Guest guest Posted January 8, 2005 Report Share Posted January 8, 2005 Hi All, It seems to me to be that the pdf-available paper below is telling us to eat our fruit and vegetables to avoid breast cancer for the ladies. BMI was apparently not a factor and was controlled for. Not only, as stated in the abstract, was the nodal spread form of the cancers more susceptible to association with less alpha-carotene, the differentiated tumor cells were more susceptible. For the odds ratio of breast cancer with differentiated cells, the values were well differentiated, 1.45; moderately differentiated, 0.74; and poorly differentiated, 0.40. This was when the highest versus lowest quintile of alpha-carotene was examined. Lycopene and beta-cryptoxanthin not being associated with breast cancer reduced the total carotenoid relative risk. Retinol had a highest versus lowest quintile odds ratio of 0.78. These values for alpha- and gamma-tocopherols were 0.79 and 0.96, respectively. These values, as for those of lycopene and retinol, were not significant statistically. I believe, that the bottom line is eat your vegetables. The results fail to match the epidemiological studies showing a five-fold variation of breast cancer in different countries. More studies are needed, as they? Tamimi RM, Hankinson SE, Campos H, Spiegelman D, Zhang S, Colditz GA, Willett WC, Hunter DJ. Plasma Carotenoids, Retinol, and Tocopherols and Risk of Breast Cancer. Am J Epidemiol. 2005 Jan 15;161(2):153-160. PMID: 15632265 [PubMed - as supplied by publisher] The roles of carotenoids, retinol, and tocopherols in breast cancer etiology have been inconclusive. The authors prospectively assessed the relations between plasma alpha-carotene, beta-carotene, beta-cryptoxanthin, lycopene, lutein/zeaxanthin, retinol, alpha-tocopherol, and gamma-tocopherol and breast cancer risk by conducting a nested case-control study using plasma collected from women enrolled in the Nurses' Health Study. A total of 969 cases of breast cancer diagnosed after blood draw and prior to June 1, 1998, were individually matched to controls. The multivariate risk of breast cancer was 25- 35% less for women with the highest quintile compared with that for women with the lowest quintile of alpha-carotene (odds ratio (OR) = 0.64, 95% confidence interval (CI): 0.47, 0.88; p(trend) = 0.01), beta-carotene (OR = 0.73, 95% CI: 0.53, 1.02; p(trend) = 0.01), lutein/zeaxanthin (OR = 0.74, 95% CI: 0.55, 1.01; p(trend) = 0.04), and total carotenoids (OR = 0.76, 95% CI: 0.55, 1.05; p(trend) = 0.05). The inverse association observed with alpha-carotene and breast cancer was greater for invasive cancers with nodal metastasis. The authors conclude that some carotenoids are inversely associated with breast cancer. Although the association was strongest for alpha-carotene, the high degree of collinearity among plasma carotenoids limits our ability to conclude that this association is specific to any individual carotenoid. Incidence rates for breast cancer vary by more than five-fold worldwide, suggesting that environmental and lifestyle factors are important in the etiology of breast cancer (1). Migration studies indicate that offspring of women moving from countries of low incidence to countries of high inci-dence acquire the high breast cancer rates of the new country (2, 3). Such evidence has motivated research on diet and breast cancer. The relation of vegetable consumption to risk of breast cancer has been investigated in numerous epidemiologic studies, with inconsistent results. The majority of case-control studies have found an inverse association (4–10), while cohort studies report more modest and null associa- tions (11–16). Fruits and vegetables contain bioactive substances including carotenoids, which may exhibit anti-carcinogenic effects (17). ... MATERIALS AND METHODS Study design and population The Nurses' Health Study started in 1976, when 121,700 US registered nurses between the ages of 30 and 55 years returned an initial questionnaire. Every 2 years, information on reproductive variables, cigarette smoking, postmeno-pausal hormone use, and dietary information (in 1980, 1984, 1986, 1990, 1994, and 1998) was collected. Incident breast cancer cases were identified through self-report and were confirmed by medical record review. Histopathologic char-acteristics of breast tumors were obtained from medical records when available. Between 1989 and 1990, blood samples were collected from 32,826 women. Blood samples were