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

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

Tracking Information

• First Submitted Date: September 6, 2002
• First Posted Date: January 27, 2003
• Results First Submitted Date: October 19, 2016
• Results First Posted Date: April 27, 2017
• Last Update Posted Date: April 27, 2017
• Study Start Date: November 2001
• Actual Primary Completion Date: March 2005 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: March 17, 2017)

• Percentage of Participants With Disease-Free Survival (DFS) Events in Herceptin 1-Year Arm Compared to Observation: 1-Year Median Follow-Up [ Time Frame: 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.
• Percentage of Participants With DFS Events in Herceptin 2-Year Arm Compared to Observation: 1-Year Median Follow-Up [ Time Frame: 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.
• DFS Rate According to Kaplan-Meier Analysis in Herceptin 1-Year Arm Compared to Observation: 1-Year Median Follow-Up [ Time Frame: 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.
• DFS Rate According to Kaplan-Meier Analysis in Herceptin 2-Year Arm Compared to Observation: 1-Year Median Follow-Up [ Time Frame: 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.
• Percentage of Participants With DFS Events Compared to Observation: 8-Year Median Follow-Up [ Time Frame: 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.
• DFS Rate at Year 3 According to Kaplan-Meier Analysis Compared to Observation: 8-Year Median Follow-Up [ Time Frame: 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.
• DFS Rate at Year 5 According to Kaplan-Meier Analysis Compared to Observation: 8-Year Median Follow-Up [ Time Frame: 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.
• DFS Rate at Year 7 According to Kaplan-Meier Analysis Compared to Observation: 8-Year Median Follow-Up [ Time Frame: 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.
• DFS Rate at Year 8 According to Kaplan-Meier Analysis Compared to Observation: 8-Year Median Follow-Up [ Time Frame: 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.
• Percentage of Participants With DFS Events Compared to Observation: 10-Year Maximum Follow-Up [ Time Frame: 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.
• DFS Rate at Year 3 According to Kaplan-Meier Analysis Compared to Observation: 10-Year Maximum Follow-Up [ Time Frame: 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.
• DFS Rate at Year 5 According to Kaplan-Meier Analysis Compared to Observation: 10-Year Maximum Follow-Up [ Time Frame: 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.
• DFS Rate at Year 7 According to Kaplan-Meier Analysis Compared to Observation: 10-Year Maximum Follow-Up [ Time Frame: 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.
• DFS Rate at Year 8 According to Kaplan-Meier Analysis Compared to Observation: 10-Year Maximum Follow-Up [ Time Frame: 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.
• DFS Rate at Year 9 According to Kaplan-Meier Analysis Compared to Observation: 10-Year Maximum Follow-Up [ Time Frame: 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.
• DFS Rate at Year 10 According to Kaplan-Meier Analysis Compared to Observation: 10-Year Maximum Follow-Up [ Time Frame: 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.

• Original Primary Outcome Measures: Not Provided

Current Secondary Outcome Measures (submitted: March 17, 2017)

