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PurposeHER-2/neu is overexpressed in breast cancer and is the source of immunogenic peptides. CD4+T-helper peptides for HER-2/neu are being evaluated in vaccine trials. The addition of Ii-Key, a four–amino-acid LRMK modification, increases vaccine potency when compared with unmodified class II epitopes. We present the results of the first human phase I trial of the Ii-Key hybrid HER-2/neu peptide (AE37) vaccine in disease-free, node-negative breast cancer patients.Patients and MethodsThe dose escalation trial included five dose groups, to determine safety and optimal dose of the hybrid peptide (100 μg, 500 μg, 1,000 μg) and granulocyte-macrophage colony-stimulating factor (GM-CSF; range, 0 to 250 μg). In the event of significant local toxicity, GM-CSF (or peptide in absence of GM-CSF) was reduced by 50%. Immunologic response was monitored by delayed-type hypersensitivity and [3H]thymidine proliferative assays for both the hybrid AE37 (LRMK-positive HER-2/neu:776-790) and AE36 (unmodified HER-2/neu:776-790).ResultsAll 15 patients completed the trial with no grade 3 to 5 toxicities. Dose reductions occurred in 47% of patients. In the second group (peptide, 500 μg; GM-CSF, 250 μg), all patients required dose reductions, prompting peptide-only inoculations in the third group. The vaccine induced dose-dependent immunologic responses in vitro and in vivo to AE37, as well as AE36.ConclusionThe hybrid AE37 vaccine seems safe and well tolerated with minimal toxicity if properly dosed. AE37 is capable of eliciting HER-2/neu–specific immune responses, even without the use of an adjuvant. This trial represents the first human experience with the Ii-Key modification, and to our knowledge, AE37 is the first peptide vaccine to show potency in the absence of an immunoadjuvant.

Stroke is a leading cause of disability and the third leading cause of death. Landmark studies have demonstrated that carotid endarterectomy (CEA) reduced the risk of stroke among selected patients with carotid stenosis. Renal insufficiency is a known risk factor for stroke and appears to be an independent risk factor for poor outcome after CEA. Studies have reported high morbidity and mortality after CEA in patients on dialysis. However, our experience has been that patients undergoing dialysis have no greater risk for a poor outcome. This study was a retrospective review of our CEA patients to ascertain our morbidity and mortality results in dialysis patients versus patients not on dialysis. An institutional retrospective chart review of CEAs from January 1999 to December 2007 was conducted. Patients on dialysis at the time of CEA were identified. Their charts were reviewed for complications 30 days after surgery. This was compared with our total experience with CEAs from January 1999 to December 2007. Of the 28 patients undergoing CEA while dialysis dependent, none had complications in the 30-day postoperative period. This compares favorably with the cohort of all CEAs by the same surgeons. In that group, 13 complications were identified (13 of 1,141). Patients undergoing dialysis are at no greater risk for complications when undergoing carotid endarterectomy than the general population.

E75, a HER2/neu immunogenic peptide, is expressed in breast cancer (BCa). We have performed clinical trials of E75 + GM-CSF vaccine in disease-free, node-positive and node-negative BCa patients at high recurrence risk and recurrences were noted in both control and vaccine groups.Among the 186 BCa patients enrolled, 177 completed the study. Patients were HLA typed; the HLA-A2(+)/A3(+) patients were vaccinated; HLA-A2(-)/A3(-) patients were followed as controls. Standard clinicopathological factors, immunologic response to the vaccine, and recurrences were collected and assessed.The control group recurrence rate was 14.8 and 8.3% in the vaccinated group (P = 0.17). Comparing the 8 vaccinated recurrences (V-R) to the 88 vaccinated nonrecurrent patients (V-NR), the V-R group had higher nodal stage (or = N2: 75 vs. 5%, P = 0.0001) and higher grade tumors (%grade 3: 88 vs. 31%, P = 0.003). The V-R group did not fail to respond immunologically as noted by equivalent dimer responses and post-DTH responses. Compared to control recurrent patients (C-R), V-R patients trended toward higher-grade tumors and hormone-receptor negativity. C-R patients had 50% bone-only recurrences, compared to V-R patients with no bone-only recurrences (P = 0.05). Lastly, V-R mortality rate was 12.5% compared with 41.7% for the C-R group (P = 0.3).The vaccinated patients who recurred had more aggressive disease compared to V-NR patients. V-R patients had no difference in immune response to the vaccine either in vitro or in vivo. V-R patients, when compared to C-R patients, trended towards more aggressive disease, decreased recurrence rates, decreased mortality, and no bone-only recurrences.

