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

• Sponsor: Hoffmann-La Roche (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00045032
• Collaborator: Breast International Group (Other), European Organisation for Research and Treatment of Cancer - EORTC (Other), NCIC Clinical Trials Group (Other), ETOP IBCSG Partners Foundation (Other)
• Enrollment: 5,099
• Locations: 203
• Arms: 3
• Duration (Months): 163
• Patients Per Site: 25.1
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

The purpose of this trial is to evaluate Herceptin treatment for 1 year and 2 years (versus observation/no Herceptin) in women with HER2-overexpressing primary breast cancer who have completed (neo-)adjuvant systemic chemotherapy, definitive surgery, and radiotherapy, if applicable. Efficacy and safety will be assessed for 10 years from randomization for each participant. All participants will continue to be followed for survival until 10 years after enrollment of the last participant.

Condition or Disease	Intervention/Treatment	Phase
Breast Cancer	Drug: Herceptin; Drug: Herceptin	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 5099 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Randomized Three-Arm, Multicenter Comparison of 1 Year and 2 Years of Herceptin Versus No Herceptin in Women With HER2-Positive Primary Breast Cancer Who Have Completed Adjuvant Chemotherapy
• Study Start Date: Nov 1, 2001
• Actual Primary Completion Date: Mar 1, 2005
• Actual Study Completion Date: Jun 1, 2015

Arms and Interventions

Arm	Intervention/Treatment
No Intervention: Observation Arm Participants who have completed definitive surgery and systemic adjuvant chemotherapy will be 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 will be provided.
Experimental: Herceptin 1-Year Arm Participants who have completed definitive surgery and systemic adjuvant chemotherapy will receive Herceptin for 1 year or until disease recurrence, whichever occurs first. Participants will be observed for efficacy and safety until 10 years from individual randomization and for survival until 10 years after enrollment of the last participant.	Drug: Herceptin; Herceptin will be given as a loading dose of 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.; Other Names: Trastuzumab
Experimental: Herceptin 2-Year Arm Participants who have completed definitive surgery and systemic adjuvant chemotherapy will receive Herceptin for 2 years or until disease recurrence, whichever occurs first. Participants will be observed for efficacy and safety until 10 years from individual randomization and for survival until 10 years after enrollment of the last participant.	Drug: Herceptin; Herceptin will be given as a loading dose of 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.; Other Names: Trastuzumab

Outcome Measures

Primary Outcome Measures

1. Percentage of Participants With Disease-Free Survival (DFS) Events in Herceptin 1-Year Arm Compared to Observation: 1-Year Median Follow-Up [From Baseline until time of event (median of 1 year)]

   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.

2. Percentage of Participants With DFS Events in Herceptin 2-Year Arm Compared to Observation: 1-Year Median Follow-Up [From Baseline until time of event (median of 1 year)]

   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.

3. DFS Rate According to Kaplan-Meier Analysis in Herceptin 1-Year Arm Compared to Observation: 1-Year Median Follow-Up [Year 2]

   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.

4. DFS Rate According to Kaplan-Meier Analysis in Herceptin 2-Year Arm Compared to Observation: 1-Year Median Follow-Up [Year 2]

   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.

5. Percentage of Participants With DFS Events Compared to Observation: 8-Year Median Follow-Up [From Baseline until time of event (median of 8 years)]

   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.

6. DFS Rate at Year 3 According to Kaplan-Meier Analysis Compared to Observation: 8-Year Median Follow-Up [Year 3]

   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.

7. DFS Rate at Year 5 According to Kaplan-Meier Analysis Compared to Observation: 8-Year Median Follow-Up [Year 5]

   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.

8. DFS Rate at Year 7 According to Kaplan-Meier Analysis Compared to Observation: 8-Year Median Follow-Up [Year 7]

   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.

9. DFS Rate at Year 8 According to Kaplan-Meier Analysis Compared to Observation: 8-Year Median Follow-Up [Year 8]

   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.

10. Percentage of Participants With DFS Events Compared to Observation: 10-Year Maximum Follow-Up [From Baseline until time of event (maximum of 10 years)]

    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.

11. DFS Rate at Year 3 According to Kaplan-Meier Analysis Compared to Observation: 10-Year Maximum Follow-Up [Year 3]

    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.

12. DFS Rate at Year 5 According to Kaplan-Meier Analysis Compared to Observation: 10-Year Maximum Follow-Up [Year 5]

    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.

13. DFS Rate at Year 7 According to Kaplan-Meier Analysis Compared to Observation: 10-Year Maximum Follow-Up [Year 7]

    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.

14. DFS Rate at Year 8 According to Kaplan-Meier Analysis Compared to Observation: 10-Year Maximum Follow-Up [Year 8]

    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.

15. DFS Rate at Year 9 According to Kaplan-Meier Analysis Compared to Observation: 10-Year Maximum Follow-Up [Year 9]

    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.

16. DFS Rate at Year 10 According to Kaplan-Meier Analysis Compared to Observation: 10-Year Maximum Follow-Up [Year 10]

    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.

Secondary Outcome Measures

1. Percentage of Participants With DFS Events in 1-Year Versus 2-Year Herceptin: 10-Year Maximum Follow-Up [From Baseline until time of event (maximum of 10 years)]

   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.

2. DFS Rate According to Kaplan-Meier Analysis in 1-Year Versus 2-Year Herceptin: 10-Year Maximum Follow-Up [Years 3, 5, 7, 8, 9, 10]

   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.

3. Percentage of Participants With Overall Survival (OS) Events in Herceptin 1-Year Arm Compared to Observation: 1-Year Median Follow-Up [From Baseline until time of event (median of 1 year)]

   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.

4. Percentage of Participants With OS Events in Herceptin 2-Year Arm Compared to Observation: 1-Year Median Follow-Up [From Baseline until time of event (median of 1 year)]

   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.

5. OS Rate According to Kaplan-Meier Analysis in Herceptin 1-Year Arm Compared to Observation: 1-Year Median Follow-Up [Year 2]

   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.

6. OS Rate According to Kaplan-Meier Analysis in Herceptin 2-Year Arm Compared to Observation: 1-Year Median Follow-Up [Year 2]

   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.

7. Percentage of Participants With OS Events Compared to Observation: 8-Year Median Follow-Up [From Baseline until time of event (median of 8 years)]

   OS events referred to death from any cause. The percentage of participants who died was reported.

8. OS Rate According to Kaplan-Meier Analysis Compared to Observation: 8-Year Median Follow-Up [Years 3, 5, 7, 8]

   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.

9. Percentage of Participants With OS Events Compared to Observation: 11-Year Median Follow-Up [From Baseline until time of event (median of 11 years)]

   OS events referred to death from any cause. The percentage of participants who died was reported.

10. OS Rate According to Kaplan-Meier Analysis Compared to Observation: 11-Year Median Follow-Up [Years 3, 5, 7, 9, 10, 11, 12]

    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.

11. Percentage of Participants With OS Events in 1-Year Versus 2-Year Herceptin: 11-Year Median Follow-Up [From Baseline until time of event (median of 11 years)]

    OS events referred to death from any cause. The percentage of participants who died was reported.

12. OS Rate According to Kaplan-Meier Analysis in 1-Year Versus 2-Year Herceptin: 11-Year Median Follow-Up [Years 3, 5, 7, 9, 10, 11, 12]

    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.

13. Percentage of Participants With Recurrence-Free Survival (RFS) Events Compared to Observation: 8-Year Median Follow-Up [From Baseline until time of event (median of 8 years)]

    RFS events included local, regional, or distant tumor recurrence. The percentage of participants with at least one RFS event was reported.

14. RFS Rate According to Kaplan-Meier Analysis Compared to Observation: 8-Year Median Follow-Up [Years 3, 5, 7, 8]

    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.

15. Percentage of Participants With RFS Events in 1-Year Versus 2-Year Herceptin: 8-Year Median Follow-Up [From Baseline until time of event (median of 8 years)]

    RFS events included local, regional, or distant tumor recurrence. The percentage of participants with at least one RFS event was reported.

16. RFS Rate According to Kaplan-Meier Analysis in 1-Year Versus 2-Year Herceptin: 8-Year Median Follow-Up [Years 3, 5, 7, 8]

    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.

17. Percentage of Participants With Distant Disease-Free Survival (DDFS) Events Compared to Observation: 8-Year Median Follow-Up [From Baseline until time of event (median of 8 years)]

    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.

18. DDFS Rate According to Kaplan-Meier Analysis Compared to Observation: 8-Year Median Follow-Up [Years 3, 5, 7, 8]

    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.

19. Percentage of Participants With DDFS Events in 1-Year Versus 2-Year Herceptin: 8-Year Median Follow-Up [From Baseline until time of event (median of 8 years)]

    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.

20. DDFS Rate According to Kaplan-Meier Analysis in 1-Year Versus 2-Year Herceptin: 8-Year Median Follow-Up [Years 3, 5, 7, 8]

    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.

21. Percentage of Participants With Tumor Recurrence (TR) Compared to Observation: 8-Year Median Follow-Up [From Baseline until time of event (median of 8 years)]

    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.

22. TR-Free Rate According to Kaplan-Meier Analysis Compared to Observation: 8-Year Median Follow-Up [Years 3, 5, 7, 8]

    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.

23. Percentage of Participants With TR in 1-Year Versus 2-Year Herceptin: 8-Year Median Follow-Up [From Baseline until time of event (median of 8 years)]

    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.

24. TR-Free Rate According to Kaplan-Meier Analysis in 1-Year Versus 2-Year Herceptin: 8-Year Median Follow-Up [Years 3, 5, 7, 8]

    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.

25. Percentage of Participants With Distant Tumor Recurrence (DTR) Compared to Observation: 8-Year Median Follow-Up [From Baseline until time of event (median of 8 years)]

    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.

26. DTR-Free Rate According to Kaplan-Meier Analysis Compared to Observation: 8-Year Median Follow-Up [Years 3, 5, 7, 8]

    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.

27. Percentage of Participants With DTR in 1-Year Versus 2-Year Herceptin: 8-Year Median Follow-Up [From Baseline until time of event (median of 8 years)]

    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.

28. DTR-Free Rate According to Kaplan-Meier Analysis in 1-Year Versus 2-Year Herceptin: 8-Year Median Follow-Up [Years 3, 5, 7, 8]

    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.

29. Percentage of Participants With Restricted Disease-Free Survival (RDFS) Events in 1-Year Versus 2-Year Herceptin: 8-Year Median Follow-Up [From Baseline until time of event (median of 8 years)]

    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.

30. RDFS Rate According to Kaplan-Meier Analysis in 1-Year Versus 2-Year Herceptin: 8-Year Median Follow-Up [Years 3, 5, 7, 8]

    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.

31. Percentage of Participants With Primary Cardiac Endpoint Events Compared to Observation: 10-Year Maximum Follow-Up [From Baseline until time of event (maximum up to 10 years)]

    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.

