Faculty Bibliography

A polyvalent melanoma vaccine prepared from shed antigens stimulates humoral and cellular immune responses and improves survival compared with historical controls. We conducted a double-blind, prospectively randomized, placebo-controlled trial to assess whether this vaccine could slow the progression of resected melanoma. Thirty-eight patients with resected melanoma metastatic to regional nodes (American Joint Committee on Cancer stage III) who had a particularly poor prognosis on the basis of the nodes being clinically positive or two or more histologically positive nodes were randomly assigned in a 2:1 ratio to treatment with 40 microg of melanoma or placebo (human albumin) vaccine, both of which were bound to alum as an adjuvant. Immunizations were given intradermally into the extremities every 3 weeks x 4, monthly x 3, every 3 months x 2, and then every 6 months for 5 years or until disease progression. Twenty-four patients were treated with the melanoma, and 14 patients were treated with the placebo vaccine. The groups were evenly balanced with respect to prognostic factors. Median length of observation was 2.5 years. There was no local or systemic toxicity. By Kaplan-Meier analysis, median time to disease progression was two and a half times longer in patients treated with melanoma vaccine compared with that in patients treated with placebo vaccine, i.e., 1.6 years (95% confidence interval, 1.0-3.0 years) compared with 0.6 year [95% confidence interval, 0.3-1.9 year(s)]. By Cox proportional hazards analysis, this difference was significant at P = 0.03. Overall survival was 40% longer in the melanoma vaccine-treated group (median overall survival of 3.8 years versus 2.7 years), but this difference was not statistically significant. In a double-blind and placebo-controlled trial, these results suggest that immunization with a melanoma vaccine may be able to slow the progression of melanoma. Although statistically significant, these results must be interpreted with caution because they are based on a small number of patients

In large-scale epidemiological studies on endogenous sex steroids and cancer risk, direct immunoassays of circulating hormone levels have the advantage of being fast and comparatively inexpensive while requiring only small sample volumes. On the other hand, indirect assays after organic extraction and chromatographic prepurification have the advantage of reducing specific interferences and matrix effects and hence are thought to have better validity. We compared direct assays of testosterone (T, six different assays), Delta4-androstenedione (A, four assays), estrone (E(1), one assay), and 17beta-estradiol (E(2), five assays) with measurements obtained by an indirect assay in a representative subset of 20 postmenopausal women who were part of a large prospective cohort study. Within-batch reproducibilities of the subject rankings by relative hormone levels were good (intraclass correlations >0.89) for all direct assays tested. Between batches, reproducibilities generally were also acceptable (r > 0.80) to good (r > 0.90) in terms of Pearson's correlations. The between-batch reproducibility in terms of intraclass correlations was systematically lower in terms of Pearson's correlations, however, because of between-batch variations in the absolute scale of measurements. The relative validity of direct versus indirect assays in terms of the subjects' ranking by relative hormone levels was also high for most of the kits tested for T, A, and E(1) (Pearson's correlations between 0.70 and 0.89) but was high for only two kits of five tested for E(2) (correlations of 0.86 and 0.84). On an absolute scale, mean measurement values were generally higher for direct assays than for the indirect assay and, for each hormone, varied substantially, depending on the kit used. Overall, the results of this study show that, with careful selection, commercial kits for direct radioimmunoassays of steroid hormones in postmenopausal serum can be found that may allow a reliable estimation of relative risks in epidemiological studies. However, standardization of the absolute scale of assays remains problematic