• Percentage of Participants With DFS Events in 1-Year Versus 2-Year Herceptin: 10-Year Maximum Follow-Up [ Time Frame: 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.
• DFS Rate According to Kaplan-Meier Analysis in 1-Year Versus 2-Year Herceptin: 10-Year Maximum Follow-Up [ Time Frame: 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.
• Percentage of Participants With Overall Survival (OS) Events in Herceptin 1-Year Arm Compared to Observation: 1-Year Median Follow-Up [ Time Frame: 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.
• Percentage of Participants With OS Events in Herceptin 2-Year Arm Compared to Observation: 1-Year Median Follow-Up [ Time Frame: 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.
• OS Rate According to Kaplan-Meier Analysis in Herceptin 1-Year Arm Compared to Observation: 1-Year Median Follow-Up [ Time Frame: 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.
• OS Rate According to Kaplan-Meier Analysis in Herceptin 2-Year Arm Compared to Observation: 1-Year Median Follow-Up [ Time Frame: 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.
• Percentage of Participants With OS Events Compared to Observation: 8-Year Median Follow-Up [ Time Frame: 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.
• OS Rate According to Kaplan-Meier Analysis Compared to Observation: 8-Year Median Follow-Up [ Time Frame: 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.
• Percentage of Participants With OS Events Compared to Observation: 11-Year Median Follow-Up [ Time Frame: 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.
• OS Rate According to Kaplan-Meier Analysis Compared to Observation: 11-Year Median Follow-Up [ Time Frame: 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.
• Percentage of Participants With OS Events in 1-Year Versus 2-Year Herceptin: 11-Year Median Follow-Up [ Time Frame: 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.
• OS Rate According to Kaplan-Meier Analysis in 1-Year Versus 2-Year Herceptin: 11-Year Median Follow-Up [ Time Frame: 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.
• Percentage of Participants With Recurrence-Free Survival (RFS) Events Compared to Observation: 8-Year Median Follow-Up [ Time Frame: 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.
• RFS Rate According to Kaplan-Meier Analysis Compared to Observation: 8-Year Median Follow-Up [ Time Frame: 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.
• Percentage of Participants With RFS Events in 1-Year Versus 2-Year Herceptin: 8-Year Median Follow-Up [ Time Frame: 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.
• RFS Rate According to Kaplan-Meier Analysis in 1-Year Versus 2-Year Herceptin: 8-Year Median Follow-Up [ Time Frame: 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.
• Percentage of Participants With Distant Disease-Free Survival (DDFS) Events Compared to Observation: 8-Year Median Follow-Up [ Time Frame: 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.
• DDFS Rate According to Kaplan-Meier Analysis Compared to Observation: 8-Year Median Follow-Up [ Time Frame: 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.
• Percentage of Participants With DDFS Events in 1-Year Versus 2-Year Herceptin: 8-Year Median Follow-Up [ Time Frame: 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.
• DDFS Rate According to Kaplan-Meier Analysis in 1-Year Versus 2-Year Herceptin: 8-Year Median Follow-Up [ Time Frame: 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.
• Percentage of Participants With Tumor Recurrence (TR) Compared to Observation: 8-Year Median Follow-Up [ Time Frame: 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.
• TR-Free Rate According to Kaplan-Meier Analysis Compared to Observation: 8-Year Median Follow-Up [ Time Frame: 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.
• Percentage of Participants With TR in 1-Year Versus 2-Year Herceptin: 8-Year Median Follow-Up [ Time Frame: 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.
• TR-Free Rate According to Kaplan-Meier Analysis in 1-Year Versus 2-Year Herceptin: 8-Year Median Follow-Up [ Time Frame: 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.
• Percentage of Participants With Distant Tumor Recurrence (DTR) Compared to Observation: 8-Year Median Follow-Up [ Time Frame: 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.
• DTR-Free Rate According to Kaplan-Meier Analysis Compared to Observation: 8-Year Median Follow-Up [ Time Frame: 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.
• Percentage of Participants With DTR in 1-Year Versus 2-Year Herceptin: 8-Year Median Follow-Up [ Time Frame: 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.
• DTR-Free Rate According to Kaplan-Meier Analysis in 1-Year Versus 2-Year Herceptin: 8-Year Median Follow-Up [ Time Frame: 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.
• Percentage of Participants With Restricted Disease-Free Survival (RDFS) Events in 1-Year Versus 2-Year Herceptin: 8-Year Median Follow-Up [ Time Frame: 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.
• RDFS Rate According to Kaplan-Meier Analysis in 1-Year Versus 2-Year Herceptin: 8-Year Median Follow-Up [ Time Frame: 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.
• Percentage of Participants With Primary Cardiac Endpoint Events Compared to Observation: 10-Year Maximum Follow-Up [ Time Frame: 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.
• Percentage of Participants With Secondary Cardiac Endpoint Events Compared to Observation: 10-Year Maximum Follow-Up [ Time Frame: 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.

