Faculty Bibliography

Migrant and experimental animal studies suggest that differences in breast cancer incidence rates may be related, in part, to intake of dietary fat. The experimental evidence indicates that total fat, saturated, and n-6 polyunsaturated fatty acids (PUFAs) may stimulate both mammary tumor growth and metastasis, whereas n-3 PUFAs may have a tumor-inhibiting effect. Overall, epidemiological studies do not appear to confirm such observations. Within a cohort of women in the New York University Women's Health Study, the fatty acid composition of serum phospholipids was analyzed by gas chromatography among 197 pre- and postmenopausal clinically identified breast cancer subjects and their matched controls. Individual fatty acids in serum phospholipids were expressed as a percentage of total fatty acids. No significant difference was observed in the proportion of saturated fatty acids (SFAs), monounsaturated fatty acids, or n-6 and n-3 PUFAs between cases and controls. After menopause, total SFAs were positively associated with the risk of breast cancer [odds ratio (OR) = 1.96, 95% confidence interval (CI): 0.73-5.25; P = 0.05] after adjustment for potential confounding factors. Myristc acid (C14:0) was suggestive of a small increase in breast cancer risk in premenopausal women (OR = 2.22, 95% CI: 0.78-6.31), whereas palmitic acid (C16:0) showed similar trends in postmenopausal women (OR = 2.57, 95% CI: 0.99-6.61). Overall, total PUFAs (n-6 and n-3) were suggestive of a small protective effect (OR = 0.59, 95% CI: 0.31-1.09). No significant associations were found between other fatty acids and the risk of breast cancer. The study suggested evidence of an association between serum levels of SFAs and the risk of breast cancer in postmenopausal women. Neither individual n-3 fatty acids of marine origin, eicosapentaenoic acid (C20:5 n-3), and docosahexaenoic acid (C22:6 n-3), nor n-6 PUFAs were related to cancer risk in this study

Insulin-like growth factor (IGF)-I, a mitogenic and anti-apoptotic peptide, has been implicated in the development of several cancers. We hypothesized that high circulating IGF-I concentrations may be associated with an increased risk of ovarian cancer. A case-control study was nested within 3 prospective cohorts in New York (USA), Umea (Sweden) and Milan (Italy). One hundred thirty-two women with primary invasive epithelial ovarian cancer diagnosed at least 1 year after blood donation were case subjects. For each case, 2 control subjects were selected, matching the case subject on cohort, menopausal status, age and date of recruitment (n = 263). Only women who did not use exogenous hormones at blood donation were included in the study. There was no association between IGF-I concentrations and ovarian cancer risk in the study group as a whole. In analyses restricted to subjects who had developed ovarian cancer at a young age (<55), circulating IGF-I was directly and strongly associated with ovarian cancer risk (OR = 4.97; 95% CI = 1.22-20.2 for the top vs. the bottom IGF-I tertile after adjustment for parity, BMI categories and smoking). There was no significant association of IGF binding protein-3 with ovarian cancer risk. We found a strong direct relationship between circulating IGF-I levels and risk of developing ovarian cancer before age 55. Additional, larger studies of this association are needed to provide more precise estimates of effect

In this study, we validated measurements of free testosterone (fT) and free estradiol (fE(2)) concentrations calculated from total serum concentrations of testosterone (T), estradiol (E(2)), and sex hormone-binding globulin (SHBG), measured by direct, commercial radioimmunoassays, by comparison with reference measurements obtained by dialysis plus an in-house radioimmunoassay after extraction and chromatographic purification. The study was conducted in serum samples from 19 postmenopausal women who were part of an ongoing prospective cohort study. We also performed sensitivity analyses to examine the robustness of the theoretical calculations. Sensitivity analyses showed that in this population, competitive binding of dihydrotestosterone and total T could be ignored in the calculation of fE(2), and competitive binding by dihydrotestosterone does not need to be taken into account for calculation of fT. Furthermore, variations in albumin and SHBG concentrations had negligible effects on fT and fE(2) calculations. Values of fT and fE(2), calculated from total T and E(2) concentrations obtained by the same in-house radioimmunoassay used for the dialysis method, correlated highly with the measurements by dialysis (Pearson's coefficients of correlation above 0.97). When calculating fT and fE(2) using total T and total E(2) concentrations obtained by different direct radioimmunoassays, almost all kits gave good correlations with the reference method for fT (Pearson's r > 0.83), but only a few gave good correlations for fE(2) (Diagnostic System Laboratories and DiaSorin; r > 0.80). The direct radioimmunoassays giving the best correlation for fT and fE(2) with the dialysis method were those that best measured total concentrations of T and E(2). Furthermore, mean values of fT and fE(2) corresponded well to mean values by the reference method if SHBG measurements were also well calibrated. We conclude that in postmenopausal women, theoretical calculations are valid for the determination of fT and fE(2) concentrations and can give reliable estimation of cancer risk in epidemiological studies when the total concentrations of T, E(2), and SHBG are measured accurately

