Cancer
Critical Findings - Plasma/Serum Lycopene and Disease Risk

Disease type	First Author	Study Title and Complete Citation	Date	Abstract	Study Type	G.Tom +, N,	P.Tom +, N,	F.Tom +, N, -	Lyco +, N,	Other +, N,
Cancer: bladder	Hung RJ	Protective effects of plasma carotenoids on the risk of bladder cancer. Hung RJ, Zhang ZF, Rao JY, Pantuck A, Reuter VE, Heber D, Lu QY. J Urol. 2006 Sep;176(3):1192-7.	2006	PURPOSE: We examined the associations between plasma micronutrients and bladder cancer risk, and evaluated the combined effects of carotenoid and cigarette smoke. MATERIALS AND METHODS: We performed a case-control study in 242 patients with bladder cancer and 204 healthy controls at Memorial Sloan-Kettering Cancer Center from 1993 to 1997. Epidemiological data and blood specimens were collected on 84 cases and 173 controls. Plasma micronutrients, including lutein, zeaxanthin, beta-cryptoxanthin, lycopene, alpha-carotene, beta-carotene, retinol, alpha-tocopherol and gamma-tocopherol, were determined by high performance liquid chromatography. The logistic regression model was used to estimate the effects from carotenoid, tocopherol and retinol on the risk of bladder cancer. RESULTS: Based on quartiles of plasma micronutrient levels and continuous variables, adjusted ORs were estimated for bladder cancer after controlling for potential confounders, including patient age, sex, education and pack-years of smoking. When using plasma levels of micronutrients as continuous variables, the adjusted OR was 0.22 (95% CI 0.05 to 0.92) for alpha-carotene, 0.42 (95% CI 0.18 to 1.00) for lutein, 0.16 (95% CI 0.02 to 1.06) for zeaxanthin, 0.94 (95% CI 0.89 to 0.99) for lycopene and 0.90 (95% CI 0.81 to 1.00) for beta-cryptoxanthin. The adjusted OR for the joint effect of plasma carotenoids and tobacco smoking was 6.22 (95% CI 1.87 to 20.8) in smokers with lower lutein and 5.18 (95% CI 1.57 to 17.1) in smokers with lower zeaxanthin. CONCLUSIONS: Our results show protective effects of carotenoids on bladder cancer. They suggest that bladder cancer may be a preventable disease through nutritional intervention, especially in smokers.	CC				(-)/N ↓ risk

 

Disease type	First Author	Study Title and Complete Citation	Date	Abstract	Study Type	G.Tom +, N,	P.Tom +, N,	F.Tom +, N, -	Lyco +, N,	Other +, N,
Cancer: breast	Potischman N	Breast cancer and dietary and plasma concentrations of carotenoids and vitamin A. Potischman N, McCulloch CE, Byers T, Nemoto T, Stubbe N, Milch R, Parker R, Rasmussen KM, Root M, Graham S, et al. Am J Clin Nutr. 1990 Nov;52(5):909-15.	1990	A case-control study of breast cancer was conducted in Buffalo. Participants completed a food frequency questionnaire and donated a fasting blood sample before definitive workup for breast masses. Dietary and plasma concentrations of carotenoids and retinol for 83 women found to have breast cancer were compared with those of 113 women found to be free of breast cancer (control subjects). There were no case-control differences in dietary estimates of vitamin A intake or in plasma alpha-carotene and lycopene. However, subjects with breast cancer had lower concentrations of plasma beta-carotene than did control subjects (P = 0.02). There was no overall association between plasma retinol and breast cancer but a positive relationship was observed between retinol and breast cancer in the subgroup with low beta-carotene values. These results suggest that low plasma beta-carotene is associated with increased risk of breast cancer. Other studies will need to determine whether low carotene concentrations are a subtle effect of the disease or might be causally related to breast cancer.	CC				N
Cancer: breast	Simon MS	An Evaluation of Plasma the Risk of Breast Antioxidant Levels and Cancer: A Pilot Case Control Study. Simon MS, Djuric Z, Dunn B, Stephens D, Lababidi S, Heilbrun LK. Breast J. 2000 Nov;6(6):388-395.	2000	Antioxidant micronutrients found in fruits and vegetables have been shown in numerous studies to be protective against cancer. There is limited information on the relationship between blood antioxidant micronutrient levels and cancer among ethnic minorities. We conducted a pilot case-control study to evaluate the potential for accrual to a study of the association of plasma levels of beta-carotene, retinol, lycopene, alpha-tocopherol, and gamma-tocopherol with breast cancer risk among African American and Caucasian women seen at a large university medical center in Detroit. Cases included women with newly diagnosed invasive breast cancer who had not yet had any cancer-related therapy and who were age-matched to controls within 5 years. Plasma levels of micronutrients were analyzed by high-pressure liquid chromatography. Compared to the expected accrual based on cancer registry data, only 26% (11/42) of African American women with breast cancer enrolled, while 100% (16/16) of Caucasian cases enrolled. Control women were quickly accrued with only a 6% refusal rate. Among African American women, there was a weak inverse association between plasma lycopene levels and breast cancer risk, with a mean level of 0.17 &mgr;mol/L (SD = 0.18) among cases, and 0.24 &mgr;mol/L (SD = 0.18) among controls (p = 0.09). There was a weak direct association between plasma retinol levels and breast cancer risk among African American women, with a mean retinol level of 2.37 &mgr;mol/L (SD = 0.73) among cases and 1.98 &mgr;mol/L (SD = 0.49) among controls (p = 0.132). The interaction effect of race and lycopene was statistically significant (p = 0.048). Among the lowest lycopene tertile, the risk of breast cancer among Caucasian women was 0.76 and the risk of breast cancer among African American women was 2.29, although these odds ratios were not statistically significant. Our recruitment efforts were largely successful among Caucasian cases and controls, and African American controls, but were unsuccessful among African American cases. The results suggest a possible relationship between plasma lycopene level and breast cancer among African American women, but these results should be confirmed by a larger, more definitive study.	CC				N

 

Disease type	First Author	Study Title and Complete Citation	Date	Abstract	Study Type	G.Tom +, N,	P.Tom +, N,	F.Tom +, N, -	Lyco +, N,	Other +, N,
Cancer: breast	Ching S	Serum levels of micronutrients, antioxidants and total antioxidant status predict risk of breast cancer in a case control study. Ching S, Ingram D, Hahnel R, Beilby J, Rossi E. J Nutr. 2002 Feb;132(2):303-6.	2002	We performed a case control study to assess the association between serum micronutrient and antioxidant levels and the risk of breast cancer. Newly diagnosed breast cancer cases were recruited before any treatment and matched with controls randomly selected from the electoral roll. Blood samples were collected from 153 breast cancer cases and 151 controls. Serum samples were analyzed for retinol, alpha-tocopherol, lycopene, alpha- and beta-carotene by HPLC, and total antioxidant status by the Trolox-equivalent antioxidant assay. Serum albumin, bilirubin and uric acid levels were also determined. After adjustment for age at menarche, parity, dietary fat and alcohol intake, we observed the following reductions in odds ratios for breast cancer risk comparing the highest with the lowest quartiles: 0.47 [95% confidence interval (CI) 0.24, 0.91] for beta-carotene; 0.53 (CI 0.28, 1.01) for retinol; 0.50 (CI 0.26, 0.97) for bilirubin and 0.47 (CI 0.24, 0.94) for total antioxidant status. We conclude that increased serum levels of beta-carotene, retinol, bilirubin and total antioxidant status are associated with reductions in breast cancer risk.	CC				N?
Cancer: breast	Dorgan JF	Relationships of serum carotenoids, retinol, alpha-tocopherol, and selenium with breast cancer risk: results from a prospective study in Columbia, Missouri (United States) Dorgan JF, Sowell A, Swanson CA, Potischman N, Miller R, Schussler N, Stephenson HE Jr. Cancer Causes Control. 1998 Jan;9(1):89-97.	1998	To evaluate relationships of serum carotenoids, alpha-tocopherol, selenium, and retinol with breast cancer prospectively, we conducted a case-control study nested in a cohort from the Breast Cancer Serum Bank in Columbia, Missouri (United States). Women free of cancer donated blood to this bank in 1977-87. During up to 9.5 years of follow-up (median = 2.7 years), 105 cases of histologically confirmed breast cancer were diagnosed. For each case, two women alive and free of cancer at the age of the case's diagnosis and matched on age and date of blood collection were selected as controls. A nonsignificant gradient of decreasing risk of breast cancer with increasing serum beta-cryptoxanthin was apparent for all women. Serum lycopene also was associated inversely with risk, and among women who donated blood at least two years before diagnosis, a significant gradient of decreasing breast cancer risk with increasing lycopene concentration was evident. A marginally significant gradient of decreasing risk with increasing serum lutein/zeaxanthin also was apparent among these women. We did not observe any evidence for protective effects of alpha- and beta-carotene, alpha-tocopherol, retinol, or selenium for breast cancer. Results of this study suggest that the carotenoids beta-cryptoxanthin, lycopene, and lutein/zeaxanthin may protect against breast cancer.	CC nested				(-)

 

Disease type	First Author	Study Title and Complete Citation	Date	Abstract	Study Type	G.Tom +, N,	P.Tom +, N,	F.Tom +, N, -	Lyco +, N,	Other +, N,
Cancer: breast	Hulten K	Carotenoids, alphatocopherols, and retinol in plasma and breast cancer risk in northern Sweden. Hulten K, Van Kappel AL, Winkvist A, Kaaks R, Hallmans G, Lenner P, Riboli E. Cancer Causes Control. 2001 Aug;12(6):529-37.	2001	OBJECTIVE: Using a nested case-referent design we evaluated the relationship between plasma levels of six carotenoids, alpha-tocopherol, and retinol, sampled before diagnosis, and later breast cancer risk. METHODS: In total, 201 cases and 290 referents were selected from three population-based cohorts in northern Sweden, where all subjects donated blood samples at enrolment. All blood samples were stored at -80 degrees C. Cases and referents were matched for age, age of blood sample, and sampling centre. Breast cancer cases were identified through the regional and national cancer registries. RESULTS: Plasma concentrations of carotenoids were positively intercorrelated. In analysis of three cohorts as a group none of the carotenoids was found to be significantly related to the risk of developing breast cancer. Similarly, no significant associations between breast cancer risk and plasma levels of alpha-tocopherol or retinol were found. However, in postmenopausal women from a mammography cohort with a high number of prevalent cases, lycopene was significantly associated with a decreased risk of breast cancer. A significant trend of an inverse association between lutein and breast cancer risk was seen in premenopausal women from two combined population-based cohorts with only incident cases. A non-significant reduced risk with higher plasma alpha-carotene was apparent throughout all the sub-analyses. CONCLUSION: In conclusion, no significant associations were found between plasma levels of carotenoids, alpha-tocopherol or retinol and breast cancer risk in analysis of three combined cohorts. However, results from stratified analysis by cohort membership and menopausal status suggest that lycopene and other plasma-carotenoids may reduce the risk of developing breast cancer and that menopausal status has an impact on the mechanisms involved.	CC nested				(-)
Cancer: breast	Toniolo P	Serum carotenoids and breast cancer. Toniolo P, Van Kappel AL, Akhmedkhanov A, Ferrari P, Kato I, Shore RE, Riboli E. Am J Epidemiol. 2001 Jun 15;153(12):1142-7.	2001	The consumption of vegetables and fruit may protect against many types of cancer, but research evidence is not compelling for breast cancer. Carotenoids are pigments that are present in most plants and have known antioxidant properties. Blood concentrations of carotenoids have been proposed as integrated biochemical markers of vegetable, fruit, and synthetic supplements consumed. In a case-control study (270 cases, 270 controls) nested within a cohort in New York during 1985-1994, the carotenoids lutein, zeaxanthin, beta-cryptoxanthin, lycopene, alpha-carotene, and beta-carotene were measured in archived serum samples using liquid chromatography. There was an evident increase in the risk of breast cancer for decreasing beta-carotene, lutein, alpha-carotene, and beta-cryptoxanthin. The risk of breast cancer approximately doubled among subjects with blood levels of beta-carotene at the lowest quartile, as compared with those at the highest quartile (odds ratio = 2.21; 95% confidence interval (CI): 1.29, 3.79). The risk associated with the other carotenoids was similar, varying between 2.08 (95% CI: 1.11, 3.90) for lutein and 1.68 (95% CI: 0.99, 2.86) for beta-cryptoxanthin. The odds ratio for the lower quartile of total carotenoids was 2.31 (95% CI: 1.35, 3.96). These observations offer evidence that a low intake of carotenoids, through poor diet and/or lack of vitamin supplementation, may be associated with increased risk of breast cancer and may have public health relevance for people with markedly low intakes.	CC nested				N?