Background We have treated disease-free breast cancer patients with an HER2/ neu -derived peptide, E75, as an adjuvant vaccine. E75 was originally described as HLA-A2−restricted and has been previously tested in this population. Based on computer modeling, E75 is predicted to bind to HLA-A3, and preclinical data support this. We conducted a clinical trial of E75 in HLA-A3 + , A2 − (A3) patients. Study Design Disease-free breast cancer patients were enrolled after standard therapy in phase I/II trials. A3 patients were enrolled in parallel with A2 patients and vaccinated with E75 and granulocyte-macrophage colony-stimulating factor immunoadjuvant. A2 − , A3 − patients were followed as controls. Toxicities were graded. Immunologic responses were assessed by delayed-type hypersensitivity reactions and E75-specific interferon-γ enzyme-linked immunosorbent spot assay. Clinical recurrences were documented. Results Thirteen A3 patients completed the vaccine schedule. Clinicopathologic features were similar between A3, A2, and control patients, except for more HER2/ neu -overexpressing tumors in the A2 group and more estrogen-receptor/progesterone-receptor−negative tumors in A2 and A3 groups. Toxicity profiles and postvaccination delayed-type hypersensitivity were similar in A3 and A2 patients. Enzyme-linked immunosorbent spot assay results varied, but A3 patients' median spots increased pre- to postvaccination (p = 0.2). Recurrences were lower in the A3 group (7.7%) at 30-month median follow-up compared with published recurrence in A2-vaccinated (8.3%) and control groups (14.8%) at 26-month median follow-up. Conclusions HLA restriction limits potential use of peptide-based cancer vaccines. This trial demonstrates that HLA-A3 patients respond similarly to E75 vaccination as HLA-A2 patients, suggesting the potential use of the E75 vaccine in up to 76% of the population.

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.

Background and Objectives: To examine mammographic screening compliance among young military healthcare beneficiaries and to examine factors related to one time and recent mammographic compliance. Methods: Medical records were reviewed for 1,073 subjects (age 41‐47) recording dates of the two most recent screening mammograms. Examined outcomes were: whether the woman ever had mammography and, if so, whether she had a mammogram within 400 days. Examined predictors were: ethnicity, age, Gail Model risk score, family history, whether the woman knew a young woman with breast cancer, and importance attributed to breast cancer screening. Results: 90.4% of women studied had at least one mammogram. 71.1% underwent screening within 400 days. Rates of ever having mammography were higher for women with family history of breast cancer and Asian, Pacific Islander, Black or Hispanic women. No measured covariate correlated with having mammography within 400 days. Conclusions: One time screening participation was high in this select group of women for whom cost and access barriers were removed, but was lower with regard to having a recent mammogram. Correlates of ever having and recent mammography are not synonymous. J. Surg. Oncol. 2008;97:20–24. 2007 Wiley-Liss, Inc. {

Ongoing cancer vaccine trials are limited by the inability of immunologic assays to monitor clinically relevant surrogates of response. Recent advances in the ability to quantify and phenotype circulating tumor cells (CTCs) in breast cancer patients may lead to a role for CTCs in monitoring response to vaccine-based immunotherapy. The CellSearch System (Veridex-LLC, Warren, NJ) was used to enumerate total and HER2/neu + CTCs in 20 mL of blood from all 16 node-positive (NP) breast cancer patients active in our NP HER2/neu E75 peptide vaccine trial at the initiation of this pilot study. These patients were vaccinated with E75 (1000 μg)/GM-CSF (250 μg) monthly × 6 after completion of multimodality therapy. Mean (±SEM) number of CTCs and HER2/neu + CTCs were compared in unmatched (n = 16) and matched (n = 9) prevaccination and postvaccination cases. CTCs were detected in 14 of 16 (88%) patients (mean: 3.4 ± 0.2 CTC/20 mL). After vaccination, a reduction in CTC/20 mL (prevaccination 3.9 ± 1.5 vs postvaccination 0.7 ± 0.4, P = .077) and HER2/neu + CTC/20 mL (prevaccination 2.8 ± 1.0 vs postvaccination 0.5 ± 0.2, P = .048) was demonstrated. A significant delayed-type hypersensitivity (DTH) response suggesting that vaccination was effective in eliciting a peptide-specific immune response was confirmed (22.3 ± 4.1 vs 3.0 ± 2.2 [controls] mm, P