32. Percentage of Participants With Secondary Cardiac Endpoint Events Compared to Observation: 10-Year Maximum Follow-Up [From Baseline until time of event (maximum up to 10 years)]

    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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Non-metastatic primary invasive breast cancer overexpressing HER2 (determined by immunohistochemistry 3+ or positive fluorescence in situ hybridization test) that has been histologically confirmed, adequately excised, axillary node positive or negative, and tumor size at least T1c according to Tumor/Node/Metastasis (TNM) staging

• Completion of at least 4 cycles of (neo-)adjuvant systemic chemotherapy, definitive surgery, and radiotherapy, if applicable

• Known hormone receptor status

• Baseline left ventricular ejection fraction (LVEF) greater than or equal to (≥) 55 percent (%)

Exclusion Criteria:

• Prior invasive breast carcinoma

• Other malignancies except for curatively treated basal and squamous cell carcinoma of the skin or in situ carcinoma of the cervix

• Clinical T4 tumors

• Cumulative doxorubicin exposure greater than (>) 360 milligrams per meter-squared (mg/m^{2) or epirubicin >720 mg/m}2 or any prior anthracyclines unrelated to the present breast cancer

• Peripheral stem cell or bone marrow stem cell support

• Prior mediastinal irradiation except for internal mammary node irradiation for the present breast cancer

• Non-irradiated internal mammary nodes or supraclavicular lymph node involvement

• Prior anti-HER2 therapy for any other reason or other prior biologic or immunotherapy for breast cancer

• Concurrent anti-cancer treatment in another investigational trial

• Serious cardiac or pulmonary conditions/illness, or any other conditions that could interfere with planned treatment

• Poor hematologic, hepatic, or renal function

• Pregnancy or lactation

• Women of childbearing potential or less than 1 year post-menopause unwilling to use adequate contraceptive measures

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Hospital Aleman de Buenos Aires	Buenos Aires		Argentina	1118
2	Saint John of God Hospital	Geelong	Australian Capital Territory	Australia	3220
3	Toowoomba Hospital	Toowoomba	Queensland	Australia	4350
4	Andrew Love Cancer Centre	Geelong	Victoria	Australia	3220
5	Mount Hospital	Perth	Western Australia	Australia	6000
6	Landeskrankenhaus Feldkirch	Feldkirch-Tisis		Austria	6807
7	Innsbruck Universitaetsklinik	Innsbruck		Austria	A-6020
8	Landeskrankenhaus Klagenfurt	Klagenfurt		Austria	9026
9	St. Vincent's Hospital	Linz Donau		Austria	A-4010
10	Landeskrankenanstalten - Salzburg	Salzburg		Austria	A-5020
11	Landeskrankenhaus St. Poelten	St. Poelten		Austria	3100
12	Universitaetsklinik fuer Innere Medizin I	Vienna		Austria	1090
13	Wilhelminenspital der Stadt Wien	Vienna		Austria	A-1160
14	LKH Villach	Villach		Austria	9500
15	LKH Voecklabruck	Voecklabruck		Austria	4840
16	A. oe. Krankenhaus Wiener Neustadt	Wiener Neustadt		Austria	A-2700
17	Ziekenhuis Netwerk Antwerpen Middelheim	Antwerp		Belgium	2020
18	Reseau Hospitalier De Medecine Sociale	Baudour		Belgium	7331
19	Hopital Universitaire Erasme	Brussels		Belgium	1070
20	Academisch Ziekenhuis der Vrije Universiteit Brussel	Brussels		Belgium	1090
21	Institut Jules Bordet	Brussels		Belgium	B-1000
22	Centre Hospitalier Notre Dame - Reine Fabiola	Charleroi		Belgium	6000
23	Cazk Groeninghe - Campus St-Niklaas	Kortrijk		Belgium	B-8500
24	Centre Hospitalier Universitaire de Tivoli	La Louviere		Belgium	7100
25	U.Z. Gasthuisberg	Leuven		Belgium	B-3000
26	Clinique Saint-Joseph	Liege		Belgium	B 4000
27	CHU Liege - Domaine Universitaire du Sart Tilman	Liege		Belgium	B-4000
28	Clinique Sainte Elisabeth	Namur		Belgium	5000
29	Hospital Serruys Ziekenhuis	Oostende		Belgium	8400
30	Centre Hospitalier Peltzer-La Tourelle	Verviers		Belgium	B-4800
31	Porto Alegre Hospital	Porto Alegre	Rio Grande do Sul	Brazil	90035-003
32	Hospital Sao Lucas da PUCRS	Porto Alegre		Brazil	90610-000
33	Hospital Santa Rita	Porto Alegre		Brazil	91330-490
34	Instituto Nacional de Cancer	Rio de Janeiro		Brazil	20560-120
35	Faculdade De Medicina Do ABC	Santo Andre		Brazil	09060-650
36	Tom Baker Cancer Centre - Calgary	Calgary	Alberta	Canada	T2N 4N2
37	British Columbia Cancer Agency - Centre for the Southern Interior	Kelowna	British Columbia	Canada	V1Y 5L3
38	Fraser Valley Cancer Centre at British Columbia Cancer Agency	Surrey	British Columbia	Canada	V3V 1Z2
39	British Columbia Cancer Agency - Vancouver Cancer Centre	Vancouver	British Columbia	Canada	V5Z 4E6
40	British Columbia Cancer Agency - Vancouver Island Cancer Centre	Victoria	British Columbia	Canada	V8R 6V5
41	CancerCare Manitoba	Winnipeg	Manitoba	Canada	R2H 2A6
42	Royal Victoria Hospital of Barrie	Barrie	Ontario	Canada	L4M 6M2
43	Margaret and Charles Juravinski Cancer Centre	Hamilton	Ontario	Canada	L8V 5C2
44	Trillium Health Centre - Mississauga Site	Mississauga	Ontario	Canada	L5B 1B8
45	Algoma Regional Cancer Program at Sault Area Hospital	Sault Sainte Marie	Ontario	Canada	P6A 2C4
46	Hotel Dieu Health Sciences Hospital - Niagara	St. Catharines	Ontario	Canada	L2R 5K3
47	Toronto East General Hospital	Toronto	Ontario	Canada	M4C 3E7
48	Mount Sinai Hospital - Toronto	Toronto	Ontario	Canada	M5G 1X5
49	Princess Margaret Hospital	Toronto	Ontario	Canada	M5G 2M9
50	Windsor Regional Cancer Centre at Windsor Regional Hospital	Windsor	Ontario	Canada	N8W 2X3
51	Prince Edward Island Cancer Centre at Queen Elizabeth Hospital	Charlottetown	Prince Edward Island	Canada	C1A 8T5
52	Hopital du Saint-Sacrement, Quebec	Quebec City	Quebec	Canada	G1S 4L8
53	Allan Blair Cancer Centre at Pasqua Hospital	Regina	Saskatchewan	Canada	S4T 7T1
54	Saskatoon Cancer Centre at the University of Saskatchewan	Saskatoon	Saskatchewan	Canada	S7N 4H4
55	Fundacion Arturo Lopez Perez	Santiago		Chile	29
56	Hospital Clinico San Borja Arriaran	Santiago		Chile
57	Hospital Dr. Sotero Del Rio	Santiago		Chile
58	Hospital Militar	Santiago		Chile
59	Instituto Nacional Del Cancer	Santiago		Chile
60	Queen Mary Hospital	Hong Kong		China
61	Tuen Mun Hospital	Hong Kong		China
62	Tongji Medical University	Wuhan		China	430030
63	Instituto Nacional De Cancerologia	Bogota		Colombia
64	Clinical Hospital Center Split	Split		Croatia	21000
65	Centralsygehus I Esbjerg	Esbjerg		Denmark	6700
66	Herning Central Hospital	Herning		Denmark	7400
67	Hillerod Hospital	Hillerod		Denmark	3400
68	Centralsygehuset I Naestved	Naestved		Denmark	4700
69	Sonderborg Sygehus	Sonderborg		Denmark	6400
70	Centre Regional Francois Baclesse	Caen		France	14076
71	Centre Hospital Regional Universitaire de Limoges	Limoges		France	87042
72	Hopital Clinique Claude Bernard	Metz		France	57072
73	Charite - Campus Charite Mitte	Berlin		Germany	D-10117
74	Evangelisches Bethesda Krankenhaus GmbH	Essen		Germany	D-45355
75	Universitaetsklinikum Freiburg	Freiburg		Germany	D-79106
76	Martin Luther Universitaet	Halle		Germany	D-06097
77	Henriettenstiftung Krankenhaus	Hanover		Germany	D-30559
78	Universitaets-Hautklinik Heidelberg	Heidelberg		Germany	D-69115
79	St. Vincentius-Kliniken	Karlsruhe		Germany	D-76137
80	University Hospital Schleswig-Holstein - Kiel Campus	Kiel		Germany	D-24105
81	Kreiskrankenhaus Leonberg - Frauenklinik	Leonberg		Germany	D-71229
82	Universitaetsklinkum Magdeburg der Otto-von-Guericke-Universitaet Magdeburg	Magdeburg		Germany	D-39120
83	Frauenklinik Vom Roten Kreuz	Munich		Germany	80637
84	Klinikum Rechts Der Isar - Technische Universitaet Muenchen	Munich		Germany	D-81675
85	Frauenklinik - Universitaetsklinikum Rostock am Klinikum Sudstadt	Rostock		Germany	D-18059
86	Universitaet Ulm	Ulm		Germany	D-89075
87	Dr. Horst-Schmidt-Kliniken	Wiesbaden		Germany	D-65199
88	University of Crete School of Medicine	Heraklion	Crete	Greece	71110
89	Evaggelismos Hospital	Athens		Greece	10676
90	Centro Medico	Guatemala City		Guatemala	01010
91	Hospital Roosevelt	Guatemala City		Guatemala	01010
92	Prince of Wales Hospital	Shatin, New Territories		Hong Kong
93	Semmelweis University	Budapest		Hungary	1082
94	National Institute of Oncology	Budapest		Hungary	1122
95	Fovarosi Onkormanyzat Szent Margit Korhaz, Okologia	Budapest		Hungary	H-1032
96	Cork University Hospital	Cork		Ireland
97	Sieff Hospital	Safed		Israel	13110
98	Ospedale San Lazzaro	Alba		Italy	12051
99	Ospedale Presenti Fenaroli	Alzano-Lombardo		Italy	24022
100	Centro di Riferimento Oncologico - Aviano	Aviano		Italy	33081
101	Ospedali Riuniti di Bergamo	Bergamo		Italy	24100
102	Ospedale degli Infermi - ASL 12	Biella		Italy	13900
103	Ospedale Bellaria	Bologna		Italy	I-40139
104	Spedali Civili di Brescia	Brescia		Italy	25124
105	Ospedale Oncologico A. Businco	Cagliari		Italy	09100
106	Ospedale B. Ramazzini	Carpi		Italy	41012
107	Ospedale Valduce	Como		Italy	22100
108	Ospedale Santa Croce	Cuneo		Italy	12100
109	Universita Degli Studi Di Florence	Firenze (Florence)		Italy	50121
110	Azienda Ospedaliero Careggi	Florence		Italy	50139
111	Morgagni-Pierantoni Ospedale	Forli		Italy	47100
112	Istituto Nazionale per la Ricerca sul Cancro	Genoa		Italy	16132
113	Ospedale A. Manzoni	Lecco		Italy	23900
114	Presidio Ospedaliero	Livorno		Italy	57100
115	Carlo Poma Hospital	Mantova		Italy	46100
116	European Institute of Oncology	Milan		Italy	20141
117	Ospedale Niguarda Ca'Granda	Milan		Italy	20162
118	University of Modena Hospital and Reggio Emilia School of Medicine	Modena		Italy	41100
119	Azienda Ospedaliera Di Parma	Parma		Italy	43100
120	I.R.C.C.S. Policlinico San Matteo	Pavia		Italy	27100
121	Policlinico Monteluce	Perugia		Italy	06122
122	Azienda Ospedaliera	Reggio Emilia		Italy	42100
123	Ospedale San Filippo Neri	Rome		Italy	00135
124	Ospedale Sant' Eugenio	Rome		Italy	00144
125	Istituto Clinico Humanitas	Rozzano		Italy	20089
126	Ospedale Civile ASL 1	Sassari		Italy	07100
127	Primario U.O. di Oncologia Medica	Trento		Italy	38100
128	Ospedale Ostetrico Ginecologica Sant Anna	Turin		Italy	10126
129	Universita di Torino	Turin		Italy	10126
130	Tokai University School Of Medicine	Kanagawa		Japan	259-1193
131	Tokyo Metropolitan - Komagome Hospital	Tokyo		Japan	113-8677
132	Seoul National University Hospital	Seoul		Korea, Republic of	110-744
133	Yonsei Cancer Center at Yonsei University Medical Center	Seoul		Korea, Republic of	120-752
134	Academisch Ziekenhuis Maastricht	Maastricht		Netherlands	6202 AZ
135	Maasland Hospital	Sittard		Netherlands	6131 BK
136	Diakonessenhuis Utrecht	Utrecht		Netherlands	3508 TG
137	Medical University of Gdansk	Gdansk		Poland	80-211
138	Oncologic Center	Gliwice		Poland	44-101
139	Medical University	Poznan		Poland	61-878
140	Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology	Warsaw		Poland	02-781
141	Instituto Portugues de Oncologia, Centro Regional de Coimbra	Coimbra		Portugal	3000-075
142	Hospitais da Universidade de Coimbra (HUC)	Coimbra		Portugal	3000
143	Maternidade Byssaia Barreto	Coimbra		Portugal	3000
144	Hospital Distrital De Faro	Faro		Portugal	8000
145	University Hospital of Santa Maria	Lisboa		Portugal	1649-035
146	Instituto Portugues de Oncologia de Francisco Gentil - Centro Regional de Oncologia de Lisboa, S.A.	Lisbon		Portugal	1099-023 Codex
147	Moscow Oncology Hospital	Moscow		Russian Federation	107005
148	P.A. Hertzen Research Oncology Institute	Moscow		Russian Federation	125284
149	Johns Hopkins Singapore International Medical Centre	Singapore		Singapore	308433
150	Groote Schuur Hospital	Cape Town		South Africa	7925
151	Parklands Hospital	Durban		South Africa	4001
152	Sandton Oncology Centre	Johannesburg		South Africa	2121
153	Medical Oncology Centre of Rosebank	Johannesburg		South Africa	2193
154	Pretoria - East Hospital	Lynnwood		South Africa	0081
155	Hospital De La Ribera	Alzira		Spain	46600
156	Hospital Del Mar	Barcelona		Spain	08003
157	Hospital Universitario San Cecilio de Granada	Granada		Spain	18003
158	Hospital General Universitario De Guadalajara	Guadalajara		Spain	19002
159	Hospital Juan Ramon Jimenez	Huelva		Spain	21005
160	Hospital Cuidad de Jaen	Jaen		Spain	23007
161	Centro Oncologico De Galicia Jose Antonio Quirogay Pineyro	La Coruna		Spain	15009
162	Hospital Universitario Canarias	La Laguna		Spain	38320
163	Hospital de Gran Canaria Dr. Negrin	Las Palmas de Gran Canaria		Spain	35020
164	Hospital Insular de Gran Canaria	Las Palmas		Spain	G.C.
165	Hospital de la Princesa	Madrid		Spain	28006
166	Complejo Hospitalario Santa Maria	Orense		Spain	32005
167	Complejo Hospitalario de Pontevedra	Pontevedra		Spain	36001
168	Consorci Hospitalari del Parc Tauli	Sabadell		Spain	08208
169	Hospital Universitario Nuestra Senora de la Candelaria	Santa Cruz de Tenerife		Spain	38010
170	Hospital Universidad Virgen Del Rocio	Sevilla		Spain	E- 41013
171	Hospital Virgen Del La Salud	Toledo		Spain	45004
172	Hospital General Universitario Valencia	Valencia		Spain	41014
173	Complexo Hospitalario Xeral de Vigo	Vigo Pontevedra		Spain	36204
174	Hospital Universitario Miguel Servet	Zaragoza		Spain	59009
175	University Hospital of Linkoping	Linkoping		Sweden	S-581 85
176	University Hospital of Malmoe	Malmo		Sweden	20502
177	Sahlgrenska University Hospital - Molndal at Gothenburg University	Molndal		Sweden	S-43180
178	Karolinska University Hospital - Huddinge	Stockholm		Sweden	S-171 76
179	Umea Universitet	Umea		Sweden	SE-901 87
180	Uppsala University Hospital	Uppsala		Sweden	SE-75185
181	Kantonspital Aarau	Aarau		Switzerland	5001
182	Universitaetsspital-Basel	Basel		Switzerland	CH-4031
183	Inselspital Bern	Bern		Switzerland	CH-3010
184	Spitaeler Chur AG	Chur		Switzerland	CH-7000
185	Centre Hospitalier Universitaire Vaudois	Lausanne		Switzerland	CH-1011
186	Ospedale Beata Vergine	Mendrisio		Switzerland	CH-6850
187	Kantonsspital - St. Gallen	St. Gallen		Switzerland	CH-9007
188	UniversitaetsSpital Zuerich	Zurich		Switzerland	CH-8091
189	Chulalongkorn University Hospital	Bangkok		Thailand	10330
190	Ramathibodi Hospital	Bangkok		Thailand	10400
191	Bradford Hospitals NHS Trust	Bradford	England	United Kingdom	BD9 6RJ
192	Broomfield Hospital	Chelmsford, Essex	England	United Kingdom	CM1 7ET
193	Saint Margaret's Hospital	Epping Essex	England	United Kingdom	CM16 6TN
194	Diana Princess of Wales Hospital	Grimsby	England	United Kingdom	DN33 2BA
195	Huddersfield Royal Infirmary	Huddersfield, West Yorks	England	United Kingdom	HD3 3EA
196	Princess Royal Hospital	Hull	England	United Kingdom	HU8 9HE
197	Cookridge Hospital at Leeds Teaching Hospital NHS Trust	Leeds	England	United Kingdom	LS16 6QB
198	Imperial College of Medicine	London	England	United Kingdom	W12 0NN
199	James Cook University Hospital	Middlesbrough	England	United Kingdom	TS4 3BW
200	Northern Centre for Cancer Treatment at Newcastle General Hospital	Newcastle-Upon-Tyne	England	United Kingdom	NE4 6BE
201	Cancer Research Centre at Weston Park Hospital	Sheffield	England	United Kingdom	S1O 2SJ
202	Airedale General Hospital	West Yorkshire	England	United Kingdom	BD20 6TD
203	Southend NHS Trust Hospital	Westcliff-On-Sea	England	United Kingdom	SS0 0RY

