The Associations of Multivitamin and Antioxidant Use With Mortality Among Women and Men Diagnosed With Colorectal Cancer.

BACKGROUND: Colorectal cancer survivors often use multivitamins and other over-the-counter dietary supplements, but evidence is limited regarding their potential associations with mortality. METHODS: This prospective analysis included women and men from the Cancer Prevention Study-II Nutrition Cohort who were cancer-free at baseline (1992 or 1993) and diagnosed with colorectal cancer through June 2015. Detailed information on multivitamin use, vitamin C supplements, and vitamin E supplements was self-reported on questionnaires at baseline, in 1997, and every 2 years thereafter. Pre- and postdiagnosis data were available for 3176 and 2006 colorectal cancer survivors, respectively, among whom 2116 (648 from colorectal cancer) and 1256 (242 from colorectal cancer) died. Multivariable-adjusted Cox proportional hazards regression models examined associations. All statistical tests were 2-sided. RESULTS: Among colorectal cancer survivors, 49.7% and 58.5% reported multivitamin use before and after diagnosis, respectively (vitamin C use before and after diagnosis: 27.8% and 28.1%; vitamin E use before and after diagnosis: 27.5% and 29.4%, respectively). There were no statistically significant associations of pre- or postdiagnosis multivitamin use with all-cause, colorectal cancer-specific, or noncolorectal cancer mortality. Vitamin C was also not associated with any mortality outcomes. However, prediagnosis vitamin E use was associated with a non-statistically significant increased risk of all-cause mortality (multivariable adjusted hazard ratio = 1.08, 95% confidence intervals = 0.96 to 1.23) and all other noncolorectal cancer mortality (multivariable adjusted hazard ratio = 1.13, 95% confidence intervals = 0.97 to 1.31). CONCLUSIONS: These results suggest that multivitamin use before or after diagnosis is not associated with mortality in colorectal cancer survivors. However, vitamin E use may be associated with increased risk of mortality and merits further investigation.

Coffee Consumption and Invasive Breast Cancer Incidence among Postmenopausal Women in the Cancer Prevention Study-II Nutrition Cohort.

BACKGROUND: There is limited evidence of a potential inverse association between coffee, particularly caffeinated coffee, consumption and postmenopausal breast cancer risk, and few studies have examined this association by tumor hormone receptor status. To provide further evidence, we examined total, caffeinated, and decaffeinated coffee consumption in relation to postmenopausal invasive breast cancer incidence overall, and by tumor estrogen receptor (ER) and/or progesterone receptor (PR) subtype. METHODS: Among 57,075 postmenopausal women in the Cancer Prevention Study-II Nutrition Cohort who were cancer free and reported coffee intake in 1999, we identified 2,980 women diagnosed with invasive breast cancer during follow-up through June 2015. Multivariable-adjusted Cox proportional hazards regression was used to compute hazard ratios (HR) and 95% confidence intervals (CI). RESULTS: Neither total, caffeinated, nor decaffeinated coffee consumption was associated with invasive breast cancer risk; HRs (95% CIs) comparing consumption of ≥2 cups per day with <1 cup per month were 0.99 (0.89-1.11), 0.96 (0.87-1.06), and 1.06 (0.95-1.19), respectively. Similarly, coffee consumption was not associated with risk of hormone receptor-positive (ER+ or PR+) or hormone receptor-negative (ER- and PR-) breast tumors. CONCLUSIONS: These findings do not support an association between coffee consumption and invasive breast cancer risk among postmenopausal women. IMPACT: This large prospective study contributes to the limited evidence on coffee consumption and breast cancer risk, finding no association overall or by tumor receptor subtype.

Coffee consumption and risk of colorectal cancer in the Cancer Prevention Study-II Nutrition Cohort.