Recently, a number of prospective studies showed evidence that the growth hormone/insulin-like growth factor I (IGF-I) axis may be important in the development of colorectal cancer. However, only a few studies have reported on the possible relationship of colorectal cancer risk with circulating levels of IGF-II, which are not growth hormone dependent and which do not vary with alterations in energy balance. In a case-control study of 102 cases and 200 matched controls nested within a cohort of 14,275 women in New York, we examined the relationship between colorectal cancer risk and prediagnostic serum levels of IGF-II. Conditional logistic regression analysis showed an odds ratio (OR) for colorectal cancer of 2.02 (95% confidence interval (CI): 0.83-4.93), comparing the upper to lower quintile of IGF-II. This association was slightly attenuated after excluding IGF-II measurements in serum samples taken within 1 year before case diagnosis (OR of 1.81; 95% CI: 0.71-4.64) and moderately attenuated after excluding IGF-II measurements in serum samples taken within 2 years before case diagnosis (OR of 1.47; 95% CI: 0.56-3.91). Adjustment for IGF-1, IGF binding protein (BP)-1, IGFBP-3, smoking, or body mass index did not substantially alter the association, whereas adjustment for IGFBP-2 moderately attenuated the relationship. Our results confirm those of three recent case-control studies, and collectively these results suggest a possible increase in colorectal cancer risk among subjects with comparatively elevated serum IGF-II. Mechanisms that might cause the increase in IGF-II levels are unknown but may include loss of parental imprinting of the IGF-II gene

Prostate cancer is the most common male malignancy in western countries. Although primary prevention of prostate cancer is not possible, screening using prostate-specific antigen (PSA) may eliminate prostate cancers by definitive treatments. Prevention of clinically detectable prostate cancer requires earlier chemoprevention interventions. Because prostate cancer is histologically present in 30-50% of 30- to 50-year-old men, effective chemoprevention needs to inhibit not only prostate carcinogenesis but also growth and progression of these cancers. A prostate carcinogenesis animal model has been used to screen chemopreventive agents; inhibitory effects were found with 9-cis-retinoic acid, dehydroepiandrosterone, fluasterone, and the Bowman-Birk inhibitor and an isoflavone mixture which both occur in soy. Such results can be used to select agents for clinical trials. Besides large-scale long-duration prevention trials, trials of short/intermediate duration using smaller cohorts prior to or following radical prostatectomy may provide excellent and cost-effective approaches for chemopreventive agent efficacy testing. Intervention prior to surgery allows measurements of intervention agents and intermediate end-points in the prostate. These peri-surgical trials only assess inhibition of growth and progression of preexisting cancer, not real preventive effects, but they focus on clinically significant cancers. Such trials are an essential step in the development of antiprostate cancer chemoprevention agents

The association between aspirin use and lung cancer risk in women was examined in a case-control study nested in the New York University Women's Health Study, a large cohort in New York. Case subjects were all the 81 incident lung cancer cases who had provided information about aspirin use at enrollment and during the 1994-1996 follow up. Ten controls per case were randomly selected from among study participants who matched a case by age, menopausal status, and dates of enrollment and follow-up. Relative to no aspirin use, the odds ratio for lung cancer (all histological sub-types combined) among subjects who reported aspirin use three or more times per week for at least 6 months was 0.66 (95% confidence interval 0.34-1.28), after adjustment for smoking and education. A stronger inverse association was observed in analyses restricted to non-small cell lung cancer (adjusted odds ratio 0.39, 95% confidence interval 0.16-0.96). These results suggest that regular aspirin use might be inversely associated with risk of lung cancer in women, particularly the non-small cell sub-type