Sponsors and Collaborators

• Hoffmann-La Roche
• Breast International Group
• European Organisation for Research and Treatment of Cancer - EORTC
• NCIC Clinical Trials Group
• ETOP IBCSG Partners Foundation

Investigators

• Study Chair: Martine J. Piccart-Gebhart, MD, PhD, Jules Bordet Institute
• Study Chair: Robert E. Coleman, MD, FRCP, Cancer Research Centre at Weston Park Hospital
• Study Chair: Karen A. Gelmon, MD, British Columbia Cancer Agency
• Study Chair: Kathleen I. Pritchard, MD, Toronto Sunnybrook Regional Cancer Centre
• Study Chair: Olivia Pagani, MD, Ospedale Beata Vergine

Study Documents (Full-Text)

None provided.

More Information

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. Review.
• 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. Epub 2007 Jul 28.

• 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 Posted: Jan 27, 2003
• Last Update Posted: Apr 27, 2017
• Last Verified: Mar 1, 2017

• Additional relevant MeSH terms: Breast Neoplasms; Trastuzumab

Study Results

Participant Flow

Pre-assignment Detail	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	1702	1700
Crossover to Adjuvant Herceptin	888	0	0
COMPLETED	834	994	974
NOT COMPLETED	863	708	726

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 Participants	1697	1702	1700	5099
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	49.2 (10.08)	49.0 (10.06)	49.2 (10.09)	49.1 (10.08)
Sex: Female, Male (Count of Participants)
Female	1697 100%	1702 100%	1700 100%	5099 100%
Male	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.
Measure Participants	1693	1693
Number [percentage of participants]	12.9 0.8%	7.5 0.4%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Observation Arm, Herceptin 1-Year Arm
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Log Rank
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Observation Arm, Herceptin 1-Year Arm
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.54
	Confidence Interval	(2-Sided) 95%; 0.44 to 0.67
	Parameter Dispersion	Type: Value:
	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.
Measure Participants	1693	1694
Number [percentage of participants]	13.0 0.8%	7.6 0.4%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Observation Arm, Herceptin 1-Year Arm
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.000
	Comments
	Method	Log Rank
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Observation Arm, Herceptin 1-Year Arm
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.43
	Confidence Interval	(2-Sided) 95%; 0.34 to 0.53
	Parameter Dispersion	Type: Value:
	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.
Measure Participants	1693	1693
Number (95% Confidence Interval) [percentage of participants]	78.18 4.6%	85.80 5%

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.
Measure Participants	1693	1694
Number (95% Confidence Interval) [percentage of participants]	73.60 4.3%	87.50 5.1%

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.
Measure Participants	1697	1702	1700
Number [percentage of participants]	33.6 2%	27.7 1.6%	27.8 1.6%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Observation Arm, Herceptin 1-Year Arm
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Log Rank
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Observation Arm, Herceptin 1-Year Arm
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.76
	Confidence Interval	(2-Sided) 95%; 0.67 to 0.86
	Parameter Dispersion	Type: Value:
	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
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Log Rank
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Observation Arm, Herceptin 2-Year Arm
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.75
	Confidence Interval	(2-Sided) 95%; 0.67 to 0.85
	Parameter Dispersion	Type: Value:
	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.
Measure Participants	1697	1702	1700
Number (95% Confidence Interval) [percentage of participants]	75.2 4.4%	81.3 4.8%	83.5 4.9%

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.
Measure Participants	1697	1702	1700
Number (95% Confidence Interval) [percentage of participants]	70.0 4.1%	75.9 4.5%	76.5 4.5%

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.
Measure Participants	1697	1702	1700
Number (95% Confidence Interval) [percentage of participants]	66.0 3.9%	72.4 4.3%	72.5 4.3%

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.
Measure Participants	1697	1702	1700
Number (95% Confidence Interval) [percentage of participants]	64.8 3.8%	71.2 4.2%	71.0 4.2%

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.
Measure Participants	1697	1702	1700
Number [percentage of participants]	35.8 2.1%	29.7 1.7%	30.5 1.8%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Observation Arm, Herceptin 1-Year Arm
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.76
	Confidence Interval	(2-Sided) 95%; 0.68 to 0.86
	Parameter Dispersion	Type: Value:
	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
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.77
	Confidence Interval	(2-Sided) 95%; 0.69 to 0.87
	Parameter Dispersion	Type: Value:
	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.
Measure Participants	1697	1702	1700
Number (95% Confidence Interval) [percentage of participants]	75.2 4.4%	81.3 4.8%	83.4 4.9%

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.
Measure Participants	1697	1702	1700
Number (95% Confidence Interval) [percentage of participants]	70.0 4.1%	75.9 4.5%	76.4 4.5%

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.
Measure Participants	1697	1702	1700
Number (95% Confidence Interval) [percentage of participants]	65.8 3.9%	72.4 4.3%	72.5 4.3%

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.
Measure Participants	1697	1702	1700
Number (95% Confidence Interval) [percentage of participants]	64.7 3.8%	71.2 4.2%	70.7 4.2%

