Kerry Rodabaugh

Vaccination with an NY-ESO-1 peptide of HLA class I/II specificities induces integrated humoral and T cell responses in ovarian cancer.

NY-ESO-1 is a “cancer-testis” antigen expressed in epithelial ovarian cancer (EOC) and is among the most immunogenic tumor antigens defined to date. The NY-ESO-1 peptide epitope, ESO157–170, is recognized by HLA-DP4-restricted CD4+ T cells and HLA-A2- and A24-restricted CD8+ T cells. To test whether providing cognate helper CD4+ T cells would enhance the antitumor immune response, we conducted a phase I clinical trial of immunization with ESO157–170 mixed with incomplete Freunds adjuvant (Montanide ISA51) in 18 HLA-DP4+ EOC patients with minimal disease burden. NY-ESO-1-specific Ab responses and/or specific HLA-A2-restricted CD8+ and HLA-DP4-restricted CD4+ T cell responses were induced by a course of at least five vaccinations at three weekly intervals in a high proportion of patients. There were no serious vaccine-related adverse events. Vaccine-induced CD8+ and CD4+ T cell clones were shown to recognize NY-ESO-1-expressing tumor targets. T cell receptor analysis indicated that tumor-recognizing CD4+ T cell clones were structurally distinct from non-tumor-recognizing clones. Long-lived and functional vaccine-elicited CD8+ and CD4+ T cells were detectable in some patients up to 12 months after immunization. These results confirm the paradigm that the provision of cognate CD4+ T cell help is important for cancer vaccine design and provides the rationale for a phase II study design using ESO157–170 epitope or the full-length NY-ESO-1 protein for immunotherapy in patients with EOC.

Phase I Study of Abagovomab in Patients with Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancer

Purpose: This open-label study assessed the safety and immunogenicity of two doses and two routes of the anti-idiotypic monoclonal antibody abagovomab (formerly ACA125) in patients with epithelial ovarian, fallopian tube, or primary peritoneal cancer. Experimental Design: Eligible patients from the three participating institutions were any stage at diagnosis, had relapsed, and had complete or partial response to additional chemotherapy. Patients were randomized to receive abagovomab at 2.0 versus 0.2 mg and i.m. versus s.c. for four immunizations every 2 weeks and then monthly for two additional immunizations. Planned evaluation included interval physical examinations and laboratory assessments with immune assessment, including HLA typing, human anti-mouse antibody, ELISA, and enzyme-linked immunospot. Patients were required to remain on study until week 10 (the first post-baseline Ab3 determination) to be considered for immunologic assessment. The primary end points were safety and immunogenicity primarily determined by Ab3 response. Results: Forty-two patients received at least one vaccination and were eligible for safety analysis. Thirty-three patients were available for Ab3 analysis (removed for progression of disease, 6; withdrawal of consent, 2; unrelated adverse event, 1). The most common adverse events were self-limited pain at injection site, myalgia, and fever. No hematologic or nonhematologic toxicity grade >2 related to immunization was seen. Ab3 was detectable in all patients (median, 236,794 ng/mL); none of route of administration (P = 0.6268), dose (P = 0.4602), or cohort (P = 0.4944) was statistically significant in terms of effect on maximum post-baseline Ab3 titer. Human anti-mouse antibody was not detectable at baseline but was present in all patients at week 16 (range, 488-45,000 ng/mL). Conclusions: Immunization with abagovomab is well tolerated and induced robust Ab3 responses at the two doses and routes tested. A phase III randomized study with abagovomab (2.0 mg s.c.) is warranted.

Consumption of black tea or coffee and risk of ovarian cancer.

The goal of this study was to investigate the associations between ovarian cancer risk and usual consumption of black tea, regular coffee, or decaffeinated coffee. Using a hospital-based case–control design, participants included 414 women with primary epithelial ovarian, fallopian, or peritoneal cancer and 868 age- and region-matched women with nonneoplastic conditions. All participants completed a comprehensive epidemiologic questionnaire. Black tea consumption was associated with a linear decline in ovarian cancer risk (P for trend 0.03), with individuals consuming two or more cups daily experiencing a 30% decline in risk (adjusted OR 0.70, 95% CI 0.51–0.97). Similar declines were noted among individuals consuming two or more cups of decaffeinated coffee daily (adjusted OR 0.71, 95% CI 0.51–0.99; P for trend 0.002). However, no association was noted between any level of regular coffee consumption and risk of ovarian cancer. The chemoprotective effects of phytochemicals in black tea and decaffeinated coffee may be important, although the effects of phytochemicals in regular coffee may be counteracted by the elevated risk associated with its higher caffeine content.

