Combined Clinical Trial Results Of A HER2/Neu (E75) Vaccine For Prevention Of Recurrence In High-Risk Breast Cancer Patients

Reviewer: John P. Plastaras, MD, PhD
The Abramson Cancer Center of the University of Pennsylvania
Last Modified: December 14, 2006

Presenter: G. E. Peoples
Affiliation: Walter Reed Army Medical Center, Washington, DC


  • Immunotherapy to treat cancer has been a popular idea for decades. Interferon therapy is FDA-approved and has been used in a variety of settings, such as in renal cell cancer. Cancer vaccines can potentially harness specific immune responses, but there are no cancer vaccines currently approved, despite numerous early phase trials.
  • HER2/neu is overexpressed in up to 25% of breast cancers and is a marker of worse prognosis
  • E75 is an immunogenic peptide derived from the extracellular domain of HER2/neu (amino acids 369-377). It can be presented in the context of HLA-A2 and A3.
  • Three Phase I trials of intradermal E75 mixed with GM-CSF in metastatic breast cancer has shown that it is safe and immunogenic, but efficacy was not tested
  • These results are from 2 early phase trials in the adjuvant setting to prevent recurrence using a cancer vaccine


  • Combined analysis of two Phase I/II trials of immunocompetent women with HER2/neu positive breast cancer who underwent standard surgery and adjuvant treatment and were believed to be disease free at enrollment. Non-randomized, but only HLA-A2 and A3 positive patients were immunized (n = 90). HLA-A2 negative patients served as controls (n = 81).
  • Node-positive trial (n = 90): dose escalation safety study
    • Dose escalation: 100, 500, 1000 mcg E75 with 250 mcg GM-CSF, monthly x6)
  • Node-negative trial (n = 81): dose optimization study
    • Dose optimization: 500 mcg E75 with varying (lower) doses of GM-CSF on differing schedules
  • Immunologic responses monitored by several assays including:
    • Delayed type hypersensitivity (DTH)
    • Antibody assay of HLA-A2 dimer to detect specifically responding T cells


  • These analyses pooled the immunized (HLA-A2/3 positive) and control patients from both studies
  • The groups were well matched except immunized patients had fewer hormone receptor negative patients (30% ER-/PR- vs. 18%)
  • Vaccination was associated with more Grade 1 side-effects, an actual desired side-effect indicating an immune reaction
  • The vaccine was immunogenic as measured by DTH (12.4 mm vs 2.8 mm) and the HLA-A2 dimer assay. After immunization was stopped, it appeared that reactivity returned to pre-immunization levels
  • Vaccination was associated with a decreased recurrence rate, but not overall survival:
    • At 20 months follow-up the difference was significant
      • Recurrence rate: 5.7% vaccinated, 14.1% control (p = 0.04)
      • Overall survival: 99% vaccinated, 95% control
    • But at 24 months follow-up, significance was “lost”:
        • Recurrence rate: 8.3% vaccinated, 16% control (p = 0.07)
          • Node negative: 2% vaccinated, 5.7% control
          • Node positive: 14.2% vaccinated, 24% control
  • In the 8 women treated with the optimum biological dose of the vaccine, there was only 1 recurrence

Author's Conclusions

  • Although there are a small number of patients on these combined trials, this is the largest vaccine prevention trial in breast cancer
  • Non-randomization and heterogeneous treatment make it difficult to draw conclusions, but the nearly 50% reduction in recurrence rate in vaccinated patients is intriguing
  • These results justify a Phase III trial in the adjuvant setting in node positive and high-risk node negative women with breast cancer and HLA-A2

Clinical/Scientific Implications

  • This study was not designed to compare efficacy of this vaccine, although the subset analysis is certainly intriguing. This question will require a randomized Phase III trial where the enrollment criteria and treatment is more uniform.
  • The choice of HER2 as a target for a vaccine is interesting. Herceptin, an antibody against HER2, has efficacy in the adjuvant setting in HER2 positive cancers. It is unclear whether the immune response generated by E75 blocks this receptor or stimulates a cytotoxic immune response. Therefore, it will be important to test whether this vaccine has additional efficacy over the HER2 targets, Herceptin or lapatinib alone.