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.
Measure Participants	1697	1702	1700
Number (95% Confidence Interval) [percentage of participants]	63.5 3.7%	70.3 4.1%	69.2 4.1%

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.
Measure Participants	1697	1702	1700
Number (95% Confidence Interval) [percentage of participants]	62.5 3.7%	69.3 4.1%	68.5 4%

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.
Measure Participants	1552	1553
Number [percentage of participants]	25.8 1.5%	26.6 1.6%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Observation Arm, Herceptin 1-Year Arm
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.7962
	Comments
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.02
	Confidence Interval	(2-Sided) 95%; 0.89 to 1.17
	Parameter Dispersion	Type: Value:
	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.
Measure Participants	1552	1553
Year 3	86.7 5.1%	89.0 5.2%
Year 5	81.0 4.8%	81.6 4.8%
Year 7	77.2 4.5%	77.4 4.5%
Year 8	75.9 4.5%	75.5 4.4%
Year 9	75.0 4.4%	73.9 4.3%
Year 10	73.9 4.4%	73.1 4.3%

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.
Measure Participants	1693	1693
Number [percentage of participants]	2.4 0.1%	1.8 0.1%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Observation Arm, Herceptin 1-Year Arm
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.2379
	Comments
	Method	Log Rank
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Observation Arm, Herceptin 1-Year Arm
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.75
	Confidence Interval	(2-Sided) 95%; 0.47 to 1.21
	Parameter Dispersion	Type: Value:
	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.
Measure Participants	1693	1694
Number [percentage of participants]	2.2 0.1%	1.4 0.1%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Observation Arm, Herceptin 1-Year Arm
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.003
	Comments
	Method	Log Rank
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Observation Arm, Herceptin 1-Year Arm
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.47
	Confidence Interval	(2-Sided) 95%; 0.28 to 0.79
	Parameter Dispersion	Type: Value:
	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.
Measure Participants	1693	1693
Number (95% Confidence Interval) [percentage of participants]	94.98 5.6%	95.88 5.6%

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.
Measure Participants	1693	1694
Number (95% Confidence Interval) [percentage of participants]	94.39 5.6%	97.28 5.7%

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.
Measure Participants	1697	1702	1700
Number [percentage of participants]	20.6 1.2%	16.3 1%	16.1 0.9%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Observation Arm, Herceptin 1-Year Arm
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0005
	Comments
	Method	Log Rank
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Observation Arm, Herceptin 1-Year Arm
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.76
	Confidence Interval	(2-Sided) 95%; 0.65 to 0.88
	Parameter Dispersion	Type: Value:
	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
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0001
	Comments
	Method	Log Rank
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Observation Arm, Herceptin 2-Year Arm
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.74
	Confidence Interval	(2-Sided) 95%; 0.63 to 0.86
	Parameter Dispersion	Type: Value:
	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.
Measure Participants	1697	1702	1700
Year 3	90.7 5.3%	92.7 5.4%	94.4 5.6%
Year 5	84.5 5%	86.9 5.1%	88.7 5.2%
Year 7	79.5 4.7%	83.9 4.9%	84.6 5%
Year 8	77.4 4.6%	82.7 4.9%	82.4 4.8%

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.
Measure Participants	1697	1702	1700
Number [percentage of participants]	23.9 1.4%	18.8 1.1%	18.4 1.1%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Observation Arm, Herceptin 1-Year Arm
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.74
	Confidence Interval	(2-Sided) 95%; 0.64 to 0.86
	Parameter Dispersion	Type: Value:
	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
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.72
	Confidence Interval	(2-Sided) 95%; 0.62 to 0.83
	Parameter Dispersion	Type: Value:
	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.
Measure Participants	1697	1702	1700
Year 3	90.7 5.3%	92.7 5.4%	94.4 5.6%
Year 5	84.5 5%	86.9 5.1%	88.7 5.2%
Year 7	79.4 4.7%	83.8 4.9%	84.7 5%
Year 9	76.5 4.5%	81.9 4.8%	81.8 4.8%
Year 10	75.0 4.4%	80.7 4.7%	81.0 4.8%
Year 11	73.7 4.3%	80.0 4.7%	80.3 4.7%
Year 12	72.9 4.3%	79.4 4.7%	79.5 4.7%

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.
Measure Participants	1552	1553
Number [percentage of participants]	14.7 0.9%	14.9 0.9%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Observation Arm, Herceptin 1-Year Arm
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.9156
	Comments
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.01
	Confidence Interval	(2-Sided) 95%; 0.84 to 1.21
	Parameter Dispersion	Type: Value:
	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.
Measure Participants	1552	1553
Year 3	96.5 5.7%	97.4 5.7%
Year 5	91.4 5.4%	92.6 5.4%
Year 7	88.6 5.2%	88.7 5.2%
Year 9	86.7 5.1%	85.9 5%
Year 10	85.4 5%	85.1 5%
Year 11	84.7 5%	84.4 5%
Year 12	84.1 5%	83.6 4.9%

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.
Measure Participants	1697	1702	1700
Number [percentage of participants]	29.8 1.8%	23.4 1.4%	22.6 1.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Observation Arm, Herceptin 1-Year Arm
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Log Rank
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Observation Arm, Herceptin 1-Year Arm
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.73
	Confidence Interval	(2-Sided) 95%; 0.64 to 0.83
	Parameter Dispersion	Type: Value:
	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
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Log Rank
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Observation Arm, Herceptin 2-Year Arm
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.69
	Confidence Interval	(2-Sided) 95%; 0.61 to 0.79
	Parameter Dispersion	Type: Value:
	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.
Measure Participants	1697	1702	1700
Year 3	76.4 4.5%	82.7 4.9%	86.0 5.1%
Year 5	71.9 4.2%	78.4 4.6%	79.9 4.7%
Year 7	69.0 4.1%	75.7 4.4%	76.7 4.5%
Year 8	68.4 4%	75.1 4.4%	75.8 4.5%

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.
Measure Participants	1552	1553
Number [percentage of participants]	19.7 1.2%	18.8 1.1%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Observation Arm, Herceptin 1-Year Arm
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.4755
	Comments
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.94
	Confidence Interval	(2-Sided) 95%; 0.80 to 1.11
	Parameter Dispersion	Type: Value:
	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.
Measure Participants	1552	1553
Year 3	87.7 5.2%	90.9 5.3%
Year 5	83.1 4.9%	84.5 5%
Year 7	80.2 4.7%	81.3 4.8%
Year 8	79.6 4.7%	80.3 4.7%

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.
Measure Participants	1697	1702	1700
Number [percentage of participants]	28.8 1.7%	23.4 1.4%	23.2 1.4%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Observation Arm, Herceptin 1-Year Arm
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Log Rank
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Observation Arm, Herceptin 1-Year Arm
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.76
	Confidence Interval	(2-Sided) 95%; 0.67 to 0.87
	Parameter Dispersion	Type: Value:
	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
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Log Rank
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Observation Arm, Herceptin 2-Year Arm
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.75
	Confidence Interval	(2-Sided) 95%; 0.65 to 0.85
	Parameter Dispersion	Type: Value:
	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.
Measure Participants	1697	1702	1700
Year 3	78.6 4.6%	84.4 5%	85.9 5.1%
Year 5	74.2 4.4%	79.6 4.7%	80.2 4.7%
Year 7	70.8 4.2%	76.7 4.5%	76.7 4.5%
Year 8	69.6 4.1%	75.5 4.4%	75.6 4.4%

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.
Measure Participants	1552	1553
Number [percentage of participants]	19.5 1.1%	19.5 1.1%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Observation Arm, Herceptin 1-Year Arm
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.9626
	Comments
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.00
	Confidence Interval	(2-Sided) 95%; 0.85 to 1.17
	Parameter Dispersion	Type: Value:
	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.
Measure Participants	1552	1553
Year 3	89.4 5.3%	90.8 5.3%
Year 5	84.5 5%	84.7 5%
Year 7	81.4 4.8%	81.1 4.8%
Year 8	80.1 4.7%	79.9 4.7%

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.
Measure Participants	1697	1702	1700
Number [percentage of participants]	29.8 1.8%	23.4 1.4%	22.6 1.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Observation Arm, Herceptin 1-Year Arm
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Log Rank
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Observation Arm, Herceptin 1-Year Arm
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.73
	Confidence Interval	(2-Sided) 95%; 0.64 to 0.83
	Parameter Dispersion	Type: Value:
	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
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Log Rank
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Observation Arm, Herceptin 2-Year Arm
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.69
	Confidence Interval	(2-Sided) 95%; 0.61 to 0.79
	Parameter Dispersion	Type: Value:
	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.
Measure Participants	1697	1702	1700
Year 3	76.5 4.5%	82.8 4.9%	86.1 5.1%
Year 5	72.1 4.2%	78.6 4.6%	80.1 4.7%
Year 7	69.2 4.1%	75.9 4.5%	77.0 4.5%
Year 8	68.6 4%	75.3 4.4%	76.2 4.5%

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.
Measure Participants	1552	1553
Number [percentage of participants]	19.7 1.2%	18.8 1.1%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Observation Arm, Herceptin 1-Year Arm
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.4500
	Comments
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.94
	Confidence Interval	(2-Sided) 95%; 0.80 to 1.10
	Parameter Dispersion	Type: Value:
	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.
Measure Participants	1552	1553
Year 3	87.7 5.2%	90.9 5.3%
Year 5	83.2 4.9%	84.7 5%
Year 7	80.4 4.7%	81.5 4.8%
Year 8	79.8 4.7%	80.6 4.7%

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.
Measure Participants	1697	1702	1700
Number [percentage of participants]	25.3 1.5%	19.4 1.1%	18.8 1.1%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Observation Arm, Herceptin 1-Year Arm
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Log Rank
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Observation Arm, Herceptin 1-Year Arm
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.72
	Confidence Interval	(2-Sided) 95%; 0.62 to 0.83
	Parameter Dispersion	Type: Value:
	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
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Log Rank
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Observation Arm, Herceptin 2-Year Arm
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.69
	Confidence Interval	(2-Sided) 95%; 0.59 to 0.79
	Parameter Dispersion	Type: Value:
	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.
Measure Participants	1697	1702	1700
Year 3	79.8 4.7%	85.9 5%	88.1 5.2%
Year 5	76.5 4.5%	82.1 4.8%	83.4 4.9%
Year 7	74.0 4.4%	80.1 4.7%	80.7 4.7%
Year 8	73.3 4.3%	79.5 4.7%	80.3 4.7%

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.
Measure Participants	1552	1553
Number [percentage of participants]	15.5 0.9%	15.1 0.9%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Observation Arm, Herceptin 1-Year Arm
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.6823
	Comments
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.96
	Confidence Interval	(2-Sided) 95%; 0.80 to 1.15
	Parameter Dispersion	Type: Value:
	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.
Measure Participants	1552	1553
Year 3	90.5 5.3%	92.4 5.4%
Year 5	86.7 5.1%	87.5 5.1%
Year 7	84.6 5%	84.9 5%
Year 8	83.9 4.9%	84.4 5%

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.
Measure Participants	1552	1553
Number [percentage of participants]	22.2 1.3%	21.9 1.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Observation Arm, Herceptin 1-Year Arm
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.7251
	Comments
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.97
	Confidence Interval	(2-Sided) 95%; 0.84 to 1.13
	Parameter Dispersion	Type: Value:
	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.
Measure Participants	1552	1553
Year 3	87.3 5.1%	89.9 5.3%
Year 5	81.9 4.8%	83.0 4.9%
Year 7	78.5 4.6%	78.9 4.6%
Year 8	77.2 4.5%	77.7 4.6%