Regular Analgesic Use and Risk of Endometrial Cancer

Background: Analgesic use has been implicated in the chemoprevention of a number of solid tumors, but thus far, no previous research has focused on the role of aspirin in endometrial cancer etiology. Methods: We conducted a hospital-based case-control study of 427 women with primary, incident endometrial cancer, and 427 age- and residence-matched controls without benign or malignant neoplasms. All participants received medical services at Roswell Park Cancer Institute in Buffalo, NY, and completed a comprehensive epidemiologic questionnaire. Women who reported analgesic use at least once a week for at least 6 months were classified as regular users and served as the reference group throughout the analyses. We used unconditional logistic regression analyses to compute crude and adjusted odds ratios (OR) with corresponding 95% confidence intervals (CI). Results: Compared with nonusers, regular aspirin users were not at reduced risk of endometrial cancer (adjusted OR, 0.91; 95% CI, 0.66-1.26), nor were women with the highest frequency, duration, or cumulative lifetime aspirin use. When the sample was divided by body mass index status, regular aspirin use was not associated with risk among women classified as normal weight or overweight, but a significant risk reduction was seen for obese women (adjusted OR, 0.50; 95% CI, 0.27-0.92). Significant decreases in risk were also observed for obese women with the greatest frequency, duration, and cumulative aspirin use. No significant associations in the overall sample or among obese women were noted for acetaminophen use. Conclusion: We observed no evidence of an overall chemoprotective effect of aspirin on endometrial cancer risk, but the significant risk reductions among obese women warrant further investigation. (Cancer Epidemiol Biomarkers Prev 2005;14(12):2923–8)

Higher regular coffee and tea consumption is associated with reduced endometrial cancer risk.

Several studies have investigated the associations between diet and endometrial cancer, but few have focused specifically on coffee and tea. In a hospital‐based case–control study, we examined the associations between endometrial cancer risk and usual consumption of coffee, decaffeinated coffee, and black tea among 541 women with endometrial cancer and 541 women with an intact uterus but without a cancer diagnosis seen at Roswell Park Cancer Institute (Buffalo, New York) between 1982 and 1998. Daily frequency of consumption of coffee, decaffeinated coffee, and black tea in the few years prior to diagnosis in cases and questionnaire completion in controls was assessed with a self‐administered epidemiologic questionnaire and categorized as none, 0.5 cups/d, 1–2 cups/d and >2 cups/d. Odds ratios (OR) and 95% confidence intervals (CI) for each category referent to nondrinkers were estimated with unconditional logistic regression adjusting for age, endometrial cancer risk factors and each beverage mutually adjusted for other beverages. Compared to nondrinkers, we observed a nonsignificant negative association with endometrial cancer risk among women who reported >2 cups/d regular coffee (OR 0.71, 95% CI 0.49–1.03), a significant inverse association with >2 cups/d black tea (OR 0.56, 95% CI 0.35–0.90) and a significant inverse association with >4 cups/d combined coffee and tea consumption (OR 0.47, 95% CI 0.28–0.80). These findings suggest coffee and tea may be important in reducing endometrial cancer risk.

Higher Intakes of Vegetables and Vegetable-Related Nutrients Are Associated with Lower Endometrial Cancer Risks

A limited number of studies have investigated diet in association with endometrial cancer (EC). We examined the association between intakes of selected food groups and nutrients with EC risk among 541 women with histologically confirmed EC and 541 women with an intact uterus and noncancer diagnoses seen at Roswell Park Cancer Institute between 1982 and 1998. Self-reported dietary and other epidemiologic data were collected by questionnaire. Unconditional logistic regression was used to estimate odds ratios (OR) and 95% CI, adjusting for age, BMI, hormone replacement therapy use, cigarette smoking, lifetime duration of menstruation, and total energy intake. We observed significant inverse associations for women in the highest vs. lowest quartiles of intake of total vegetables (OR, 0.51; 95% CI, 0.34-0.75), vitamin E (OR, 0.44; 95% CI, 0.27-0.70), dietary fiber (OR, 0.60; 95% CI, 0.39-0.94), beta-carotene (OR, 0.55; 95% CI, 0.37-0.82), lutein (OR, 0.52; 95% CI, 0.34-0.78), and folate (OR, 0.57; 95% CI, 0.36-0.91). Our results support that vegetables and related nutrients are associated with decreased risk of EC.