returned within 26 hours of being drawn; immediately centrifuged; aliquoted into plasma, red blood cells, and buffy coat fractions; and stored in liquid nitrogen freezers main-tained at –130 °C or colder. Follow-up for this subcohort has been greater than 96 percent for all questionnaire cycles. This study was approved by the Committee on Human Subjects at Brigham and Women's Hospital. Eligible cases in this study consisted of women with pathologically confirmed, incident invasive and in situ breast cancer from the subcohort of women who returned a blood sample and were diagnosed by June 1, 1998. Cases were excluded if they had any other prior cancer diagnosis except for nonmelanoma skin cancer. Controls were randomly selected from the subcohort of women who returned a blood sample and never reported a diagnosis of cancer (except for nonmelanoma skin cancer) up to and including the 2-year interval during which the case was diagnosed. Controls were matched to cases on year of birth, menopausal status, post-menopausal hormone use, and time of day, month, and fasting status at the time of blood draw. Although blood draw characteristics are unlikely to confound the plasma micronutrient-breast cancer relation, matching on these characteristics was necessary for analyses involving other plasma biomarkers in this nested case-control study. There were 974 eligible cases and 973 controls with plasma micro-nutrient data. Because of the following laboratory issues, a total of nine samples were left unmatched and were dropped from the matched analyses: six lost during extraction, two not received by the laboratory, and one with invalid data possibly due to oxidation. This nested case-control study consists of 969 matched pairs for which plasma carotenoids, retinol, and tocopherols were prospectively collected. ... RESULTS The mean age of women in this study was 57 (standard deviation, 7) years, with a range from 43 to 70 years. There were 418 (cases = 206) premenopausal and 1,329 (cases = 666) postmenopausal women at blood draw, with mean ages of 48.5 (standard deviation, 3) years and 61 (standard devia-tion, 5) years, respectively. Blood samples were collected from 4 months to 9 years prior to diagnosis (median = 4 years). Cases and controls had the same mean body mass index at blood draw (25 kg/m 2 ). Compared with controls, cases had nonsignificantly earlier age at menarche (12.5 vs. 12.6 years), lower mean parity (2.89 vs. 2.97), and older mean age at first birth (25.1 vs. 24.9 years) among parous women. Cases had a later mean age of menopause (48.2 vs. 47.7 years, p = 0.01), higher prevalence of family history of breast cancer (21.0 vs. 13.6 percent, p = 0.001), and more frequent history of benign breast disease (64.6 vs. 52.5 percent, p = 0.001) compared with controls. The median values and range of plasma micronutrient concentrations are presented in table 1. For all of the micro- nutrients assayed, median concentrations were higher in the controls compared with the cases, although none of the differences was statistically different. In conditional logistic regression analyses, significant inverse associations were observed between alpha-carotene (linear p trend = 0.03) and beta--carotene (linear p trend = 0.02) and risk of breast cancer (table 2), although the inverse trends were primarily due to lower odds ratios in the highest quin-tiles (alpha-carotene: odds ratio (OR) = 0.75, 95 percent confi-dence interval (CI): 0.56, 1.00; beta--carotene: OR = 0.74, 95 percent CI: 0.56, 1.00). After adjustment for breast cancer risk factors, these inverse trends remained significant. Women with the highest quintile of alpha-carotene had 35 percent lower risk of breast cancer compared with women with the lowest quintile (OR = 0.64, 95 percent CI: 0.47, 0.88). Women with the highest quintile of lutein/zeaxanthin (OR = 0.74, 95 percent CI: 0.55, 1.01; linear p trend = 0.04) and total carotenoids (OR = 0.76, 95 percent CI: 0.55, 1.05; linear p trend = 0.05) had an approximately 25 percent lower risk of breast cancer compared with women with the lowest quintile. Upon adjustment for alpha-carotene, inverse associations with breast cancer observed with respect to the highest quintiles of beta--carotene and lutein/zeaxanthin were attenuated, and the inverse trends were abolished. The odds ratio comparing the highest quintile of alpha-carotene with the lowest remained unchanged after mutual adjustment for all of the other nutri- tional factors, although the confidence