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.
Measure Participants	1744	1682	1673
Number (95% Confidence Interval) [percentage of participants]	0.11 0%	1.07 0.1%	1.02 0.1%

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.
Measure Participants	1744	1682	1673
Number (95% Confidence Interval) [percentage of participants]	0.86 0.1%	4.40 0.3%	7.29 0.4%

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 (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Observation Arm		Herceptin 1-Year Arm		Herceptin 2-Year Arm
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	143/1744 (8.2%)		269/1682 (16%)		344/1673 (20.6%)
Blood and lymphatic system disorders
Leukopenia	1/1744 (0.1%)		0/1682 (0%)		0/1673 (0%)
Lymphadenopathy	0/1744 (0%)		1/1682 (0.1%)		0/1673 (0%)
Thrombocytopenia	0/1744 (0%)		0/1682 (0%)		1/1673 (0.1%)
Cardiac disorders
Acute coronary syndrome	1/1744 (0.1%)		1/1682 (0.1%)		1/1673 (0.1%)
Acute myocardial infarction	0/1744 (0%)		1/1682 (0.1%)		1/1673 (0.1%)
Angina pectoris	2/1744 (0.1%)		2/1682 (0.1%)		1/1673 (0.1%)
Arrhythmia	0/1744 (0%)		1/1682 (0.1%)		0/1673 (0%)
Atrial fibrillation	1/1744 (0.1%)		1/1682 (0.1%)		2/1673 (0.1%)
Atrial flutter	1/1744 (0.1%)		0/1682 (0%)		0/1673 (0%)
Atrioventricular block	0/1744 (0%)		0/1682 (0%)		1/1673 (0.1%)
Atrioventricular block complete	0/1744 (0%)		1/1682 (0.1%)		0/1673 (0%)
Bradycardia	0/1744 (0%)		1/1682 (0.1%)		0/1673 (0%)
Cardiac arrest	0/1744 (0%)		1/1682 (0.1%)		0/1673 (0%)
Cardiac failure	0/1744 (0%)		1/1682 (0.1%)		0/1673 (0%)
Cardiac failure chronic	0/1744 (0%)		2/1682 (0.1%)		0/1673 (0%)
Cardiac failure congestive	1/1744 (0.1%)		19/1682 (1.1%)		24/1673 (1.4%)
Cardiomyopathy	0/1744 (0%)		0/1682 (0%)		1/1673 (0.1%)
Coronary artery disease	0/1744 (0%)		1/1682 (0.1%)		2/1673 (0.1%)
Coronary artery stenosis	1/1744 (0.1%)		1/1682 (0.1%)		1/1673 (0.1%)
Extrasystoles	0/1744 (0%)		1/1682 (0.1%)		0/1673 (0%)
Hypertensive heart disease	0/1744 (0%)		1/1682 (0.1%)		0/1673 (0%)
Left ventricular dysfunction	0/1744 (0%)		0/1682 (0%)		1/1673 (0.1%)
Left ventricular failure	1/1744 (0.1%)		0/1682 (0%)		0/1673 (0%)
Myocardial infarction	2/1744 (0.1%)		4/1682 (0.2%)		4/1673 (0.2%)
Palpitations	0/1744 (0%)		1/1682 (0.1%)		0/1673 (0%)
Pericarditis lupus	0/1744 (0%)		1/1682 (0.1%)		0/1673 (0%)
Sinus node dysfunction	1/1744 (0.1%)		0/1682 (0%)		0/1673 (0%)
Supraventricular tachycardia	0/1744 (0%)		1/1682 (0.1%)		1/1673 (0.1%)
Tachyarrhythmia	0/1744 (0%)		1/1682 (0.1%)		0/1673 (0%)
Tachycardia	0/1744 (0%)		1/1682 (0.1%)		1/1673 (0.1%)
Ventricular fibrillation	0/1744 (0%)		1/1682 (0.1%)		0/1673 (0%)
Congenital, familial and genetic disorders
Dermoid cyst	1/1744 (0.1%)		0/1682 (0%)		0/1673 (0%)
Odontogenic cyst	0/1744 (0%)		0/1682 (0%)		1/1673 (0.1%)
Tooth hypoplasia	0/1744 (0%)		0/1682 (0%)		1/1673 (0.1%)
Ventricular septal defect	0/1744 (0%)		1/1682 (0.1%)		0/1673 (0%)
Ear and labyrinth disorders
Otosclerosis	0/1744 (0%)		0/1682 (0%)		1/1673 (0.1%)
Sudden hearing loss	0/1744 (0%)		1/1682 (0.1%)		0/1673 (0%)
Vertigo	1/1744 (0.1%)		0/1682 (0%)		0/1673 (0%)
Endocrine disorders
Basedow's disease	1/1744 (0.1%)		0/1682 (0%)		0/1673 (0%)
Goitre	1/1744 (0.1%)		1/1682 (0.1%)		3/1673 (0.2%)
Eye disorders
Cataract	0/1744 (0%)		1/1682 (0.1%)		0/1673 (0%)
Eyelid ptosis	1/1744 (0.1%)		0/1682 (0%)		0/1673 (0%)
Glaucoma	0/1744 (0%)		0/1682 (0%)		1/1673 (0.1%)
Retinal detachment	1/1744 (0.1%)		0/1682 (0%)		0/1673 (0%)
Visual impairment	0/1744 (0%)		0/1682 (0%)		2/1673 (0.1%)
Gastrointestinal disorders
Abdominal hernia	0/1744 (0%)		0/1682 (0%)		1/1673 (0.1%)
Abdominal pain	1/1744 (0.1%)		1/1682 (0.1%)		2/1673 (0.1%)
Anal fissure	0/1744 (0%)		2/1682 (0.1%)		0/1673 (0%)
Diarrhoea	1/1744 (0.1%)		1/1682 (0.1%)		3/1673 (0.2%)
Dyspepsia	0/1744 (0%)		0/1682 (0%)		1/1673 (0.1%)
Gastritis	1/1744 (0.1%)		0/1682 (0%)		1/1673 (0.1%)
Gastrointestinal haemorrhage	0/1744 (0%)		1/1682 (0.1%)		1/1673 (0.1%)
Haemorrhoidal haemorrhage	0/1744 (0%)		0/1682 (0%)		1/1673 (0.1%)
Haemorrhoids	0/1744 (0%)		0/1682 (0%)		1/1673 (0.1%)
Hiatus hernia	0/1744 (0%)		0/1682 (0%)		1/1673 (0.1%)
Ileus	0/1744 (0%)		1/1682 (0.1%)		0/1673 (0%)
Inguinal hernia	0/1744 (0%)		1/1682 (0.1%)		0/1673 (0%)
Intestinal ischaemia	0/1744 (0%)		0/1682 (0%)		1/1673 (0.1%)
Intestinal obstruction	0/1744 (0%)		0/1682 (0%)		1/1673 (0.1%)
Large intestine polyp	0/1744 (0%)		1/1682 (0.1%)		1/1673 (0.1%)
Nausea	1/1744 (0.1%)		1/1682 (0.1%)		0/1673 (0%)
Oesophagitis	0/1744 (0%)		0/1682 (0%)		1/1673 (0.1%)
Pancreatitis	1/1744 (0.1%)		0/1682 (0%)		0/1673 (0%)
Pancreatitis acute	0/1744 (0%)		0/1682 (0%)		1/1673 (0.1%)
Pancreatitis chronic	0/1744 (0%)		0/1682 (0%)		1/1673 (0.1%)
Paraesthesia oral	0/1744 (0%)		0/1682 (0%)		1/1673 (0.1%)
Rectal haemorrhage	0/1744 (0%)		0/1682 (0%)		1/1673 (0.1%)
Upper gastrointestinal haemorrhage	0/1744 (0%)		0/1682 (0%)		1/1673 (0.1%)
Vomiting	2/1744 (0.1%)		1/1682 (0.1%)		0/1673 (0%)
General disorders
Adverse drug reaction	0/1744 (0%)		1/1682 (0.1%)		0/1673 (0%)
Axillary pain	0/1744 (0%)		1/1682 (0.1%)		0/1673 (0%)
Breast complication associated with device	0/1744 (0%)		0/1682 (0%)		1/1673 (0.1%)
Catheter site haemorrhage	0/1744 (0%)		0/1682 (0%)		1/1673 (0.1%)
Chest pain	1/1744 (0.1%)		3/1682 (0.2%)		0/1673 (0%)
Chills	0/1744 (0%)		4/1682 (0.2%)		1/1673 (0.1%)
Death	0/1744 (0%)		1/1682 (0.1%)		0/1673 (0%)
Device breakage	0/1744 (0%)		1/1682 (0.1%)		0/1673 (0%)
Device dislocation	0/1744 (0%)		0/1682 (0%)		2/1673 (0.1%)
Device failure	0/1744 (0%)		0/1682 (0%)		1/1673 (0.1%)
Device leakage	0/1744 (0%)		0/1682 (0%)		1/1673 (0.1%)
Fat necrosis	0/1744 (0%)		0/1682 (0%)		1/1673 (0.1%)
Fatigue	0/1744 (0%)		1/1682 (0.1%)		0/1673 (0%)
Granuloma	1/1744 (0.1%)		0/1682 (0%)		0/1673 (0%)
Ill-defined disorder	0/1744 (0%)		0/1682 (0%)		1/1673 (0.1%)
Local swelling	0/1744 (0%)		0/1682 (0%)		1/1673 (0.1%)
Medical device complication	0/1744 (0%)		2/1682 (0.1%)		0/1673 (0%)
Medical device pain	0/1744 (0%)		1/1682 (0.1%)		0/1673 (0%)
Mucosal haemorrhage	0/1744 (0%)		0/1682 (0%)		1/1673 (0.1%)
Multi-organ disorder	0/1744 (0%)		0/1682 (0%)		1/1673 (0.1%)
Non-cardiac chest pain	0/1744 (0%)		0/1682 (0%)		1/1673 (0.1%)
Pain	1/1744 (0.1%)		0/1682 (0%)		0/1673 (0%)
Peripheral swelling	0/1744 (0%)		1/1682 (0.1%)		0/1673 (0%)
Pyrexia	0/1744 (0%)		3/1682 (0.2%)		6/1673 (0.4%)
Sudden death	0/1744 (0%)		1/1682 (0.1%)		1/1673 (0.1%)
Hepatobiliary disorders
Cholecystitis	1/1744 (0.1%)		0/1682 (0%)		0/1673 (0%)
Cholecystitis chronic	1/1744 (0.1%)		0/1682 (0%)		0/1673 (0%)
Cholelithiasis	2/1744 (0.1%)		3/1682 (0.2%)		3/1673 (0.2%)
Cholestasis	0/1744 (0%)		0/1682 (0%)		1/1673 (0.1%)
Hepatitis toxic	0/1744 (0%)		1/1682 (0.1%)		0/1673 (0%)
Portal vein thrombosis	0/1744 (0%)		0/1682 (0%)		1/1673 (0.1%)
Immune system disorders
Anaphylactic reaction	0/1744 (0%)		0/1682 (0%)		1/1673 (0.1%)
Anaphylactic shock	0/1744 (0%)		1/1682 (0.1%)		0/1673 (0%)