Consideration of hereditary nonpolyposis colorectal cancer in BRCA mutation-negative familial ovarian cancers

Inherited mutations account for approximately 10% of all epithelial ovarian cancers. Breast cancer (BRCA1 and BRACA2) gene mutations are responsible for up to 85% of inherited breast and/or ovarian cancer. Another condition that has been associated with ovarian cancer is hereditary nonpolyposis colorectal cancer syndrome (HNPCC), which carries a lifetime risk of up to 13% for ovarian cancer. The objective of this study was to determine the incidence of HNPCC‐related gene mutations in patients with familial ovarian cancer who previously tested negative for BRCA1 and BRCA2 gene mutations.

Prostate-derived Ets factor is overexpressed in serous epithelial ovarian tumors.

The frequent overexpression of prostate-derived Ets factor (PDEF) mRNA in ovarian cancer has been previously reported. The aim of this study was to evaluate PDEF protein expression in ovarian cancer and how this expression might vary at different stages of epithelial ovarian tumors in comparison to normal ovary. A new rabbit polyclonal antibody to PDEF was prepared, and immunohistochemistry was performed on tissue sections from 12 normal ovaries, 10 cases of benign serous cystadenoma, 17 cases of low malignant potential tumor, 19 cases of stage 1, and 15 cases of advanced stage primary epithelial (serous) ovarian carcinomas and their peritoneal metastases. Expression levels were assessed based on the percentage of positively staining cells and the intensity of staining. All 12 normal ovary and 10 benign serous cystadenoma cases were negative for PDEF expression. In contrast, 6 of 17 (35%) low malignant potential tumors, 5 of 19 (27%) stage 1, and 5 of 15 (33%) advanced stage ovarian tumors stained positive for PDEF expression. Together, these results show frequent overexpression of PDEF protein in epithelial ovarian tumors and its lack of expression in normal ovary and cystadenomas, and this supports a role for PDEF in ovarian tumorigenesis. Furthermore, these results suggest that PDEF is a potential marker and target in ovarian cancer.

Uterine carcinosarcoma associated with hereditary nonpolyposis colorectal cancer.

BACKGROUND: Hereditary nonpolyposis colorectal cancer (HNPCC) was originally described as a genetic disorder predominantly involving colorectal cancer. Numerous neoplasms are known to be associated with this condition. Sarcomas have also been reported within families with HNPCC. The challenge is determining if these cancers are sporadic or hereditary. CASE: We report on a 46-year-old woman with uterine carcinosarcoma and a family history suspicious for HNPCC. Genetic testing identified a germline MLH1 mutation. Immunohistochemistry testing of the carcinosarcoma revealed loss of MLH1 expression with preservation of MSH2 expression. CONCLUSION: The loss of MLH1 protein expression suggests the germline mutation contributed to the development of the carcinosarcoma. Hereditary nonpolyposis colorectal cancer should be included in the differential diagnosis of persons with uterine carcinosarcoma when noted within a family history suspicious for HNPCC.

Antioxidant inhibits tamoxifen-DNA adducts in endometrial explant culture

Fresh human endometrial explants were incubated for 24h at 37 degrees C with either tamoxifen (10-100 micro M) or the vehicle (0.1% ethanol). Three metabolites namely, alpha-hydroxytamoxifen, 4-hydroxytamoxifen, and N-desmethyltamoxifen were identified in the culture media. Tissue size was limited but DNA adducts formed by the alpha-hydroxytamoxifen pathway were detected using authentic alpha-(deoxyguanosyl-N(2)) tamoxifen standards. Relative DNA-adduct levels of 2.45, 1.12, and 0.44 per 10(6) nucleotides were detected following incubations with 100, 25, and 10 micro M tamoxifen, respectively. The concurrent exposure of the explants to 100 micro M tamoxifen with 1mM ascorbic acid reduced the level of alpha-hydroxytamoxifen substantially (68.9%). The formation of tamoxifen-DNA adducts detectable in the explants from the same specimens exposed to 100 micro M tamoxifen with 1mM ascorbic acid were also inhibited. These results support the role of oxidative biotransformation of tamoxifen in the subsequent formation of DNA adducts in this tissue.