BACKGROUND: The association between coffee consumption and colorectal cancer risk generally appears null, but recent evidence suggests that risk may vary by coffee type. We examined associations of caffeinated and decaffeinated coffee intake with colorectal cancer risk overall and with colon and rectum separately, among older U.S. men and women. METHODS: In 1999, 47,010 men and 60,051 women with no previous diagnosis of cancer, aged 47-96 years, in the Cancer Prevention Study-II Nutrition Cohort completed a food frequency questionnaire that assessed caffeinated and decaffeinated coffee intake; consumption was updated in 2003. A total of 1829 colorectal cancer cases were verified through June 2015. Cox proportional hazards regression was used to estimate multivariable-adjusted hazard rate ratios (HRs) and 95% confidence intervals (CIs), adjusting for smoking history, alcohol, caffeinated/decaffeinated coffee intake (depending on the model), and other colorectal cancer risk factors. RESULTS: Consumption of ≥2 cups/day of decaffeinated coffee, compared to no decaffeinated coffee, was associated with lower risk of overall colorectal cancer (HR = 0.82, 95% CI: 0.69-0.96, P-trend = 0.04), colon cancer (HR = 0.82, 95% CI: 0.69-0.99, P-trend = 0.05) and rectal cancer (HR = 0.63, 95% CI: 0.40-0.99, P-trend = 0.17). Consumption of ≥2 cups/day of caffeinated coffee was associated with higher risk of rectal cancer (HR = 1.37, 95% CI: 0.99-1.89, P-trend = 0.04), but not with colorectal or colon cancer. CONCLUSION: In this prospective study, higher intake of decaffeinated coffee was associated with lower risk of colorectal, colon, and rectal cancers. Further study on associations of caffeinated and decaffeinated coffee with colorectal cancer risk by subsite is needed.

Associations of calcium and dairy product intakes with all-cause, all-cancer, colorectal cancer and CHD mortality among older women in the Iowa Women's Health Study.

Ca and dairy product intakes may be inversely associated with all-cause and cause-specific mortality, and non-Ca components of dairy products, such as insulin-like growth factor-1, may be independently associated with mortality. We investigated associations of Ca and dairy product intakes with all-cause, all-cancer, colorectal cancer (CRC) and CHD mortality among 35 221 55- to 69-year-old women in the prospective Iowa Women's Health Study, who were cancer-free in 1986. We assessed diet using a Willett FFQ, and associations using multivariable Cox proportional hazards regression. We estimated residuals from linear regression models of dairy products with dietary Ca to investigate total and specific dairy products independent of their Ca content. Through 2012, 18 687 participants died, including 4665 from cancer (including 574 from CRC) and 3603 from CHD. For those in the highest relative to the lowest quintiles of intake, the multivariable-adjusted hazard ratios (HR) and 95 % CI for total Ca (dietary plus supplemental) were 0·88 (0·83, 0·93; P trend=0·001) for all-cause mortality, 0·91 (0·81, 1·02; P trend=0·34) for all-cancer mortality, 0·60 (0·43, 0·83; P trend=0·002) for CRC mortality and 0·73 (0·64, 0·83; P trend <0·0001) for CHD mortality. The corresponding HR for associations of whole milk, whole milk residuals, and low-/non-fat milk residuals with all-cause mortality were 1·20 (95 % CI 1·13, 1·27), 1·20 (95 % CI 1·13, 1·28) and 0·91 (95 % CI 0·86, 0·96), respectively. These results suggest that Ca may be associated with lower risk of all-cause, CRC and CHD mortality, and that non-Ca components of milk may be independently associated with mortality.

Effects of vitamin D and calcium on expression of MSH2 and transforming growth factors in normal-appearing colorectal mucosa of sporadic colorectal adenoma patients: A randomized clinical trial.