Drug hypersensitivity	1/1744 (0.1%)		0/1682 (0%)		0/1673 (0%)
Infections and infestations
Abdominal wall abscess	0/1744 (0%)		1/1682 (0.1%)		0/1673 (0%)
Anal abscess	0/1744 (0%)		0/1682 (0%)		1/1673 (0.1%)
Appendicitis	0/1744 (0%)		2/1682 (0.1%)		4/1673 (0.2%)
Arthritis infective	0/1744 (0%)		0/1682 (0%)		1/1673 (0.1%)
Atypical pneumonia	0/1744 (0%)		0/1682 (0%)		1/1673 (0.1%)
Bartholin's abscess	0/1744 (0%)		0/1682 (0%)		1/1673 (0.1%)
Breast abscess	0/1744 (0%)		2/1682 (0.1%)		0/1673 (0%)
Breast cellulitis	1/1744 (0.1%)		0/1682 (0%)		0/1673 (0%)
Bronchitis	0/1744 (0%)		0/1682 (0%)		1/1673 (0.1%)
Catheter site cellulitis	0/1744 (0%)		1/1682 (0.1%)		0/1673 (0%)
Catheter site infection	1/1744 (0.1%)		0/1682 (0%)		1/1673 (0.1%)
Cellulitis	1/1744 (0.1%)		5/1682 (0.3%)		5/1673 (0.3%)
Device related infection	2/1744 (0.1%)		9/1682 (0.5%)		8/1673 (0.5%)
Device related sepsis	0/1744 (0%)		1/1682 (0.1%)		0/1673 (0%)
Diverticulitis	1/1744 (0.1%)		0/1682 (0%)		0/1673 (0%)
Endocarditis	0/1744 (0%)		1/1682 (0.1%)		0/1673 (0%)
Endometritis	1/1744 (0.1%)		0/1682 (0%)		0/1673 (0%)
Erysipelas	1/1744 (0.1%)		8/1682 (0.5%)		4/1673 (0.2%)
Extradural abscess	0/1744 (0%)		0/1682 (0%)		1/1673 (0.1%)
Gastroenteritis	1/1744 (0.1%)		0/1682 (0%)		2/1673 (0.1%)
Genital infection female	1/1744 (0.1%)		0/1682 (0%)		0/1673 (0%)
Hepatitis B	1/1744 (0.1%)		0/1682 (0%)		0/1673 (0%)
Herpes zoster	0/1744 (0%)		1/1682 (0.1%)		1/1673 (0.1%)
Infection	0/1744 (0%)		0/1682 (0%)		1/1673 (0.1%)
Influenza	0/1744 (0%)		2/1682 (0.1%)		0/1673 (0%)
Labyrinthitis	1/1744 (0.1%)		0/1682 (0%)		0/1673 (0%)
Lower respiratory tract infection	0/1744 (0%)		0/1682 (0%)		2/1673 (0.1%)
Lymphangitis	0/1744 (0%)		1/1682 (0.1%)		1/1673 (0.1%)
Mastitis	2/1744 (0.1%)		2/1682 (0.1%)		2/1673 (0.1%)
Muscle abscess	1/1744 (0.1%)		0/1682 (0%)		0/1673 (0%)
Neutropenic sepsis	1/1744 (0.1%)		0/1682 (0%)		0/1673 (0%)
Parotitis	1/1744 (0.1%)		0/1682 (0%)		0/1673 (0%)
Peritonitis	0/1744 (0%)		1/1682 (0.1%)		1/1673 (0.1%)
Pneumonia	0/1744 (0%)		4/1682 (0.2%)		5/1673 (0.3%)
Pneumonia bacterial	0/1744 (0%)		1/1682 (0.1%)		0/1673 (0%)
Postoperative wound infection	1/1744 (0.1%)		0/1682 (0%)		1/1673 (0.1%)
Pulmonary mycosis	0/1744 (0%)		0/1682 (0%)		1/1673 (0.1%)
Pulmonary sepsis	1/1744 (0.1%)		0/1682 (0%)		0/1673 (0%)
Pyelonephritis acute	0/1744 (0%)		0/1682 (0%)		1/1673 (0.1%)
Rectal abscess	0/1744 (0%)		1/1682 (0.1%)		0/1673 (0%)
Respiratory tract infection	0/1744 (0%)		2/1682 (0.1%)		0/1673 (0%)
Salmonellosis	0/1744 (0%)		1/1682 (0.1%)		1/1673 (0.1%)
Salpingo-oophoritis	0/1744 (0%)		0/1682 (0%)		1/1673 (0.1%)
Soft tissue infection	0/1744 (0%)		0/1682 (0%)		1/1673 (0.1%)
Spinal cord abscess	0/1744 (0%)		0/1682 (0%)		1/1673 (0.1%)
Staphylococcal sepsis	0/1744 (0%)		1/1682 (0.1%)		0/1673 (0%)
Streptococcal sepsis	0/1744 (0%)		1/1682 (0.1%)		0/1673 (0%)
Tonsillitis	0/1744 (0%)		0/1682 (0%)		1/1673 (0.1%)
Tuberculosis	0/1744 (0%)		1/1682 (0.1%)		1/1673 (0.1%)
Upper respiratory tract infection	1/1744 (0.1%)		0/1682 (0%)		0/1673 (0%)
Urinary tract infection	1/1744 (0.1%)		1/1682 (0.1%)		0/1673 (0%)
Wound infection	2/1744 (0.1%)		3/1682 (0.2%)		0/1673 (0%)
Injury, poisoning and procedural complications
Acetabulum fracture	0/1744 (0%)		0/1682 (0%)		1/1673 (0.1%)
Alcohol poisoning	0/1744 (0%)		0/1682 (0%)		1/1673 (0.1%)
Ankle fracture	2/1744 (0.1%)		0/1682 (0%)		4/1673 (0.2%)
Concussion	0/1744 (0%)		0/1682 (0%)		1/1673 (0.1%)
Femoral neck fracture	0/1744 (0%)		0/1682 (0%)		1/1673 (0.1%)
Femur fracture	1/1744 (0.1%)		0/1682 (0%)		0/1673 (0%)
Fibula fracture	1/1744 (0.1%)		0/1682 (0%)		0/1673 (0%)
Fractured coccyx	0/1744 (0%)		0/1682 (0%)		1/1673 (0.1%)
Hand fracture	0/1744 (0%)		0/1682 (0%)		1/1673 (0.1%)
Humerus fracture	0/1744 (0%)		0/1682 (0%)		1/1673 (0.1%)
Joint dislocation	0/1744 (0%)		0/1682 (0%)		1/1673 (0.1%)
Laceration	0/1744 (0%)		1/1682 (0.1%)		0/1673 (0%)
Lower limb fracture	0/1744 (0%)		2/1682 (0.1%)		1/1673 (0.1%)
Meniscus injury	0/1744 (0%)		0/1682 (0%)		1/1673 (0.1%)
Nerve injury	0/1744 (0%)		1/1682 (0.1%)		0/1673 (0%)
Patella fracture	0/1744 (0%)		0/1682 (0%)		1/1673 (0.1%)
Pneumothorax traumatic	0/1744 (0%)		1/1682 (0.1%)		1/1673 (0.1%)
Post procedural haematoma	1/1744 (0.1%)		0/1682 (0%)		0/1673 (0%)
Post procedural haemorrhage	0/1744 (0%)		0/1682 (0%)		1/1673 (0.1%)
Post-traumatic neck syndrome	1/1744 (0.1%)		0/1682 (0%)		0/1673 (0%)
Postoperative hernia	0/1744 (0%)		0/1682 (0%)		1/1673 (0.1%)
Procedural pain	0/1744 (0%)		0/1682 (0%)		1/1673 (0.1%)
Pubis fracture	0/1744 (0%)		1/1682 (0.1%)		0/1673 (0%)
Pulmonary contusion	0/1744 (0%)		0/1682 (0%)		1/1673 (0.1%)
Radiation pneumonitis	0/1744 (0%)		0/1682 (0%)		1/1673 (0.1%)
Radius fracture	0/1744 (0%)		1/1682 (0.1%)		0/1673 (0%)
Rib fracture	1/1744 (0.1%)		0/1682 (0%)		0/1673 (0%)
Road traffic accident	0/1744 (0%)		2/1682 (0.1%)		0/1673 (0%)
Scar	0/1744 (0%)		1/1682 (0.1%)		0/1673 (0%)
Spinal column injury	1/1744 (0.1%)		0/1682 (0%)		0/1673 (0%)
Spinal fracture	0/1744 (0%)		0/1682 (0%)		1/1673 (0.1%)
Tendon rupture	0/1744 (0%)		0/1682 (0%)		2/1673 (0.1%)
Toxicity to various agents	0/1744 (0%)		1/1682 (0.1%)		0/1673 (0%)
Upper limb fracture	2/1744 (0.1%)		0/1682 (0%)		1/1673 (0.1%)
Wound	0/1744 (0%)		0/1682 (0%)		1/1673 (0.1%)
Wound dehiscence	0/1744 (0%)		1/1682 (0.1%)		0/1673 (0%)
Wound secretion	0/1744 (0%)		0/1682 (0%)		1/1673 (0.1%)
Investigations
Ejection fraction decreased	0/1744 (0%)		0/1682 (0%)		1/1673 (0.1%)
Gamma-glutamyltransferase increased	0/1744 (0%)		1/1682 (0.1%)		0/1673 (0%)
Hepatic enzyme increased	0/1744 (0%)		0/1682 (0%)		1/1673 (0.1%)
Metabolism and nutrition disorders
Decreased appetite	1/1744 (0.1%)		0/1682 (0%)		1/1673 (0.1%)
Hypokalaemia	0/1744 (0%)		0/1682 (0%)		1/1673 (0.1%)
Musculoskeletal and connective tissue disorders
Arthralgia	0/1744 (0%)		2/1682 (0.1%)		1/1673 (0.1%)
Arthritis	1/1744 (0.1%)		0/1682 (0%)		1/1673 (0.1%)
Back pain	0/1744 (0%)		2/1682 (0.1%)		0/1673 (0%)
Fistula	0/1744 (0%)		0/1682 (0%)		1/1673 (0.1%)
Intervertebral disc protrusion	0/1744 (0%)		0/1682 (0%)		2/1673 (0.1%)
Lumbar spinal stenosis	0/1744 (0%)		0/1682 (0%)		1/1673 (0.1%)
Muscle tightness	0/1744 (0%)		0/1682 (0%)		1/1673 (0.1%)
Neck pain	1/1744 (0.1%)		0/1682 (0%)		0/1673 (0%)
Osteoarthritis	1/1744 (0.1%)		1/1682 (0.1%)		0/1673 (0%)
Pain in extremity	0/1744 (0%)		0/1682 (0%)		2/1673 (0.1%)
Spondylolisthesis	0/1744 (0%)		0/1682 (0%)		1/1673 (0.1%)
Tendon disorder	1/1744 (0.1%)		0/1682 (0%)		0/1673 (0%)
Tenosynovitis	1/1744 (0.1%)		0/1682 (0%)		0/1673 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Acute myeloid leukaemia	0/1744 (0%)		0/1682 (0%)		3/1673 (0.2%)
Adenocarcinoma	0/1744 (0%)		1/1682 (0.1%)		0/1673 (0%)
Adenocarcinoma of colon	1/1744 (0.1%)		1/1682 (0.1%)		1/1673 (0.1%)
Adenocarcinoma pancreas	0/1744 (0%)		1/1682 (0.1%)		1/1673 (0.1%)
Adenoid cystic carcinoma	0/1744 (0%)		1/1682 (0.1%)		0/1673 (0%)
