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Combined Clinical Trial Results of a HER2/neu (E75) Vaccine for the Prevention of Recurrence in High-Risk Breast Cancer Patients: U.S. Military Cancer Institute Clinical Trials Group Study I-01 and I-02

Authors' Affiliations: ¹ Department of Surgery, General Surgery Service, Brooke Army Medical Center, Fort Sam Houston, San Antonio, Texas; ² Cancer Vaccine Development Program, U.S. Military Cancer Institute, Uniformed Services University of the Health Sciences; ³ Department of Medicine, Division of Hematology and Medical Oncology, National Naval Medical Center, Bethesda, Maryland; ⁴ Department of Surgery, General Surgery Service, Walter Reed Army Medical Center, Washington, District of Columbia; ⁵ U.T.M.D. Anderson Cancer Center, Houston, Texas; and ⁶ Joyce Murtha Breast Care Center, Windber Medical Center, Windber, Pennsylvania

Requests for reprints: George E. Peoples, M.D., FACS, Department of Surgery, General Surgery Service, Brooke Army Medical Center, 3851 Roger Brooke Drive, Fort Sam Houston, San Antonio, TX 78234. Phone: 210-916-1117; Fax: 210-916-6658; E-mail: george.peoples{at}amedd.army.mil.

Purpose: E75 is an immunogenic peptide from the HER2/neu protein, which is overexpressed in many breast cancer patients. We have conducted two overlapping E75 vaccine trials to prevent recurrence in node-positive (NP) and node-negative (NN) breast cancer patients.

Experimental Design: E75 (HER2/neu 369-377) + granulocyte macrophage colony-stimulating factor was given intradermally to previously treated, disease-free NP breast cancer patients in a dose escalation safety trial and to NN breast cancer patients in a dose optimization study. Local and systemic toxicity was monitored. Immunologic responses were assessed using in vitro assays and in vivo delayed-type hypersensitivity responses. Clinical recurrences were documented.

Results: One hundred and eighty-six patients were enrolled in the two studies (NP, 95; NN, 91). Human leucocyte antigen A2 (HLA-A2) and HLA-A3 patients were vaccinated (n = 101), whereas all others (n = 85) were followed prospectively as controls. Toxicities were minimal, and a dose-dependent immunologic response to the vaccine was shown. Planned primary analysis revealed a recurrence rate of 5.6% in vaccinated patients compared with 14.2% in the controls (P = 0.04) at a median of 20 months follow-up. As vaccine-specific immunity waned over time, the difference in recurrence lost significance at 26 months median follow-up (8.3% versus 14.8%); however, a significant difference in the pattern of recurrence persisted.

Conclusions: E75 is safe and effective in raising a dose-dependent HER2/neu immunity in HLA-A2 and HLA-A3 NP and NN breast cancer patients. More importantly, E75 may reduce recurrences in disease-free, conventionally treated, high-risk breast cancer patients. These findings warrant a prospective, randomized phase III trial of the E75 vaccine with periodic booster to prevent breast cancer recurrences.

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