The incidence of ovarian cancer is up to 10 times higher in Western countries than in rural Asia and Africa. One common consequence of a Western lifestyle is the development of excessive body weight and obesity. A multi-centre prospective study was conducted to investigate the association between body mass index (BMI) and ovarian cancer risk. A case-control study was nested within 3 prospective cohorts in New York (USA), Umea (Sweden) and Milan (Italy). Information on anthropometry, demographic characteristics, medical history and lifestyle was obtained at the time of subjects' recruitment in each cohort. Women diagnosed with primary, invasive epithelial ovarian cancer from the 3 cohorts (n = 122) diagnosed 12 months or later after recruitment into the respective cohort served as case subjects. For each case subject, 2 control subjects that matched the case subject on cohort, menopausal status, age and date of recruitment were randomly identified. Data were analyzed by conditional logistic regression. There was an inverse association between BMI and ovarian cancer risk. For increasing quartiles of BMI above the lowest, the ORs were 0.62 (0.32-1.21), 0.59 (0.30-1.17) and 0.46 (0.23-0.92), p = 0.03. Analyses limited to women diagnosed 3 or more years after recruitment into the cohorts did not alter these findings. When obese women (BMI > 30) were compared to lean women (BMI < or = 23), the inverse association became stronger, with an OR of 0.38 (0.17-0.85), p < 0.02. There was some evidence of direct association of ovarian cancer with height, which was limited to cancers diagnosed before age 55. Our data suggest that increasing body weight may confer a protection against ovarian cancer

Background: Reproductive and hormonal factors are involved in the etiology of breast cancer, but there are only a few prospective studies on endogenous sex hormone levels and breast cancer risk. We reanalyzed the worldwide data from prospective studies to examine the relationship between the levels of endogenous sex hormones and breast cancer risk in postmenopausal women. Methods: We analyzed the individual data from nine prospective studies on 663 women who developed breast cancer and 1765 women who did not. None of the women was taking exogenous sex hormones when their blood was collected to determine hormone levels. The relative risks (RRs) for breast cancer associated with increasing hormone concentrations were estimated by conditional logistic regression on case-control sets matched within each study. Linear trends and heterogeneity of RRs were assessed by two-sided tests or chi-square tests, as appropriate. Results: The risk for breast cancer increased statistically significantly with increasing concentrations of all sex hormones examined: total estradiol, free estradiol, non-sex hormone-binding globulin (SHBG)-bound estradiol (which comprises free and albumin-bound estradiol), estrone, estrone sulfate, androstenedione, dehydroepiandrosterone, dehydroepiandrosterone sulfate, and testosterone. The RRs for women with increasing quintiles of estradiol concentrations, relative to the lowest quintile, were 1.42 (95% confidence interval [CI] = 1.04 to 1.95), 1.21 (95% CI = 0.89 to 1.66), 1.80 (95% CI = 1.33 to 2.43), and 2.00 (95% CI = 1.47 to 2.71; Ptrend<.001); the RRs for women with increasing quintiles of free estradiol were 1.38 (95% CI = 0.94 to 2.03), 1.84 (95% CI = 1.24 to 2.74), 2.24 (95% CI = 1.53 to 3.27), and 2.58 (95% CI = 1.76 to 3.78; Ptrend<.001). The magnitudes of risk associated with the other estrogens and with the androgens were similar. SHBG was associated with a decrease in breast cancer risk (Ptrend = .041). The increases in risk associated with increased levels of all sex hormones remained after subjects who were diagnosed with breast cancer within 2 years of blood collection were excluded from the analysis. Conclusion: Levels of endogenous sex hormones are strongly associated with breast cancer risk in postmenopausal women

BACKGROUND: More than 20 studies have investigated the relation between meat and dairy food consumption and breast cancer risk with conflicting results. Our objective was to evaluate the risk of breast cancer associated with meat and dairy food consumption and to assess whether non-dietary risk factors modify the relation. METHODS: We combined the primary data from eight prospective cohort studies from North America and Western Europe with at least 200 incident breast cancer cases, assessment of usual food and nutrient intakes, and a validation study of the dietary assessment instrument. The pooled database included 351,041 women, 7379 of whom were diagnosed with invasive breast cancer during up to 15 years of follow-up. RESULTS: We found no significant association between intakes of total meat, red meat, white meat, total dairy fluids, or total dairy solids and breast cancer risk. Categorical analyses suggested a J-shaped association for egg consumption where, compared to women who did not eat eggs, breast cancer risk was slightly decreased among women who consumed < 2 eggs per week but slightly increased among women who consumed > or = 1 egg per day. CONCLUSIONS: We found no significant associations between intake of meat or dairy products and risk of breast cancer. An inconsistent relation between egg consumption and risk of breast cancer merits further investigation