 

Disease type	First Author	Study Title and Complete Citation	Date	Abstract	Study Type	G.Tom +, N,	P.Tom +, N,	F.Tom +, N, -	Lyco +, N,	Other +, N,
Cancer: breast	Sato R	Prospective study of carotenoids, tocopherols, and retinoid concentrations and the risk of breast cancer. Sato R, Helzlsouer KJ, Alberg AJ, Hoffman SC, Norkus EP, Comstock GW. Cancer Epidemiol Biomarkers Prev. 2002 May;11(5):451-7.	2002	Previous prospective studies have raised the possibility that the antioxidantproperties of carotenoids and vitamin E (alpha-tocopherol) and the role of vitamin A (retinol) in cellular differentiation may be associated with a reduced risk of subsequent breast cancer. To investigate the association between serum and plasma concentrations of retinol, retinyl palmitate, alpha-carotene, beta-carotene, beta-cryptoxanthin, lutein, lycopene, total-carotenoids, alpha-tocopherol, and gamma-tocopherol with subsequent development of breast cancer, a nested case control study was conducted among female residents of Washington County, Maryland, who had donated blood for a serum bank in 1974 or 1989. Cases (n = 295) and controls (n = 295) were matched on age, race, menopausal status, and date of blood donation, and the analyses were stratified by cohort participation. Median concentrations of beta-carotene, lycopene, and total carotene were significantly lower in cases compared with controls in the 1974 cohort (13.1, 12.5, and 7.9% difference; P = 0.01, 0.04, and 0.04, respectively) and for lutein in the 1989 cohort (6.7% difference; P = 0.02). The risk of developing breast cancer in the highest fifth was approximately half of that of women in the lowest fifth for beta-carotene [odds ratio (OR) = 0.41; 95% confidence interval (CI) 0.22-0.79; P trend = 0.007], lycopene (OR = 0.55; 95% CI 0.29-1.06; P trend = 0.04), and total carotene (OR = 0.55; 95% CI 0.29-1.03; P trend = 0.02) in the 1974 cohort. There was generally a protective association for other micronutrients in both cohorts, although none reached statistical significance. The results suggest that carotenoids may protect against the development of breast cancer.	CC nested				(-)
Cancer: breast	Ito Y	A study on serum carotenoid levels in breast cancer patients of Indian women in Chennai (Madras), India. Ito Y, Gajalakshmi KC, Sasaki R, Suzuki K, Shanta V. J Epidemiol. 1999 Nov;9(5):306-14.	1999	Two-hundred and six breast cancer cases were histologically confirmed breast cancer diagnoses at the Cancer Institute in Chennai (Madras), India. One-hundred and fifty hospital controls were patients who had cancer at any site other than breast and gynecological organs, and 61 healthy controls were persons accompanying patients in the Cancer Institute. Serum levels of carotenoids such as beta-carotene, lycopene, cryptoxanthin, and zeaxanthin & lutein were determined by HPLC. Serum levels of total carotenes and total carotenoids including beta-carotene, which reflects food intake of colored vegetables and fruits and has a protective role for certain sites of cancer, were significantly lower among breast cancer cases and hospital controls compared to healthy controls, especially in post-menopausal women. Serum carotenoid levels appeared to change with menopausal status. Serum beta-carotene levels tended to be lower among breast cancer cases than among hospital controls in premenopausal women. Serum xanthophyll levels were significantly lower among breast cancer cases than among healthy controls in post-menopausal women, but not in premenopausal women. Serum levels of retinol and alpha-tocopherol among breast cancer cases were not significantly different from those in post-menopausal healthy controls, but were higher than those in hospital controls. Serum estrone levels were significantly higher among breast cancer cases than among healthy controls, but serum levels of estradiol and estriol were not. In conclusion, Indian women with cancer of breast or of other sites might have low intake of green-yellow vegetables rich in fiber and carotenoids such as beta-carotene and zeaxanthin & lutein.	CC serum				N?

 

Disease type	First Author	Study Title and Complete Citation	Date	Abstract	Study Type	G.Tom +, N,	P.Tom +, N,	F.Tom +, N, -	Lyco +, N,	Other +, N,
Cancer: breast	Zhang S	Measurement of retinoids and carotenoids in breast adipose tissue and a comparison of concentrations in breast cancer cases and control subjects. Zhang S, Tang G, Russell RM, Mayzel KA, Stampfer MJ, Willett WC, Hunter DJ. Am J Clin Nutr. 1997 Sep;66(3):626-32.	1997	A case-control study of the associations of retinoids and specific carotenoids with breast cancer using concentrations of these nutrients in breast adipose tissue was conducted among women attending a breast clinic in the Boston area in 1989-1992. Breast adipose tissue was collected during breast biopsy. Cases (n = 46) were women whose biopsies revealed invasive or in situ breast cancer; control subjects (n = 63) were women whose biopsies revealed benign disease. We observed inverse associations between breast adipose concentrations of retinoids and carotenoids and risk of breast cancer, although not all were statistically significant. The multivariate-adjusted odds ratio comparing women above the median value of the control group for retinol with those below or equal to the median was 0.71 (95% CI: 0.26, 1.93; NS); corresponding odds ratios were 0.61 (95% CI: 0.23, 1.64; NS) for retinyl palmitate, 0.30 (95% CI: 0.11, 0.85) for beta-carotene, 0.32 (95% CI: 0.11, 0.94) for lycopene, and 0.68 (95% CI: 0.27, 1.73; NS) for lutein/zeaxanthin. There was a nonsignificant positive correlation (r = 0.23, P = 0.15) between breast adipose tissue concentrations of retinol and dietary intake of preformed vitamin A, including supplements measured by using a food-frequency questionnaire. No correlation was found between breast adipose concentrations of carotenoids and intake of dietary carotenoids. These data suggest that higher breast adipose concentrations of retinoids and some carotenoids may be associated with decreased risk of breast cancer and that further examination of these relations is warranted.	CC tissue				(-)
Cancer: breast	Thomson CA	Plasma and dietary carotenoids are associated with reduced oxidative stress in women previously treated for breast cancer. Thomson CA, Stendell-Hollis NR, Rock CL, Cussler EC, Flatt SW, Pierce JP. Cancer Epidemiol Biomarkers Prev. 2007 Oct;16(10):2008-15.	2007	Dietary carotenoids show numerous biological activities, including antioxidant activity, induction of apoptosis, and inhibition of mammary cell proliferation. Studies examining the role of carotenoid consumption in relation to breast cancer recurrence are limited and report mixed results. We tested the hypothesis that breast cancer survivors with high dietary and plasma carotenoids would show significantly lower levels of oxidative stress than breast cancer survivors with low dietary and plasma carotenoid levels. Two hundred seven postmenopausal breast cancer survivors from the Women's Healthy Eating and Living Study volunteered for this ancillary study. Dietary data were analyzed by the Arizona Food Frequency Questionnaire and plasma carotenoids alpha-carotene, beta-carotene, lutein plus zeaxanthin, lycopene, and beta-cryptoxanthin and quantified with high-performance liquid chromatography, and immunoaffinity chromatography-monoclonal antibody-based ELISAs were used to analyze the urine samples for 8-hydroxy-2'-deoxyguanosine (8-OhdG) and 8-iso-prostaglandin-F2alpha (8-iso-PGF2alpha). The correlations between dietary and plasma carotenoids were 0.34 for beta-carotene, 0.46 for alpha-carotene, 0.39 for beta-cryptoxanthin, 0.27 for lycopene, 0.30 for lutein plus zeaxanthin, and 0.30 for total carotenoids. The 8-OHdG oxidative stress biomarker was significantly reduced at the highest quartile of total plasma carotenoid concentrations (P = 0.001) and 8-iso-PGF2alpha was moderately reduced (P = 0.088). Dietary carotenoid levels were not significantly associated with oxidative, stress indicators, although dietary lycopene and lutein/zeaxanthin were modestly associated with 8-OHdG levels (P = 0.054 and 0.088, respectively). Key findings include a significant inverse association between total plasma carotenoid concentrations and oxidative stress as measured by urinary 8-OHdG and a moderately significant inverse association with 8-iso-PGF2alpha, a protective association that was not shown for dietary carotenoid intake.	CS				(-) ↓ 8-OHdG (ox stress marker) with plasma [lyco]

 

Disease type	First Author	Study Title and Complete Citation	Date	Abstract	Study Type	G.Tom +, N,	P.Tom +, N,	F.Tom +, N, -	Lyco +, N,	Other +, N,
Cancer: breast	Kabat GC	Longitudinal study of serum carotenoid, retinol, and tocopherol concentrations in relation to breast cancer risk among postmenopausal women. Kabat GC, Kim M, Adams Campbell LL, Caan BJ, Chlebowski RT, Neuhouser ML, Shikany JM, Rohan TE; WHI Investigators. Am J Clin Nutr. 2009 Jul;90(1):162-9. Epub 2009 May 27.	2009	BACKGROUND: Prospective studies have examined the association of serum and plasma carotenoids and micronutrients and breast cancer; however, to date, studies have only assessed exposure at one point in time. OBJECTIVE: This study analyzed baseline and repeated serum measurements of carotenoids, retinol, and tocopherols to assess their associations with postmenopausal breast cancer risk. DESIGN: Serum concentrations of alpha-carotene, beta-carotene, beta-cryptoxanthin, lycopene, lutein + zeaxanthin, retinol, alpha-tocopherol, and gamma-tocopherol were measured in a 6% sample of women in the Women's Health Initiative clinical trials at baseline and at years 1, 3, and 6 and in a 1% sample of women in the observational study at baseline and at year 3. The association of baseline compounds and breast cancer risk was estimated by Cox proportional hazards models. In addition, repeated measurements were analyzed as time-dependent covariates. Of 5450 women with baseline measurements, 190 incident cases of breast cancer were ascertained over a median of 8.0 y of follow-up. RESULTS: After multivariable adjustment, risk of invasive breast cancer was inversely associated with baseline serum alpha-carotene concentrations (hazard ratio for highest compared with the lowest tertile: 0.55; 95% CI: 0.34, 0.90; P = 0.02) and positively associated with baseline lycopene (hazard ratio: 1.47; 95% CI: 0.98, 2.22; P = 0.06). Analysis of repeated measurements indicated that alpha-carotene and beta-carotene were inversely associated with breast cancer and that gamma-tocopherol was associated with increased risk. CONCLUSIONS: The present study, which was the first to assess repeated measurements of serum carotenoids and micronutrients in relation to breast cancer, adds to the evidence of an inverse association of specific carotenoids with breast cancer. The positive associations observed for lycopene and gamma-tocopherol require confirmation. This trial was registered at ClinicalTrials.gov as NCT00000611.	PC				(+) ↑ risk
Cancer: cervical	Potischman N	A case-control study of nutrient status and invasive cervical cancer. II. Serologic indicators. Potischman N, Herrero R, Brinton LA, Reeves WC, Stacewicz-Sapuntzakis M, Jones CJ, Brenes MM, Tenorio F, de Britton RC, Gaitan E. Am J Epidemiol. 1991 Dec 1;134(11):1347-55.	1991	A study of 387 cases and 670 controls from four Latin American countries evaluated the hypothesis that lower serum levels of eight micronutrients were associated with a higher risk of invasive cervical cancer. The serologic analyses were restricted to a sample of subjects with stage I and II disease to minimize effects of the disease on the serologic markers. Ninety-four percent of eligible subjects donated blood samples, which were analyzed for carotenoids, retinol, and tocopherols by high-pressure liquid chromatography. Cases did not differ significantly from controls in mean serum levels of retinol, cryptoxanthin, lycopene, alpha-carotene, lutein, or alpha-tocopherol. The mean level of beta-carotene was lower and the mean level of gamma-tocopherol was higher among cases as compared with controls. After adjustment for age, study site, sexual and reproductive behavior, socioeconomic status, screening practices, detection of human papillomavirus types 16/18, cholesterol, and triglycerides, a trend of decreasing risk was associated with higher levels of beta-carotene (p for trend = 0.05), with the adjusted odds ratio decreasing to 0.72 for the highest versus the lowest quartile. beta-Carotene results were similar by stage of disease, which argues against an effect of disease progression on nutrient values. Unexpectedly, increasing risks were observed as the level of gamma-tocopherol increased (odds ratio = 2.09; p for trend = 0.03); however, levels were higher among stage II cases as compared with stage I cases, suggesting a metabolic alteration resulting from the disease process. The concordance in the strength and direction of the blood and dietary results, presented in the accompanying report (Herrero R, Potischman N, Brinton LA, et al., American Journal of Epidemiology 1991;134:1335-46), supports a role for beta-carotene or foods rich in beta-carotene in the etiology of cervical cancer. This study also indicates that simultaneous analysis using serologic and dietary nutrient indicators allows better discrimination of the association.	CC				N

 

Disease type	First Author	Study Title and Complete Citation	Date	Abstract	Study Type	G.Tom +, N,	P.Tom +, N,	F.Tom +, N, -	Lyco +, N,	Other +, N,
Cancer: cervical	VanEenwyk J	Dietary and serum carotenoids and cervical intraepithelial neoplasia. VanEenwyk J, Davis FG, Bowen PE. Int J Cancer. 1991 Apr 22;48(1):34-8.	1991	A case-control study examined the association between cervical intra-epithelial neoplasia (CIN) and serum and dietary alpha-carotene, beta-carotene, cryptoxanthin, lutein, and lycopene. Cases (n = 102) had biopsy confirmed CIN I, II or III. Controls matched for age, ethnic origin and clinic (n = 102) had normal Pap smears. Participants completed health history and food frequency questionnaires. Fasting venous blood samples were assayed for serum carotenoids. Multivariable conditional logistic regression analyses yielded odds ratios and 95% confidence intervals (CIs) for those in quartiles 3, 2, and 1 (lowest) compared to quartile 4 (highest) of serum lycopene of 3.5 (1.1-11.5), 4.7 (1.2-17.7) and 3.8 (1.1-12.4), respectively. Similar analyses yielded adjusted odds ratios (ORaS) and 95% CIs of 4.6 (1.1-19.7), 5.8 (1.6-21.3) and 5.4 (1.3-23.3) for dietary intake of lycopene. The findings for lycopene-rich foods (tomatoes) were consistent with this result. CIN was not associated with the lutein. Findings for alpha-carotene, beta-carotene and cryptoxanthin were ambiguous. Quartile of vitamin C intake was also inversely associated with CIN with ORaS and 95% CIs of 3.7 (0.9-14.6), 4.1 (1.0-17.2), and 6.4 (1.4-30.0) for those in quartiles 3, 2, and 1 compared to quartile 4.	CC				(-)
Cancer: cervical	Potischman N	The relations between cervical cancer and serological markers of nutritional status. Potischman N, Hoover RN, Brinton LA, Swanson CA, Herrero R, Tenorio F, de Britton RC, Gaitan E, Reeves WC. Nutr Cancer. 1994;21(3):193-201.	1994	We evaluated whether differences in serological nutrient indicators between cases and controls were likely to be due to different usual levels for cases or to altered metabolism due to disease. Blood samples obtained as part of a case-control study of invasive cervical cancer conducted in Latin America were evaluated for case-control differences and for trends with stage of disease. Serum alpha- and beta-carotene, cryptoxanthin, and alpha- and gamma-tocopherol showed no trend with extent of disease, although Stage IV cases had lower alpha- and beta-carotene values than did other cases. A slight trend of decreasing values with stage was observed for serum retinol, lycopene, and lutein. For cholesterol and triglyceride concentrations, an inverse trend was observed with stage of disease, which suggested a clinical effect of the disease on blood lipids. Adjustment for smoking, alcohol intake, or oral contraceptive use did not alter observed relations, nor was there evidence that the altered blood nutrient levels differed by histological type. These data suggest that serum values for some carotenoids from Stage I, II, and III cervical cancer are suitable for etiological studies, but spurious results may be obtained if late-stage cases are included. Evidence of trends with severity of disease for cholesterol and triglycerides, and possibly for retinol, lycopene, and lutein, suggest that special attention be given to disease effects of these nutrients in studies of cervical cancer.	CC				N?

