Thyroid cancer incidence has been rising in the United States, and this trend has often been attributed to heightened medical surveillance and the use of improved diagnostics. Thyroid cancer incidence varies by sex and race/ethnicity, and these factors also influence access to and utilization of healthcare. We therefore examined thyroid cancer incidence rates by demographic and tumor characteristics based on 48,403 thyroid cancer patients diagnosed during 1980 -2005 from the Surveillance, Epidemiology and End Results program of the National Cancer Institute. The rates varied by histologic type, sex, and race/ ethnicity. Papillary carcinoma was the only histologic type for which incidence rates increased consistently among all racial/ethnic groups. Subsequent analyses focused on the 39,706 papillary thyroid cancers diagnosed during this period. Papillary carcinoma rates increased most rapidly among females. Between 1992 -1995 and 2003 -2005, they increased nearly 100% among White non-Hispanics and Black females but only 20% to 50% among White Hispanics, Asian/ Pacific Islanders, and Black males. The increases were most rapid for localized stage and small tumors; however, rates also increased for large tumors and tumors of regional and distant stage. Since 1992 -1995, half the overall increase in papillary carcinoma rates was due to increasing rates of very small (V1.0 cm) cancers, 30% to cancers 1.1 to 2 cm, and 20% to cancers >2 cm. Among White females, the rate of increase for cancers >5 cm almost equaled that for the smallest cancers. Medical surveillance and more sensitive diagnostic procedures cannot completely explain the observed increases in papillary thyroid cancer rates. Thus, other possible explanations should be explored. (Cancer Epidemiol Biomarkers Prev 2009;18(3):784 -91)

The identification of antigenic peptides presented on the tumor cell surface by HLA class I molecules and recognized by tumor-specific cytotoxic T lymphocytes may lead to a peptide vaccine capable of inducing protective cellular immunity. We demonstrate that both HLA-A2-restricted breast and ovarian tumor-specific cytotoxic T lymphocytes recognize shared (3) and MART (melanoma antigen recognized by T cells) (4) in melanoma. The discovery of these genes and peptides substantiates the existence of such antigen systems, but unfortunately, melanoma accounts for only 3% of all malignancies and 1% of all cancer deaths (5).HLA-A2 is expressed in approximately 50% of Caucasians (6) and has been demonstrated to play a critical role in antigen presentation of both viral antigens (7) and tumor antigens from a variety of cancers (8-10). HER2/neu is a 185-kDa transmembrane glycoprotein with tyrosine kinase activity and extensive homology to the epidermal growth factor receptor (11). HER2/neu is ubiquitously expressed in many tumors and known to be overexpressed in approximately 30-40% of all ovarian and breast cancers (12).We have shown that tumor-specific CTLs can be demonstrated in the tumor-infiltrating lymphocytes (TILs) isolated from ovarian cancers (13). We have also found that HLA-A2 presents TAA in this disease (14). The level of expression of the HER2/neu oncogene in ovarian cancer positively correlates with recognition by HLA-A2+ ovarian tumor-specific CTLs, and HLA-A2+ melanoma cells transfected with the HER2/neu gene become sensitive to ovarian cancer-specific CTLs (15). Therefore, HLA-A2-presented, HER2/neuderived antigenic peptides may be recognized by ovarian cancer-specific CTLs and, potentially, by breast cancerspecific CTLs as well.In this study, we have searched the HER2/neu sequence (16) for HLA-A2-binding peptides (17), and we have found that both ovarian and breast cancer-specific CTLs recognize a nine-amino acid peptide from the transmembrane portion of the HER2/neu protein (GP2; amino acids 654-662). This peptide is widely expressed in HER2/neu+ tumors and is capable of inducing HLA-A2-restricted, tumor-specific CTL populations in vitro. METHODSGeneration of Tumor-Specific CTLs. Tumor-specific CTLs were generated from fresh tumor specimens obtained through the Departments of Surgery, Gynecologic Oncology, and Pathology at Brigham and Women's Hospital (BWH) and Beth Israel Hospital in Boston, under approval of the Institutional Review Boards. Solid tumor specimens were processed as previously described (14). Briefly, specimens were minced manually and enzymatically digested, and the lymphocytes and tumor cells were separated by centrifugation over discontinuous Ficoll (Organon Teknika-Cappel) gradients. TILs were suspended in RPMI-1640 medium (BioWhittaker) supplemented with 10% fetal calf serum (BioWhittaker) and antibiotics. Cultures were suspended at 5 x 105 cells per ml on solid-phase, anti-CD3 polystyrene plates (Orthoclone OKT3, Ortho Pharmaceuticals) for 48 h. T cells were then mainta...