Abnormal expression of the DNA mismatch repair protein MSH2 and autocrine/paracrine transforming growth factors TGFα (growth promoter) and TGFß1 (growth inhibitor) is common during colorectal carcinogenesis. To estimate vitamin D and calcium effects on these biomarkers in the normal-appearing colorectal mucosa of sporadic colorectal adenoma patients, we conducted a pilot, randomized, double-blinded, placebo-controlled, modified 2 × 2 factorial chemoprevention clinical trial (N = 104) of supplemental vitamin D3 (1000 IU daily) and calcium (1200 mg daily), alone and in combination, versus placebo over 1 year. The expression of the three biomarkers and Ki-67/mib-1 in colorectal crypts in biopsies of normal-appearing rectal mucosa were detected using automated immunohistochemistry and quantified using image analysis. In the vitamin D3 and vitamin D3 plus calcium groups, relative to their reference groups, in the upper 40% (differentiation zone) of crypts, it was estimated that, respectively, the MSH2/mib-1 ratio increased by 47% (P = 0.14) and 62% (P = 0.08), TGFß1 expression increased by 41% (P = 0.25) and 78% (P = 0.14), and the TGFα/TGFß1 ratio decreased by 25% (P = 0.31) and 44% (P = 0.13). Although not statistically significant, these results support further research into (i) whether supplemental vitamin D3 , alone or in combination with calcium, may increase DNA mismatch repair relative to proliferation, increase TGFß1 expression, and decrease autocrine/paracrine growth promotion relative to growth inhibition in the colorectal epithelium, all hypothesized to reduce risk for colorectal carcinogenesis; and (ii) the expression of MSH2 relative to mib-1, TGFß1 alone, and TGFα relative to TGFß1 in the normal-appearing rectal mucosa as potential modifiable, pre-neoplastic markers of risk for colorectal neoplasms.

Combined Mineral Intakes and Risk of Colorectal Cancer in Postmenopausal Women.

BACKGROUND: Despite considerable biological plausibility, other than for calcium, there are few reported epidemiologic studies on mineral intake-colorectal cancer associations, none of which investigated multiple minerals in aggregate. METHODS: Accordingly, we incorporated 11 minerals into a mineral score and investigated its association with incident colorectal cancer in the Iowa Women's Health Study, a prospective cohort study of 55- to 69-year-old women who completed a food frequency questionnaire in 1986. In the analytic cohort (n = 35, 221), 1,731 incident colorectal cancer cases were identified via the State Health Registry of Iowa. Participants' calcium, magnesium, manganese, zinc, selenium, potassium, and iodine intakes were ranked 1 to 5, with higher ranks indicating higher, potentially anticarcinogenic, intakes, whereas for iron, copper, phosphorus, and sodium intakes, the rankings were reversed to account for their possible procarcinogenic properties. The rankings were summed to create each woman's mineral score. The mineral score-incident colorectal cancer association was estimated using multivariable Cox proportional hazards regression. RESULTS: There was decreasing risk with an increasing score (P trend = 0.001). The hazard ratios and 95% confidence intervals (CI) for those in mineral score quintiles 2 to 5 relative to those in the lowest were 0.91 (CI, 0.88-1.08), 0.85 (CI, 0.75-0.95), 0.86 (CI, 0.75-0.97), and 0.75 (CI, 0.71-0.95), respectively. CONCLUSIONS: Our findings suggest that a predominance of putative anti- relative to pro-colorectal carcinogenic mineral intakes may be inversely associated with colorectal cancer risk. IMPACT: These results support further investigation of colorectal cancer etiology using composite mineral intake scores.

Effects of supplemental vitamin D and calcium on markers of proliferation, differentiation, and apoptosis in the normal colorectal mucosa of colorectal adenoma patients.

