%)	0/1682 (0.00%)	0/1673 (0.00%)
Spinal fracture * 1	0/1744 (0.00%)	0/1682 (0.00%)	1/1673 (0.06%)
Tendon rupture * 1	0/1744 (0.00%)	0/1682 (0.00%)	2/1673 (0.12%)
Toxicity to various agents * 1	0/1744 (0.00%)	1/1682 (0.06%)	0/1673 (0.00%)
Upper limb fracture * 1	2/1744 (0.11%)	0/1682 (0.00%)	1/1673 (0.06%)
Wound * 1	0/1744 (0.00%)	0/1682 (0.00%)	1/1673 (0.06%)
Wound dehiscence * 1	0/1744 (0.00%)	1/1682 (0.06%)	0/1673 (0.00%)
Wound secretion * 1	0/1744 (0.00%)	0/1682 (0.00%)	1/1673 (0.06%)
Investigations
Ejection fraction decreased * 1	0/1744 (0.00%)	0/1682 (0.00%)	1/1673 (0.06%)
Gamma-glutamyltransferase increased * 1	0/1744 (0.00%)	1/1682 (0.06%)	0/1673 (0.00%)
Hepatic enzyme increased * 1	0/1744 (0.00%)	0/1682 (0.00%)	1/1673 (0.06%)
Metabolism and nutrition disorders
Decreased appetite * 1	1/1744 (0.06%)	0/1682 (0.00%)	1/1673 (0.06%)
Hypokalaemia * 1	0/1744 (0.00%)	0/1682 (0.00%)	1/1673 (0.06%)
Musculoskeletal and connective tissue disorders
Arthralgia * 1	0/1744 (0.00%)	2/1682 (0.12%)	1/1673 (0.06%)
Arthritis * 1	1/1744 (0.06%)	0/1682 (0.00%)	1/1673 (0.06%)
Back pain * 1	0/1744 (0.00%)	2/1682 (0.12%)	0/1673 (0.00%)
Fistula * 1	0/1744 (0.00%)	0/1682 (0.00%)	1/1673 (0.06%)
Intervertebral disc protrusion * 1	0/1744 (0.00%)	0/1682 (0.00%)	2/1673 (0.12%)
Lumbar spinal stenosis * 1	0/1744 (0.00%)	0/1682 (0.00%)	1/1673 (0.06%)
Muscle tightness * 1	0/1744 (0.00%)	0/1682 (0.00%)	1/1673 (0.06%)
Neck pain * 1	1/1744 (0.06%)	0/1682 (0.00%)	0/1673 (0.00%)
Osteoarthritis * 1	1/1744 (0.06%)	1/1682 (0.06%)	0/1673 (0.00%)
Pain in extremity * 1	0/1744 (0.00%)	0/1682 (0.00%)	2/1673 (0.12%)
Spondylolisthesis * 1	0/1744 (0.00%)	0/1682 (0.00%)	1/1673 (0.06%)
Tendon disorder * 1	1/1744 (0.06%)	0/1682 (0.00%)	0/1673 (0.00%)
Tenosynovitis * 1	1/1744 (0.06%)	0/1682 (0.00%)	0/1673 (0.00%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Acute myeloid leukaemia * 1	0/1744 (0.00%)	0/1682 (0.00%)	3/1673 (0.18%)
Adenocarcinoma * 1	0/1744 (0.00%)	1/1682 (0.06%)	0/1673 (0.00%)
Adenocarcinoma of colon * 1	1/1744 (0.06%)	1/1682 (0.06%)	1/1673 (0.06%)
Adenocarcinoma pancreas * 1	0/1744 (0.00%)	1/1682 (0.06%)	1/1673 (0.06%)
Adenoid cystic carcinoma * 1	0/1744 (0.00%)	1/1682 (0.06%)	0/1673 (0.00%)
Adenoma benign * 1	0/1744 (0.00%)	1/1682 (0.06%)	2/1673 (0.12%)
Adenosquamous cell carcinoma * 1	0/1744 (0.00%)	0/1682 (0.00%)	1/1673 (0.06%)
Angiosarcoma * 1	0/1744 (0.00%)	1/1682 (0.06%)	1/1673 (0.06%)
Basal cell carcinoma * 1	1/1744 (0.06%)	2/1682 (0.12%)	1/1673 (0.06%)
Benign breast neoplasm * 1	0/1744 (0.00%)	0/1682 (0.00%)	1/1673 (0.06%)
Benign neoplasm * 1	0/1744 (0.00%)	0/1682 (0.00%)	2/1673 (0.12%)
Benign neoplasm of bladder * 1	0/1744 (0.00%)	0/1682 (0.00%)	1/1673 (0.06%)
Benign neoplasm of skin * 1	0/1744 (0.00%)	1/1682 (0.06%)	0/1673 (0.00%)
Benign ovarian tumour * 1	0/1744 (0.00%)	0/1682 (0.00%)	1/1673 (0.06%)
Bladder cancer * 1	0/1744 (0.00%)	0/1682 (0.00%)	1/1673 (0.06%)
Bladder neoplasm * 1	0/1744 (0.00%)	1/1682 (0.06%)	0/1673 (0.00%)
Bladder papilloma * 1	0/1744 (0.00%)	0/1682 (0.00%)	1/1673 (0.06%)
Bladder transitional cell carcinoma * 1	0/1744 (0.00%)	0/1682 (0.00%)	1/1673 (0.06%)
Brain neoplasm * 1	1/1744 (0.06%)	0/1682 (0.00%)	0/1673 (0.00%)
Breast cancer * 1	9/1744 (0.52%)	27/1682 (1.61%)	36/1673 (2.15%)
Breast cancer in situ * 1	1/1744 (0.06%)	1/1682 (0.06%)	0/1673 (0.00%)
Breast neoplasm * 1	0/1744 (0.00%)	1/1682 (0.06%)	0/1673 (0.00%)
Carcinoid tumour of the gastrointestinal tract * 1	0/1744 (0.00%)	0/1682 (0.00%)	1/1673 (0.06%)
Cervix carcinoma * 1	1/1744 (0.06%)	2/1682 (0.12%)	3/1673 (0.18%)