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NCT00841399, NCT00584789.

This HER2/neu (E75) vaccine is safe and effective in eliciting a peptide-specific immune response in vivo. Induced HER2/neu immunity seems to reduce the recurrence rate in patients with NPBC.

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.Breast cancer is the most common cancer diagnosis in women and the second leading cause of cancer-related death among women.7 Despite advances in standard treatment, a significant proportion of breast cancer patients will ultimately die from recurrent disease, especially aggressive subsets, such as those overexpressing HER2/neu. HER2/neu is a protooncogene expressed in many epithelial malignancies (1). Overexpression of HER2/neu is found in 20% to 25% of breast cancer and confers a poor prognosis (2).Novel approaches are needed to further improve outcomes among breast cancer patients, and one such approach is immunotherapy. Trastuzumab is a monoclonal antibody that targets the HER2/neu protein and is an effective treatment of metastatic breast cancer (3). Several recent large trials have shown that adjuvant trastuzumab decreases recurrence rates compared with chemotherapy alone (4 -6).Another mode of immunotherapy in treating cancer is vaccines. Tumor-associated antigens are proteins expressed by 7 Ries LAG, Harkins D, Krapcho M, et al. (eds.).

BACKGROUND The authors conducted exploratory phase 1–2 clinical trials vaccinating breast cancer patients with E75, a human leukocyte antigen (HLA) A2/A3–restricted HER-2/neu (HER2) peptide, and granulocyte-macrophage colony-stimulating factor. The vaccine is given as adjuvant therapy to prevent disease recurrence. They previously reported that the vaccine is safe and effective in stimulating expansion of E75-specific cytotoxic T cells. Here, they report 24-month landmark analyses of disease-free survival (DFS). METHODS These dose escalation/schedule optimization trials enrolled lymph node-positive and high-risk lymph node-negative patients with HER2 (immunohistochemistry [IHC] 1-3+) expressing tumors. HLA-A2/A3+ patients were vaccinated; others were followed prospectively as controls for recurrence. DFS was analyzed by Kaplan-Meier curves; groups were compared using log-rank tests. RESULTS Of 195 enrolled patients, 182 were evaluable: 106 (58.2%) in the vaccinated group and 76 (41.8%) in the control group. The 24-month landmark analysis DFS was 94.3% in the vaccinated group and 86.8% in the control group (P = .08). Importantly, because of trial design, 65% of patients received a lower than optimal vaccine dose. In subset analyses, patients who benefited most from vaccination (vaccinated group vs control group) had lymph node-positive (DFS, 90.2% vs 79.1%; P = .13), HER2 IHC 1+-2+ (DFS, 94.0% vs 79.4%; P = .04), or grade 1 or 2 (DFS, 98.4% vs 86.0%; P = .01) tumors and were optimally dosed (DFS, 97.3% vs 86.8%; P = .08). A booster program has been initiated; no patients receiving booster inoculations have recurred. CONCLUSIONS The E75 vaccine has clinical efficacy that is more prominent in certain patients. A phase 3 trial enrolling lymph node-positive patients with HER2 low-expressing tumors is warranted.