 

Disease type	First Author	Study Title and Complete Citation	Date	Abstract	Study Type	G.Tom +, N,	P.Tom +, N,	F.Tom +, N, -	Lyco +, N,	Other +, N,
Cancer: cervical	Goodman MT	The association of plasma micronutrients with the risk of cervical dysplasia in Hawaii. Goodman MT, Kiviat N, McDuffie K, Hankin JH, Hernandez B, Wilkens LR, Franke A, Kuypers J, Kolonel LN, Nakamura J, Ing G, Branch B, Bertram CC, Kamemoto L, Sharma S, Killeen J. Cancer Epidemiol Biomarkers Prev. 1998 Jun;7(6):537-44.	1998	Limited data from hematological studies suggest that certain nutrients, including carotenoids, tocopherols, and vitamin C, may protect against malignant change in cervical tissue. Recognizing that human papillomavirus (HPV) infection induces most neoplastic transformation of cervical tissue, the authors conducted a case-control study to examine the association of plasma micronutrient concentrations with the risk of cervical dysplasia after careful adjustment for HPV infection, using a sensitive and reliable HPV detection method. The sample included 147 multiethnic women, between 18 and 65 years of age, with biopsy-confirmed squamous intraepithelial lesions (SILs) of the cervix and 191 clinic controls identified between 1992 and 1996. Cases were identified through cytology and pathology logs in three clinics on Oahu, Hawaii. Controls were selected randomly from admission logs of the participating clinics. In-person interviews were conducted in the subjects' homes, and a fasting blood sample was drawn to measure plasma levels of lutein, lycopene, cryptoxanthin, total carotene, retinol, tocopherol, ascorbic acid, and cholesterol. The presence and type of HPV was determined in exfoliated cell samples using PCR dot blot hybridization. Mean plasma lycopene, total cryptoxanthin, and alpha-cryptoxanthin levels were lower among cases than controls. We found an inverse dose-response of alpha-cryptoxanthin, total tocopherol, and alpha-tocopherol to the odds ratios for cervical SIL after adjustment for HPV and other confounders. The odds ratio among women in the highest compared with the lowest quartile was 0.3 (95% confidence interval, 0.1-0.7) for alpha-cryptoxanthin and 0.3 (95% confidence interval, 0.1-0.8) for alpha-tocopherol. Negative trends in the odds ratios were suggested for other carotenoids and vitamin C, but these were weak, and confidence intervals were wide. Our results support existing evidence that high plasma levels of antioxidants may reduce the risk of cervical SILs independent of HPV infection. These findings are significant because diet is potentially modifiable, and nutrition education and dietary intervention might be targeted at specific high-risk groups.	CC				N
Cancer: cervical	Nagata C	Serum carotenoids and vitamins and risk of cervical dysplasia from a case-control study in Japan. Nagata C, Shimizu H, Yoshikawa H, Noda K, Nozawa S, Yajima A, Sekiya S, Sugimori H, Hirai Y, Kanazawa K, Sugase M, Kawana T. Br J Cancer. 1999 Dec;81(7):1234-7.	1999	The relationships between risk of cervical dysplasia and dietary and serum carotenoids and vitamins were investigated in a case-control study. Cases were 156 women who attended Papanicolaou test screening in nine institutes affiliated with Japan Study Group of Human Papillomavirus (HPV) and Cervical Cancer and had cervical dysplasia newly histologically confirmed. Age-matched controls were selected from women with normal cervical cytology attending the same clinic. Blood sample and cervical exfoliated cells were obtained for measuring serum retinol, alpha-carotene, beta-carotene, zeaxanthin/lutein, cryptoxanthin, lycopene and alpha-tocopherol and for HPV detection. Higher serum level of alpha-carotene was significantly associated with decreased risk of cervical dysplasia after controlling for HPV infection and smoking status (odds ratio (OR) = 0.16, 95% confidence interval (CI) 0.04-0.62 for the highest as compared with the lowest tertile). Decreased risk for the highest tertile of serum lycopene (OR = 0.28) was marginally significant. Decreased risks observed for the highest tertiles of beta-carotene (OR = 0.65) and zeaxanthin/lutein (OR = 0.53), were not statistically significant.	CC				(-)

 

Disease type	First Author	Study Title and Complete Citation	Date	Abstract	Study Type	G.Tom +, N,	P.Tom +, N,	F.Tom +, N, -	Lyco +, N,	Other +, N,
Cancer: cervical	Schiff MA	Serum carotenoids and risk of cervical intraepithelial neoplasia in Southwestern American Indian women. Schiff MA, Patterson RE, Baumgartner RN, Masuk M, van Asselt-King L, Wheeler CM, Becker TM. Cancer Epidemiol Biomarkers Prev. 2001 Nov;10(11):121922.	2001	The objective of this research was to evaluate the association between serum carotenoids and cervical intraepithelial neoplasia (CIN) among Southwestern American Indian women. Cases were American Indian women with biopsy-proven CIN II/III cervical lesions (n = 81) diagnosed between November 1994 and October 1997. Controls were American Indian women from the same clinics with normal cervical epithelium (n = 160). All of the subjects underwent interviews and laboratory evaluations. Interviews evaluated demographic information, sexual history, and cigarette smoking. Serum concentrations of alpha-carotene, beta-carotene, beta-cryptoxanthin, lycopene, and lutein/zeaxanthin were measured by high performance liquid chromatography. Cervical humanpapillomavirus infection was detected using a PCR-based test. Increasing levels of alpha-carotene, beta-cryptoxanthin, and lutein/zeaxanthin were associated with decreasing risk of CIN II/III. In addition, the highest tertiles of beta-cryptoxanthin (odds ratio = 0.39, 95% confidence interval = 0.17-0.91) and lutein/zeaxanthin (odds ratio = 0.40, 95% confidence interval = 0.17-0.95) were associated with the lowest risk of CIN. In conclusion, specially targeted intervention efforts to increase consumption of fruits and vegetables may protect Southwestern American Indian women from developing CIN.	CC				NR/N
Cancer: cervical	Batieha AM	Serum micronutrients and the subsequent risk of cervical cancer in a population-based nested case-control study. Batieha AM, Armenian HK, Norkus EP, Morris JS, Spate VE, Comstock GW. Cancer Epidemiol Biomarkers Prev. 1993 Jul-Aug;2(4):335-9.	1993	A nested case-control study was conducted in Washington County, MD, to determine whether low serum micronutrients are related to the subsequent risk of cervical cancer. Among the 15,161 women who donated blood for future cancer research during a serum collection campaign in 1974, 18 developed invasive cervical cancer and 32 developed carcinoma in situ during the period January 1975 through May 1990. For each of these 50 cases, two matched controls were selected from the same cohort. The frozen sera of the cases and their matched controls were analyzed for a number of nutrients. The mean serum levels of total carotenoids, alpha-carotene, beta-carotene, cryptoxanthin, and lycopene were lower among cases than they were among controls. When examined by tertiles, the risk of cervical cancer was significantly higher among women in the lower tertiles of total carotenoids (odds ratio 2.7; 95% confidence limit, 1.1-6.4), alpha-carotene (odds ratio, 3.1; 95% confidence limit, 1.3-7.6), and beta-carotene (odds ratio, 3.1; 95% confidence limit, 1.2-8.1) as compared to women in the upper tertiles and the trends were statistically significant. Cryptoxanthin was significantly associated with a lower risk of cervical cancer when examined as a continuous variable. Retinol, lutein, alpha- and gamma-tocopherol, and selenium were not related to cervical cancer risk. Smoking was also strongly associated with cervical cancer. These findings are suggestive of a protective role for total carotenoids, alpha-carotene and beta-carotene in cervical carcinogenesis and possibly for cryptoxanthin and lycopene as well.	CC nested				N

 

Disease type	First Author	Study Title and Complete Citation	Date	Abstract	Study Type	G.Tom +, N,	P.Tom +, N,	F.Tom +, N, -	Lyco +, N,	Other +, N,
Cancer: cervical	Peng YM	Concentrations of carotenoids, tocopherols, and retinol in paired plasma and cervical tissue of patients with cervical cancer, precancer, and noncancerous diseases. Peng YM, Peng YS, Childers JM, Hatch KD, Roe DJ, Lin Y, Lin P. Cancer Epidemiol Biomarkers Prev. 1998 Apr;7(4):347-50.	1998	Paired blood (collected after an overnight fast) and cervical tissue (cancerous, precancerous, and noncancerous) samples were obtained from 87 patients (age, 21-86 years) who had a hysterectomy or biopsy due to cervical cancer, precancer (cervical intraepithelial neoplasia I, II, and III), or noncancerous diseases. The samples were analyzed using high-performance liquid chromatography for 10 micronutrients (lutein, zeaxanthin, beta-cryptoxanthin, lycopene, alpha-carotene, beta-carotene, cis-beta-carotene, alpha-tocopherol, gamma-tocopherol, and retinol). The results indicated that: (a) among the three patient groups, the mean plasma concentrations of all micronutrients except gamma-tocopherol were lowest in the cancer patients; however, the mean tissue concentrations of the two tocopherols and certain carotenoids were highest in the cancerous tissue; and (b) among the 10 micronutrients, only the concentrations of beta-carotene and cis-beta-carotene were lower in both the plasma and tissue of cancer and precancer patients than in those of noncancer controls. These results suggest that: (a) not all of the micronutrient concentrations in plasma reflect the micronutrient concentrations in cervical tissue; thus, in some cases, it may be necessary to measure the tissue micronutrient concentrations to define the role of the micronutrients in cervical carcinogenesis; and (b) maintaining an adequate plasma and tissue concentration of beta-carotene may be necessary for the prevention of cervical cancer and precancer.	CC serum + tissue				N
Cancer: cervical	Palan PR	Plasma levels of betacarotene, lycopene, canthaxanthin, retinol, and alpha- and tau-tocopherol in cervical intraepithelial neoplasia and cancer. Palan PR, Mikhail MS, Goldberg GL, Basu J, Runowicz CD, Romney SL. Clin Cancer Res. 1996 Jan;2(1):181-5.	1996	Epidemiological studies continue to identify an association of dietary antioxidant micronutrients in cancer prevention. A number of case-control and cohort studies have demonstrated a relationship between high intake of foods rich in carotenoids, tocopherols, and vitamin C with a reduced risk of certain human malignancies. The purpose of this study was to investigate the comparative plasma levels of a profile of known dietary antioxidants, namely, beta-carotene, lycopene, canthaxanthin, retinol, alpha-tocopherol, and tau-tocopherol. The target population was women with a histopathological diagnosis of cervical intraepithelial neoplasia (CIN) or cervical cancer and a control group. All women resided in the same catchment area (Bronx Borough, New York City) and were of similar inner-city socioeconomic backgrounds representing a fairly homogenous population group. A cross-sectional sample of 235 women was recruited with informed consent. Plasma nutrient levels were measured by reverse-phase high pressure liquid chromatography under study codes. The mean plasma levels of carotenoids (beta-carotene, lycopene, and canthaxanthin), as well as alpha-tocopherol, were significantly lower in women with CIN and cervical cancer. In contrast, the mean plasma level of tau-tocopherol was higher among patients with CIN, while the mean plasma level of retinol was comparable among the groups. There were significant linear trends for all three carotenoids and quadratic trends for alpha- and tau-tocopherol with the degree of cervical histopathology. Plasma beta-carotene concentrations in cigarette smokers were significantly lower regardless of cervical pathology, whereas plasma lycopene and canthaxanthin levels were significantly lower in smokers with CIN. The findings of a decrease in all plasma antioxidant nutrient levels except tau-tocopherol in women with CIN and cancer suggest a potential role for antioxidant deficiency in the pathogenesis of CIN and carcinoma of the cervix, which requires further investigation.	CS				(-)

 