Cervix carcinoma stage 0 * 1	1/1744 (0.06%)	0/1682 (0.00%)	1/1673 (0.06%)
Cervix carcinoma stage II * 1	0/1744 (0.00%)	0/1682 (0.00%)	1/1673 (0.06%)
Chronic myeloid leukaemia * 1	0/1744 (0.00%)	1/1682 (0.06%)	1/1673 (0.06%)
Colon cancer * 1	1/1744 (0.06%)	3/1682 (0.18%)	0/1673 (0.00%)
Colorectal adenocarcinoma * 1	0/1744 (0.00%)	0/1682 (0.00%)	1/1673 (0.06%)
Colorectal cancer * 1	0/1744 (0.00%)	1/1682 (0.06%)	1/1673 (0.06%)
Diffuse large B-cell lymphoma * 1	0/1744 (0.00%)	0/1682 (0.00%)	1/1673 (0.06%)
Endometrial adenocarcinoma * 1	2/1744 (0.11%)	0/1682 (0.00%)	0/1673 (0.00%)
Endometrial cancer * 1	2/1744 (0.11%)	2/1682 (0.12%)	1/1673 (0.06%)
Fibroadenoma of breast * 1	0/1744 (0.00%)	0/1682 (0.00%)	1/1673 (0.06%)
Gastric adenoma * 1	0/1744 (0.00%)	0/1682 (0.00%)	1/1673 (0.06%)
Gastric cancer * 1	1/1744 (0.06%)	2/1682 (0.12%)	3/1673 (0.18%)
Gastrointestinal stromal tumour * 1	0/1744 (0.00%)	0/1682 (0.00%)	1/1673 (0.06%)
Hepatic cancer * 1	0/1744 (0.00%)	0/1682 (0.00%)	1/1673 (0.06%)
Hepatocellular carcinoma * 1	0/1744 (0.00%)	0/1682 (0.00%)	1/1673 (0.06%)
Hodgkin's disease * 1	0/1744 (0.00%)	0/1682 (0.00%)	1/1673 (0.06%)
Infected neoplasm * 1	0/1744 (0.00%)	0/1682 (0.00%)	1/1673 (0.06%)
Inflammatory myofibroblastic tumour * 1	0/1744 (0.00%)	0/1682 (0.00%)	1/1673 (0.06%)
Intraductal proliferative breast lesion * 1	0/1744 (0.00%)	2/1682 (0.12%)	0/1673 (0.00%)
Invasive ductal breast carcinoma * 1	0/1744 (0.00%)	1/1682 (0.06%)	0/1673 (0.00%)
Invasive papillary breast carcinoma * 1	0/1744 (0.00%)	0/1682 (0.00%)	1/1673 (0.06%)
Lipofibroma * 1	0/1744 (0.00%)	0/1682 (0.00%)	1/1673 (0.06%)
Lung adenocarcinoma * 1	1/1744 (0.06%)	1/1682 (0.06%)	1/1673 (0.06%)
Lung neoplasm malignant * 1	0/1744 (0.00%)	6/1682 (0.36%)	2/1673 (0.12%)
Lymphoma * 1	0/1744 (0.00%)	0/1682 (0.00%)	1/1673 (0.06%)
Malignant melanoma * 1	0/1744 (0.00%)	8/1682 (0.48%)	8/1673 (0.48%)
Mantle cell lymphoma * 1	0/1744 (0.00%)	0/1682 (0.00%)	1/1673 (0.06%)
Meningioma * 1	0/1744 (0.00%)	1/1682 (0.06%)	0/1673 (0.00%)
Metastatic renal cell carcinoma * 1	0/1744 (0.00%)	1/1682 (0.06%)	0/1673 (0.00%)
Myelodysplastic syndrome * 1	0/1744 (0.00%)	0/1682 (0.00%)	2/1673 (0.12%)
Neoplasm * 1	1/1744 (0.06%)	0/1682 (0.00%)	0/1673 (0.00%)
Oesophageal squamous cell carcinoma * 1	0/1744 (0.00%)	0/1682 (0.00%)	1/1673 (0.06%)
Ovarian adenoma * 1	0/1744 (0.00%)	1/1682 (0.06%)	0/1673 (0.00%)
Ovarian cancer * 1	1/1744 (0.06%)	3/1682 (0.18%)	3/1673 (0.18%)
Paget's disease of nipple * 1	1/1744 (0.06%)	1/1682 (0.06%)	0/1673 (0.00%)
Pancreatic carcinoma * 1	3/1744 (0.17%)	0/1682 (0.00%)	0/1673 (0.00%)
Papillary thyroid cancer * 1	1/1744 (0.06%)	1/1682 (0.06%)	3/1673 (0.18%)
Rectal adenocarcinoma * 1	0/1744 (0.00%)	2/1682 (0.12%)	2/1673 (0.12%)
Rectal cancer * 1	1/1744 (0.06%)	0/1682 (0.00%)	2/1673 (0.12%)
Renal cancer * 1	0/1744 (0.00%)	0/1682 (0.00%)	3/1673 (0.18%)
Renal cell carcinoma * 1	0/1744 (0.00%)	1/1682 (0.06%)	0/1673 (0.00%)
Retro-orbital neoplasm * 1	0/1744 (0.00%)	0/1682 (0.00%)	1/1673 (0.06%)
Sarcoma * 1	1/1744 (0.06%)	0/1682 (0.00%)	0/1673 (0.00%)
Second primary malignancy * 1	1/1744 (0.06%)	1/1682 (0.06%)	2/1673 (0.12%)
Squamous cell carcinoma * 1	0/1744 (0.00%)	0/1682 (0.00%)	1/1673 (0.06%)
Squamous cell carcinoma of skin * 1	0/1744 (0.00%)	1/1682 (0.06%)	2/1673 (0.12%)
Squamous cell carcinoma of the vulva * 1	0/1744 (0.00%)	1/1682 (0.06%)	0/1673 (0.00%)
Thyroid cancer * 1	0/1744 (0.00%)	0/1682 (0.00%)	4/1673 (0.24%)
Thyroid neoplasm * 1	1/1744 (0.06%)	0/1682 (0.00%)	0/1673 (0.00%)
