Abstract
PurposeAE37 and GP2 are HER2 derived peptide vaccines. AE37 primarily elicits a CD4+ response while GP2 elicits a CD8+ response against the HER2 antigen. These peptides were tested in a large randomized trial to assess their ability to prevent recurrence in HER2 expressing breast cancer patients. The primary analyses found no difference in 5-year overall disease-free survival (DFS) but possible benefit in subgroups. Here, we present the final landmark analysis.MethodsIn this 4-arm, prospective, randomized, single-blinded, multi-center phase II trial, disease-free node positive and high-risk node negative breast cancer patients enrolled after standard of care therapy. Six monthly inoculations of vaccine (VG) vs. control (CG) were given as the primary vaccine series with 4 boosters at 6-month intervals. Demographic, safety, immunologic, and DFS data were evaluated.Results456 patients were enrolled; 154 patients in the VG and 147 in CG for AE37, 89 patients in the VG and 91 in CG for GP2. The AE37 arm had no difference in DFS as compared to CG, but pre-specified exploratory subgroup analyses showed a trend towards benefit in advanced stage (p = 0.132, HR 0.573 CI 0.275–1.193), HER2 under-expression (p = 0.181, HR 0.756 CI 0.499–1.145), and triple-negative breast cancer (p = 0.266, HR 0.443 CI 0.114–1.717). In patients with both HER2 under-expression and advanced stage, there was significant benefit in the VG (p = 0.039, HR 0.375 CI 0.142–0.988) as compared to CG. The GP2 arm had no significant difference in DFS as compared to CG, but on subgroup analysis, HER2 positive patients had no recurrences with a trend toward improved DFS (p = 0.052) in VG as compared to CG.ConclusionsThis phase II trial reveals that AE37 and GP2 are safe and possibly associated with improved clinical outcomes of DFS in certain subgroups of breast cancer patients. With these findings, further evaluations are warranted of AE37 and GP2 vaccines given in combination and/or separately for specific subsets of breast cancer patients based on their disease biology.
Highlights
Despite progress via early detection and improved treatment, breast cancer recurrence remains a significant problem
The primary objectives of this study were to determine if AE37 in combination with granulocyte–macrophage colony-stimulating factor (GM-CSF) vaccination improves the disease-free survival (DFS) in any level HER2 expressing, node positive or high-risk node negative breast cancer patients, and to determine if GP2 in combination with GM-CSF vaccination improves the DFS in any level HER2 expressing, human leukocyte antigen (HLA)-A2 positive, node positive or high-risk node negative breast cancer patients
The trial was designed to detect a 0.48 hazard ratio corresponding to an improvement in 2-year DFS from 85% for GM-CSF control to 93% for vaccine (AE37 and GP2)
Summary
Despite progress via early detection and improved treatment, breast cancer recurrence remains a significant problem. Increasing evidence suggests breast cancer is more immunogenic than once realized, given the important prognostic role that the host immune response and tumor microenvironment play [1,2,3]. Immune-mediated surveillance and clearance of disease likely plays an important role in preventing recurrence in clinically disease-free patients after standard of care therapy. Cancer vaccines may help generate a tumor-specific immunity to prevent disease recurrence. HER2 is a tumor-associated antigen expressed at some level in 60–70% of breast cancers, over-expressed in 20–30% of patients, and is one potential target for breast cancer vaccines [4, 5]. Monoclonal antibodies targeting HER2 provide clinical benefit, at least in part due to an immunologic mechanism in HER2 over-expressing breast cancer [6]. Vaccines targeting immunogenic HER2 peptides may provide benefit via immune-mediated cancer cell elimination
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