Disease type	First Author	Study Title and Complete Citation	Date	Abstract	Study Type	G.Tom +, N,	P.Tom +, N,	F.Tom +, N, -	Lyco +, N,	Other +, N,
Cancer: cervical	Giuliano AR	Antioxidant nutrients: associations with persistent human papillomavirus infection. Giuliano AR, Papenfuss M, Nour M, Canfield LM, Schneider A, Hatch K. Cancer Epidemiol Biomarkers Prev. 1997 Nov;6(11):917-23.	1997	Research from the past several years has definitively shown intermediate and high risk-type human papillomavirus (HPV) infection to play a significant role in cervical carcinogenesis. Persistent compared with intermittent infection appears to confer an elevated risk, and cofactors may be necessary to allow the virus to progress to cervical cancer. We explored the association between circulating concentrations of the antioxidant nutrients (alpha- and beta-carotene, lutein, lycopene, beta-cryptoxanthin, alpha-tocopherol, gamma-tocopherol, and ascorbate) and persistent HPV infection among 123 low-income Hispanic women who were all nonsmokers and were not currently using vitamin and mineral supplements. In addition, the association between these nutrients and grade of cervical pathology, independent of HPV status, was assessed. Intermediate and high risk-type HPV infection was assessed by the Digene Hybrid Capture System at two time points, 3 months apart. At the second interview, cytology, colposcopy, and a fasting blood draw were conducted. Mean concentrations of serum and plasma antioxidant nutrients were calculated within categories of HPV status (two times HPV negative, one time HPV positive, and two times HPV positive) and colposcopy. Adjusted mean concentrations of serum beta-carotene, beta-cryptoxanthin, lutein, and alpha- and gamma-tocopherol were on average 24% (P < 0.05) lower among women two times HPV positive compared with either two times HPV negative or one time HPV positive. Independent of HPV status, alpha-tocopherol was significantly inversely associated with grade of cervical dysplasia (normal, 21.57 microM; cervical intraepithelial neoplasia III, 17.27 microM). The results obtained in this study need to be confirmed in larger cohort studies with a longer follow-up period.	CS				N
Cancer: cervical	Sedjo RL	Vitamin A, carotenoids, and risk of persistent oncogenic human papillomavirus infection. Sedjo RL, Roe DJ, Abrahamsen M, Harris RB, Craft N, Baldwin S, Giuliano AR. Cancer Epidemiol Biomarkers Prev. 2002 Sep;11(9):876-84.	2002	Oncogenic human papillomavirus (HPV) infection is the main etiologic factor for cervical neoplasia, although infection alone is insufficient to produce disease. Cofactors such as nutritional factors may be necessary for viral progression to neoplasia. Results from previous studies have suggested that higher dietary consumption and circulating levels of certain micronutrients may be protective against cervical neoplasia. This study evaluated the role of vitamin A and carotenoids on HPV persistence comparing women with intermittent and persistent infections. As determined by the Hybrid Capture II system, oncogenic HPV infections were assessed at baseline and at approximately 3 and 9 months postbaseline. Multivariate logistic regression analysis was used to determine the risk of persistent HPV infection associated with each tertile of dietary and circulating micronutrients. Higher levels of vegetable consumption were associated with a 54% decrease risk of HPV persistence (adjusted odds ratio, 0.46; 95% confidence interval, 0.21-0.97). Also, a 56% reduction in HPV persistence risk was observed in women with the highest plasma cis-lycopene concentrations compared with women with the lowest plasma cis-lycopene concentrations (adjusted odds ratio, 0.44; 95% confidence interval, 0.19-1.01). These data suggest that vegetable consumption and circulating cis-lycopene may be protective against HPV persistence.	PC				(-)

 

Disease type	First Author	Study Title and Complete Citation	Date	Abstract	Study Type	G.Tom +, N,	P.Tom +, N,	F.Tom +, N, -	Lyco +, N,	Other +, N,
Cancer: cervical	Goodman MT	Hawaii cohort study of serum micronutrient concentrations and clearance of incident oncogenic human papillomavirus infection of the cervix. Goodman MT, Shvetsov YB, McDuffie K, Wilkens LR, Zhu X, Franke AA, Bertram CC, Kessel B, Bernice M, Sunoo C, Ning L, Easa D, Killeen J, Kamemoto L, Hernandez BY. Cancer Res. 2007 Jun 15;67(12):5987-96. Epub 2007 Jun 6.	2007	The degree to which the resolution of human papillomavirus (HPV) infection parallels exposure to other factors, particularly those related to nutritional status, is a relatively unexplored area of research. We established a cohort of women for long-term follow-up to examine the association of serum retinol, carotenoid, and tocopherol concentrations with the clearance of incident cervical HPV infection. Interviews and biological specimens were obtained at baseline and at 4-month intervals. At each visit, a cervical cell specimen for HPV DNA analysis and cytology and a fasting blood sample to measure micronutrient levels were collected. A Cox proportional hazards model was used to study the relationship between clearance of 189 incident (type-specific) oncogenic HPV infections and the levels of 20 serum micronutrients among 122 women. Higher circulating levels of trans-zeaxanthin, total trans-lutein/zeaxanthin, cryptoxanthin (total and beta), total trans-lycopene and cis-lycopene, carotene (alpha, beta, and total), and total carotenoids were associated with a significant decrease in the clearance time of type-specific HPV infection, particularly during the early stages of infection (<or=120 days). HPV clearance time was also significantly shorter among women with the highest compared with the lowest serum levels of alpha-tocopherol and total-tocopherol, but significant trends in these associations were limited to infections lasting <or=120 days. Clearance of persistent HPV infection (lasting >120 days) was not significantly associated with circulating levels of carotenoids or tocopherols. Results from this investigation support an association of micronutrients with the rapid clearance of incident oncogenic HPV infection of the uterine cervix.	PC				(-) ↓ clearance time of HPV in early infection
Cancer: colorectal	Pappalardo G	Plasma (carotenoids, retinol, alpha-tocopherol) and tissue (carotenoids) levels after supplementation with beta-carotene in subjects with precancerous and cancerous lesions of sigmoid colon. Pappalardo G, Maiani G, Mobarhan S, Guadalaxara A, Azzini E, Raguzzini A, Salucci M, Serafini M, Trifero M, Illomei G, Ferro-Luzzi A. Eur J Clin Nutr. 1997 Oct;51(10):661-6.	1997	OBJECTIVES: (1) To compare tissue and plasma carotenoids status of healthy subjects and subjects with pre-cancer and cancer lesions; (2) to evaluate the effect of beta-carotene supplementation on the concentrations of other carotenoids in tissue (luteine + zeaxanthin, cryptoxanthin, lycopene, alpha-carotene) and in plasma and also retinol and alpha-tocopherol levels. DESIGN: Eighteen subjects were divided into three groups on the basis of colonoscopy and histological analytical findings: four healthy subjects (control group A); seven subjects affected by adenomatous polyps (group B with pre-cancer lesions); seven subjects suffering from colonic cancer (group C). Blood and colonic biopsy samples were taken (of colon and rectal mucosa) before and after beta-carotene supplementation in all subjects. Groups A and B received a daily dose of beta-carotene (30 mg/die) for 43 d. Group C's supplementation was terminated at the time which was performed, usually within 15 d. The tissue and plasma concentration of carotenoids, retinol and alpha-tocopherol were determined by high-performance liquid chromatography. RESULTS: The tissue concentrations of each carotenoid were similar in all the intestinal sites examined as regards groups A and B, although there was a high degree of intra individual variability within each group. Only beta-carotene made significant increases (P < 0.001) after supplementation. The subjects with cancer show tissue levels for each carotenoid lower than those of healthy subjects or subjects with polypous. The plasma levels of alpha-tocopherol did not change after supplementation while significant increases were noted of retinol, alpha-carotene (P < 0.01) and of beta-carotene (P < 0.001). CONCLUSIONS: The patients with colonic cancer seemed to undergo a significant reduction in their antioxidant reserves with respect to the normal subjects and or polyps. We can confirm that oral B-carotene supplementation induces also an increase in plasma alpha-carotene in all groups.	CC				(-)	weakness small study no regressio n analysis

 

Disease type	First Author	Study Title and Complete Citation	Date	Abstract	Study Type	G.Tom +, N,	P.Tom +, N,	F.Tom +, N, -	Lyco +, N,	Other +, N,
Cancer: colorectal	Erhardt JG	Lycopene, beta-carotene, and colorectal adenomas. Erhardt JG, Meisner C, Bode JC, Bode C. Am J Clin Nutr. 2003 Dec;78(6):1219-24.	2003	BACKGROUND: Epidemiologic studies found that high tomato intakes reduce the risk of colorectal cancers. This beneficial effect is assumed to be caused by high intakes of lycopene, a carotenoid with strong antioxidant activity that is present predominantly in tomatoes. OBJECTIVE: We assessed the relation between plasma lycopene concentrations and colorectal adenomas, the precursors for most colorectal cancers. In addition, the concentrations of 2 other antioxidants, beta-carotene and alpha-tocopherol, were measured. DESIGN: White subjects undergoing a complete colonoscopy were included in the study (73 with adenomas, 63 without any polyps, and 29 with hyperplastic polyps). A detailed dietary history and information on alcohol consumption and smoking habits were collected from all subjects. Plasma lycopene, beta-carotene, and alpha-tocopherol concentrations were measured by using HPLC. RESULTS: Patients with adenomas and control subjects without polyps did not differ significantly in body mass index; intakes of energy, fat, protein, carbohydrates, fiber, beta-carotene, and alcohol; or prevalence of smoking, but patients with adenomas were slightly older. The median plasma lycopene concentration was significantly lower in the adenoma group than in the control group (-35%; P = 0.016). The median plasma beta-carotene concentration also tended to be lower in the adenoma group (-25.5%), but the difference was not significant. In the multiple logistic regression, only smoking (odds ratio: 3.02; 95% CI: 1.46, 6.25; P = 0.003) and a plasma lycopene concentration < 70 microg/L (odds ratio: 2.31; 1.12, 4.77; P = 0.023) were risk factors for adenomatous polyps. Patients with hyperplastic polyps did not differ significantly from control subjects in any variable. CONCLUSION: Our findings support the hypothesis that lycopene contributes to the protective effect of high tomato intakes against the risk of colorectal adenomas.	CC				(-) ↑ risk in adenoma group if ↓ plasma [lyco]
Cancer: colorectal	Leung EY	Vitamin antioxidants, lipid peroxidation, tumour stage, the systemic inflammatory response and survival in patients with colorectal cancer. Leung EY, Crozier JE, Talwar D, O'Reilly DS, McKee RF, Horgan PG, McMillan DC. Int J Cancer. 2008 Nov 15;123(10):2460-4.	2008	Both the tumour growth and progression and the systemic inflammatory response have the potential to increase oxidative stress. We therefore examined the relationship between lipid-soluble antioxidant vitamins, lipid peroxidation, the systemic inflammatory response and survival in patients with primary operable (n = 53) and advanced inoperable (n = 53) colorectal cancer. Compared with those patients with primary operable colorectal cancer, patients with unresectable liver disease had significantly lower median concentrations of alpha-tocopherol (p < 0.001), lutein (p < 0.001), lycopene (p < 0.001), alpha-carotene (p < 0.01) and beta-carotene (p < 0.001) and higher malondialdehyde concentrations. An elevated systemic inflammatory response (Glasgow prognostic score, mGPS) was associated with a greater proportion of females (p < 0.05) and more advanced tumour stage (p < 0.05), lower circulating levels of retinol (p < 0.01), lutein (p < 0.01), lycopene (p < 0.01) and alpha- (p < 0.01) and beta-carotene but not MDA (p = 0.633). In the liver metastases group 41 patients died of their cancer and a further 1 patient died of intercurrent disease on follow-up. On univariate survival analysis, mGPS (p < 0.01), retinol (p < 0.001), alpha-tocopherol (p < 0.05) and alpha-carotene (p < 0.05) were associated significantly with cancer-specific survival. On multivariate survival analysis of these significant variables, only mGPS (p < 0.01) and retinol (p < 0.001) were independently associated with cancer-specific survival. The results of the present study showed that the systemic inflammatory response was associated with a reduction of lipid-soluble antioxidant vitamins, whereas advanced tumour stage was associated with increased lipid peroxidation in patients with colorectal cancer. Of the antioxidant vitamins measured, only retinol was independently associated with cancer-specific survival. (c) 2008 Wiley-Liss, Inc.	CC					N ↓ lyco in inop group

 

Disease type	First Author	Study Title and Complete Citation	Date	Abstract	Study Type	G.Tom +, N,	P.Tom +, N,	F.Tom +, N, -	Lyco +, N,	Other +, N,
Cancer: colorectal	Ito Y	Cancer mortality and serum levels of carotenoids, retinol, and tocopherol: a population-based follow-up study of inhabitants of a rural area of Japan. Ito Y, Kurata M, Hioki R, Suzuki K, Ochiai J, Aoki K. Asian Pac J Cancer Prev. 2005 Jan-Mar;6(1):10-5.	2005	A total of 3,182 subjects (1,239 males and 1,943 females) aged from 39y to 79y, were recruited from the inhabitants of a rural area in Japan who participated in health check-up programs from 1988 to 1995. During the 10.5 year follow-up, 287 deaths (175 males and 112 females) from all causes, 134 (81 males and 53 females) from cancer of all sites, 31 from lung cancer, 21 from colorectal cancer, 20 from stomach cancer, and 62 from other cancers, were identified among the cohort subjects. Fasting serum samples were taken at the time of the health check-ups, and serum levels of carotenoids, retinol and tocopherols were separately determined by HPLC. Statistical analyses were performed using Cox's proportional hazard model after adjusting for sex, age, and other confounding factors. High serum levels of alpha- and beta- carotenes and lycopene were found to marginally significantly or significantly reduce the risk for mortality rates of cancer of all sites and of colorectal cancers. High serum levels of beta-cryptoxanthin also showed an inversely relation with the risk of mortality from lung and stomach cancers, but this was not statistically significant. High intake of green-yellow vegetables contributing to serum levels of alpha- and beta- carotenes, as well as lycopene, may reduce the risk of cancer mortality, especially from colorectal cancer, in rural Japanese.	PC				(-) ↓ risk with ↑ serum [lyco]
Cancer: endometri al	Jeong NH	Preoperative levels of plasma micronutrients are related to endometrial cancer risk. Jeong NH, Song ES, Lee JM, Lee KB, Kim MK, Yun YM, Lee JK, Son SK, Lee JP, Kim JH, Hur SY, Kwon YI. Acta Obstet Gynecol Scand. 2009;88(4):371-2.	2009	OBJECTIVE: To examine the relation between the plasma concentration of antioxidant micronutrients and endometrial cancer risk in Korean women. DESIGN: Hospital-based case-control study. SETTING: Seven tertiary medical institutes in Korea. POPULATION: Incidence of 28 endometrial cancer cases were identified and 140 age-matched controls selected for the same period. METHODS: Preoperative plasma concentrations of beta-carotene, lycopene, zeaxanthin plus lutein, retinol, alpha-tocopherol, and gamma-tocopherol were measured by reverse-phase, gradient high-pressure liquid chromatography. Conditional logistic regression was used to evaluate micronutrient effect after adjustment for body mass index (BMI), menopause, parity, oral contraceptive use, smoking status, and alcohol consumption status. MAIN OUTCOME MEASURES: Effect of micronutrients on endometrial cancer risk. RESULTS: The mean concentration of plasma beta-carotene (p=0.001), lycopene (p=0.008), zeaxanthin plus lutein (p=0.031), retinol (p=0.048), and gamma-tocopherol (p=0.046) were significantly lower in endometrial cancer patients than in controls. Plasma levels of beta-carotene (p for trend=0.0007) and lycopene (p for trend=0.007) were inversely associated with endometrial cancer risk across tertiles. Women in the highest tertile of plasma beta-carotene and lycopene had a 0.12-fold (95% confidence intervals (CIs) 0.03-0.48) and 0.15-fold (95% CIs 0.04-0.61) decreased risk of endometrial cancer compared to women in the lowest tertile, respectively. Other micronutrients such as zeaxanthin plus lutein (p for trend=0.142), retinol (p for trend=0.108), alpha-tocopherol (p for trend=0.322), and gamma-tocopherol (p for trend=0.087) showed no association with endometrial cancer risk. CONCLUSIONS: Plasma levels of beta-carotene and lycopene are inversely associated with the risk of endometrial cancer in Korean women.	CC				(-) ↓ risk endometri al cancer