To clarify the roles of vitamin D and calcium as potential chemopreventive agents against colorectal cancer in humans, and to develop "treatable", pre-neoplastic, phenotypic biomarkers of risk for colorectal neoplasms, we estimated the effects of supplemental vitamin D3 (1,000 IU/day [25 µg/day]) and calcium (1,200 mg/day), alone and in combination, on biomarkers of proliferation (mib-1), differentiation (p21), and apoptosis (bax [apoptosis-promoting] and bcl-2 [apoptosis-inhibiting]), in the normal-appearing rectal mucosa in a subsample of participants (n = 104) in a larger randomized, double-blind, placebo-controlled clinical trial among colorectal adenoma patients. The biomarkers were measured in rectal biopsies at baseline and after one year of follow up, using automated immunohistochemistry and quantitative image analysis. In the vitamin D plus calcium group relative to control, in the crypt differentiation zone (upper 40% of crypts), mib-1 expression decreased 24% (P = 0.28); p21 expression alone and relative to mib-1 expression increased 29% (P = 0.06) and 73% (P = 0.06), respectively; and bax expression relative to mib-1 expression increased 58% (P = 0.21). The estimated vitamin D alone treatment effects were similar but of lesser magnitudes, and those for calcium alone were mixed. All estimated treatment effects on bcl-2 expression were close to the null. These pilot study results support further investigation of whether 1) vitamin D and calcium promote colorectal epithelial cell differentiation, reduce proliferation, and promote apoptosis in the normal-appearing human colorectal mucosa, 2) vitamin D and calcium act as chemopreventive agents against colorectal neoplasms, and 3) mib-1, p21, and bax are potential "treatable", pre-neoplastic, biomarkers of risk for colorectal neoplasms.

Association of Coffee and Tea Intake with the Oral Microbiome: Results from a Large Cross-Sectional Study.

Background: The oral microbiota play a central role in oral health, and possibly in carcinogenesis. Research suggests that coffee and tea consumption may have beneficial health effects. We examined the associations of these common beverages with the oral ecosystem in a large cross-sectional study.Methods: We assessed oral microbiota in mouthwash samples from 938 participants in two U.S. cohorts using 16S rRNA gene sequencing. Coffee and tea intake were assessed from food frequency questionnaires. We examined associations of coffee and tea intake with overall oral microbiota diversity and composition using linear regression and permutational MANOVA, respectively, and with taxon abundance using negative binomial generalized linear models; all models adjusted for age, sex, cohort, body mass index, smoking, ethanol intake, and energy intake.Results: Higher tea intake was associated with greater oral microbiota richness (P = 0.05) and diversity (P = 0.006), and shifts in overall community composition (P = 0.002); coffee was not associated with these microbiome parameters. Tea intake was associated with altered abundance of several oral taxa; these included Fusobacteriales, Clostridiales, and Shuttleworthia satelles (higher with increasing tea) and Bifidobacteriaceae, Bergeyella, Lactobacillales, and Kingella oralis (lower with increasing tea). Higher coffee intake was only associated with greater abundance of Granulicatella and Synergistetes.Conclusions: In the largest study to date of tea and coffee consumption in relation to the oral microbiota, the microbiota of tea drinkers differed in several ways from nondrinkers.Impact: Tea-driven changes to the oral microbiome may contribute to previously observed associations between tea and oral and systemic diseases, including cancers. Cancer Epidemiol Biomarkers Prev; 27(7); 814-21. ©2018 AACR.

Associations of Calcium and Dairy Products with All-Cause and Cause-Specific Mortality in the REasons for Geographic and Racial Differences in Stroke (REGARDS) Prospective Cohort Study.

Associations of calcium and dairy product intakes with cardiovascular disease risk and cancer mortality are controversial. We investigated associations of calcium and dairy product intakes with mortality in the prospective REasons for Geographic and Racial Differences in Stroke study (n = 30,239). Of 2,966 total deaths, 32.3% were from CVD and 28.8% from cancer. For those in the upper relative to the lowest quintile of intakes, from Cox proportional hazards regression models, the multivariable-adjusted hazard ratios (HRs) for all-cause mortality were 1.13 (95% confidence intervals [CI] 0.95-1.35; P-trend 0.004) for whole milk, and 0.75 (CI 0.61-0.93; P-trend 0.001) for nonfat milk; for CVD mortality the corresponding HRs were 0.80 (CI 0.55-1.16; P-trend 0.80) and 0.72 (CI 0.49-1.05; P-trend 0.06); and for cancer mortality they were 1.56 (CI 1.17-2.08; P-trend 0.006) and 0.89 (CI 0.62-1.28; P-trend 0.86). Calcium (total, dietary, supplemental) and total dairy product intakes were not associated with all-cause, cardiovascular, or cancer mortality. These results suggest that whole milk consumption may be directly associated with cancer mortality; non-fat milk consumption may be inversely associated with all-cause and cardiovascular- and cancer-specific mortality; and calcium intake independent of milk product intakes may not be associated with mortality.