Recently, there has been interest in whether intakes of specific types of fat are associated with breast cancer risk independently of other types of fat, but results have been inconsistent. We identified 8 prospective studies that met predefined criteria and analyzed their primary data using a standardized approach. Holding total energy intake constant, we calculated relative risks for increments of 5% of energy for each type of fat compared with an equivalent amount of energy from carbohydrates or from other types of fat. We combined study-specific relative risks using a random effects model. In the pooled database, 7,329 incident invasive breast cancer cases occurred among 351,821 women. The pooled relative risks (95% confidence intervals [CI]) for an increment of 5% of energy were 1.09 (1.00-1.19) for saturated, 0.93 (0.84-1.03) for monounsaturated and 1.05 (0.96-1.16) for polyunsaturated fat compared with equivalent energy intake from carbohydrates. For a 5% of energy increment, the relative risks were 1.18 (95% CI 0.99-1.42) for substituting saturated for monounsaturated fat, 0.98 (95% CI 0.85-1.12) for substituting saturated for polyunsaturated fat and 0.87 (95% CI 0.73-1.02) for substituting monounsaturated for polyunsaturated fat. No associations were observed for animal or vegetable fat intakes. These associations were not modified by menopausal status. These data are suggestive of only a weak positive association with substitution of saturated fat for carbohydrate consumption; none of the other types of fat examined was significantly associated with breast cancer risk relative to an equivalent reduction in carbohydrate consumption

OBJECTIVE: To investigate the usefulness of serum carotenoids as biomarkers of fruit and vegetable consumption. DESIGN:: Reproducibility study on three repeat measurements of serum carotenoids. Correlation analysis of carotenoids and dietary food intake, and regression analysis of potential predictive parameters for serum carotenoid levels. SETTING: New York, USA. SUBJECT:: Women participating in the New York Women's Health Study, a prospective study of sex hormones, diet and breast cancer. Forty-eight women with three repeat blood samples and 302 women having a blood sample and a dietary history questionnaire (including 47 subjects from the reproducibility study). RESULTS: Serum carotenoid concentrations were highly reproducible between one- and two-year repeat samples. Estimated fruit and vegetable consumption was positively correlated with serum carotenoid concentrations but correlation coefficients were low. Consumption of fruit was predictive for serum levels of beta-carotene, alpha-carotene and beta-cryptoxanthin, while vegetable consumption was predictive for serum beta-carotene, lutein, zeaxanthin and lycopene. Serum concentrations of cholesterol and triglycerides were predictive for serum carotenoids but adjustment for their levels had little or no influence on the correlation between fruit and vegetable consumption and serum carotenoid concentrations. CONCLUSIONS: One single serum measurement of alpha-carotene, beta-carotene and lutein can accurately rank subjects according to their usual serum level. Serum concentrations, however, correlate only moderately with estimated dietary intake of fruits or vegetables and should therefore be used with caution as biomarkers of fruit and vegetable intake

We assessed the association of postmenopausal serum levels of oestrogens and sex hormone-binding globulin (SHBG) with endometrial cancer risk in a case-control study nested within the NYU Women's Health Study cohort. Among 7054 women postmenopausal at enrolment, 57 cases of endometrial cancer were diagnosed a median of 5.5 years after blood donation. Each case was compared to 4 controls matched on age, menopausal status at enrolment, and serum storage duration. Endometrial cancer risk increased with higher levels of oestradiol (odds ratio = 2.4 in highest vs lowest tertile, P for trend = 0.02), percent free oestradiol (OR = 3.5, P< 0.001), and oestrone (OR = 3.9, P< 0.001). Risk decreased with higher levels of percent SHBG-bound oestradiol (OR = 0.43, P = 0.03) and SHBG (OR = 0.39, P = 0.01). Trends remained in the same directions after adjusting for height and body mass index. A positive association of body mass index with risk was substantially reduced after adjusting for oestrone level. Our results indicate that risk of endometrial cancer increases with increasing postmenopausal oestrogen levels but do not provide strong support for a role of body mass index independent of its effect on oestrogen levels.

This article discusses the basic elements of chemoprevention trial designs using cohorts of men following radical prostatectomy who either have prostate-specific antigen (PSA) failure indicative of recurrence or are at high risk for recurrence (positive surgical margins, extracapsular extension, seminal vesicle invasion, positive lymph nodes, Gleason score of greater than or equal to 8, preoperative serum PSA less than 20 ng/mL). Two ongoing randomized, double-blind, placebo-controlled clinical trials with soy protein as intervention in these 2 populations are described. In the trial with men at high risk for recurrence, participants started intervention within 4 months after surgery and were followed for up to 2 years; primary endpoints were PSA failure rate and time-to-PSA failure. In the trial with men with PSA failure (PSA 0.1 to 2.0 ng/mL), participants received treatment for 8 months and the primary endpoint is rise in PSA over time. The strengths and limitations of these designs are discussed and interim experience using studies with soy protein as the intervention agent are summarized