 

Disease type	First Author	Study Title and Complete Citation	Date	Abstract	Study Type	G.Tom +, N,	P.Tom +, N,	F.Tom +, N, -	Lyco +, N,	Other +, N,
Cancer: gastric	Nagao T	Serum antioxidant micronutrients and the risk of oral leukoplakia among Japanese. Nagao T, Ikeda N, Warnakulasuriya S, Fukano H, Yuasa H, Yano M, Miyazaki H, Ito Y. Oral Oncol. 2000 Sep;36(5):466-70.	2000	A population-based case-control study was designed for the investigation of any association between serum micronutrient levels and oral leukoplakia. Out of a total of 9536 subjects over the age of 40 years who participated in the oral mucosal screening programme in Tokoname city, 48 cases detected with oral leukoplakia (38 male:10 female) were recruited. For each case, four controls matched by age and sex were selected from the same cohort. We examined the fasting serum levels of retinol, alpha-tocopherol, zeaxanthin and lutein, cryptoxanthin, lycopene and carotenoids (alpha-carotene and beta-carotene) by high-performance liquid chromatography. Among males with leukoplakia mean serum lycopene and beta-carotene levels (0.175+/-0.202, 0.357+/-0.295 micromol/l) were significantly lower than those of controls (0.257+/-0.252, 0.555+/-0.408 micromol/l) (P<0.05, P<0.005). Logistic regression analysis with leukoplakia as the dependent variable showed that high serum levels of beta-carotene were related to low risk of oral leukoplakia (odds ratio 0.160, 95% C.I.: 0.029-0.866, P<0.05). There were no significant differences in any of the serum nutrients estimated in female subjects. Our results suggest for the first time that high serum levels of beta-carotene may provide protection against oral precancer for the Japanese male.	CC				(-)/N risk est
Cancer: gastric	Nomura AM	Serum micronutrients and upper aerodigestive tract cancer. Nomura AM, Ziegler RG, Stemmermann GN, Chyou PH, Craft NE. Cancer Epidemiol Biomarkers Prev. 1997 Jun;6(6):407-12.	1997	Numerous dietary studies have found that vegetables and fruits protect against upper aerodigestive tract cancer. To evaluate the role of beta-carotene and other specific carotenoids, a nested case-control study using prediagnostic serum was conducted among 6832 American men of Japanese ancestry examined from 1971 to 1975. During a surveillance period of 20 years, the study identified 28 esophageal, 23 laryngeal, and 16 oral-pharyngeal cancer cases in this cohort. The 69 cases were matched to 138 controls. A liquid chromatography technique, designed to optimize recovery and separation of the individual carotenoids, was used to measure serum levels of lutein, zeaxanthin, beta-cryptoxanthin, lycopene, alpha-carotene, beta-carotene, retinol, retinyl palmitate, and alpha-, delta-, and gamma-tocopherol. With adjustment for cigarette smoking and alcohol intake, we found that alpha-carotene, beta-carotene, beta-cryptoxanthin, total carotenoids and gamma-tocopherol levels were significantly lower in the 69 upper aerodigestive tract cancer patients than in their controls. Trends in risk by tertile of serum level were significant for these five micronutrients. These significant trends persisted in cases diagnosed 10 or more years after phlebotomy for the three individual carotenoids and total carotenoid measurements. The odds ratios for the highest tertile were 0.19 (95% confidence interval, 0.05-0.75) for alpha-carotene, 0.10 (0.02-0.46) for beta-carotene, 0.25 (0.06-1.04) for beta-cryptoxanthin, and 0.22 (0.05-0.88) for total carotenoids. When the cases were separated into esophageal, laryngeal, and oral-pharyngeal cancer, both alpha-carotene and beta-carotene were consistently and strongly associated with reduced risk at each site. The findings suggest that alpha-carotene and other carotenoids, as well as beta-carotene, may be involved in the etiology of upper aerodigestive tract cancer.	CC nested				N

 

Disease type	First Author	Study Title and Complete Citation	Date	Abstract	Study Type	G.Tom +, N,	P.Tom +, N,	F.Tom +, N, -	Lyco +, N,	Other +, N,
Cancer: gastric	Yuan JM	Prediagnostic levels of serum micronutrients in relation to risk of gastric cancer in Shanghai, China. Yuan JM, Ross RK, Gao YT, Qu YH, Chu XD, Yu MC. Cancer Epidemiol Biomarkers Prev. 2004 Nov;13(11 Pt 1):1772-80.	2004	Data on blood levels of specific carotenoids and vitamins in relation to gastric cancer are scarce. Little is known about the relationship between prediagnostic serum levels of carotenoids other than beta-carotene and risk of gastric cancer especially in non-Western populations. Prediagnostic serum concentrations of alpha-carotene, beta-carotene, beta-cryptoxanthin, lycopene, lutein/zeaxanthin, retinol, alpha-tocopherol, gamma-tocopherol, and vitamin C were determined on 191 cases and 570 matched controls within a cohort of 18,244 middle-aged or older men in Shanghai, China, with a follow-up of 12 years. High serum levels of alpha-carotene, beta-carotene, and lycopene were significantly associated with reduced risk of developing gastric cancer (all Ps for trend </= 0.05); the odds ratios (95% confidence intervals) for the highest versus the lowest quartile of alpha-carotene, beta-carotene, and lycopene were 0.38 (0.13-1.11), 0.54 (0.32-0.89), and 0.55 (0.30-1.00), respectively. Increased serum level of vitamin C was significantly associated with reduced risk of gastric cancer among men who neither smoked cigarettes over lifetime nor consumed >/=3 drinks of alcohol per day; the odds ratios (95% confidence intervals) for the second, third, and fourth quartile categories were 0.69 (0.28-1.70), 0.36 (0.14-0.94), and 0.39 (0.15-0.98), respectively, compared with the lowest quartile of vitamin C (P for trend = 0.02). There were no statistically significant relationships of serum levels of beta-cryptoxanthin, lutein/zeaxanthin, retinol, alpha-tocopherol, and gamma-tocopherol with gastric cancer risk. The present study implicates that dietary carotenes, lycopene, and vitamin C are potential chemopreventive agents for gastric cancer in humans.	CC nested				(-) modest ↓ risk with ↑ serum [lyco]
Cancer: gastric	Tsugane S	Cross-sectional study with multiple measurements of biological markers for assessing stomach cancer risks at the population level. Tsugane S, Tsuda M, Gey F, Watanabe S. Environ Health Perspect. 1992 Nov;98:207-10.	1992	A cross-sectional study to determine correlations between measurable biologic markers and mortality from stomach cancer was performed in various areas of Japan. Blood and urine were collected from randomly selected 40- to 49-year-old men and their spouses in four areas with different rates of mortality from stomach cancer. The samples were analyzed for levels of the micronutrients vitamins A, C, and E, beta-carotene, and lycopene in plasma and for levels of NaCl, nitrate, and N-nitrosamino acids (N-nitrosoproline, N-nitrosothioproline [NTPRO] and N-nitrosomethylthioproline [NMTPRO]) in 24-hr urine. A significant, strong correlation was found between the amount of salt excreted in urine and stomach cancer mortality in both men and women. Although the amounts of nitrate and of the three N-nitrosamino acids in 24-hr urine were not correlated with stomach cancer rates, the low excretion levels of NTPRO and NMTPRO in the lowest risk area for stomach cancer were noteworthy, regardless of the high level of nitrate excretion in the same area. This suggests a lesser degree of endogenous nitrosation in the body. No protective effect of micronutrients was observed in this correlation study; there was, however, a negative correlation between plasma lycopene level and stomach cancer mortality. Salt intake was thus confirmed to play an important role in the development of stomach cancer and is likely to be a rate-regulating factor in Japanese populations. N-Nitrosamino acids and lycopene may also be related to stomach cancer mortality.	CS				(-)

 

Disease type	First Author	Study Title and Complete Citation	Date	Abstract	Study Type	G.Tom +, N,	P.Tom +, N,	F.Tom +, N, -	Lyco +, N,	Other +, N,
Cancer: gastric	Tsubono Y	Plasma antioxidant vitamins and carotenoids in five Japanese populations with varied mortality from gastric cancer. Tsubono Y, Tsugane S, Gey KF. Nutr Cancer. 1999;34(1):56-61.	1999	To examine the geographic associations between plasma antioxidant levels and gastric cancer risk, we conducted an ecological study in five regions of Japan representing the threefold variation in the disease mortality within the country. Subjects were 634 men aged 40-49 years sampled randomly from the five regions with 72% response rates. Plasma concentrations of five carotenoids (beta-carotene, alpha-carotene, lycopene, lutein, and zeaxanthin), alpha-tocopherol, and ascorbic acid were measured, and the mean levels were correlated with age-adjusted mortality rates from gastric cancer. beta-Carotene and alpha-tocopherol were inversely correlated with gastric cancer rates (r = -0.31 and -0.89, respectively). alpha-Carotene and lycopene showed stronger inverse correlation than did beta-carotene (r = -0.67 and -0.56, respectively), but these relations disappeared after the exclusion of one outlying region in Okinawa with the lowest mortality. In contrast, ascorbic acid revealed a negative correlation with the exclusion of this outlier (r = -0.61). Lutein and zeaxanthin were not inversely associated with risk. The results suggest that plasma levels of beta-carotene and alpha-tocopherol, and possibly alpha-carotene, lycopene, and ascorbic acid, may partly account for the regional difference in gastric cancer mortality in Japan.	Eco				N
Cancer: lung	Comstock GW	The risk of developing lung cancer associated with antioxidants in the blood: ascorbic acid, carotenoids, alpha-tocopherol, selenium, and total peroxyl radical absorbing capacity. Comstock GW, Alberg AJ, Huang HY, Wu K, Burke AE, Hoffman SC, Norkus EP, Gross M, Cutler RG, Morris JS, Spate VL, Helzlsouer KJ. Cancer Epidemiol Biomarkers Prev. 1997 Nov;6(11):907-16.	1997	Lung cancer cases diagnosed during the period 1975 through 1993 and matched controls were identified in the rosters of Washington County, Maryland residents who had donated blood for a serum bank in 1974 or 1989. Plasma from participants in the 1989 project was assayed for ascorbic acid; serum or plasma was assayed for participants in either project for alpha- and beta-carotene, cryptoxanthin, lutein/zeaxanthin, lycopene, alpha-tocopherol, selenium, and peroxyl radical absorption capacity. Among the total group of 258 cases and 515 controls, serum/plasma concentrations were significantly lower among cases than controls for cryptoxanthin, beta-carotene, and lutein/zeaxanthin with case-control differences of -25.5, -17.1, and -10.1%, respectively. Modest nonsignificant case-control differences in a protective direction were noted for alpha-carotene and ascorbic acid. There were only trivial differences for lycopene, alpha-tocopherol, selenium, and peroxyl radical absorption capacity. Findings are reported for males and females and for persons who had never smoked cigarettes, former smokers, and current smokers at baseline. These results and those from previous studies suggest that beta-carotene is a marker for some protective factor(s) against lung cancer; that cryptoxanthin, alpha-carotene, and ascorbic acid need to be investigated further as potentially protective factors or associates of a protective factor; and that lycopene, alpha-tocopherol, selenium, and peroxyl radical absorption capacity are unlikely to be associated with lung cancer risk. Until specific preventive factors are identified, the best protection against lung cancer is still the avoidance of airborne carcinogens, especially tobacco smoke; second best is the consumption of a diet rich in fruits and vegetables.	CC nested				N

 