interval did include one (OR = 0.62, 95 percent CI: 0.38, 1.02). Plasma folate is considered a possible protective factor for breast cancer (40) and, thus, a potential confounder of the micronutrient-breast cancer relation. Plasma folate levels were available for cases diagnosed through June 1, 1996, and their matched controls. Adjustment for plasma folate levels resulted in no appreciable change in relative risks for the carotenoids and tocopherols. Because vitamin E and most carotenoids are transported in the blood by lipoproteins, accounting for cholesterol level in the analysis is thought to provide results unconfounded by blood lipid concentrations (41). Information on serum cholesterol levels was available on cases diagnosed through June 1, 1996, and their matched controls. Inclusion of total cholesterol in multivariate models resulted in no appreciable difference in odds ratios, and it was not included in the final models. Studies of dietary intake of carotenoids, retinol, and tocopherol and breast cancer suggested that the effect of these nutritional factors on breast cancer risk differs according to menopausal status and may be more pronounced among premenopausal women (42). In this nested case-control study, there were only 102 premeno-pausal breast cancer cases, and we were underpowered to draw any conclusions regarding these micronutrients and breast cancer risk in these women. Multivariate comparisons of highest with lowest quintiles of plasma nutrients among only premenopausal women did not suggest a more pronounced effect on breast cancer risk. Statistical tests of interaction revealed that the associations between plasma nutrients and breast cancer were not statistically different for premenopausal women compared with postmenopausal women; therefore, the analyses are not stratified by meno-pausal status. To assess if preclinical disease may have affected plasma micronutrient levels (23), we excluded 161 cases diagnosed within 2 years of the date of blood collection and their matched controls. Multivariate results were essentially unchanged (e.g., comparison of the top quintile with the bottom: alpha-carotene: OR = 0.62, 95 percent CI: 0.43, 0. 88; linear p trend = 0.009; beta--carotene: OR = 0.74, 95 percent CI: 0.52, 1.07; linear p trend = 0.02). When analyses were limited to invasive breast cancer cases only (n = 776) and their matched controls, multivariate risks for women with the highest quintile compared with those with the lowest quintile were 0.64 (95 percent CI: 0.45, 0.93; linear p trend = 0.01) for alpha-carotene and 0.72 (95 percent CI: 0.50, 1.05; linear p trend = 0.03) for beta--carotene. Exogenous factors that contribute to oxidative stress in populations include smoking (43) and alcohol consumption (18). Individuals exposed to high levels of oxidative stress may benefit to a greater extent by increased plasma levels of antioxidants. There was weak evidence that smoking may modify the risk of breast cancer associated with plasma alpha-carotene (test for interaction: p = 0.10 (LRT ord )). In multi-variate analyses, alpha-carotene was inversely associated with breast cancer among never smokers (OR = 0.5, 95 percent CI: 0.3, 0.8; linear p trend = 0.01) and past smokers (OR = 0.6, 95 percent CI: 0.3, 0.9; linear p trend = 0.005) but not among current smokers (OR = 0.9, 95 percent CI: 0.3, 2.6; linear p trend = 0.30). An increased risk of breast cancer associated with drinking six or more alcoholic drinks per week tended to be restricted to women with the lowest quintiles of plasma micronutri-ents, although lutein/zeaxanthin was the only one exhibiting a significant inverse trend in risk among moderate drinkers (test for interaction: p = 0.06 (LRT ord ); linear p trend = 0.03). Among women with the lowest quintile of lutein/zeaxanthin, those who consumed six or more drinks per week had a 60 percent increased risk of developing breast cancer compared with women who drank less (OR = 1.6, 95 percent CI: 0.8, 3.1). Some carotenoids and vitamin E may also inhibit prolifer-ation and tumor progression (23), and oxidative stress may be associated with metastasis (44). alpha-carotene (linear p trend = 0.002) (table 3), beta--carotene (linear p trend = 0.002), retinol (linear p trend = 0.03), and a -tocopherol (linear p trend = 0.01) levels were associated with a significant decreased risk of breast cancer with nodal metastasis. In multivariate analyses, women with the highest quintile of alpha-carotene (OR = 0.39, 95 percent