CONTEXT: Some epidemiologic studies suggest that elevated fruit and vegetable consumption is associated with a reduced risk of breast cancer. However, most have been case-control studies in which recall and selection bias may influence the results. Additionally, publication bias may have influenced the literature on associations for specific fruit and vegetable subgroups. OBJECTIVE: To examine the association between breast cancer and total and specific fruit and vegetable group intakes using standardized exposure definitions. DATA SOURCES/STUDY SELECTION: Eight prospective studies that had at least 200 incident breast cancer cases, assessed usual dietary intake, and completed a validation study of the diet assessment method or a closely related instrument were included in these analyses. DATA EXTRACTION: Using the primary data from each of the studies, we calculated study-specific relative risks (RRs) that were combined using a random-effects model. DATA SYNTHESIS: The studies included 7377 incident invasive breast cancer cases occurring among 351 825 women whose diet was analyzed at baseline. For comparisons of the highest vs lowest quartiles of intake, weak, nonsignificant associations were observed for total fruits (pooled multivariate RR, 0.93; 95% confidence interval [CI], 0.86-1.00; P for trend =.08), total vegetables (RR, 0.96; 95% CI, 0.89-1.04; P for trend =.54), and total fruits and vegetables (RR, 0.93; 95% CI, 0.86-1.00; P for trend =.12). No additional benefit was apparent in comparisons of the highest and lowest deciles of intake. No associations were observed for green leafy vegetables, 8 botanical groups, and 17 specific fruits and vegetables. CONCLUSION: These results suggest that fruit and vegetable consumption during adulthood is not significantly associated with reduced breast cancer risk

Insulin-like growth factor I (IGF-I) is a systemic hormone with potent mitogenic and anti-apoptotic properties, which could influence the proliferative behavior of normal breast cells. Limited epidemiological observations suggest that the hormone may play a role in the etiology of breast cancer, especially at pre-menopausal ages. In a prospective case-control study nested within a cohort of New York City women, IGF-I, IGF-binding protein 3 (IGFBP-3) and C peptide were measured in frozen serum samples from 172 pre-menopausal and 115 post-menopausal subjects who were subsequently diagnosed with breast cancer. Subjects were eligible if diagnosed 6 months or more after recruitment into the study (7 to 120 months). Cohort members who matched the cases on age, menopausal status, date of blood sampling and day of menstrual cycle at blood collection served as controls. Post-menopausal breast cancer was not associated with serum IGF-I, IGFBP-3 or C-peptide levels. However, the risk of breast cancer increased with increasing serum concentrations of IGF-I in pre-menopausal women. The odds ratio (OR) for the highest quartile of IGF-I (>256 ng/ml) compared to the lowest (<168 ng/ml) was 1.60 [95% confidence interval (CI) 0.91-2. 81]. The OR decreased to 1.49 (95% CI 0.80-2.79) after adjustment for IGFBP-3. In analyses restricted to subjects who were pre-menopausal at the time of blood sampling and whose cancer was diagnosed before age 50, the top vs. bottom quartile OR increased appreciably to 2.30 (95% CI 1.07-4.94). Adjustment for IGFBP-3 reduced the OR to 1.90 (95% CI 0.82-4.42). There was no association between pre-menopausal breast cancer and IGFBP-3, IGF-I:IGFBP-3 ratio or non-fasting levels of C peptide. Elevated circulating levels of IGF-I may be an indicator of increased risk of breast cancer occurring before age 50