Disease type	First Author	Study Title and Complete Citation	Date	Abstract	Study Type	G.Tom +, N,	P.Tom +, N,	F.Tom +, N, -	Lyco +, N,	Other +, N,
Cancer: lung	Yuan JM	Prediagnostic levels of serum beta-cryptoxanthin and retinol predict smoking-related lung cancer risk in Shanghai, China. Yuan JM, Ross RK, Chu XD, Gao YT, Yu MC. Cancer Epidemiol Biomarkers Prev. 2001 Jul;10(7):767-73.	2001	Higher blood levels of beta-carotene have been found to be associated with reduced risk of lung cancer, but large intervention trials have failed to demonstrate reduced lung cancer incidence after prolonged high-dose beta-carotene supplementation. Data on blood levels of specific carotenoids other than beta-carotene in relation to lung cancer are scarce. Little is known about the relationship between prediagnostic serum levels of carotenoids, retinol, and tocopherols, and risk of lung cancer especially in non-Western populations. Between January 1986 and September 1989, 18,244 men ages 45-64 years participated in a prospective study of diet and cancer in Shanghai, China. Information on tobacco smoking and other lifestyle factors was obtained through in-person interviews. A serum sample was collected from each study participant at baseline. During the first 12 years of follow-up, 209 lung cancer cases, excluding those diagnosed within 2 years of enrollment, were identified. For each cancer case, three cancer-free control subjects were randomly selected from the cohort and matched to the index case by age (within 2 years), month and year of blood sample collection, and neighborhood of residence. Serum concentrations of retinol, alpha- and gamma-tocopherols, and specific carotenoids including alpha-carotene, beta-carotene, beta-cryptoxanthin, lycopene, and lutein/zeaxanthin were determined on the 209 cases and 622 matched controls by high-performance liquid chromatography methods. A high prediagnostic serum level of beta-cryptoxanthin was significantly associated with reduced risk of lung cancer; relative to the lowest quartile, the smoking-adjusted relative risks (95% confidence intervals) for the 2nd, 3rd, and 4th quartile categories were 0.72 (0.41-1.26), 0.42 (0.21-0.84), and 0.45 (0.22-0.92), respectively (P for trend = 0.02). Increased serum levels of other specific carotenoids including alpha-carotene, beta-carotene, lycopene, and lutein/zeaxanthinwere related to reduced risk of lung cancer although the inverse associations were no longer statistically significant after adjustment for smoking. A statistically significant 37% reduction in risk of lung cancer was noted in smokers with above versus below median level of total carotenoids. Serum retinol levels showed a threshold effect on lung cancer risk. Compared with the lowest quartile (<40 microg/dl), the smoking-adjusted relative risk (95% confidence interval) was 0.60 (0.39-0.92) for men in the 2nd-4th quartiles of retinol values combined; no additional decrease in risk was observed between individuals from the 2nd to 4th quartiles. There were no associations between prediagnostic serum levels of alpha- and gamma-tocopherols and lung cancer (all Ps for trend > or =0.4). The present data indicate that higher prediagnostic serum levels of total carotenoids and beta-cryptoxanthin were associated with lower smoking-related lung cancer risk in middle-aged and older men in Shanghai, China. Low level of serum retinol (with a threshold effect) is associated with increased lung cancer risk in this oriental population.	CC nested				N
Cancer: lung	Ito Y	Serum carotenoids and mortality from lung cancer: a case-control study nested in the Japan Collaborative Cohort (JACC) study. Ito Y, Wakai K, Suzuki K, Tamakoshi A, Seki N, Ando M, Nishino Y, Kondo T, Watanabe Y, Ozasa K, Ohno Y; JACC Study Group. Cancer Sci. 2003 Jan;94(1):57-63.	2003	To investigate whether high serum levels of carotenoids, tocopherols, and folic acid decrease risk of lung cancer in Japanese, we conducted a case-control study nested in the Japan Collaborative Cohort (JACC) Study. A total of 39,140 subjects provided serum samples at baseline between 1988 and 1990. We identified 147 cases (113 males and 34 females) of death from lung cancer during an 8-year follow-up. Of the subjects who survived to the end of this follow-up, 311 controls (237 males and 74 females) were selected, matched to each case of lung cancer death for gender, age and participating institution. We measured serum levels of antioxidants in cases of lung cancer death and controls. Odds ratios (ORs) for lung cancer death were estimated using conditional logistic models. The risk of lung cancer death for the highest quartile of serum alpha-carotene, beta-carotene, lycopene, beta-cryptoxanthin, and canthaxanthin was significantly or marginally significantly lower than for the lowest quartile: the ORs, adjusted for smoking and other covariates, were 0.35 (95% confidence interval (CI), 0.14-0.88), 0.21 (0.08-0.58), 0.46 (0.21-1.04), 0.44 (0.17-1.16) and 0.37 (0.15-0.91), respectively. The ORs for the highest serum levels of zeaxanthin/lutein and folic acid tended to be low, but the differences were not statistically significant. Serum total cholesterol was also inversely related to risk of lung cancer death: the OR for the highest vs. the lowest quartile was 0.39 (95% CI, 0.19-0.79). Higher serum levels of carotenoids such as alpha- and beta-carotenes may play a role in preventing death from lung cancer among Japanese.	CC nested				N

 

Disease type	First Author	Study Title and Complete Citation	Date	Abstract	Study Type	G.Tom +, N,	P.Tom +, N,	F.Tom +, N, -	Lyco +, N,	Other +, N,
Cancer: ovarian	Jeong NH	Plasma carotenoids, retinol and tocopherol levels and the risk of ovarian cancer. Jeong NH, Song ES, Lee JM, Lee KB, Kim MK, Cheon JE, Lee JK, Son SK, Lee JP, Kim JH, Hur SY, Kwon YI. Acta Obstet Gynecol Scand. 2009;88(4):45762.	2009	OBJECTIVE: We investigated the relation between plasma carotenoids, retinol and tocopherol levels and ovarian cancer risk in Korean women. DESIGN: Hospital-based case-control study. SETTING: Six tertiary medical institutes in Korea. POPULATION: Forty-five epithelial ovarian cancers and 135 age-matched controls. METHODS: Preoperative plasma concentrations of beta-carotene, lycopene, zeaxanthin plus lutein, retinol, alpha-tocopherol, and gamma-tocopherol were measured by reverse-phase, gradient high-pressure liquid chromatography. MAIN OUTCOME MEASURES: Odds ratios (OR) and 95% confidence intervals (95%CI) were estimated by tertiles to evaluate the effect of micronutrients on endometrial cancer risk after adjustment for body mass (BMI) index, menopause, parity, oral contraceptive use, smoking status, and alcohol consumption status. RESULTS: Women in the highest tertile for beta-carotene had 0.12-times the risk of ovarian cancer of in the lowest tertile (OR 0.12; 95%CI 0.04-0.36). Women with the highest tertiles of lycopene (OR 0.09; 95%CI 0.03-0.32), zeaxanthin/lutein (OR 0.21; 95%CI 0.09-0.52), retinol (OR 0.45; 95%CI 0.21-0.98), alpha-tocopherol (OR 0.23; 95%CI 0.10-0.53) and gamma-tocopherol (OR 0.28; 95%CI 0.11-0.70) had lower risk of ovarian cancer than women in the lowest tertiles. Results were consistent across strata of socio-epidemiologic factors. CONCLUSIONS: Micronutrients, specifically ss-carotene, lycopene, zeaxanthin, lutein, retinol, alpha-tocopherol, and gamma-tocopherol, may play a role in reducing the risk of ovarian cancer	CC				(-)
Cancer: ovarian	Helzlsouer KJ	Prospective study of serum micronutrients and ovarian cancer. Helzlsouer KJ, Alberg AJ, Norkus EP, Morris JS, Hoffman SC, Comstock GW. J Natl Cancer Inst. 1996 Jan 3;88(1):32-7.	1996	BACKGROUND: Antioxidant micronutrients, such as alpha-tocopherol (vitamin E), the carotenoids, and selenium, may protect against the development of cancer by preventing free radical damage at the cellular level. PURPOSE: A nested case--control study was conducted among donors to a serum bank to examine the association between levels of serum micronutrients and/or cholesterol and the development of ovarian cancer. METHODS: In 1974, sera were collected from 20,305 residents of Washington County, MD, over a 4-month period and stored at -70 ºC. Serum micronutrient concentrations of women who developed ovarian cancer (case subjects, n = 35) were compared with those of women who remained free of cancer and who were matched to case subjects on age and menopausal status (control subjects, n = 67). Serum levels of retinol (vitamin A), alpha- and beta-carotene, lycopene, and alpha- and gamma-tocopherol were measured using high-performance liquid chromatography. Serum selenium (Se) was measured by neutron activation analysis. Cholesterol was measured by enzymatic assay. The data were categorized into thirds and conditional logistic regression analyses were performed to determine the association between prediagnostic serum cholesterol and micronutrient levels and the development of ovarian cancer; matched odds ratios (ORs) were determined from these regression analyses. P values for trend and for interaction were calculated with the use of two-sided likelihood ratio tests. RESULTS: Higher serum alpha-tocopherol levels were associated with an increased risk of ovarian cancer (P for trend = .04); however, this association diminished after adjustment for cholesterol. Women with higher serum cholesterol levels had an increased risk of ovarian cancer compared with women in the lowest third of cholesterol levels (OR = 3.2; 95% confidence interval = 0.9-11.3). The association between serum cholesterol levels and the risk of ovarian cancer was examined, stratifying by micronutrient level. The general pattern observed was an increased risk of ovarian cancer associated with cholesterol levels greater than 200 mg/dL, regardless of the micronutrient level. Serum selenium was associated with a decreased risk of ovarian cancer only among case participants diagnosed 4 or more years after blood collections (P for trend = .02). Concentrations of carotenoids and retinol were not associated with the development of ovarian cancer. CONCLUSIONS: Se may have a protective role against the development of ovarian cancer. Higher serum cholesterol levels were associated with an increased risk of developing ovarian cancer, which persisted regardless of serum micronutrient level. IMPLICATIONS: Given the small size of this study and the inconsistency of results among the few prospective studies of ovarian cancer conducted to test these associations, replications of these findings are highly desirable.	CC nested				N

 

Disease type	First Author	Study Title and Complete Citation	Date	Abstract	Study Type	G.Tom +, N,	P.Tom +, N,	F.Tom +, N, -	Lyco +, N,	Other +, N,
Cancer: pancreati c	Burney PG	Serologic precursors of cancer: serum micronutrients and the subsequent risk of pancreatic cancer. Burney PG, Comstock GW, Morris JS. Am J Clin Nutr. 1989 May;49(5):895-900.	1989	In a nested case-control study the stored, frozen sera from 22 cases of cancer of the pancreas and 44 matched control subjects were assayed for retinol, retinol-binding protein, total carotenoids, beta-carotene, lycopene, vitamin E (alpha-tocopherol), and selenium. Prediagnostic serum levels of lycopene and Se were lower among cases than among matched control subjects. These differences remained after adjustment was made for possible confounding by smoking, educational level, and the other measured serum levels. Low levels of serum vitamin E appeared to have a protective effect but a chance association between vitamin E and cancer of the pancreas could not reasonably be excluded. The association between cancer of the pancreas and serum Se was significant when the data were analyzed as a whole but its effect was seen principally in men.	CC nested				(-)
Cancer: prostate	Rao AV	Serum and tissue lycopene and biomarkers of oxidation in prostate cancer patients: a case-control study. Rao AV, Fleshner N, Agarwal S. Nutr Cancer. 1999;33(2):159-64	1999	Dietary intake of tomatoes and tomato products containing lycopene, an antioxidant carotenoid, has been shown in recent studies to reduce the risk of cancer. This study was conducted to investigate the serum and prostate tissue lycopene and other major carotenoid concentrations in cancer patients and their controls. Serum lipid and protein oxidation was also measured. Twelve prostate cancer patients and 12 age-matched subjects were used in the study. Significantly lower serum and tissue lycopene levels (44%, p = 0.04; 78%, p = 0.050, respectively) were observed in the cancer patients than in their controls. Serum and tissue beta-carotene and other major carotenoids did not differ between the two groups (p = 0.395 and p = 0.280, respectively). Although there was no difference (p = 0.760) in serum lipid peroxidation between cancer patients and their controls (7.09 +/- 0.74 and 6.81 +/- 0.56 mumol/l, respectively), serum protein thiol levels were significantly lower among the cancer patients (p = 0.026). This study demonstrates that the status of lycopene but not other carotenoids in prostate cancer patients is different from controls. The role of dietary lycopene in preventing oxidative damage of biomolecules and thereby reducing the risk of prostate cancer needs to be evaluated in future studies.	CC				(-)

 