Heparin/heparan sulfate (Hp/HS)-binding proteins are implicated in a variety of cell biological processes including cell adhesion, modulation of blood coagulation, and cytokine/growth factor action. Hp/HS-interacting protein (HIP) has been identified in various adult tissues in humans. HIP supports high affinity, selective binding to Hp/HS, promotes cell adhesion, and modulates blood coagulation activities via Hp/HS-dependent mechanisms. Herein, a murine ortholog of human HIP is described that is 78.8% identical to human HIP and 99.8% identical at the cDNA level and identical at the amino acid level to a previously described murine ribosomal protein, L29. Western blot analyses and immunohistological staining with affinity-purified antibodies generated against two distinct peptide sequences of murine HIP/L29 indicate that HIP/L29 is differentially expressed in adult murine tissues and cell types. In the normal murine mammary epithelial cell line, NMuMG, HIP/L29 is enriched in the 100,000 × g particulate fraction. HIP/L29 can be solubilized from the 100,000 × g particulate fraction with 0.8 m NaCl, suggesting that it is a peripheral membrane protein. HIP/L29 directly binds 125I-Hp in gel overlay assays and requires 0.75 m NaCl for elution from Hp-agarose. In addition, recombinant murine HIP expressed inEscherichia coli binds Hp in a saturable and highly selective manner, compared with other glycosaminoglycans including dermatan sulfate, chondroitin sulfate, keratan sulfate, and hyaluronic acid. Collectively, these data indicate that murine HIP/L29, like its human ortholog, is a Hp-binding protein expressed in a restricted manner in adult tissues.

22215 Background: HER2/neu is a tumor associated antigen that is over-expressed in several epithelial cancers. HER2/neu-specific immunity can prevent breast cancer in animal models. Immune surveillance against HER2/neu is a potential defense mechanism against cancer and is pursued as immunotherapy of breast cancer. Prior studies demonstrated that peptides from HER2/neu display varying binding affinities to different MHC Class II DR alleles. HLA-DR3 had the lowest affinity for HER2/neu peptides suggesting that DR3+ individuals may have reduced immunosurveillance against HER2/neu and thereby be susceptible to developing HER2/neu related cancers. We hypothesized that the presence of the DR3 allele may predispose patients to develop breast cancer, and if true, might expect to find higher numbers of DR3+ individuals among BrCa patients compared to the general population. Methods: Serologic and molecular testing for HLA-DR3 was performed on 52 HER2/neu+ (IHC 1–3+) breast cancer patients. We compared clinicopath...

3014 Background: We are conducting clinical trials of the HER2/neu E75-peptide vaccine in clinically disease-free breast cancer (BCa) patients. Our Phase I/II trials have shown that the E75+GM-CSF vaccine is safe and effective in stimulating clonal expansion of E75-specific CD8+ T-cells. Since peptide vaccines may not lead to long term immunity, we have assessed the need for and response to a vaccine booster for patients after completion of their primary vaccination series. Methods: BCa patients enrolled in our E75 vaccine trials who were >6 months from the completion of their primary vaccination series were offered a single 1000 mcg dose of E75 peptide with 250 mcg of GM-CSF. Patients were monitored for local and systemic toxicity. E75-specific CD8+ T-cells were quantified using the HLA-A2:IgG dimer before and after booster administration. Results: 19 patients have received the vaccine booster. Median time from primary vaccine series was 12 months (range 6–25) and median residual E75-specific immunity was 0.61% (range 0- 3.43%). Significant residual immunity (SRI=CD8+ E75-specific T-cells >0.5%) was seen in 71% of patients + E75-specific T-cells pre-booster vs. post-booster was 0.37±0.03% vs. 1.06 ± 0.14% (p=0.07). Conclusions: The HER2/neu peptide vaccine E75 stimulates specific immunity in disease-free BCa patients. However, only about half of patients show SRI at median follow-up of 12 months. A vaccine booster is safe and highly effective in stimulating E75-specific immunity especially in those patients without SRI. Initial results suggest that the booster should be given within a year of completion of the initial vaccine series. No significant financial relationships to disclose.