Adenoma benign	0/1744 (0%)		1/1682 (0.1%)		2/1673 (0.1%)
Adenosquamous cell carcinoma	0/1744 (0%)		0/1682 (0%)		1/1673 (0.1%)
Angiosarcoma	0/1744 (0%)		1/1682 (0.1%)		1/1673 (0.1%)
Basal cell carcinoma	1/1744 (0.1%)		2/1682 (0.1%)		1/1673 (0.1%)
Benign breast neoplasm	0/1744 (0%)		0/1682 (0%)		1/1673 (0.1%)
Benign neoplasm	0/1744 (0%)		0/1682 (0%)		2/1673 (0.1%)
Benign neoplasm of bladder	0/1744 (0%)		0/1682 (0%)		1/1673 (0.1%)
Benign neoplasm of skin	0/1744 (0%)		1/1682 (0.1%)		0/1673 (0%)
Benign ovarian tumour	0/1744 (0%)		0/1682 (0%)		1/1673 (0.1%)
Bladder cancer	0/1744 (0%)		0/1682 (0%)		1/1673 (0.1%)
Bladder neoplasm	0/1744 (0%)		1/1682 (0.1%)		0/1673 (0%)
Bladder papilloma	0/1744 (0%)		0/1682 (0%)		1/1673 (0.1%)
Bladder transitional cell carcinoma	0/1744 (0%)		0/1682 (0%)		1/1673 (0.1%)
Brain neoplasm	1/1744 (0.1%)		0/1682 (0%)		0/1673 (0%)
Breast cancer	9/1744 (0.5%)		27/1682 (1.6%)		36/1673 (2.2%)
Breast cancer in situ	1/1744 (0.1%)		1/1682 (0.1%)		0/1673 (0%)
Breast neoplasm	0/1744 (0%)		1/1682 (0.1%)		0/1673 (0%)
Carcinoid tumour of the gastrointestinal tract	0/1744 (0%)		0/1682 (0%)		1/1673 (0.1%)
Cervix carcinoma	1/1744 (0.1%)		2/1682 (0.1%)		3/1673 (0.2%)
Cervix carcinoma stage 0	1/1744 (0.1%)		0/1682 (0%)		1/1673 (0.1%)
Cervix carcinoma stage II	0/1744 (0%)		0/1682 (0%)		1/1673 (0.1%)
Chronic myeloid leukaemia	0/1744 (0%)		1/1682 (0.1%)		1/1673 (0.1%)
Colon cancer	1/1744 (0.1%)		3/1682 (0.2%)		0/1673 (0%)
Colorectal adenocarcinoma	0/1744 (0%)		0/1682 (0%)		1/1673 (0.1%)
Colorectal cancer	0/1744 (0%)		1/1682 (0.1%)		1/1673 (0.1%)
Diffuse large B-cell lymphoma	0/1744 (0%)		0/1682 (0%)		1/1673 (0.1%)
Endometrial adenocarcinoma	2/1744 (0.1%)		0/1682 (0%)		0/1673 (0%)
Endometrial cancer	2/1744 (0.1%)		2/1682 (0.1%)		1/1673 (0.1%)
Fibroadenoma of breast	0/1744 (0%)		0/1682 (0%)		1/1673 (0.1%)
Gastric adenoma	0/1744 (0%)		0/1682 (0%)		1/1673 (0.1%)
Gastric cancer	1/1744 (0.1%)		2/1682 (0.1%)		3/1673 (0.2%)
Gastrointestinal stromal tumour	0/1744 (0%)		0/1682 (0%)		1/1673 (0.1%)
Hepatic cancer	0/1744 (0%)		0/1682 (0%)		1/1673 (0.1%)
Hepatocellular carcinoma	0/1744 (0%)		0/1682 (0%)		1/1673 (0.1%)
Hodgkin's disease	0/1744 (0%)		0/1682 (0%)		1/1673 (0.1%)
Infected neoplasm	0/1744 (0%)		0/1682 (0%)		1/1673 (0.1%)
Inflammatory myofibroblastic tumour	0/1744 (0%)		0/1682 (0%)		1/1673 (0.1%)
Intraductal proliferative breast lesion	0/1744 (0%)		2/1682 (0.1%)		0/1673 (0%)
Invasive ductal breast carcinoma	0/1744 (0%)		1/1682 (0.1%)		0/1673 (0%)
Invasive papillary breast carcinoma	0/1744 (0%)		0/1682 (0%)		1/1673 (0.1%)
Lipofibroma	0/1744 (0%)		0/1682 (0%)		1/1673 (0.1%)
Lung adenocarcinoma	1/1744 (0.1%)		1/1682 (0.1%)		1/1673 (0.1%)
Lung neoplasm malignant	0/1744 (0%)		6/1682 (0.4%)		2/1673 (0.1%)
Lymphoma	0/1744 (0%)		0/1682 (0%)		1/1673 (0.1%)
Malignant melanoma	0/1744 (0%)		8/1682 (0.5%)		8/1673 (0.5%)
Mantle cell lymphoma	0/1744 (0%)		0/1682 (0%)		1/1673 (0.1%)
Meningioma	0/1744 (0%)		1/1682 (0.1%)		0/1673 (0%)
Metastatic renal cell carcinoma	0/1744 (0%)		1/1682 (0.1%)		0/1673 (0%)
Myelodysplastic syndrome	0/1744 (0%)		0/1682 (0%)		2/1673 (0.1%)
Neoplasm	1/1744 (0.1%)		0/1682 (0%)		0/1673 (0%)
Oesophageal squamous cell carcinoma	0/1744 (0%)		0/1682 (0%)		1/1673 (0.1%)
Ovarian adenoma	0/1744 (0%)		1/1682 (0.1%)		0/1673 (0%)
Ovarian cancer	1/1744 (0.1%)		3/1682 (0.2%)		3/1673 (0.2%)
Paget's disease of nipple	1/1744 (0.1%)		1/1682 (0.1%)		0/1673 (0%)
Pancreatic carcinoma	3/1744 (0.2%)		0/1682 (0%)		0/1673 (0%)
Papillary thyroid cancer	1/1744 (0.1%)		1/1682 (0.1%)		3/1673 (0.2%)
Rectal adenocarcinoma	0/1744 (0%)		2/1682 (0.1%)		2/1673 (0.1%)
Rectal cancer	1/1744 (0.1%)		0/1682 (0%)		2/1673 (0.1%)
Renal cancer	0/1744 (0%)		0/1682 (0%)		3/1673 (0.2%)
Renal cell carcinoma	0/1744 (0%)		1/1682 (0.1%)		0/1673 (0%)
Retro-orbital neoplasm	0/1744 (0%)		0/1682 (0%)		1/1673 (0.1%)
Sarcoma	1/1744 (0.1%)		0/1682 (0%)		0/1673 (0%)
Second primary malignancy	1/1744 (0.1%)		1/1682 (0.1%)		2/1673 (0.1%)
Squamous cell carcinoma	0/1744 (0%)		0/1682 (0%)		1/1673 (0.1%)
Squamous cell carcinoma of skin	0/1744 (0%)		1/1682 (0.1%)		2/1673 (0.1%)
Squamous cell carcinoma of the vulva	0/1744 (0%)		1/1682 (0.1%)		0/1673 (0%)
Thyroid cancer	0/1744 (0%)		0/1682 (0%)		4/1673 (0.2%)
Thyroid neoplasm	1/1744 (0.1%)		0/1682 (0%)		0/1673 (0%)
Transitional cell carcinoma	1/1744 (0.1%)		0/1682 (0%)		0/1673 (0%)
Undifferentiated sarcoma	0/1744 (0%)		1/1682 (0.1%)		0/1673 (0%)
Uterine cancer	1/1744 (0.1%)		1/1682 (0.1%)		0/1673 (0%)
Uterine leiomyoma	2/1744 (0.1%)		1/1682 (0.1%)		7/1673 (0.4%)
Uterine leiomyosarcoma	0/1744 (0%)		0/1682 (0%)		1/1673 (0.1%)
Vulval cancer stage 0	0/1744 (0%)		0/1682 (0%)		1/1673 (0.1%)
Nervous system disorders
Brain oedema	0/1744 (0%)		0/1682 (0%)		1/1673 (0.1%)
Carpal tunnel syndrome	0/1744 (0%)		0/1682 (0%)		1/1673 (0.1%)
Central nervous system haemorrhage	0/1744 (0%)		0/1682 (0%)		1/1673 (0.1%)
Cerebellar atrophy	0/1744 (0%)		1/1682 (0.1%)		0/1673 (0%)
Cerebral haemorrhage	0/1744 (0%)		1/1682 (0.1%)		1/1673 (0.1%)
Cerebral infarction	0/1744 (0%)		0/1682 (0%)		1/1673 (0.1%)
Cerebral ischaemia	1/1744 (0.1%)		0/1682 (0%)		0/1673 (0%)
Cerebrovascular accident	0/1744 (0%)		3/1682 (0.2%)		2/1673 (0.1%)
Dementia Alzheimer's type	1/1744 (0.1%)		0/1682 (0%)		0/1673 (0%)
Headache	1/1744 (0.1%)		0/1682 (0%)		3/1673 (0.2%)
Hypoaesthesia	0/1744 (0%)		0/1682 (0%)		1/1673 (0.1%)
Ischaemic stroke	0/1744 (0%)		1/1682 (0.1%)		1/1673 (0.1%)
Migraine	0/1744 (0%)		0/1682 (0%)		1/1673 (0.1%)
Myoclonus	0/1744 (0%)		0/1682 (0%)		1/1673 (0.1%)
Nystagmus	1/1744 (0.1%)		0/1682 (0%)		0/1673 (0%)
Optic neuritis	0/1744 (0%)		1/1682 (0.1%)		0/1673 (0%)
Paresis	1/1744 (0.1%)		0/1682 (0%)		0/1673 (0%)
Sciatica	1/1744 (0.1%)		0/1682 (0%)		0/1673 (0%)
Seizure	1/1744 (0.1%)		0/1682 (0%)		0/1673 (0%)
Subarachnoid haemorrhage	0/1744 (0%)		0/1682 (0%)		1/1673 (0.1%)
Syncope	0/1744 (0%)		1/1682 (0.1%)		1/1673 (0.1%)
Transient ischaemic attack	0/1744 (0%)		2/1682 (0.1%)		0/1673 (0%)
Tremor	0/1744 (0%)		1/1682 (0.1%)		1/1673 (0.1%)
Pregnancy, puerperium and perinatal conditions
Abortion missed	0/1744 (0%)		0/1682 (0%)		1/1673 (0.1%)
Abortion spontaneous	0/1744 (0%)		7/1682 (0.4%)		1/1673 (0.1%)
Complication of pregnancy	1/1744 (0.1%)		0/1682 (0%)		0/1673 (0%)
Delivery	1/1744 (0.1%)		0/1682 (0%)		0/1673 (0%)
Ectopic pregnancy	0/1744 (0%)		2/1682 (0.1%)		0/1673 (0%)
Pregnancy	11/1744 (0.6%)		22/1682 (1.3%)		29/1673 (1.7%)
Psychiatric disorders
Alcohol abuse	0/1744 (0%)		0/1682 (0%)		1/1673 (0.1%)
Anxiety	0/1744 (0%)		0/1682 (0%)		1/1673 (0.1%)
Completed suicide	1/1744 (0.1%)		2/1682 (0.1%)		1/1673 (0.1%)
Delusion	0/1744 (0%)		1/1682 (0.1%)		0/1673 (0%)
Depression	1/1744 (0.1%)		0/1682 (0%)		5/1673 (0.3%)
Major depression	1/1744 (0.1%)		0/1682 (0%)		0/1673 (0%)
Renal and urinary disorders
Hydronephrosis	1/1744 (0.1%)		1/1682 (0.1%)		0/1673 (0%)