Disease type	First Author	Study Title and Complete Citation	Date	Abstract	Study Type	G.Tom +, N,	P.Tom +, N,	F.Tom +, N, -	Lyco +, N,	Other +, N,
Cancer: prostate	Vogt TM	Serum lycopene, other serum carotenoids, and risk of prostate cancer in US Blacks and Whites. Vogt TM, Mayne ST, Graubard BI, Swanson CA, Sowell AL, Schoenberg JB, Swanson GM, Greenberg RS, Hoover RN, Hayes RB, Ziegler RG. Am J Epidemiol. 2002 Jun 1;155(11):102332.	2002	Epidemiologic studies investigating the relation between individual carotenoids and risk of prostate cancer have produced inconsistent results. To further explore these associations and to search for reasons prostate cancer incidence is over 50% higher in US Blacks than Whites, the authors analyzed the serum levels of individual carotenoids in 209 cases and 228 controls in a US multicenter, population-based case-control study (1986-1989) that included comparable numbers of Black men and White men aged 40-79 years. Lycopene was inversely associated with prostate cancer risk (comparing highest with lowest quartiles, odds ratio (OR) = 0.65, 95% confidence interval (CI): 0.36, 1.15; test for trend, p = 0.09), particularly for aggressive disease (comparing extreme quartiles, OR = 0.37, 95% CI: 0.15, 0.94; test for trend, p = 0.04). Other carotenoids were positively associated with risk. For all carotenoids, patterns were similar for Blacks and Whites. However, in both the controls and the Third National Health and Nutrition Examination Survey, serum lycopene concentrations were significantly lower in Blacks than in Whites, raising the possibility that differences in lycopene exposure may contribute to the racial disparity in incidence. In conclusion, the results, though not statistically significant, suggest that serum lycopene is inversely related to prostate cancer risk in US Blacks and Whites.	CC				(-)/N
Cancer:	Chang S	Relationship between	2005	Carotenoids, particularly lycopene, are thought to decrease prostate cancer risk, but the relationship between plasma carotenoid	CC				N/(-)
prostate		plasma carotenoids and		concentrations and risk in various populations has not been well characterized. Comparing 118 non-Hispanic Caucasian men
		prostate cancer.		mainly from southeast Texas with nonmetastatic prostate cancer with 52 healthy men from the same area, we conducted a					only ↓ risk
		Chang S, Erdman JW Jr, Clinton SK, Vadiveloo M, Strom SS, Yamamura Y, Duphorne CM, Spitz MR, Amos CI, Contois JH, Gu X, Babaian RJ, Scardino PT, Hursting SD. Nutr Cancer. 2005;53(2):127-34.		case-control analysis evaluating associations between risk and plasma levels of total carotenoids, beta-cryptoxanthin, alpha-and trans-beta-carotene, lutein and zeaxanthin, total lycopenes, trans-lycopene, total cis-lycopenes, and cis-lycopene isoforms 1, 2, 3, and 5. Risk for men with high plasma levels of alpha-carotene, trans-beta-carotene, beta-cryptoxanthin, and lutein and zeaxanthin was less than half that for those with lower levels. In contrast, we observed no significant associations for total lycopenes, all-trans-lycopene, and cis-lycopene isomer peaks 2, 3, and 5, although high levels of cis-lycopene isomer peak 1 were inversely associated with risk. Analysis of men with aggressive disease (Gleason scores of > or =7, n = 88) vs. less aggressive cases (Gleason scores of <7, n = 30) failed to reveal significant associations between carotenoid levels and the risk of diagnosis with aggressive disease. These findings suggest that, in these men, higher circulating levels of alpha-cryptoxanthin, alpha-carotene, trans-beta-carotene, and lutein and zeaxanthin may contribute to lower prostate cancer risk but not to disease progression.					with cislyco isomer 1

 

Disease type	First Author	Study Title and Complete Citation	Date	Abstract	Study Type	G.Tom +, N,	P.Tom +, N,	F.Tom +, N, -	Lyco +, N,	Other +, N,
Cancer: prostate	Key TJ	Plasma carotenoids, retinol, and tocopherols and the risk of prostate cancer in the European Prospective Investigation into Cancer and Nutrition study. Key TJ, Appleby PN, Allen NE, Travis RC, Roddam AW, Jenab M, Egevad L, Tjanneland A, Johnsen NF, Overvad K, Linseisen J, Rohrmann S, Boeing H, Pischon T, Psaltopoulou T, Trichopoulou A, Trichopoulos D, Palli D, Vineis P, Tumino R, Berrino F, Kiemeney L, Bueno-de-Mesquita HB, Quiras JR, Gonzalez CA, Martinez C, Larranaga N, Chirlaque MD, Ardanaz	2007	BACKGROUND: Previous studies suggest that high plasma concentrations of carotenoids, retinol, or tocopherols may reduce the risk of prostate cancer. OBJECTIVE: We aimed to examine the associations between plasma concentrations of 7 carotenoids, retinol, alpha-tocopherol, and gamma-tocopherol and prostate cancer risk. DESIGN: A total of 137,001 men in 8 European countries participated. After a mean of 6 y, 966 incident cases of prostate cancer with plasma were available. A total of 1064 control subjects were selected and were matched for study center, age, and date of recruitment. The relative risk of prostate cancer was estimated by conditional logistic regression, which was adjusted for smoking status, alcohol intake, body mass index, marital status, physical activity, and education level. RESULTS: Overall, none of the micronutrients examined were significantly associated with prostate cancer risk. For lycopene and the sum of carotenoids, there was evidence of heterogeneity between the associations with risks of localized and advanced disease. These carotenoids were not associated with the risk of localized disease but were inversely associated with the risk of advanced disease. The risk of advanced disease for men in the highest fifth of plasma concentrations compared with men in the lowest fifth was 0.40 (95% CI: 0.19, 0.88) for lycopene and 0.35 (95% CI: 0.17, 0.78) for the sum of carotenoids. CONCLUSIONS: We observed no associations between plasma concentrations of carotenoids, retinol, or tocopherols and overall prostate cancer risk. The inverse associations of lycopene and the sum of carotenoids with the risk of advanced disease may involve a protective effect, an association of dietary choice with delayed detection of prostate cancer, reverse causality, or other factors.	CC				(-) ↓ risk
Cancer: prostate	Peters U	Serum lycopene, other carotenoids, and prostate cancer risk: a nested case-control study in the prostate, lung, colorectal, and ovarian cancer screening trial. Peters U, Leitzmann MF, Chatterjee N, Wang Y, Albanes D, Gelmann EP, Friesen MD, Riboli E, Hayes RB. Cancer Epidemiol Biomarkers Prev. 2007 May;16(5):962-8.	2007	BACKGROUND: Reports from several studies have suggested that carotenoids, and in particular lycopene, could be prostate cancer-preventive agents. This has stimulated extensive laboratory and clinical research, as well as much commercial and public enthusiasm. However, the epidemiologic evidence remains inconclusive. MATERIALS AND METHODS: We investigated the association between prediagnostic serum carotenoids (lycopene, alpha-carotene, beta-carotene, beta-cryptoxanthin, lutein, and zeaxanthin) and risk of prostate cancer in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial, a multicenter study designed to examine methods of early detection and risk factors for cancer. The study included 692 incident prostate cancer cases, diagnosed 1 to 8 years after study entry, including 270 aggressive cases, with regional or distant stage (n = 90) or Gleason score >or=7 (n = 235), and 844 randomly selected, matched controls. As study participants were selected from those who were assigned to annual standardized screening for prostate cancer, results are unlikely to be biased by differential screening, a circumstance that is difficult to attain under non-trial conditions. RESULTS: No association was observed between serum lycopene and total prostate cancer [odds ratios (OR), 1.14; 95% confidence intervals (95% CI), 0.82-1.58 for highest versus lowest quintile; P for trend, 0.28] or aggressive prostate cancer (OR, 0.99; 95% CI, 0.62-1.57 for highest versus lowest quintile; P for trend, 0.433). beta-Carotene was associated with an ncreased risk of aggressive prostate cancer (OR, 1.67; 95% CI, 1.03-2.72 for highest versus lowest quintile; P for trend, 0.13); in particular, regional or distant stage disease (OR, 3.16; 95% CI, 1.37-7.31 for highest versus lowest quintile; P for trend, 0.02); other carotenoids were not associated with risk. CONCLUSION: In this large prospective study, high serum beta-carotene concentrations were associated with increased risk for aggressive, clinically relevant prostate cancer. Lycopene and other carotenoids were unrelated to prostate cancer. Consistent with other recent publications, these results suggest that lycopene or tomato-based regimens will not be effective for prostate cancer prevention.	CC				N

 

Disease type	First Author	Study Title and Complete Citation	Date	Abstract	Study Type	G.Tom +, N,	P.Tom +, N,	F.Tom +, N, -	Lyco +, N,	Other +, N,
Cancer: prostate	Zhang J	Plasma carotenoids and prostate cancer: a population-based case-control study in Arkansas. Zhang J, Dhakal I, Stone A, Ning B, Greene G, Lang NP, Kadlubar FF. Nutr Cancer. 2007;59(1):46-53.	2007	Carotenoids possess antioxidant properties and thus may protect against prostate cancer. Epidemiological studies of dietary carotenoids and this malignancy were inconsistent, partially due to dietary assessment error. In this study, we aimed to investigate the relation between plasma concentrations of carotenoids and the risk of prostate cancer in a population-based case-control study in Arkansas. Cases (n = 193) were men with prostate cancer diagnosed in 3 major hospitals, and controls (n = 197) were matched to cases by age, race, and county of residence. After adjustment for confounders, plasma levels of lycopene, lutein/zeaxanthin, and beta-cryptoxanthin were inversely associated with prostate cancer risk. Subjects in the highest quartile of plasma lycopene (513.7 microg/l) had a 55% lower risk of prostate cancer than those in the lowest quartile (140.5 microg/l; P trend = 0.042). No apparent association was observed for plasma alpha-carotene and beta-carotene. Further adjustment for the other 4 carotenoids did not materially alter the risk estimates for plasma lycopene, lutein/zeaxanthin, and beta-cryptoxanthin but appeared to result in an elevated risk with high levels of plasma alpha-carotene and beta-carotene. The results of all analyses did not vary substantially by age, race, and smoking status. This study added to the emerging evidence that high circulating levels of lycopene, lutein/zeaxanthin, and beta-cryptoxanthin are associated with a low risk of prostate cancer.	CC				(-) ↓ risk
Cancer: prostate	Mikhak B	Manganese superoxide dismutase (MnSOD) gene polymorphism, interactions with carotenoid levels and prostate cancer risk. Mikhak B, Hunter DJ, Spiegelman D, Platz EA, Wu K, Erdman JW Jr, Giovannucci E. Carcinogenesis. 2008 Dec;29(12):2335-40. Epub 2008 Sep 10. Gene.	2008	BACKGROUND: The manganese superoxide dismutase (MnSOD) gene encodes an antioxidant enzyme (SOD2) that may protect cells from oxidative damage. The MnSOD allele with Val as amino acid 16 encodes a protein that has 30-40% lower activity compared with the MnSOD Ala variant, hence possibly increasing susceptibility to oxidative stress. On the other hand, some epidemiologic studies suggest that the Ala allele is associated with a higher risk of cancer, including prostate cancer. METHODS: We conducted a nested case-control study in the Health Professionals Follow-up Study with 612 incident prostate cancer cases and 612 matched controls to investigate the role of the MnSOD gene Ala16Val polymorphism and its joint association with plasma carotenoid concentrations in relation to risk of total prostate cancer and aggressive prostate cancer (advanced stage or Gleason sum > or =7). RESULTS: The allele frequencies in the controls were 49.8% for Ala and 50.2% for Val. No association was found between the MnSOD genotype and risk of total and aggressive prostate cancer. Furthermore, no statistically significant interaction was observed between the MnSOD genotype and any of the plasma carotenoids in relation to risk of total and aggressive prostate cancer. In analyses in which we combined data from plasma and dietary carotenoids and created a quintile score to reflect long-term carotenoid status, a 3-fold [95% confidence interval: 1.37-7.02] increased risk of aggressive prostate cancer was observed among men with the Ala/Ala genotype in the presence of low long-term lycopene status (P-value, test for interaction = 0.02) as compared with men with the Ala/Val+Val/Val genotypes with low long-term lycopene status. CONCLUSION: In this cohort of mainly white men, the MnSOD gene Ala16Val polymorphism was not associated with total or aggressive prostate cancer risk. However, men with the MnSOD Ala/Ala genotype who had low long-term lycopene status had a higher risk of aggressive prostate cancer compared with individuals with the other genotypes. These results are consistent with findings from earlier studies that reported when antioxidant status is low, the MnSOD Ala/Ala genotype may be associated with an increased risk of aggressive prostate cancer.	CC				(-) ↓ long term lyco status ↑ PC risk IF have Ala/Ala genotype

 

Disease type	First Author	Study Title and Complete Citation	Date	Abstract	Study Type	G.Tom +, N,	P.Tom +, N,	F.Tom +, N, -	Lyco +, N,	Other +, N,
Cancer: prostate	Lee KM	Nitric oxide synthase gene polymorphisms and prostate cancer risk. Lee KM, Kang D, Park SK, Berndt SI, Reding D, Chatterjee N, Chanock S, Huang WY, Hayes RB. Carcinogenesis. 2009 Apr;30(4):621-5. Epub 2009 Jan 23.	2009	Nitric oxide (NO) induces cytotoxicity and angiogenesis, and may play a role in prostate carcinogenesis, potentially modulated by environmental exposures. We evaluated the association of prostate cancer with genetic polymorphisms in two genes related to intracellular NO: NOS2A [inducible nitric oxide synthase (NOS); -2892T>C, Ex16 + 14C>T (S608L), IVS16 + 88T>G and IVS20 + 524G>A] and NOS3 [endothelial NOS; IVS1-762C>T, Ex7-43C>T (D258D), IVS7-26A>G, Ex8-63G>T (E298D) and IVS15-62G>T]. Prostate cancer cases (n = 1320) from the screening arm of the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial were frequency matched to controls (n = 1842), by age, race, time since initial screening and year of blood draw. An antioxidant score [range 3-12; low (3-7) versus high (8-12)] was created by summing the quartile levels of vitamin E, beta-carotene and lycopene, which were coded from 1 to 4, respectively. The global tests for all eight single-nucleotide polymorphisms (SNPs) (excluding NOS2A-2892T>C, with low minor allele frequency) were statistically significant for prostate cancer (P = 0.005), especially for aggressive cancer (stage III-IV or Gleason score > or = 7) (P = 0.01). The NOS2A IVS16 + 88 GT/TT was associated with increased prostate cancer risk (odds ratio = 1.24, 95% confidence interval = 1.00-1.54), whereas the IVS20 + 524 AG/GG was associated with decreased risk (0.77, 0.66-0.90). The NOS3 IVS7-26GG was associated with increased prostate cancer risk (1.33, 1.07-1.64). All these SNPs showed significant associations with aggressive cancer and not for non-aggressive cancer. In the evaluation of effect modification, the effect of the NOS2A IVS16 + 88 GT/TT on aggressive cancer was stronger among subjects with higher antioxidant intake (1.61, 1.18-2.19; P(interaction) = 0.01). Our results suggest that NOS gene polymorphisms are genetic susceptibility factors for aggressive prostate cancer.	CC				(-) ↑ [lyco] modified effect of NOS2A IVS16 SNP
Cancer: prostate	Hsing AW	Serologic precursors of cancer. Retinol, carotenoids, and tocopherol and risk of prostate cancer. Hsing AW, Comstock GW, Abbey H, Polk BF. J Natl Cancer Inst. 1990 Jun 6;82(11):941-6.	1990	We investigated the associations of serum retinol, the carotenoids beta-carotene and lycopene, and tocopherol (vitamin E) with the risk of prostate cancer in a nested case-control study. For the study, serum obtained in 1974 from 25,802 persons inWashington County, MD, was used. Serum levels of the nutrients in 103 men who developed prostate cancer during the subsequent 13 years were compared with levels in 103 control subjects matched for age and race. Although no significant associations were observed with beta-carotene, lycopene, or tocopherol, the data suggested an inverse relationship between serum retinol and risk of prostate cancer. We analyzed data on the distribution of serum retinol by quartiles, using the lowest quartile as the reference value. Odds ratios were 0.67, 0.39, and 0.40 for the second, third, and highest quartiles, respectively.	CC nested				N