• Original Secondary Outcome Measures: Not Provided
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Herceptin (Trastuzumab) in Treating Women With Human Epidermal Growth Factor Receptor (HER) 2-Positive Primary Breast Cancer
• 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
• 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.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Breast Cancer

Intervention

• 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 Name: Trastuzumab
• 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 Name: Trastuzumab

Study Arms

• 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.
  Intervention: Drug: Herceptin
• 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.
  Intervention: Drug: Herceptin

Publications *

• Jahanzeb M. Adjuvant trastuzumab therapy for HER2-positive breast cancer. Clin Breast Cancer. 2008 Aug;8(4):324-33. doi: 10.3816/CBC.2008.n.037.
• Shiroiwa T, Fukuda T, Shimozuma K, Ohashi Y, Tsutani K. The model-based cost-effectiveness analysis of 1-year adjuvant trastuzumab treatment: based on 2-year follow-up HERA trial data. Breast Cancer Res Treat. 2008 Jun;109(3):559-66. doi: 10.1007/s10549-007-9679-4. Epub 2007 Jul 28.
• Gianni L, Dafni U, Gelber RD, Azambuja E, Muehlbauer S, Goldhirsch A, Untch M, Smith I, Baselga J, Jackisch C, Cameron D, Mano M, Pedrini JL, Veronesi A, Mendiola C, Pluzanska A, Semiglazov V, Vrdoljak E, Eckart MJ, Shen Z, Skiadopoulos G, Procter M, Pritchard KI, Piccart-Gebhart MJ, Bell R; Herceptin Adjuvant (HERA) Trial Study Team. Treatment with trastuzumab for 1 year after adjuvant chemotherapy in patients with HER2-positive early breast cancer: a 4-year follow-up of a randomised controlled trial. Lancet Oncol. 2011 Mar;12(3):236-44. doi: 10.1016/S1470-2045(11)70033-X. Epub 2011 Feb 25.
• Procter M, Suter TM, de Azambuja E, Dafni U, van Dooren V, Muehlbauer S, Climent MA, Rechberger E, Liu WT, Toi M, Coombes RC, Dodwell D, Pagani O, Madrid J, Hall M, Chen SC, Focan C, Muschol M, van Veldhuisen DJ, Piccart-Gebhart MJ. Longer-term assessment of trastuzumab-related cardiac adverse events in the Herceptin Adjuvant (HERA) trial. J Clin Oncol. 2010 Jul 20;28(21):3422-8. doi: 10.1200/JCO.2009.26.0463. Epub 2010 Jun 7.
• Dowsett M, Procter M, McCaskill-Stevens W, de Azambuja E, Dafni U, Rueschoff J, Jordan B, Dolci S, Abramovitz M, Stoss O, Viale G, Gelber RD, Piccart-Gebhart M, Leyland-Jones B. Disease-free survival according to degree of HER2 amplification for patients treated with adjuvant chemotherapy with or without 1 year of trastuzumab: the HERA Trial. J Clin Oncol. 2009 Jun 20;27(18):2962-9. doi: 10.1200/JCO.2008.19.7939. Epub 2009 Apr 13.
• Untch M, Gelber RD, Jackisch C, Procter M, Baselga J, Bell R, Cameron D, Bari M, Smith I, Leyland-Jones B, de Azambuja E, Wermuth P, Khasanov R, Feng-Yi F, Constantin C, Mayordomo JI, Su CH, Yu SY, Lluch A, Senkus-Konefka E, Price C, Haslbauer F, Suarez Sahui T, Srimuninnimit V, Colleoni M, Coates AS, Piccart-Gebhart MJ, Goldhirsch A; HERA Study Team. Estimating the magnitude of trastuzumab effects within patient subgroups in the HERA trial. Ann Oncol. 2008 Jun;19(6):1090-6. doi: 10.1093/annonc/mdn005. Epub 2008 Feb 21.