Transitional cell carcinoma * 1	1/1744 (0.06%)	0/1682 (0.00%)	0/1673 (0.00%)
Undifferentiated sarcoma * 1	0/1744 (0.00%)	1/1682 (0.06%)	0/1673 (0.00%)
Uterine cancer * 1	1/1744 (0.06%)	1/1682 (0.06%)	0/1673 (0.00%)
Uterine leiomyoma * 1	2/1744 (0.11%)	1/1682 (0.06%)	7/1673 (0.42%)
Uterine leiomyosarcoma * 1	0/1744 (0.00%)	0/1682 (0.00%)	1/1673 (0.06%)
Vulval cancer stage 0 * 1	0/1744 (0.00%)	0/1682 (0.00%)	1/1673 (0.06%)
Nervous system disorders
Brain oedema * 1	0/1744 (0.00%)	0/1682 (0.00%)	1/1673 (0.06%)
Carpal tunnel syndrome * 1	0/1744 (0.00%)	0/1682 (0.00%)	1/1673 (0.06%)
Central nervous system haemorrhage * 1	0/1744 (0.00%)	0/1682 (0.00%)	1/1673 (0.06%)
Cerebellar atrophy * 1	0/1744 (0.00%)	1/1682 (0.06%)	0/1673 (0.00%)
Cerebral haemorrhage * 1	0/1744 (0.00%)	1/1682 (0.06%)	1/1673 (0.06%)
Cerebral infarction * 1	0/1744 (0.00%)	0/1682 (0.00%)	1/1673 (0.06%)
Cerebral ischaemia * 1	1/1744 (0.06%)	0/1682 (0.00%)	0/1673 (0.00%)
Cerebrovascular accident * 1	0/1744 (0.00%)	3/1682 (0.18%)	2/1673 (0.12%)
Dementia Alzheimer's type * 1	1/1744 (0.06%)	0/1682 (0.00%)	0/1673 (0.00%)
Headache * 1	1/1744 (0.06%)	0/1682 (0.00%)	3/1673 (0.18%)
Hypoaesthesia * 1	0/1744 (0.00%)	0/1682 (0.00%)	1/1673 (0.06%)
Ischaemic stroke * 1	0/1744 (0.00%)	1/1682 (0.06%)	1/1673 (0.06%)
Migraine * 1	0/1744 (0.00%)	0/1682 (0.00%)	1/1673 (0.06%)
Myoclonus * 1	0/1744 (0.00%)	0/1682 (0.00%)	1/1673 (0.06%)
Nystagmus * 1	1/1744 (0.06%)	0/1682 (0.00%)	0/1673 (0.00%)
Optic neuritis * 1	0/1744 (0.00%)	1/1682 (0.06%)	0/1673 (0.00%)
Paresis * 1	1/1744 (0.06%)	0/1682 (0.00%)	0/1673 (0.00%)
Sciatica * 1	1/1744 (0.06%)	0/1682 (0.00%)	0/1673 (0.00%)
Seizure * 1	1/1744 (0.06%)	0/1682 (0.00%)	0/1673 (0.00%)
Subarachnoid haemorrhage * 1	0/1744 (0.00%)	0/1682 (0.00%)	1/1673 (0.06%)
Syncope * 1	0/1744 (0.00%)	1/1682 (0.06%)	1/1673 (0.06%)
Transient ischaemic attack * 1	0/1744 (0.00%)	2/1682 (0.12%)	0/1673 (0.00%)
Tremor * 1	0/1744 (0.00%)	1/1682 (0.06%)	1/1673 (0.06%)
Pregnancy, puerperium and perinatal conditions
Abortion missed * 1	0/1744 (0.00%)	0/1682 (0.00%)	1/1673 (0.06%)
Abortion spontaneous * 1	0/1744 (0.00%)	7/1682 (0.42%)	1/1673 (0.06%)
Complication of pregnancy * 1	1/1744 (0.06%)	0/1682 (0.00%)	0/1673 (0.00%)
Delivery * 1	1/1744 (0.06%)	0/1682 (0.00%)	0/1673 (0.00%)
Ectopic pregnancy * 1	0/1744 (0.00%)	2/1682 (0.12%)	0/1673 (0.00%)
Pregnancy * 1	11/1744 (0.63%)	22/1682 (1.31%)	29/1673 (1.73%)
Psychiatric disorders
Alcohol abuse * 1	0/1744 (0.00%)	0/1682 (0.00%)	1/1673 (0.06%)
Anxiety * 1	0/1744 (0.00%)	0/1682 (0.00%)	1/1673 (0.06%)
Completed suicide * 1	1/1744 (0.06%)	2/1682 (0.12%)	1/1673 (0.06%)
Delusion * 1	0/1744 (0.00%)	1/1682 (0.06%)	0/1673 (0.00%)
Depression * 1	1/1744 (0.06%)	0/1682 (0.00%)	5/1673 (0.30%)
Major depression * 1	1/1744 (0.06%)	0/1682 (0.00%)	0/1673 (0.00%)
Renal and urinary disorders
Hydronephrosis * 1	1/1744 (0.06%)	1/1682 (0.06%)	0/1673 (0.00%)
Nephrolithiasis * 1	0/1744 (0.00%)	1/1682 (0.06%)	0/1673 (0.00%)
Urinary incontinence * 1	0/1744 (0.00%)	1/1682 (0.06%)	0/1673 (0.00%)
Reproductive system and breast disorders
Adnexa uteri mass * 1	1/1744 (0.06%)	0/1682 (0.00%)	0/1673 (0.00%)
Breast calcifications * 1	1/1744 (0.06%)	0/1682 (0.00%)	0/1673 (0.00%)
Breast disorder * 1	1/1744 (0.06%)	2/1682 (0.12%)	1/1673 (0.06%)
Breast dysplasia * 1	1/1744 (0.06%)	0/1682 (0.00%)	0/1673 (0.00%)
Breast fibrosis * 1	3/1744 (0.17%)	5/1682 (0.30%)	1/1673 (0.06%)
Breast haematoma * 1	0/1744 (0.00%)	1/1682 (0.06%)	0/1673 (0.00%)
Breast hyperplasia * 1	0/1744 (0.00%)	1/1682 (0.06%)	0/1673 (0.00%)