Nephrolithiasis	0/1744 (0%)		1/1682 (0.1%)		0/1673 (0%)
Urinary incontinence	0/1744 (0%)		1/1682 (0.1%)		0/1673 (0%)
Reproductive system and breast disorders
Adnexa uteri mass	1/1744 (0.1%)		0/1682 (0%)		0/1673 (0%)
Breast calcifications	1/1744 (0.1%)		0/1682 (0%)		0/1673 (0%)
Breast disorder	1/1744 (0.1%)		2/1682 (0.1%)		1/1673 (0.1%)
Breast dysplasia	1/1744 (0.1%)		0/1682 (0%)		0/1673 (0%)
Breast fibrosis	3/1744 (0.2%)		5/1682 (0.3%)		1/1673 (0.1%)
Breast haematoma	0/1744 (0%)		1/1682 (0.1%)		0/1673 (0%)
Breast hyperplasia	0/1744 (0%)		1/1682 (0.1%)		0/1673 (0%)
Breast inflammation	1/1744 (0.1%)		3/1682 (0.2%)		1/1673 (0.1%)
Breast mass	1/1744 (0.1%)		0/1682 (0%)		1/1673 (0.1%)
Breast necrosis	0/1744 (0%)		0/1682 (0%)		1/1673 (0.1%)
Breast pain	1/1744 (0.1%)		0/1682 (0%)		0/1673 (0%)
Cervical dysplasia	0/1744 (0%)		0/1682 (0%)		1/1673 (0.1%)
Cervical polyp	1/1744 (0.1%)		1/1682 (0.1%)		0/1673 (0%)
Endometrial hyperplasia	3/1744 (0.2%)		4/1682 (0.2%)		7/1673 (0.4%)
Endometriosis	0/1744 (0%)		1/1682 (0.1%)		1/1673 (0.1%)
Fibrocystic breast disease	0/1744 (0%)		0/1682 (0%)		2/1673 (0.1%)
Genital prolapse	0/1744 (0%)		0/1682 (0%)		1/1673 (0.1%)
Menorrhagia	2/1744 (0.1%)		2/1682 (0.1%)		2/1673 (0.1%)
Metrorrhagia	0/1744 (0%)		2/1682 (0.1%)		1/1673 (0.1%)
Nipple exudate bloody	0/1744 (0%)		1/1682 (0.1%)		0/1673 (0%)
Ovarian cyst	2/1744 (0.1%)		2/1682 (0.1%)		1/1673 (0.1%)
Rectocele	1/1744 (0.1%)		0/1682 (0%)		0/1673 (0%)
Uterine polyp	0/1744 (0%)		2/1682 (0.1%)		4/1673 (0.2%)
Uterine prolapse	1/1744 (0.1%)		0/1682 (0%)		0/1673 (0%)
Vaginal haemorrhage	0/1744 (0%)		0/1682 (0%)		2/1673 (0.1%)
Vaginal prolapse	0/1744 (0%)		1/1682 (0.1%)		0/1673 (0%)
Respiratory, thoracic and mediastinal disorders
Asthma	4/1744 (0.2%)		0/1682 (0%)		1/1673 (0.1%)
Chronic obstructive pulmonary disease	1/1744 (0.1%)		0/1682 (0%)		1/1673 (0.1%)
Cough	0/1744 (0%)		1/1682 (0.1%)		0/1673 (0%)
Dyspnoea	0/1744 (0%)		0/1682 (0%)		3/1673 (0.2%)
Dyspnoea exertional	1/1744 (0.1%)		0/1682 (0%)		0/1673 (0%)
Lung infiltration	0/1744 (0%)		0/1682 (0%)		1/1673 (0.1%)
Pleural effusion	0/1744 (0%)		1/1682 (0.1%)		0/1673 (0%)
Pneumothorax	1/1744 (0.1%)		2/1682 (0.1%)		1/1673 (0.1%)
Productive cough	2/1744 (0.1%)		0/1682 (0%)		0/1673 (0%)
Pulmonary embolism	2/1744 (0.1%)		1/1682 (0.1%)		4/1673 (0.2%)
Pulmonary fibrosis	0/1744 (0%)		0/1682 (0%)		1/1673 (0.1%)
Pulmonary oedema	0/1744 (0%)		0/1682 (0%)		1/1673 (0.1%)
Respiratory disorder	0/1744 (0%)		0/1682 (0%)		1/1673 (0.1%)
Throat tightness	0/1744 (0%)		1/1682 (0.1%)		0/1673 (0%)
Vocal cord polyp	1/1744 (0.1%)		0/1682 (0%)		0/1673 (0%)
Skin and subcutaneous tissue disorders
Dermal cyst	0/1744 (0%)		0/1682 (0%)		1/1673 (0.1%)
Dermatitis allergic	0/1744 (0%)		0/1682 (0%)		1/1673 (0.1%)
Diabetic foot	0/1744 (0%)		0/1682 (0%)		1/1673 (0.1%)
Drug eruption	1/1744 (0.1%)		0/1682 (0%)		0/1673 (0%)
Eczema	0/1744 (0%)		1/1682 (0.1%)		0/1673 (0%)
Erythema	0/1744 (0%)		0/1682 (0%)		1/1673 (0.1%)
Prurigo	0/1744 (0%)		0/1682 (0%)		1/1673 (0.1%)
Rash generalised	0/1744 (0%)		1/1682 (0.1%)		0/1673 (0%)
Rash papular	0/1744 (0%)		0/1682 (0%)		1/1673 (0.1%)
Scar pain	0/1744 (0%)		0/1682 (0%)		1/1673 (0.1%)
Skin mass	0/1744 (0%)		0/1682 (0%)		1/1673 (0.1%)
Telangiectasia	0/1744 (0%)		0/1682 (0%)		1/1673 (0.1%)
Toxic skin eruption	0/1744 (0%)		0/1682 (0%)		2/1673 (0.1%)
Urticaria	0/1744 (0%)		1/1682 (0.1%)		1/1673 (0.1%)
Surgical and medical procedures
Mammoplasty	1/1744 (0.1%)		0/1682 (0%)		0/1673 (0%)
Nerve block	1/1744 (0.1%)		0/1682 (0%)		0/1673 (0%)
Vascular disorders
Aortic occlusion	0/1744 (0%)		0/1682 (0%)		1/1673 (0.1%)
Deep vein thrombosis	0/1744 (0%)		4/1682 (0.2%)		0/1673 (0%)
Flushing	1/1744 (0.1%)		0/1682 (0%)		0/1673 (0%)
Haematoma	0/1744 (0%)		0/1682 (0%)		1/1673 (0.1%)
Haemorrhage	2/1744 (0.1%)		0/1682 (0%)		0/1673 (0%)
Hypertension	1/1744 (0.1%)		1/1682 (0.1%)		0/1673 (0%)
Hypertensive crisis	1/1744 (0.1%)		1/1682 (0.1%)		1/1673 (0.1%)
Hypotension	1/1744 (0.1%)		2/1682 (0.1%)		1/1673 (0.1%)
Jugular vein thrombosis	0/1744 (0%)		0/1682 (0%)		1/1673 (0.1%)
Microangiopathy	0/1744 (0%)		0/1682 (0%)		1/1673 (0.1%)
Subclavian vein thrombosis	0/1744 (0%)		1/1682 (0.1%)		1/1673 (0.1%)
Thrombophlebitis	0/1744 (0%)		1/1682 (0.1%)		0/1673 (0%)
Thrombosis	1/1744 (0.1%)		0/1682 (0%)		1/1673 (0.1%)
Vena cava thrombosis	0/1744 (0%)		0/1682 (0%)		2/1673 (0.1%)
Other (Not Including Serious) Adverse Events
	Observation Arm		Herceptin 1-Year Arm		Herceptin 2-Year Arm
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1076/1744 (61.7%)		1389/1682 (82.6%)		1440/1673 (86.1%)
Cardiac disorders
Cardiac failure congestive	18/1744 (1%)		78/1682 (4.6%)		127/1673 (7.6%)
Palpitations	20/1744 (1.1%)		72/1682 (4.3%)		84/1673 (5%)
Gastrointestinal disorders
Diarrhoea	22/1744 (1.3%)		155/1682 (9.2%)		180/1673 (10.8%)
Nausea	37/1744 (2.1%)		134/1682 (8%)		157/1673 (9.4%)
Vomiting	15/1744 (0.9%)		77/1682 (4.6%)		99/1673 (5.9%)
General disorders
Asthenia	42/1744 (2.4%)		102/1682 (6.1%)		119/1673 (7.1%)
Chest pain	37/1744 (2.1%)		63/1682 (3.7%)		84/1673 (5%)
Chills	1/1744 (0.1%)		99/1682 (5.9%)		128/1673 (7.7%)
Fatigue	83/1744 (4.8%)		198/1682 (11.8%)		246/1673 (14.7%)
Oedema peripheral	49/1744 (2.8%)		82/1682 (4.9%)		101/1673 (6%)
Pyrexia	12/1744 (0.7%)		116/1682 (6.9%)		145/1673 (8.7%)
Infections and infestations
Influenza	17/1744 (1%)		95/1682 (5.6%)		142/1673 (8.5%)
Nasopharyngitis	65/1744 (3.7%)		187/1682 (11.1%)		269/1673 (16.1%)
Upper respiratory tract infection	31/1744 (1.8%)		53/1682 (3.2%)		84/1673 (5%)
Musculoskeletal and connective tissue disorders
Arthralgia	152/1744 (8.7%)		225/1682 (13.4%)		246/1673 (14.7%)
Back pain	106/1744 (6.1%)		146/1682 (8.7%)		137/1673 (8.2%)
Muscle spasms	14/1744 (0.8%)		69/1682 (4.1%)		91/1673 (5.4%)
Musculoskeletal pain	64/1744 (3.7%)		70/1682 (4.2%)		92/1673 (5.5%)
Myalgia	28/1744 (1.6%)		88/1682 (5.2%)		104/1673 (6.2%)
Pain in extremity	74/1744 (4.2%)		97/1682 (5.8%)		107/1673 (6.4%)
Nervous system disorders
Dizziness	40/1744 (2.3%)		82/1682 (4.9%)		89/1673 (5.3%)
Headache	72/1744 (4.1%)		201/1682 (12%)		250/1673 (14.9%)
Psychiatric disorders
Depression	59/1744 (3.4%)		88/1682 (5.2%)		80/1673 (4.8%)
Insomnia	49/1744 (2.8%)		96/1682 (5.7%)		75/1673 (4.5%)
Respiratory, thoracic and mediastinal disorders
Cough	62/1744 (3.6%)		116/1682 (6.9%)		147/1673 (8.8%)
Dyspnoea	46/1744 (2.6%)		83/1682 (4.9%)		116/1673 (6.9%)
Skin and subcutaneous tissue disorders
Nail disorder	2/1744 (0.1%)		52/1682 (3.1%)		83/1673 (5%)
Onychoclasis	2/1744 (0.1%)		53/1682 (3.2%)		98/1673 (5.9%)
Rash	25/1744 (1.4%)		99/1682 (5.9%)		135/1673 (8.1%)
Vascular disorders
Hot flush	130/1744 (7.5%)		166/1682 (9.9%)		159/1673 (9.5%)
Hypertension	61/1744 (3.5%)		104/1682 (6.2%)		128/1673 (7.7%)
Lymphoedema	70/1744 (4%)		81/1682 (4.8%)		92/1673 (5.5%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

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.