CI: 0.22, 0.71) (table 3), beta--carotene (OR = 0.45, 95 percent CI: 0.24, 0.82), and a -tocopherol (OR = 0.53, 95 percent CI: 0.30, 0.93) were more than 50 percent less likely to have breast cancer with nodal metastases compared with women with the lowest. In comparison, the nutritional factors were not significantly associated with risk of invasive breast cancer with no nodal metastases. The associations between alpha-carotene (LRT, p = 0.02), beta--carotene (LRT, p = 0.05), and a -tocopherol (LRT, p = 0.03) and breast cancer risk were different for node-positive cancers compared with node-negative cancers. Odds ratios for the association between these micronutrients and invasive cancers involving metastasis were similar when the outcome was restricted to breast cancer metastasis with four or more nodes. In addition, we investigated the relation of alpha-carotene with pathohistologic characteristics of breast cancer tumors in multivariate analyses. alpha-carotene was not associated with tumors characterized as well differentiated, but it was marginally associated with moderately differentiated tumors and significantly associated with poorly differentiated tumors (table 3). The inverse association with alpha-carotene was apparent for estrogen receptor-positive and -negative tumors (table 3). In Western populations, the primary source of alpha-carotene in the diet is carrots. In this study, carrot consumption was marginally associated with a decreased risk of breast cancer. Women consuming carrots on average at least once a day had a 35 percent decreased risk of breast cancer compared with women who consumed carrots less than once a month (multivariate OR = 0.63, 95 percent CI: 0.34, 1.15; linear p trend = 0.03). DISCUSSION To date, this is the largest study to prospectively evaluate the major plasma carotenoids, tocopherols, and retinol with respect to breast cancer risk. We observed a 35 percent reduced risk of breast cancer for women with the highest quintile of alpha-carotene. In addition, there was evidence that alpha-carotene had a more pronounced inverse association with breast cancers with nodal metastasis. Early studies, which focused on plasma beta--carotene, retinol, and breast cancer, have been largely inconclusive (25–29). More recently, three studies have prospectively evaluated other carotenoids and tocopherols in relation to breast cancer risk (31, 32, 45). Dorgan et al. (45), reporting on 105 cases, found a significant inverse association with lycopene only. In contrast, Toniolo et al. (32), reporting on 270 cases, found no inverse relation with lycopene levels but found significant inverse associations for alpha-carotene, beta-- carotene, beta--cryptoxanthin, lutein, and total carotenoids. Sato et al. (31) reported results for two separate blood donation cohorts whose results were different from one another. In one cohort comprising 244 cases, beta--carotene, lycopene, and total carotenoids were inversely associated with breast cancer, yet these associations were not observed in the second cohort comprising 115 cases. This study was able to assess factors that may modify the relation between plasma micronutrients and breast cancer. Smoking and alcohol consumption are two environmental factors believed to contribute to oxidative stress. There was evidence that smoking status may modify the association between plasma alpha-carotene and breast cancer. Contrary to our a priori hypothesis, the results suggest that the inverse association observed between alpha-carotene and breast cancer is limited to former and never smokers. There was also evidence that the lutein/zeaxanthin relation with breast cancer may differ according to alcohol consump-tion. Consumption of alcohol is considered a well-estab-lished, yet modest risk factor for breast cancer (46). Our data suggest that the observed increased risk of breast cancer associated with consuming high levels of alcohol may be limited to women with low levels of lutein/zeaxanthin. Zhang et al. (42) observed an interaction between alcohol consumption and lutein/zeaxanthin among premenopausal women in this cohort. A controlled feeding study in premenopausal women reported significantly lower plasma concentrations of lutein/zeaxanthin when participants consumed high levels of alcohol. In addition, they observed slightly increased levels of anhydrolutein, an oxidative metabolite of this carotenoid (47). Lutein/zeaxanthin may have antioxidant properties specific to reactive oxygen