Breast inflammation * 1	1/1744 (0.06%)	3/1682 (0.18%)	1/1673 (0.06%)
Breast mass * 1	1/1744 (0.06%)	0/1682 (0.00%)	1/1673 (0.06%)
Breast necrosis * 1	0/1744 (0.00%)	0/1682 (0.00%)	1/1673 (0.06%)
Breast pain * 1	1/1744 (0.06%)	0/1682 (0.00%)	0/1673 (0.00%)
Cervical dysplasia * 1	0/1744 (0.00%)	0/1682 (0.00%)	1/1673 (0.06%)
Cervical polyp * 1	1/1744 (0.06%)	1/1682 (0.06%)	0/1673 (0.00%)
Endometrial hyperplasia * 1	3/1744 (0.17%)	4/1682 (0.24%)	7/1673 (0.42%)
Endometriosis * 1	0/1744 (0.00%)	1/1682 (0.06%)	1/1673 (0.06%)
Fibrocystic breast disease * 1	0/1744 (0.00%)	0/1682 (0.00%)	2/1673 (0.12%)
Genital prolapse * 1	0/1744 (0.00%)	0/1682 (0.00%)	1/1673 (0.06%)
Menorrhagia * 1	2/1744 (0.11%)	2/1682 (0.12%)	2/1673 (0.12%)
Metrorrhagia * 1	0/1744 (0.00%)	2/1682 (0.12%)	1/1673 (0.06%)
Nipple exudate bloody * 1	0/1744 (0.00%)	1/1682 (0.06%)	0/1673 (0.00%)
Ovarian cyst * 1	2/1744 (0.11%)	2/1682 (0.12%)	1/1673 (0.06%)
Rectocele * 1	1/1744 (0.06%)	0/1682 (0.00%)	0/1673 (0.00%)
Uterine polyp * 1	0/1744 (0.00%)	2/1682 (0.12%)	4/1673 (0.24%)
Uterine prolapse * 1	1/1744 (0.06%)	0/1682 (0.00%)	0/1673 (0.00%)
Vaginal haemorrhage * 1	0/1744 (0.00%)	0/1682 (0.00%)	2/1673 (0.12%)
Vaginal prolapse * 1	0/1744 (0.00%)	1/1682 (0.06%)	0/1673 (0.00%)
Respiratory, thoracic and mediastinal disorders
Asthma * 1	4/1744 (0.23%)	0/1682 (0.00%)	1/1673 (0.06%)
Chronic obstructive pulmonary disease * 1	1/1744 (0.06%)	0/1682 (0.00%)	1/1673 (0.06%)
Cough * 1	0/1744 (0.00%)	1/1682 (0.06%)	0/1673 (0.00%)
Dyspnoea * 1	0/1744 (0.00%)	0/1682 (0.00%)	3/1673 (0.18%)
Dyspnoea exertional * 1	1/1744 (0.06%)	0/1682 (0.00%)	0/1673 (0.00%)
Lung infiltration * 1	0/1744 (0.00%)	0/1682 (0.00%)	1/1673 (0.06%)
Pleural effusion * 1	0/1744 (0.00%)	1/1682 (0.06%)	0/1673 (0.00%)
Pneumothorax * 1	1/1744 (0.06%)	2/1682 (0.12%)	1/1673 (0.06%)
Productive cough * 1	2/1744 (0.11%)	0/1682 (0.00%)	0/1673 (0.00%)
Pulmonary embolism * 1	2/1744 (0.11%)	1/1682 (0.06%)	4/1673 (0.24%)
Pulmonary fibrosis * 1	0/1744 (0.00%)	0/1682 (0.00%)	1/1673 (0.06%)
Pulmonary oedema * 1	0/1744 (0.00%)	0/1682 (0.00%)	1/1673 (0.06%)
Respiratory disorder * 1	0/1744 (0.00%)	0/1682 (0.00%)	1/1673 (0.06%)
Throat tightness * 1	0/1744 (0.00%)	1/1682 (0.06%)	0/1673 (0.00%)
Vocal cord polyp * 1	1/1744 (0.06%)	0/1682 (0.00%)	0/1673 (0.00%)
Skin and subcutaneous tissue disorders
Dermal cyst * 1	0/1744 (0.00%)	0/1682 (0.00%)	1/1673 (0.06%)
Dermatitis allergic * 1	0/1744 (0.00%)	0/1682 (0.00%)	1/1673 (0.06%)
Diabetic foot * 1	0/1744 (0.00%)	0/1682 (0.00%)	1/1673 (0.06%)
Drug eruption * 1	1/1744 (0.06%)	0/1682 (0.00%)	0/1673 (0.00%)
Eczema * 1	0/1744 (0.00%)	1/1682 (0.06%)	0/1673 (0.00%)
Erythema * 1	0/1744 (0.00%)	0/1682 (0.00%)	1/1673 (0.06%)
Prurigo * 1	0/1744 (0.00%)	0/1682 (0.00%)	1/1673 (0.06%)
Rash generalised * 1	0/1744 (0.00%)	1/1682 (0.06%)	0/1673 (0.00%)
Rash papular * 1	0/1744 (0.00%)	0/1682 (0.00%)	1/1673 (0.06%)
Scar pain * 1	0/1744 (0.00%)	0/1682 (0.00%)	1/1673 (0.06%)
Skin mass * 1	0/1744 (0.00%)	0/1682 (0.00%)	1/1673 (0.06%)
Telangiectasia * 1	0/1744 (0.00%)	0/1682 (0.00%)	1/1673 (0.06%)
Toxic skin eruption * 1	0/1744 (0.00%)	0/1682 (0.00%)	2/1673 (0.12%)
Urticaria * 1	0/1744 (0.00%)	1/1682 (0.06%)	1/1673 (0.06%)
Surgical and medical procedures
Mammoplasty * 1	1/1744 (0.06%)	0/1682 (0.00%)	0/1673 (0.00%)
Nerve block * 1	1/1744 (0.06%)	0/1682 (0.00%)	0/1673 (0.00%)
Vascular disorders
Aortic occlusion * 1	0/1744 (0.00%)	0/1682 (0.00%)	1/1673 (0.06%)
Deep vein thrombosis * 1	0/1744 (0.00%)	4/1682 (0.24%)	0/1673 (0.00%)
Flushing * 1	1/1744 (0.06%)	0/1682 (0.00%)	0/1673 (0.00%)