Circulating insulin-like growth factor-related biomarkers: Correlates and responses to calcium supplementation in colorectal adenoma patients.

Circulating insulin-like growth factor 1 (IGF-1) may be directly associated with colorectal cancer risk, and IGF binding protein 3 (IGFBP-3) is one of the most abundantly expressed binding proteins in various cancers. Calcium intakes, primarily from food, have been directly associated with circulating IGF-1, but whether supplemental calcium affects IGF-1 and IGFBP-3 is unknown. We tested the effects of 1.0 and 2.0 g of supplemental elemental calcium daily on circulating IGF-1 and IGFBP-3 concentrations in colorectal adenoma patients in a randomized, double-blinded, placebo-controlled clinical trial (n = 193). IGF-1 and IGFBP-3 were quantified using enzyme-linked immunoassay and quantitative Western ligand blot, respectively. We also assessed cross-sectional associations of these biomarkers with participants' baseline characteristics. We found no appreciable effect of calcium relative to placebo on circulating IGF-1, IGFBP-3, or the IGF-1:IGFBP-3 molar ratio. Mean IGF-1 concentrations were 11.1% higher in those with greater milk intakes (P = 0.05). Mean IGF-1 and IGFBP-3 concentrations were, respectively, 18.0% (P = 0.003) and 16.5% (P = 0.01) higher in men and were monotonically lower with increasing age (both P = 0.01). IGFBP-3 was 17.7% higher among those with higher relative to no alcohol consumption (P = 0.04). While these results support previous findings that IGF-1 concentrations are higher with greater milk intakes, and IGF-1 and IGFBP-3 concentrations differ according to sex and age, they provide no evidence to suggest that supplemental calcium appreciably affects circulating IGF-1, IGFBP-3, or the IGF-1:IGFBP-3 molar ratio in sporadic colorectal adenoma patients.

Associations of Calcium and Milk Product Intakes with Incident, Sporadic Colorectal Adenomas.

Calcium intake has been consistently, modestly inversely associated with colorectal neoplasms, and supplemental calcium reduced adenoma recurrence in clinical trials. Milk products are the major source of dietary calcium in the United States, but their associations with colorectal neoplasms are unclear. Data pooled from three colonoscopy-based case-control studies of incident, sporadic colorectal adenoma (n = 807 cases, 2,185 controls) were analyzed using multivariable unconditional logistic regression. Residuals from linear regression models of milk with dietary calcium were estimated as the noncalcium, insulin-like growth factor 1-containing component of milk. For total, dietary, and supplemental calcium intakes, the adjusted odds ratios (ORs) comparing the highest to the lowest intake quintiles were 0.94 (95% confidence interval [CI] 0.69-1.30), 0.86 (CI 0.62-1.20), and 0.99 (CI 0.77-1.27), respectively. The corresponding ORs for consumption of total milk products, total milk, nonfat milk, total milk product residuals, and nonfat milk residuals were, respectively, 0.99, 0.90, 0.92, 0.94, and 0.95; all CIs included 1.0. For those who consumed any whole milk relative to those who consumed none, the OR was 1.15 (CI 0.89-1.49). These results are consistent with previous findings of modest inverse associations of calcium intakes with colorectal adenoma, but suggest that milk products may not be associated with adenoma.