• Four large randomized controlled trials:
    • Have set the stage for the treatment of early-stage HER-2 positive breast cancer with HER-2 targeted therapy in the adjuvant setting
  • Trastuzumab in the adjuvant setting:
    • Was found to improve disease-free (DFS) and overall survival (OS):
      • As a result, it has become the standard of care in this patient group
    • Treatment with trastuzumab is generally well tolerated:
      • However, one of the main concerns with trastuzumab use has been:
        • The risk of cardiomyopathy
  • The North Central Cancer Treatment Group (NCCTG) trial N9831 and the National Surgical Adjuvant Breast and Bowel Project (NSABP) B31 trial:
    • Were first reported by Romond and colleagues in 2005 in a joint analysis
  • The N9831 trial:
    • Compared three groups:
      • Group A receiving doxorubicin (Adriamycin [A]) and cyclophosphamide (C) followed by weekly paclitaxel (Taxol [T]) (AC® T)
      • Group B receiving the same regimen followed by 52 weeks of trastuzumab (Herceptin [H]) (AC® T® H)
      • Group C receiving AC followed by 52 weeks of trastuzumab beginning on day 1 of paclitaxel therapy (AC®TH)
  • The NSABP B-31 trial:
    • Group 1:
      • Compared doxorubicin and cyclophosphamide followed by paclitaxel every 3 weeks
    • Group 2:
      • The same regimen plus 52 weeks of trastuzumab
  • The combined analysis compared:
    • Groups 1 and A (as the control group) and groups 2 and C (as the treatment group). Group B was not analyzed in this joint analysis
    • The studies were terminated early:
      • At a median follow-up of 2 years
    • The combined analysis found that treatment with trastuzumab resulted in:
      • A 52% reduction in the DFS event rate (< .001) and a 33% early improvement in OS (p = .015)
      • The overall DFS at 3 years, presented in 2007:
        • Was 87.1% in the trastuzumab group compared with 75.4% in the control group
      • In addition, treatment with trastuzumab resulted in a 33% reduction (p = .015) in the risk of death at 4 years
      • With additional follow-up, the most recent analysis, performed with a median follow-up time of 8.4 years:
        • Demonstrated that trastuzumab in addition to chemotherapy led to:
          • Improvement in OS with a risk reduction of 37% and continued substantial improvement in DFS with a risk reduction in disease events of 40%
        • Improvements in OS and DFS were observed in all subgroups of patients with resected HER-2-positive breast cancer:
          • This included small or large tumors, hormone receptor positive or hormone receptor negative, low or high number of involved axillary nodes, and younger or older patients)
        • The risk of a cardiac event in these trials:
          • Ranged from 2.5 to 4%
    • In an attempt to improve efficacy while minimizing cardiotoxicity:
      • Slamon and colleagues compared two anthracycline-containing regimens with a nonanthracycline regimen
      • The Breast Cancer International Research Group (BCIRG) 006 trial, which enrolled 3,222 women with HER-2-positive, node-positive, or high-risk node-negative disease:
        • Compared three-weekly AC followed by docetaxel, with or without trastuzumab, and docetaxel, carboplatin, plus trastuzumab and found that both trastuzumab-containing regimens:
          • Resulted in an improved OS compared with chemotherapy alone
        • Patients who received trastuzumab concurrently with docetaxel following treatment with AC experienced a 51% lower risk of relapse than those receiving docetaxel alone (p < .0001)
        • Patients receiving docetaxel in combination with carboplatin and trastuzumab experienced a 39% lower risk of relapse (p = .0002)
        • The nonanthracycline group:
          • Reported lower cardiac toxicity rates
        • In the control group, grade 3 or 4 congestive heart failure (CHF) was noted in 0.3% of patients compared with 1.6% in the group receiving AC followed by docetaxel plus trastuzumab and 0.4% in the group receiving docetaxel in combination with carboplatin and trastuzumab
  • The appropriate treatment duration of trastuzumab remains a subject of interest:
    • The Herceptin Adjuvant (HERA) trial:
      • Compared 1 or 2 years of adjuvant trastuzumab with observation in women with HER-2-positive early-stage breast cancer who had completed adjuvant or neoadjuvant chemotherapy (NAC), surgery, and /or radiation
      • Trastuzumab was initiated at the completion of chemotherapy, radiation, or definitive surgery and was administered every 3 weeks
      • This study of 5,102 women with HER-2-positive early breast cancer showed that trastuzumab for 1 year following chemotherapy improved DFS
      • No difference in outcome was noted between the 1- and 2-year arms
      • At the most recent analysis of the trial:
        • There was no difference in DFS at a median follow-up of 8 years (HR 0.99; 95% CI 0.85 to 1.14; p = .86)
      • In comparison with observation, trastuzumab demonstrated:
        • A superior outcome in terms of both DFS and OS (HR 0.76; 95% CI 0.67 to 0.86; p < .0001 and HR 0.76; 95% CI 0.65 to 0.88; p = .0005, respectively)
      • Severe CHF was recorded in 0% of controls and 0.6% of trastuzumab-treated patients
  • The FinHer (Finland Herceptin) trial:
    • Was a small trial that included 232 patients with HER-2-positive disease
    • A total of 116 women were randomized to receive trastuzumab (9 weeks)
    • At a median follow-up of 3 years:
      • DFS was significantly improved (HR 0.42; 95% CI 0.21 to 0.83; p= .01)
  • Furthermore, a subsequent trial, PHARE (Protocol for Herceptin as Adjuvant therapy with Reduced Exposure), of a shorter duration of trastuzumab (6 months compared with 1 year):
    • Failed to show the noninferiority of 6 months of treatment as a result of fewer than anticipated events
    • Furthermore, the study noted a significantly higher rate of cardiac events in the 12-month group compared with the 6-month group (5.7% versus 1.9%, p < .0001)
  • One year of trastuzumab is the current standard of care for patients with HER-2-positive disease treated with anti-HER-2 therapy

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