 

Disease type	First Author	Study Title and Complete Citation	Date	Abstract	Study Type	G.Tom +, N,	P.Tom +, N,	F.Tom +, N, -	Lyco +, N,	Other +, N,
Cancer: prostate	Nomura AM	Serum micronutrients and prostate cancer in Japanese Americans in Hawaii. Nomura AM, Stemmermann GN, Lee J, Craft NE. Cancer Epidemiol Biomarkers Prev. 1997 Jul;6(7):487-91.	1997	Numerous dietary studies and several serum micronutrient studies have produced equivocal results on the relation of vitamins A and E to prostate cancer risk. To evaluate this association further, we conducted a nested case-control study in a cohort of 6860 Japanese-American men examined from 1971 to 1975. At the time of examination, a single blood specimen was obtained, and the serum was frozen. After a surveillance period of more than 20 years, 142 tissue-confirmed incident cases of prostate cancer were identified. Their stored sera and those of 142 matched controls were measured by high-performance liquid chromatography for the following: total carotenoids, lutein, zeaxanthin, beta-cryptoxanthin, lycopene, alpha-carotene, beta-carotene, total retinoids, retinol, total tocopherols, alpha-tocopherol, delta-tocopherol, and gamma-tocopherol. Odds ratios for prostate cancer, based on quartiles of serum micronutrient levels, were determined using conditional logistic regression analysis. The odds ratio for the highest quartiles were 1.8 (95% confidence interval, 0.9-3.9) for beta-cryptoxanthin, 1.6 (0.8-3.5) for beta-carotene, 0.8 (0.4-1.5) for retinol, and 0.7 (0.3-1.5) for gamma-tocopherol, but none of the differences was statistically significant. For the other micronutrients, the results were also unremarkable. The findings of this study indicate that none of the micronutrients is strongly associated with prostate cancer risk.	CC nested				N
Cancer: prostate	Gann PH	Lower prostate cancer risk in men with elevated plasma lycopene levels: results of a prospective analysis. Gann PH, Ma J, Giovannucci E, Willett W, Sacks FM, Hennekens CH, Stampfer MJ. Cancer Res. 1999 Mar 15;59(6):1225-30.	1999	Dietary consumption of the carotenoid lycopene (mostly from tomato products) has been associated with a lower risk of prostate cancer. Evidence relating other carotenoids, tocopherols, and retinol to prostate cancer risk has been equivocal. This prospective study was designed to examine the relationship between plasma concentrations of several major antioxidants and risk of prostate cancer. We conducted a nested case-control study using plasma samples obtained in 1982 from healthy men enrolled in the Physicians' Health Study, a randomized, placebo-controlled trial of aspirin and beta-carotene. Subjects included 578 men who developed prostate cancer within 13 years of follow-up and 1294 age- and smoking status-matched controls. We quantified the five major plasma carotenoid peaks (alpha- and beta-carotene, beta-cryptoxanthin, lutein, and lycopene) plus alpha- and gamma-tocopherol and retinol using high-performance liquid chromatography. Results for plasma beta-carotene are reported separately. Odds ratios (ORs), 95% confidence intervals (Cls), and Ps for trend were calculated for each quintile of plasma antioxidant using logistic regression models that allowed for adjustment of potential confounders and estimation of effect modification by assignment to either active beta-carotene or placebo in the trial. Lycopene was the only antioxidant found at significantly lower mean levels in cases than in matched controls (P = 0.04 for all cases). The ORs for all prostate cancers declined slightly with increasing quintile of plasma lycopene (5th quintile OR = 0.75, 95% CI = 0.54-1.06; P, trend = 0.12); there was a stronger inverse association for aggressive prostate cancers (5th quintile OR = 0.56, 95% CI = 0.34-0.91; P, trend = 0.05). In the placebo group, plasma lycopene was very strongly related to lower prostate cancer risk (5th quintile OR = 0.40; P, trend = 0.006 for aggressive cancer), whereas there was no evidence for a trend among those assigned to beta-carotene supplements. However, in the beta-carotene group, prostate cancer risk was reduced in each lycopene quintile relative to men with low lycopene and placebo. The only other notable association was a reduced risk of aggressive cancer with higher alpha-tocopherol levels that was not statistically significant. None of the associations for lycopene were confounded by age, smoking, body mass index, exercise, alcohol, multivitamin use, or plasma total cholesterol level. These results concur with a recent prospective dietary analysis, which identified lycopene as the carotenoid with the clearest inverse relation to the development of prostate cancer. The inverse association was particularly apparent for aggressive cancer and for men not consuming beta-carotene supplements. For men with low lycopene, beta-carotene supplements were associated with risk reductions comparable to those observed with high lycopene. These data provide further evidence that increased consumption of tomato products and other lycopene-containing foods might reduce the occurrence or progression of prostate cancer.	CC nested				(-)/N	Pbo=(-)  -caro=(N)

 

Disease type	First Author	Study Title and Complete Citation	Date	Abstract	Study Type	G.Tom +, N,	P.Tom +, N,	F.Tom +, N, -	Lyco +, N,	Other +, N,
Cancer: prostate	Lu QY	Inverse associations between plasma lycopene and other carotenoids and prostate cancer. Lu QY, Hung JC, Heber D, Go VL, Reuter VE, Cordon-Cardo C, Scher HI, Marshall JR, Zhang ZF. Cancer Epidemiol Biomarkers Prev. 2001 Jul;10(7):749-56.	2001	Although dietary intake of tomatoes and tomato products containing lycopene has been reported to reduce the risk of prostate cancer, few studies have been done on the relationship between plasma lycopene and other carotenoids and prostate cancer. This case-control study was conducted to investigate the effects of plasma lycopene, other carotenoids, and retinol, as well as alpha- and gamma-tocopherols on the risk of prostate cancer. The study included 65 patients with prostate cancer and 132 cancer-free controls; all of them were interviewed using a standard epidemiological questionnaire at the Memorial Sloan-Kettering Cancer Center from 1993 to 1997. Plasma levels of carotenoids, retinol, and tocopherols were measured by high performance liquid chromatography. An unconditional logistic regression model was used in bivariate and multivariate analyses using Statistical Analysis System (SAS). After adjusting for age, race, years of education, daily caloric intake, pack-years of smoking, alcohol consumption, and family history of prostate cancer, significantly inverse associations with prostate cancer were observed with plasma concentrations of the following carotenoids: lycopene [odds ratio (OR), 0.17; 95% confidence interval (CI), 0.04-0.78; P for trend, 0.0052] and zeaxanthin (OR, 0.22; 95% CI, 0.06-0.83; P for trend, 0.0028) when comparing highest with lowest quartiles. Borderline associations were found for lutein (OR, 0.30; 95% CI, 0.09-1.03; P for trend, 0.0064) and beta-cryptoxanthin (OR, 0.31; 95% CI, 0.08-1.24; P for trend, 0.0666). No obvious associations were found for alpha- and beta-carotenes, retinol, and alpha- and gamma-tocopherols. Our study confirmed the inverse associations between lycopene, other carotenoids such as zeaxanthin, lutein, and beta-cryptoxanthin, and prostate cancer. This study provides justification for further research on the associations between lycopene and other antioxidants and the risk of prostate cancer.	CC nested				(-)
Cancer: prostate	Huang HY	Prospective study of antioxidant micronutrients in the blood and the risk of developing prostate cancer. Huang HY, Alberg AJ, Norkus EP, Hoffman SC, Comstock GW, Helzlsouer KJ. Am J Epidemiol. 2003 Feb 15;157(4):33544.	2003	Antioxidant micronutrients may have chemopreventive effects. The authors examined the associations between prediagnostic blood levels of micronutrients and prostate cancer risk in two nested case-control studies of 9,804 and 10,456 male residents of Washington County, Maryland, who donated blood in 1974 (CLUE I) and 1989 (CLUE II), respectively. Until 1996, 182 men for whom adequate serum remained for assays in the CLUE I cohort and 142 men in the CLUE II cohort developed prostate cancer. Each case was matched with two controls by age, gender, race, and date of blood donation. In both cohorts, cases and controls had similar concentrations of alpha-carotene, beta-carotene, total carotene, beta-cryptoxanthin, lutein, lycopene, retinol, and ascorbic acid; serum alpha-tocopherol was weakly associated with prostate cancer risk. Higher retinyl palmitate concentrations were associated with a lower risk in CLUE I but not CLUE II. In CLUE I, cases had lower concentrations of gamma-tocopherol than did controls (p = 0.02), but no dose-response trend was observed. A strong inverse association between gamma-tocopherol and prostate cancer risk was observed in CLUE II. Findings do not replicate previous reports of a protective association between lycopene and prostate cancer, but they suggest potential chemopreventive effects of gamma-tocopherol on prostate cancer.	CC nested				N

 

Disease type	First Author	Study Title and Complete Citation	Date	Abstract	Study Type	G.Tom +, N,	P.Tom +, N,	F.Tom +, N, -	Lyco +, N,	Other +, N,
Cancer: prostate	Wu K	Plasma and dietary carotenoids, and the risk of prostate cancer: a nested case-control study. Wu K, Erdman JW Jr, Schwartz SJ, Platz EA, Leitzmann M, Clinton SK, DeGroff V, Willett WC, Giovannucci E. Cancer Epidemiol Biomarkers Prev. 2004 Feb;13(2):260-9.	2004	The association between plasma carotenoids and prostate cancer risk was investigated in a case-control study nested within the prospective Health Professionals Follow-up Study. We matched 450 incident prostate cancer cases diagnosed from 1993-1998 to 450 controls by age, time, month, and year of blood donation. Modest inverse, but not statistically significant, associations were observed among plasma alpha-carotene, beta-carotene, and lycopene concentrations, and overall risk of prostate cancer diagnosis [odds ratio (highest versus lowest quintile; OR), alpha-carotene: OR, 0.67 [95% confidence interval (CI), -0.40-1.09]; beta-carotene: OR, 0.78 (95% CI, 0.48-1.25); lycopene: OR, 0.66 (95% CI, 0.38-1.13)]. The inverse association between plasma lycopene concentrations and prostate cancer risk was limited to participants who were 65 years or older (OR, 0.47; 95% CI, 0.23-0.98) and without a family history of prostate cancer (OR, 0.48; 95% CI, 0.26-0.89). Combining, older age and a negative family history provided similar results (OR, 0.43; 95% CI, 0.18-1.02). Inverse associations between beta-carotene and prostate cancer risk were also found among younger participants (<65 years of age; OR, 0.36; 95% CI, 0.14-0.91; P(trend) = 0.03). Combining dietary intake and plasma data confirmed our results. We found a statistically significant inverse association between higher plasma lycopene concentrations and lower risk of prostate cancer, which was restricted to older participants and those without a family history of prostate cancer. This observation suggests that tomato products may exhibit more potent protection against sporadic prostate cancer rather than those with a stronger familial or hereditary component. In addition, our findings also suggest that among younger men, diets rich in beta-carotene may also play a protective role in prostate carcinogenesis.	CC nested				N (-) >65y, w/o FH
Cancer: prostate	Karppi J	Serum lycopene and the risk of cancer: the Kuopio Ischaemic Heart Disease Risk Factor (KIHD) study. Karppi J, Kurl S, Nurmi T, Rissanen TH, Pukkala E, Nyyssanen K. Ann Epidemiol. 2009 Jul;19(7):512-8. Epub 2009 May 13.	2009	PURPOSE: Lycopene is thought to decrease the risk of cancers, although previous epidemiologic studies have produced inconsistent results. The aim of the present study was to evaluate the protective effect of lycopene against the risk of cancer. METHODS: The study population consisted of 997 middle-aged Finnish men in the Kuopio Ischaemic Heart Disease Risk Factor (KIHD) cohort. During the mean follow-up time of 12.6 years, a total of 141 cancer cases appeared, of which 55 were prostate cancers. The association between the serum concentrations of lycopene and the risk of cancer was studied using the Cox proportional hazard models. RESULTS: An inverse association was observed between serum lycopene and overall cancer incidence. The adjusted risk ratio (RR) in the highest tertile of serum lycopene was 0.55 (95% confidence interval [CI], 0.34-0.89; p=0.015) compared with the lowest serum lycopene group. No association was observed between the lycopene concentrations and a prostate cancer risk. RR for other cancers was 0.43 (95% CI, 0.23-0.79; p=0.007). CONCLUSIONS: These findings suggest that in middle-aged men, the higher circulating concentrations of lycopene may contribute to the lower risk of cancer, with the exception of prostate cancer.	PC				(-)/N (-) ↓ risk overall cancer ~~~~~~ N prostate cancer