Faculty Bibliography

Epidemiologic evidence suggests that a full-term pregnancy may affect maternal risk of breast cancer later in life. The objective of this cross-sectional study was to compare circulating levels of maternal hormones affecting breast differentiation (human chorionic gonadotropin and prolactin) and proliferation [alpha-fetoprotein, insulin-like growth factor I (IGF-I), and estradiol] between women at a low to moderate risk (Asians and Hispanics), as compared with women at a high risk for breast cancer (Caucasians and African-Americans). Between May 2002 and December 2004, a total of 586 pregnant women were approached during a routine prenatal visit. Among them, 450 women (206 Caucasian, 126 Asian, 88 Hispanic, and 30 African-American) met the inclusion criteria and signed the informed consent. Only singleton pregnancies were considered. Blood samples were drawn during the second trimester of pregnancy. Laboratory analyses were done using the IMMULITE 2000 immunoassay system. Gestational age standardized mean levels of estradiol, IGF-I, and prolactin were significantly higher in Hispanic women compared with Caucasian women. Mean concentration of IGF-I was significantly higher in African-American women compared with Caucasian and Asian women. No significant differences in pregnancy hormone levels were observed between Caucasian and Asian (predominantly second-generation Chinese) women in this study. Irrespective of ethnicity, women who had their first pregnancy had substantially higher mean levels of alpha-fetoprotein, human chorionic gonadotropin, estradiol, and prolactin compared with women who previously had at least one full-term pregnancy. These data suggest that circulating pregnancy hormone levels may explain some of the ethnic differences in breast cancer risk

With the growing number of epidemiologic publications on the relation between dietary factors and cancer risk, pooled analyses that summarize results from multiple studies are becoming more common. Here, the authors describe the methods being used to summarize data on diet-cancer associations within the ongoing Pooling Project of Prospective Studies of Diet and Cancer, begun in 1991. In the Pooling Project, the primary data from prospective cohort studies meeting prespecified inclusion criteria are analyzed using standardized criteria for modeling of exposure, confounding, and outcome variables. In addition to evaluating main exposure-disease associations, analyses are also conducted to evaluate whether exposure-disease associations are modified by other dietary and nondietary factors or vary among population subgroups or particular cancer subtypes. Study-specific relative risks are calculated using the Cox proportional hazards model and then pooled using a random- or mixed-effects model. The study-specific estimates are weighted by the inverse of their variances in forming summary estimates. Most of the methods used in the Pooling Project may be adapted for examining associations with dietary and nondietary factors in pooled analyses of case-control studies or case-control and cohort studies combined

Fat and cholesterol are theorized to promote ovarian carcinogenesis by increasing circulating estrogen levels. Although case-control studies have reported positive associations between total and saturated fat intake and ovarian cancer risk, two cohort studies have observed null associations. Dietary cholesterol and eggs have been positively associated with ovarian cancer risk. A pooled analysis was conducted on 12 cohort studies. Among 523,217 women, 2,132 incident epithelial ovarian cancer cases were identified. Study-specific relative risks (RR) and 95% confidence intervals (CI) were calculated by Cox proportional hazards models, and then pooled using a random effects model. Total fat intake was not associated with ovarian cancer risk (pooled multivariate RR = 1.08, 95% CI 0.86-1.34 comparing > or =45 to 30-<35% of calories). No association was observed for monounsaturated, polyunsaturated, trans-unsaturated, animal and vegetable fat, cholesterol and egg intakes with ovarian cancer risk. A weakly positive, but non-linear association, was observed for saturated fat intake (pooled multivariate RR = 1.29, 95% CI: 1.01-1.66 comparing highest versus lowest decile). Results for histologic subtypes were similar. Overall, fat, cholesterol and egg intakes were not associated with ovarian cancer risk. The positive association for saturated fat intake at very high intakes merits further investigation