Haematoma * 1	0/1744 (0.00%)	0/1682 (0.00%)	1/1673 (0.06%)
Haemorrhage * 1	2/1744 (0.11%)	0/1682 (0.00%)	0/1673 (0.00%)
Hypertension * 1	1/1744 (0.06%)	1/1682 (0.06%)	0/1673 (0.00%)
Hypertensive crisis * 1	1/1744 (0.06%)	1/1682 (0.06%)	1/1673 (0.06%)
Hypotension * 1	1/1744 (0.06%)	2/1682 (0.12%)	1/1673 (0.06%)
Jugular vein thrombosis * 1	0/1744 (0.00%)	0/1682 (0.00%)	1/1673 (0.06%)
Microangiopathy * 1	0/1744 (0.00%)	0/1682 (0.00%)	1/1673 (0.06%)
Subclavian vein thrombosis * 1	0/1744 (0.00%)	1/1682 (0.06%)	1/1673 (0.06%)
Thrombophlebitis * 1	0/1744 (0.00%)	1/1682 (0.06%)	0/1673 (0.00%)
Thrombosis * 1	1/1744 (0.06%)	0/1682 (0.00%)	1/1673 (0.06%)
Vena cava thrombosis * 1	0/1744 (0.00%)	0/1682 (0.00%)	2/1673 (0.12%)
* Indicates events were collected by non-systematic assessment; 1 Term from vocabulary, MedDRA (18.0)
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	Observation Arm	Herceptin 1-Year Arm	Herceptin 2-Year Arm
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	1076/1744 (61.70%)	1389/1682 (82.58%)	1440/1673 (86.07%)
Cardiac disorders
Cardiac failure congestive * 1	18/1744 (1.03%)	78/1682 (4.64%)	127/1673 (7.59%)
Palpitations * 1	20/1744 (1.15%)	72/1682 (4.28%)	84/1673 (5.02%)
Gastrointestinal disorders
Diarrhoea * 1	22/1744 (1.26%)	155/1682 (9.22%)	180/1673 (10.76%)
Nausea * 1	37/1744 (2.12%)	134/1682 (7.97%)	157/1673 (9.38%)
Vomiting * 1	15/1744 (0.86%)	77/1682 (4.58%)	99/1673 (5.92%)
General disorders
Asthenia * 1	42/1744 (2.41%)	102/1682 (6.06%)	119/1673 (7.11%)
Chest pain * 1	37/1744 (2.12%)	63/1682 (3.75%)	84/1673 (5.02%)
Chills * 1	1/1744 (0.06%)	99/1682 (5.89%)	128/1673 (7.65%)
Fatigue * 1	83/1744 (4.76%)	198/1682 (11.77%)	246/1673 (14.70%)
Oedema peripheral * 1	49/1744 (2.81%)	82/1682 (4.88%)	101/1673 (6.04%)
Pyrexia * 1	12/1744 (0.69%)	116/1682 (6.90%)	145/1673 (8.67%)
Infections and infestations
Influenza * 1	17/1744 (0.97%)	95/1682 (5.65%)	142/1673 (8.49%)
Nasopharyngitis * 1	65/1744 (3.73%)	187/1682 (11.12%)	269/1673 (16.08%)
Upper respiratory tract infection * 1	31/1744 (1.78%)	53/1682 (3.15%)	84/1673 (5.02%)
Musculoskeletal and connective tissue disorders
Arthralgia * 1	152/1744 (8.72%)	225/1682 (13.38%)	246/1673 (14.70%)
Back pain * 1	106/1744 (6.08%)	146/1682 (8.68%)	137/1673 (8.19%)
Muscle spasms * 1	14/1744 (0.80%)	69/1682 (4.10%)	91/1673 (5.44%)
Musculoskeletal pain * 1	64/1744 (3.67%)	70/1682 (4.16%)	92/1673 (5.50%)
Myalgia * 1	28/1744 (1.61%)	88/1682 (5.23%)	104/1673 (6.22%)
Pain in extremity * 1	74/1744 (4.24%)	97/1682 (5.77%)	107/1673 (6.40%)
Nervous system disorders
Dizziness * 1	40/1744 (2.29%)	82/1682 (4.88%)	89/1673 (5.32%)
Headache * 1	72/1744 (4.13%)	201/1682 (11.95%)	250/1673 (14.94%)
Psychiatric disorders
Depression * 1	59/1744 (3.38%)	88/1682 (5.23%)	80/1673 (4.78%)
Insomnia * 1	49/1744 (2.81%)	96/1682 (5.71%)	75/1673 (4.48%)
Respiratory, thoracic and mediastinal disorders
Cough * 1	62/1744 (3.56%)	116/1682 (6.90%)	147/1673 (8.79%)
Dyspnoea * 1	46/1744 (2.64%)	83/1682 (4.93%)	116/1673 (6.93%)
Skin and subcutaneous tissue disorders
Nail disorder * 1	2/1744 (0.11%)	52/1682 (3.09%)	83/1673 (4.96%)
Onychoclasis * 1	2/1744 (0.11%)	53/1682 (3.15%)	98/1673 (5.86%)
Rash * 1	25/1744 (1.43%)	99/1682 (5.89%)	135/1673 (8.07%)
Vascular disorders
Hot flush * 1	130/1744 (7.45%)	166/1682 (9.87%)	159/1673 (9.50%)
Hypertension * 1	61/1744 (3.50%)	104/1682 (6.18%)	128/1673 (7.65%)
Lymphoedema * 1	70/1744 (4.01%)	81/1682 (4.82%)	92/1673 (5.50%)
* Indicates events were collected by non-systematic assessment; 1 Term from vocabulary, MedDRA (18.0)