• McCaskill-Stevens W, Procter M, Goodbrand J, et al.: Disease-free survival according to local immunohistochemistry for HER2 and central fluorescence in situ hydridization for patients treated with adjuvant chemotherapy with and without trastuzumab in the HERA (BIG 01-01) trial. [Abstract] Breast Cancer Res Treat 106 (1): A-71, S18, 2007.
• Smith I, Procter M, Gelber RD, Guillaume S, Feyereislova A, Dowsett M, Goldhirsch A, Untch M, Mariani G, Baselga J, Kaufmann M, Cameron D, Bell R, Bergh J, Coleman R, Wardley A, Harbeck N, Lopez RI, Mallmann P, Gelmon K, Wilcken N, Wist E, Sanchez Rovira P, Piccart-Gebhart MJ; HERA study team. 2-year follow-up of trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer: a randomised controlled trial. Lancet. 2007 Jan 6;369(9555):29-36. doi: 10.1016/S0140-6736(07)60028-2.
• Suter TM, Procter M, van Veldhuisen DJ, Muscholl M, Bergh J, Carlomagno C, Perren T, Passalacqua R, Bighin C, Klijn JG, Ageev FT, Hitre E, Groetz J, Iwata H, Knap M, Gnant M, Muehlbauer S, Spence A, Gelber RD, Piccart-Gebhart MJ. Trastuzumab-associated cardiac adverse effects in the herceptin adjuvant trial. J Clin Oncol. 2007 Sep 1;25(25):3859-65. doi: 10.1200/JCO.2006.09.1611. Epub 2007 Jul 23.
• Piccart-Gebhart MJ, Procter M, Leyland-Jones B, Goldhirsch A, Untch M, Smith I, Gianni L, Baselga J, Bell R, Jackisch C, Cameron D, Dowsett M, Barrios CH, Steger G, Huang CS, Andersson M, Inbar M, Lichinitser M, Lang I, Nitz U, Iwata H, Thomssen C, Lohrisch C, Suter TM, Ruschoff J, Suto T, Greatorex V, Ward C, Straehle C, McFadden E, Dolci MS, Gelber RD; Herceptin Adjuvant (HERA) Trial Study Team. Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med. 2005 Oct 20;353(16):1659-72. doi: 10.1056/NEJMoa052306.
• Yerushalmi R, Dong B, Chapman JW, Goss PE, Pollak MN, Burnell MJ, Levine MN, Bramwell VHC, Pritchard KI, Whelan TJ, Ingle JN, Shepherd LE, Parulekar WR, Han L, Ding K, Gelmon KA. Impact of baseline BMI and weight change in CCTG adjuvant breast cancer trials. Ann Oncol. 2017 Jul 1;28(7):1560-1568. doi: 10.1093/annonc/mdx152.
• Cameron D, Piccart-Gebhart MJ, Gelber RD, Procter M, Goldhirsch A, de Azambuja E, Castro G Jr, Untch M, Smith I, Gianni L, Baselga J, Al-Sakaff N, Lauer S, McFadden E, Leyland-Jones B, Bell R, Dowsett M, Jackisch C; Herceptin Adjuvant (HERA) Trial Study Team. 11 years' follow-up of trastuzumab after adjuvant chemotherapy in HER2-positive early breast cancer: final analysis of the HERceptin Adjuvant (HERA) trial. Lancet. 2017 Mar 25;389(10075):1195-1205. doi: 10.1016/S0140-6736(16)32616-2. Epub 2017 Feb 17. Erratum In: Lancet. 2019 Mar 16;393(10176):1100.
• Loi S, Dafni U, Karlis D, Polydoropoulou V, Young BM, Willis S, Long B, de Azambuja E, Sotiriou C, Viale G, Ruschoff J, Piccart MJ, Dowsett M, Michiels S, Leyland-Jones B. Effects of Estrogen Receptor and Human Epidermal Growth Factor Receptor-2 Levels on the Efficacy of Trastuzumab: A Secondary Analysis of the HERA Trial. JAMA Oncol. 2016 Aug 1;2(8):1040-7. doi: 10.1001/jamaoncol.2016.0339.
• O'Sullivan CC, Bradbury I, Campbell C, Spielmann M, Perez EA, Joensuu H, Costantino JP, Delaloge S, Rastogi P, Zardavas D, Ballman KV, Holmes E, de Azambuja E, Piccart-Gebhart M, Zujewski JA, Gelber RD. Efficacy of Adjuvant Trastuzumab for Patients With Human Epidermal Growth Factor Receptor 2-Positive Early Breast Cancer and Tumors </= 2 cm: A Meta-Analysis of the Randomized Trastuzumab Trials. J Clin Oncol. 2015 Aug 20;33(24):2600-8. doi: 10.1200/JCO.2015.60.8620. Epub 2015 Jun 22.