CONTEXT: Inconsistent findings from observational studies have continued the controversy over the effects of dietary fiber on colorectal cancer. OBJECTIVE: To evaluate the association between dietary fiber intake and risk of colorectal cancer. DESIGN, SETTING, AND PARTICIPANTS: From 13 prospective cohort studies included in the Pooling Project of Prospective Studies of Diet and Cancer, 725,628 men and women were followed up for 6 to 20 years across studies. Study- and sex-specific relative risks (RRs) were estimated with the Cox proportional hazards model and were subsequently pooled using a random-effects model. MAIN OUTCOME MEASURE: Incident colorectal cancer. RESULTS: During 6 to 20 years of follow-up across studies, 8081 colorectal cancer cases were identified. For comparison of the highest vs lowest study- and sex-specific quintile of dietary fiber intake, a significant inverse association was found in the age-adjusted model (pooled RR = 0.84; 95% confidence interval [CI], 0.77-0.92). However, the association was attenuated and no longer statistically significant after adjusting for other risk factors (pooled multivariate RR = 0.94; 95% CI, 0.86-1.03). In categorical analyses compared with dietary fiber intake of 10 to <15 g/d, the pooled multivariate RR was 1.18 (95% CI, 1.05-1.31) for less than 10 g/d (11% of the overall study population); and RR, 1.00 (95% CI, 0.85-1.17) for 30 or more g/d. Fiber intake from cereals, fruits, and vegetables was not associated with risk of colorectal cancer. The pooled multivariate RRs comparing the highest vs lowest study- and sex-specific quintile of dietary fiber intake were 1.00 (95% CI, 0.90-1.11) for colon cancer and 0.85 (95% CI, 0.72-1.01) for rectal cancer (P for common effects by tumor site = .07). CONCLUSIONS: In this large pooled analysis, dietary fiber intake was inversely associated with risk of colorectal cancer in age-adjusted analyses. However, after accounting for other dietary risk factors, high dietary fiber intake was not associated with a reduced risk of colorectal cancer

Prospective cohort studies on breast cancer risk among premenopausal women and insulin-like growth factor I (IGF-I) concentrations have so far included only few cases, and have shown inconsistent relative risk estimates. We pooled 220 cases of breast cancer diagnosed before age 50, and 434 control subjects, from three prospective studies in New York (USA), Umea (Northern Sweden) and Milan (Italy), and we measured IGF-I and insulin-like growth factor binding protein 3 (IGFBP-3) with common enzyme-linked immunosorbent assays. Overall, IGF-I and IGFBP-3 measurements obtained by the common method showed a positive but not significant relationship with breast cancer risk (odds ratios (ORs) 0.90 [95% confidence intervals (95% CI) 0.50-1.62], 1.63 [0.89-2.97], 1.46 [0.78-2.73] and 1.41 [0.75-2.63] for quintiles of IGF-I, and ORs 0.98 [0.54-1.75], 1.06 [0.59-1.91], 1.04 [0.58-1.87] and 1.77 [0.97-3.24] for quintiles of IGFBP-3). Our results give only moderate support for an association of blood IGF-I with breast cancer risk in young women

PURPOSE: We performed a phase I study of a day (D) 1 and D4 bortezomib administration once every 2 weeks to determine the recommended phase II dose and toxicity profile, and the extent of 20S proteasome inhibition obtained. PATIENTS AND METHODS: Patients with solid tumors or lymphomas were treated with bortezomib at 0.25 to 1.9 mg/m2 on D1 and D4, every 2 weeks. 20S proteasome levels in blood were assayed at baseline and at 1, 4, and 24 hours postdose in cycle 1. RESULTS: On this D1 and D4 every 2 weeks' schedule, dose-limiting toxicity (DLT) was evident at the 1.75 and 1.9 mg/m2 dose levels, most commonly in patients receiving individual total doses > or = 3.0 mg. The main DLT was peripheral neuropathy evident at the higher doses and in patients previously exposed to neurotoxic agents. Other DLTs included diarrhea and fatigue; grade 3 thrombocytopenia was also noted. Reversible inhibition of 20S proteasome activity was dose dependent and best fit a total dose (mg) per fraction rather than mg/m2; 70% of baseline activity was inhibited by a dose of 3.0 to 3.5 mg given on D1 and on D4 every other week. Antitumor effects short of confirmed partial responses were observed in patients with melanoma, non-small-cell lung cancer, and renal cell carcinoma. CONCLUSION: Bortezomib (PS-341) is a novel antineoplastic agent that is well tolerated at doses not exceeding 3.0 mg (equivalent to 1.75 mg/m2), repeated on D1 and D4 every other week. This dose correlates with 70% inhibition of 20S proteasome activity. DLTs include neuropathy, fatigue, and diarrhea