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.

The Study being conducted under this Agreement is part of the Overall Study. Investigator is free to publish in reputable journals or to present at professional conferences the results of the Study, but only after the first publication or presentation that involves the Overall Study. The Sponsor may request that Confidential Information be deleted and/or the publication be postponed in order to protect the Sponsor's intellectual property rights.

Results Point of Contact

• Name/Title: Medical Communications
• Organization: Hoffmann-La Roche
• Phone: 800-821-8590
• EMail: global-roche-genentech-trials@gene.com

Publications of Results:

Gianni L, Dafni U, Gelber RD, Azambuja E, Muehlbauer S, Goldhirsch A, Untch M, Smith I, Baselga J, Jackisch C, Cameron D, Mano M, Pedrini JL, Veronesi A, Mendiola C, Pluzanska A, Semiglazov V, Vrdoljak E, Eckart MJ, Shen Z, Skiadopoulos G, Procter M, Pritchard KI, Piccart-Gebhart MJ, Bell R; Herceptin Adjuvant (HERA) Trial Study Team. Treatment with trastuzumab for 1 year after adjuvant chemotherapy in patients with HER2-positive early breast cancer: a 4-year follow-up of a randomised controlled trial. Lancet Oncol. 2011 Mar;12(3):236-44. doi: 10.1016/S1470-2045(11)70033-X. Epub 2011 Feb 25.