The lack of tumor models that can reliably predict for response to anticancer agents remains a major deficiency in the field of experimental cancer therapy. Although heterotransplants of certain human solid tumors can be successfully grown in nude mice, they have never been appropriately explored for prediction of in vivo chemosensitivity to anticancer agents. We determined the tumor response rate and studied the influence of several biological and molecular tumor parameters on the in vivo sensitivity to paclitaxel in a series of heterotransplanted human non-small cell lung cancer (NSCLC) tumors. One hundred consecutive resected NSCLC tumors were heterotransplanted s.c. in nude mice. The in vivo sensitivity to i.v. paclitaxel (60 mg/kg every 3 weeks) was studied in 34 successfully grown heterotransplants. Treatment started when the tumors reached a size of 5 mm in diameter, and strict standard clinical criteria (>50% shrinkage in tumor weight or cross-sectional surface) were used to define tumor response. Baseline multidrug resistance protein (MRP), Her-2/neu, and epidermal growth factor receptor (EGFR) expression, and pre- and posttherapy bax and bcl-2 expression were determined by Western blot analysis. p53 status was determined by sequencing. The overall take rate was 46% (95% confidence interval, 36-56%) and was significantly higher (P < 0.05) for squamous carcinoma tumors (75%) than for adenocarcinoma tumors (30%) and bronchoalveolar tumors (23%). The heterotransplants were morphologically very similar to the original tumors. The response rate to paclitaxel was 21% (95% confidence interval, 9-38%). Baseline tumor parameters associated with response were no Her-2/neu expression (none of the responding tumors expressed Her-2/neu versus 48% of the nonresponding tumors, P = 0.05) and baseline bcl-2 expression (all responding tumors expressed bcl-2 versus only 43% of the nonresponding tumors, P = 0.02). There was a trend toward a higher response rate in bax-positive tumors, and MRP- and EGFR-negative tumors, but it was not statistically significant. The response was independent of baseline p53 status and baseline mitotic index. Responding tumors had a higher bax/bcl-2 ratio 24 h after therapy, but the difference was only marginally significant (2.8 for responding tumors versus 1.1 for nonresponding tumors, P = 0.07). The extent of mitotic arrest at 24 h after therapy was not associated with response. Human NSCLC heterotransplants are morphologically identical to the original tumors and have a response rate to paclitaxel that is equivalent to that reported in Phase II studies in patients with advanced NSCLC treated with single-agent paclitaxel. NSCLC heterotransplants deserve to be explored to evaluate new agents for lung cancer and to predict clinical response on an individual basis in selected groups of patients

BACKGROUND: Leading a Western lifestyle, being overweight, and being sedentary are associated with an increased risk of colorectal cancer. Recent theories propose that the effects of these risk factors may be mediated by increases in circulating insulin levels and in the bioactivity of insulin-like growth factor (IGF)-I. To test this hypothesis, we conducted a case-control study nested within a cohort of 14 275 women in New York. METHODS: We used blood samples that had been obtained from these women from March 1985 through June 1991 and stored in a biorepository. C-peptide (a marker for insulin secretion), IGF-I, and IGF-binding proteins (IGFBPs)-1, -2, and -3 were assayed in the serum of 102 women who subsequently developed colorectal cancer and 200 matched control subjects. Logistic regression was used to relate cancer risk to these peptide levels, by adjustment for other risk factors. All statistical tests used are two-sided. RESULTS: Colorectal cancer risk increased with increasing levels of C-peptide (P:(trend) =.001), up to an odds ratio (OR) of 2. 92 (95% confidence interval [CI] = 1.26-6.75) for the highest versus the lowest quintiles, after adjustment for smoking. For colon cancer alone (75 case subjects and 146 control subjects), ORs increased up to 3.96 (95% CI = 1.49-10.50; P:(trend) <.001) for the highest versus the lowest quintiles. A statistically significant decrease in colorectal cancer risk was observed for increasing levels of IGFBP-1 (P:(trend) =.02; OR in the upper quintile = 0.48 [95% CI = 0.23-1. 00]), as well as for the highest quintile of IGFBP-2 levels (P:(trend) =.06; OR = 0.38 [95% CI = 0.15-0.94]). Colorectal cancer risk showed a modest but statistically nonsignificant positive association with levels of IGF-I and was statistically significantly increased for the highest quintile of IGFBP-3 (OR = 2.46 [95% CI = 1. 09-5.57]). CONCLUSIONS: Chronically high levels of circulating insulin and IGFs associated with a Western lifestyle may increase colorectal cancer risk, possibly by decreasing IGFBP-1 and increasing the bioactivity of IGF-I