• de Azambuja E, Procter MJ, van Veldhuisen DJ, Agbor-Tarh D, Metzger-Filho O, Steinseifer J, Untch M, Smith IE, Gianni L, Baselga J, Jackisch C, Cameron DA, Bell R, Leyland-Jones B, Dowsett M, Gelber RD, Piccart-Gebhart MJ, Suter TM. Trastuzumab-associated cardiac events at 8 years of median follow-up in the Herceptin Adjuvant trial (BIG 1-01). J Clin Oncol. 2014 Jul 10;32(20):2159-65. doi: 10.1200/JCO.2013.53.9288. Epub 2014 Jun 9.
• Zabaglo L, Stoss O, Ruschoff J, Zielinski D, Salter J, Arfi M, Bradbury I, Dafni U, Piccart-Gebhart M, Procter M, Dowsett M; HERA Trial Study Team. HER2 staining intensity in HER2-positive disease: relationship with FISH amplification and clinical outcome in the HERA trial of adjuvant trastuzumab. Ann Oncol. 2013 Nov;24(11):2761-6. doi: 10.1093/annonc/mdt275. Epub 2013 Jul 25.
• Goldhirsch A, Gelber RD, Piccart-Gebhart MJ, de Azambuja E, Procter M, Suter TM, Jackisch C, Cameron D, Weber HA, Heinzmann D, Dal Lago L, McFadden E, Dowsett M, Untch M, Gianni L, Bell R, Kohne CH, Vindevoghel A, Andersson M, Brunt AM, Otero-Reyes D, Song S, Smith I, Leyland-Jones B, Baselga J; Herceptin Adjuvant (HERA) Trial Study Team. 2 years versus 1 year of adjuvant trastuzumab for HER2-positive breast cancer (HERA): an open-label, randomised controlled trial. Lancet. 2013 Sep 21;382(9897):1021-8. doi: 10.1016/S0140-6736(13)61094-6. Epub 2013 Jul 18.
• Metzger-Filho O, Procter M, de Azambuja E, Leyland-Jones B, Gelber RD, Dowsett M, Loi S, Saini KS, Cameron D, Untch M, Smith I, Gianni L, Baselga J, Jackisch C, Bell R, Sotiriou C, Viale G, Piccart-Gebhart M. Magnitude of trastuzumab benefit in patients with HER2-positive, invasive lobular breast carcinoma: results from the HERA trial. J Clin Oncol. 2013 Jun 1;31(16):1954-60. doi: 10.1200/JCO.2012.46.2440. Epub 2013 Apr 15.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: March 17, 2017): 5099
• Original Enrollment: Not Provided
• Actual Study Completion Date: June 2015
• Actual Primary Completion Date: March 2005 (Final data collection date for primary outcome measure)

Eligibility Criteria

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

Sex/Gender

• Sexes Eligible for Study: Female

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Argentina, Australia, Austria, Belgium, Brazil, Canada, Chile, China, Colombia, Croatia, Denmark, France, Germany, Greece, Guatemala, Hong Kong, Hungary, Ireland, Israel, Italy, Japan, Korea, Republic of, Netherlands, Poland, Portugal, Russian Federation, Singapore, South Africa, Spain, Sweden, Switzerland, Thailand, United Kingdom

Administrative Information

• NCT Number: NCT00045032
• Other Study ID Numbers: BO16348; BIG-01-01; EU-20216; ROCHE-B016348E; ROCHE-B016348C; EORTC-10011; CAN-NCIC-MA24; IBCSG-28-02
• Has Data Monitoring Committee: Not Provided
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: Hoffmann-La Roche
• Original Responsible Party: Not Provided
• Current Study Sponsor: Hoffmann-La Roche
• Original Study Sponsor: Breast International Group

Collaborators

• 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

• PRS Account: Hoffmann-La Roche
• Verification Date: March 2017