Procter M, Suter TM, de Azambuja E, Dafni U, van Dooren V, Muehlbauer S, Climent MA, Rechberger E, Liu WT, Toi M, Coombes RC, Dodwell D, Pagani O, Madrid J, Hall M, Chen SC, Focan C, Muschol M, van Veldhuisen DJ, Piccart-Gebhart MJ. Longer-term assessment of trastuzumab-related cardiac adverse events in the Herceptin Adjuvant (HERA) trial. J Clin Oncol. 2010 Jul 20;28(21):3422-8. doi: 10.1200/JCO.2009.26.0463. Epub 2010 Jun 7.

Dowsett M, Procter M, McCaskill-Stevens W, de Azambuja E, Dafni U, Rueschoff J, Jordan B, Dolci S, Abramovitz M, Stoss O, Viale G, Gelber RD, Piccart-Gebhart M, Leyland-Jones B. Disease-free survival according to degree of HER2 amplification for patients treated with adjuvant chemotherapy with or without 1 year of trastuzumab: the HERA Trial. J Clin Oncol. 2009 Jun 20;27(18):2962-9. doi: 10.1200/JCO.2008.19.7939. Epub 2009 Apr 13.

Untch M, Gelber RD, Jackisch C, Procter M, Baselga J, Bell R, Cameron D, Bari M, Smith I, Leyland-Jones B, de Azambuja E, Wermuth P, Khasanov R, Feng-Yi F, Constantin C, Mayordomo JI, Su CH, Yu SY, Lluch A, Senkus-Konefka E, Price C, Haslbauer F, Suarez Sahui T, Srimuninnimit V, Colleoni M, Coates AS, Piccart-Gebhart MJ, Goldhirsch A; HERA Study Team. Estimating the magnitude of trastuzumab effects within patient subgroups in the HERA trial. Ann Oncol. 2008 Jun;19(6):1090-6. doi: 10.1093/annonc/mdn005. Epub 2008 Feb 21.

McCaskill-Stevens W, Procter M, Goodbrand J, et al.: Disease-free survival according to local immunohistochemistry for HER2 and central fluorescence in situ hydridization for patients treated with adjuvant chemotherapy with and without trastuzumab in the HERA (BIG 01-01) trial. [Abstract] Breast Cancer Res Treat 106 (1): A-71, S18, 2007.

Smith I, Procter M, Gelber RD, Guillaume S, Feyereislova A, Dowsett M, Goldhirsch A, Untch M, Mariani G, Baselga J, Kaufmann M, Cameron D, Bell R, Bergh J, Coleman R, Wardley A, Harbeck N, Lopez RI, Mallmann P, Gelmon K, Wilcken N, Wist E, Sanchez Rovira P, Piccart-Gebhart MJ; HERA study team. 2-year follow-up of trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer: a randomised controlled trial. Lancet. 2007 Jan 6;369(9555):29-36. doi: 10.1016/S0140-6736(07)60028-2.

Suter TM, Procter M, van Veldhuisen DJ, Muscholl M, Bergh J, Carlomagno C, Perren T, Passalacqua R, Bighin C, Klijn JG, Ageev FT, Hitre E, Groetz J, Iwata H, Knap M, Gnant M, Muehlbauer S, Spence A, Gelber RD, Piccart-Gebhart MJ. Trastuzumab-associated cardiac adverse effects in the herceptin adjuvant trial. J Clin Oncol. 2007 Sep 1;25(25):3859-65. doi: 10.1200/JCO.2006.09.1611. Epub 2007 Jul 23.

Piccart-Gebhart MJ, Procter M, Leyland-Jones B, Goldhirsch A, Untch M, Smith I, Gianni L, Baselga J, Bell R, Jackisch C, Cameron D, Dowsett M, Barrios CH, Steger G, Huang CS, Andersson M, Inbar M, Lichinitser M, Lang I, Nitz U, Iwata H, Thomssen C, Lohrisch C, Suter TM, Ruschoff J, Suto T, Greatorex V, Ward C, Straehle C, McFadden E, Dolci MS, Gelber RD; Herceptin Adjuvant (HERA) Trial Study Team. Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med. 2005 Oct 20;353(16):1659-72. doi: 10.1056/NEJMoa052306.

Other Publications:

Jahanzeb M. Adjuvant trastuzumab therapy for HER2-positive breast cancer. Clin Breast Cancer. 2008 Aug;8(4):324-33. doi: 10.3816/CBC.2008.n.037.

Shiroiwa T, Fukuda T, Shimozuma K, Ohashi Y, Tsutani K. The model-based cost-effectiveness analysis of 1-year adjuvant trastuzumab treatment: based on 2-year follow-up HERA trial data. Breast Cancer Res Treat. 2008 Jun;109(3):559-66. doi: 10.1007/s10549-007-9679-4. Epub 2007 Jul 28.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Yerushalmi R, Dong B, Chapman JW, Goss PE, Pollak MN, Burnell MJ, Levine MN, Bramwell VHC, Pritchard KI, Whelan TJ, Ingle JN, Shepherd LE, Parulekar WR, Han L, Ding K, Gelmon KA. Impact of baseline BMI and weight change in CCTG adjuvant breast cancer trials. Ann Oncol. 2017 Jul 1;28(7):1560-1568. doi: 10.1093/annonc/mdx152.