species induced by alcohol metabolism, and women consuming high levels of alcohol may therefore have higher requirements for lutein/zeaxanthin. This is the first study to prospectively assess the relation between plasma carotenoids, retinol, and tocopherols and breast cancer nodal metastasis at diagnosis. Increased DNA damage associated with reactive oxygen species has been reported with metastatic breast cancer DNA compared with nonmetastatic tumor DNA, suggesting that oxidative stress enhances the cells' ability to metastasize (48). Previously, in vitro studies have demonstrated that carotenoids are capable of reducing proliferation in a number of cancer cell lines (23), including breast cancer lines (49). Results from this study suggest that alpha-carotene may be involved in the preven-tion of nodal metastases. Previous analyses in the full cohort of the Nurses' Health Study addressed the role of dietary intake of carotenoids and risk of breast cancer. Zhang et al. (42) reported inverse asso- ciations between the intake of carotenoids, primarily beta--caro-tene and lutein/zeaxanthin, and risk of breast cancer in premenopausal women but not among postmenopausal women. In this nested case-control study, we had few premenopausal women (n of cases = 102), but there was no evidence that carotenoids were associated with a decreased risk of breast cancer. In contrast, we observed an inverse association of carot-enoids and breast cancer among postmenopausal women, while the intake data do not support such an association. Interestingly, in the full cohort of postmenopausal women, carrot consumption was inversely associated with breast cancer risk. The correlation between carrot consumption and alpha-carotene index is 0.9, suggesting that the discrepancy in the alpha-carotene index (based on quintiles) and carrot consumption analysis (based on servings) may be due to a washing out of the association when quintiles of dietary index are used as the exposure. If women with the very highest servings of carrot consumption are the individuals with the decreased risk of breast cancer, the inverse associa-tion may not be apparent when these women are forced into the same quintile category with women consuming less alpha-carotene. One limitation of this study is that there is only one blood sample from which to assess micronutrient levels. There is evidence to suggest that a single sample is adequately repre-sentative of an individual's long-term exposure. Toniolo et al. (32) reported intraclass correlations between a single measurement and average concentrations of carotenoids over a 3-year period that ranged from 0.63 to 0.85. In addi-tion, the nutrients assayed are lipid soluble, and the long-term reproducibility from other studies is good, suggesting that these measures provide reasonable consistency over time. Variation that may occur will likely be random and would result in an attenuation of the true relation (50). With any observational study, there is potential for residual and unmeasured confounding. The analyses presented have controlled for all major breast cancer risk factors. In addition, we were able to adjust for the confounding effects of other plasma nutrients in an effort to ascertain independent nutrient effects. It is still possible that other nutritional factors yet unidentified or dietary patterns may be confounding this relation. Breast cancer is an important public health concern. To date, there is little information about modifiable risk factors. Micronutrients, specifically carotenoids, exhibit a great deal of interindividual variation in their absorption, metabolism, and excretion (51, 52). Therefore, plasma levels of micronu-trients may give a more accurate approximation of the amount available to target tissues than intake estimates. These results suggest that plasma levels of alpha- or beta--carotene may play a role in reducing breast cancer risk although, because of the high degree of collinearity between the plasma carotenoids, we have limited ability to conclude that the observed association is specific for alpha-carotene. Further studies are necessary to confirm the inverse associations observed between alpha-carotene and breast cancer risk and nodal metastases and the potential interactions observed between plasma carotenoids and smoking and alcohol consumption. Cheers, Alan Pater, PhD; 4849 Swanson St., Port Alberni, BC, V9Y 6M7; phone: 250 724-0596; email: old542000@... 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