We report on a prospective study to assess the association of postmenopausal serum levels of sex hormones with subsequent risk of breast carcinoma in situ. We conducted a case-control study nested within the cohort of the New York University Women's Health Study, a large prospective study documenting a positive association of circulating levels of estrogens and androgens with invasive breast cancer. The study included 69 cases of incident in situ carcinoma and 134 individually matched controls. No statistically significant trend of increasing risk with increasing level of any of the hormones was observed. Odds ratios (95% CIs) for the highest tertile relative to the lowest were 1.10 (0.51-2.39) for estradiol, 0.95 (0.41-2.19) for estrone, 1.63 (0.69-3.88) for testosterone, 0.99 (0.44-2.24) for androstenedione, 0.99 (0.45-2.20) for dehydroepiandrosterone sulfate and 0.81 (0.38-1.74) for sex hormone-binding globulin. Adjusting for potential confounders did not materially affect the results, nor did limiting the analysis to the 59 cases of ductal carcinoma in situ, the lesion thought to be the direct precursor of most invasive breast cancers. Our results are at variance with the positive associations observed in this same cohort with risk of invasive breast cancer. Possible explanations for our results include lack of power, an effect of sex hormones limited to the progression from in situ to invasive tumors, overrepresentation of indolent tumors or an effect of sex hormones on the induction of only a subset of in situ tumors, those that would develop into invasive tumors

Circulating insulin-like growth factor-I (IGF-I) and its major binding protein IGF binding protein-3 (IGFBP-3) have been associated with increased risk of premenopausal breast cancer, although risk estimates varied broadly. An extension of a case-control study (138 cases, 259 matched controls) on IGF-I and breast cancer in premenopausal women nested in the New York University Women's Health Study cohort offered the opportunity to address the hypothesis that such variability may have been the result of variations in the ability of different IGFBP-3 assays to specifically measure intact/functional forms of the protein. IGF-I and IGFBP-3 had originally been measured using in-house RIAs. These measurements were repeated using commercially available ELISAs [Diagnostic System Laboratories (DSL), Webster, Texas], and a third ELISA with greater specificity for active forms for IGFBP-3. Pearson's correlations between IGF-I concentrations in the original study and DSL ELISA were very high [r = 0.92; 95% CI, 0.90-0.94]. Correlations with DSL ELISA were much lower for IGFBP-3 (r = 0.58; 0.49-0.66) and even lower still with the assay for functional IGFBP-3 (r = 0.33; 0.20-0.44). IGF-I and IGFBP-3 measurements by the DSL ELISA methods showed statistically significant relationships with risk. The odds ratios (OR) for top versus bottom quartiles were 1.93 (1.00-3.72; P = 0.02) and 2.03 (1.09-3.76; P = 0.02), respectively, in agreement with the original observations. In contrast, measurements of functional IGFBP-3 tended to be unrelated to risk [ORs for the top versus bottom quartile, 0.97 (0.44-2.11)]. The association with IGF-I became substantially weaker and lost statistical significance after adjustment for IGFBP-3 using DSL ELISA, but became considerably stronger when adjusting for the functional IGFBP-3 measurements [OR = 2.43 (1.21-4.90); P = 0.005], or when considering the molar ratio of IGF-I to IGFBP-3 [OR = 2.37 (1.13-5.00); P = 0.02]. These results are consistent with an association of breast cancer risk in young women with elevated IGF-I and IGFBP-3, and show that for IGFBP-3, the strength of such an association could vary substantially depending on the assay used

BACKGROUND: Studies in animals have suggested that calcium may reduce the risk of colorectal cancer. However, results from epidemiologic studies of intake of calcium or dairy foods and colorectal cancer risk have been inconclusive. METHODS: We pooled the primary data from 10 cohort studies in five countries that assessed usual dietary intake by using a validated food frequency questionnaire at baseline. For most studies, follow-up was extended beyond that in the original publication. The studies included 534 536 individuals, among whom 4992 incident cases of colorectal cancer were diagnosed between 6 and 16 years of follow-up. Pooled multivariable relative risks for categories of milk intake and quintiles of calcium intake and 95% confidence intervals (CIs) were calculated. All statistical tests were two-sided. RESULTS: Milk intake was related to a reduced risk of colorectal cancer. Compared with the lowest category of intake (<70 g/day), relative risks of colorectal cancer for increasing categories (70-174, 175-249, and > or =250 g/day) of milk intake were 0.94 (95% CI = 0.86 to 1.02), 0.88 (95% CI = 0.81 to 0.96), and 0.85 (95% CI = 0.78 to 0.94), respectively (P(trend)<.001). Calcium intake was also inversely related to the risk of colorectal cancer. The relative risk for the highest versus the lowest quintile of intake was 0.86 (95% CI = 0.78 to 0.95; P(trend) =.02) for dietary calcium and 0.78 (95% CI = 0.69 to 0.88; P(trend)<.001) for total calcium (combining dietary and supplemental sources). These results were consistent across studies and sex. The inverse association for milk was limited to cancers of the distal colon (P(trend)<.001) and rectum (P(trend) =.02). CONCLUSION: Higher consumption of milk and calcium is associated with a lower risk of colorectal cancer