Cameron D, Piccart-Gebhart MJ, Gelber RD, Procter M, Goldhirsch A, de Azambuja E, Castro G Jr, Untch M, Smith I, Gianni L, Baselga J, Al-Sakaff N, Lauer S, McFadden E, Leyland-Jones B, Bell R, Dowsett M, Jackisch C; Herceptin Adjuvant (HERA) Trial Study Team. 11 years' follow-up of trastuzumab after adjuvant chemotherapy in HER2-positive early breast cancer: final analysis of the HERceptin Adjuvant (HERA) trial. Lancet. 2017 Mar 25;389(10075):1195-1205. doi: 10.1016/S0140-6736(16)32616-2. Epub 2017 Feb 17. Erratum In: Lancet. 2019 Mar 16;393(10176):1100.

Loi S, Dafni U, Karlis D, Polydoropoulou V, Young BM, Willis S, Long B, de Azambuja E, Sotiriou C, Viale G, Ruschoff J, Piccart MJ, Dowsett M, Michiels S, Leyland-Jones B. Effects of Estrogen Receptor and Human Epidermal Growth Factor Receptor-2 Levels on the Efficacy of Trastuzumab: A Secondary Analysis of the HERA Trial. JAMA Oncol. 2016 Aug 1;2(8):1040-7. doi: 10.1001/jamaoncol.2016.0339.

O'Sullivan CC, Bradbury I, Campbell C, Spielmann M, Perez EA, Joensuu H, Costantino JP, Delaloge S, Rastogi P, Zardavas D, Ballman KV, Holmes E, de Azambuja E, Piccart-Gebhart M, Zujewski JA, Gelber RD. Efficacy of Adjuvant Trastuzumab for Patients With Human Epidermal Growth Factor Receptor 2-Positive Early Breast Cancer and Tumors </= 2 cm: A Meta-Analysis of the Randomized Trastuzumab Trials. J Clin Oncol. 2015 Aug 20;33(24):2600-8. doi: 10.1200/JCO.2015.60.8620. Epub 2015 Jun 22.

de Azambuja E, Procter MJ, van Veldhuisen DJ, Agbor-Tarh D, Metzger-Filho O, Steinseifer J, Untch M, Smith IE, Gianni L, Baselga J, Jackisch C, Cameron DA, Bell R, Leyland-Jones B, Dowsett M, Gelber RD, Piccart-Gebhart MJ, Suter TM. Trastuzumab-associated cardiac events at 8 years of median follow-up in the Herceptin Adjuvant trial (BIG 1-01). J Clin Oncol. 2014 Jul 10;32(20):2159-65. doi: 10.1200/JCO.2013.53.9288. Epub 2014 Jun 9.

Zabaglo L, Stoss O, Ruschoff J, Zielinski D, Salter J, Arfi M, Bradbury I, Dafni U, Piccart-Gebhart M, Procter M, Dowsett M; HERA Trial Study Team. HER2 staining intensity in HER2-positive disease: relationship with FISH amplification and clinical outcome in the HERA trial of adjuvant trastuzumab. Ann Oncol. 2013 Nov;24(11):2761-6. doi: 10.1093/annonc/mdt275. Epub 2013 Jul 25.

Goldhirsch A, Gelber RD, Piccart-Gebhart MJ, de Azambuja E, Procter M, Suter TM, Jackisch C, Cameron D, Weber HA, Heinzmann D, Dal Lago L, McFadden E, Dowsett M, Untch M, Gianni L, Bell R, Kohne CH, Vindevoghel A, Andersson M, Brunt AM, Otero-Reyes D, Song S, Smith I, Leyland-Jones B, Baselga J; Herceptin Adjuvant (HERA) Trial Study Team. 2 years versus 1 year of adjuvant trastuzumab for HER2-positive breast cancer (HERA): an open-label, randomised controlled trial. Lancet. 2013 Sep 21;382(9897):1021-8. doi: 10.1016/S0140-6736(13)61094-6. Epub 2013 Jul 18.

Metzger-Filho O, Procter M, de Azambuja E, Leyland-Jones B, Gelber RD, Dowsett M, Loi S, Saini KS, Cameron D, Untch M, Smith I, Gianni L, Baselga J, Jackisch C, Bell R, Sotiriou C, Viale G, Piccart-Gebhart M. Magnitude of trastuzumab benefit in patients with HER2-positive, invasive lobular breast carcinoma: results from the HERA trial. J Clin Oncol. 2013 Jun 1;31(16):1954-60. doi: 10.1200/JCO.2012.46.2440. Epub 2013 Apr 15.

• Responsible Party: Hoffmann-La Roche
• ClinicalTrials.gov Identifier: NCT00045032
• Other Study ID Numbers: BO16348; BIG-01-01; EU-20216; ROCHE-B016348E; ROCHE-B016348C; EORTC-10011; CAN-NCIC-MA24; IBCSG-28-02
• First Submitted: September 6, 2002
• First Posted: January 27, 2003
• Results First Submitted: October 19, 2016
• Results First Posted: April 27, 2017
• Last Update Posted: April 27, 2017