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Piccart-Gebhart MJ, et al. "Trastuzumab after Adjuvant Chemotherapy in HER2-Positive Breast Cancer". The New England Journal of Medicine. 2005. 353(16):1659-72.
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Clinical Question

In patients with HER2-positive breast cancer, does trastuzumab improve disease-free survival after adjuvant chemotherapy?

Bottom Line

Trastuzumab after adjuvant chemotherapy significantly improves disease-free survival at 1 year among women with HER2-positive breast cancer.

Major Points

Trastuzumab is a monoclonal antibody against the HER2/neu gene product, which is overexpressed in 15-25% of breast cancers and is associated with an aggressive phenotype. While previous studies have shown that trastuzumab benefits those with HER2-positive metastatic breast cancer when administered alone or in combination with chemotherapy, the Herceptin Adjuvant (HERA) trial investigated the role of trastuzumab administered after primary treatment consisting of surgery, radiation, and chemotherapy.

HERA randomized 5,081 women with HER2-positive breast cancer after standard adjuvant chemotherapy to one of three arms: trastuzumab for 1 year, trastuzumab for 2 years, or observation only. At an interim efficacy analysis, the results for trastuzumab at 1 year demonstrated highly significant improvements in disease-free survival with a 46% reduction in recurrence at 1 year compared to observation alone. Thus, the data monitoring committee recommended premature release of the 1-year trial results. Long-term follow-up of patients receiving trastuzumab revealed that 2 years was not superior to 1 year of therapy in terms of disease-free survival, but did result in more cardiotoxicity.[1]


  • Multicenter, open-label, parallel-group, phase 3, randomized, controlled trial
  • N=5,081
    • Trastuzumab for 1 year (n=1,694)
    • Trastuzumab for 2 years (n=1,694)
    • Observation only (n=1,693)
  • Setting: 478 centers in 39 countries
  • Enrollment: 2001–2005
  • Median follow-up: 12 months
  • Analysis: Intention-to-treat
  • Primary outcome: Disease-free survival


Inclusion Criteria

  • Female
  • Histologically confirmed, early-stage invasive breast cancer after locoregional therapy (surgery ± radiotherapy)
    • Node-positive, irrespective of pathological tumor size
    • Node-negative (including only negative sentinel node) if tumor size ≥1cm
  • HER2 overexpression confirmed on immunohistochemistry and FISH
  • ≥4 cycles of chemotherapy completed prior to randomization:
    • Adjuvant chemotherapy postoperatively (89%)
    • Neoadjuvant chemotherapy (5%)
    • Both adjuvant and neoadjuvant chemotherapy (6%)
  • LVEF ≥55%

Exclusion Criteria

  • Previous invasive breast cancer
  • Distant metastases or stage T4 breast cancer, including inflammatory breast cancers or involvement of supraclavicular nodes or suspicious internal mammary nodes (unless irradiated)
  • Non-breast neoplasms other than breast, except for curatively treated BCC, SCC of skin or CIS of cervix
  • Prior mediastinal irradiation (except internal mammary-node irradiation)
  • Cumulative anthracycline dose exceeding 360mg/m2 for doxorubicin, or 720mg/m2 for epirubicin
  • Stem cell support for chemotherapy
  • Inadequate baseline hepatic, renal, or bone marrow function
  • Hormone-based contraceptive measures
  • Cardiac: history of CHF, CAD with previous Q-wave MI, angina pectoris requiring medication, uncontrolled HTN, clinically significant valvular disease, unstable arrhythmias

Baseline Characteristics

  • Median age: 49 years
  • Node negative disease: 33%
  • Hormone receptor negative disease: 48%
  • Chemotherapy administered:
    • Anthracycline-based: 94%
    • Taxane: 26%
  • Radiotherapy: 76%


  • Randomly assigned to 2 years of trastuzumab, 1 year of trastuzumab, or observation only
    • Within 7 wks from day 1 of last chemotherapy cycle, or 6 wks from end of radiotherapy or definitive surgery
  • Trastuzumab was administered 8mg/kg IV over 90 mins for first dose, then 6mg/kg IV for subsequent doses q 3wks
    • Temporarily withheld:
      • if nonhematologic grade 3 or 4 side effects, until recovery to grade 2 or lower
      • if asymptomatic CHF and LVEF ≤45% or LVEF <50% with absolute reduction of ≥10% from baseline
    • Discontinued:
      • if recovery took >3-5wks
      • if severe side effect recurred on readministration
      • if symptomic CHF and LVEF ≤45% or LVEF <50% with absolute reduction of ≥10% from baseline
  • Follow-up every 3 mos and blood work every 6 mos over 2 yrs, and then assessments scheduled to occur annually for year 3-10
  • Annual CXR until year 5; annual mammography until year 10
  • Cardiac monitoring included PE, 12-lead EKG, assessment of LVEF by echo or MUGA at baseline, and at 3, 6, 12, 18, 24, 30, 36, 60 mos
  • Adjuvant tamoxifen and/or aromatase inhibitors given after chemotherapy to hormone-receptor-positive disease


Comparisons are 1-year trastuzumab vs. observation alone.

Primary Outcome

Disease-free survival events
Includes recurrence, second primary event, or death without prior recurrence.
7.5% vs. 13.0% (HR 0.54; 95% CI 0.43-0.67; P<0.0001)

Secondary Outcomes

Local recurrence
1.0% vs. 2.2%
Regional recurrence
0.6% vs. 0.8%

Distant recurrence: 5.0% vs. 9.1% (HR0.49; 95% CI 0.38-0.63; P<0.0001)

Soft tissue: 0.3% vs. 1.1%
Skeletal: 1.4% vs. 2.2%
CNS: 1.2% vs. 0.9%
Other visceral site: 2.0% vs. 4.8%
Contralateral breast cancer
0.4% vs. 0.4%
Second non-breast malignant disease
0.2% vs. 0.4%
Death without prior recurrence
0.4% vs. 0.2%
Death from any cause
1.7% vs. 2.2% (HR 0.76; 95% CI 0.47-1.23; P=0.26)
Breast cancer-related death
1.4% vs. 2.0%

Death without cancer event: 0.4% vs. 0.2%

Cardiac failure: 0% vs. 0.1%
Cerebral hemorrhage: 0.1% vs. 0%
CVA: 0.1% vs. 0%

Adverse Events

≥1 grade 3 or 4 event
7.9% vs. 4.4% (P<0.001)
≥1 serious adverse event
7.0% vs. 4.7% (P=0.007)
Fatal adverse events
0.4% vs. 0.2% (P=0.34)
Treatment withdrawals
8.5% vs. --
Death due to CHF, MI, arrhythmias, SCD
0% vs. 0.06% (P=1.00)
Decrease in LVEF ≥10% from baseline to LVEF≤50% at any time
7.08% vs. 2.21% (P<0.001)
Severe CHF, as defined by decrease in LVEF and NYHA III/IV symptoms
0.54% vs. 0% (P=0.002)
Symptomatic CHF, including severe CHF and excluding death due to cardiac causes
1.73% vs. 0.06% (P<0.001)

Subgroup Analysis

No evidence of substantial heterogeneity in the relative treatment effect among subgroups.


  • Short follow-up period (median of 12 months) due to early release of results from the interim effective analysis
  • Risks of trastuzumab are not completely known, particularly risk of cardiotoxicity, with longer follow-up.


Supported by F. Hoffmann-La Roche (Roche), Basel, Switzerland. Multiple authors with disclosures.