Elizabeth T. Jacobs

Selenium supplementation, baseline plasma selenium status and incidence of prostate cancer: an analysis of the complete treatment period of the Nutritional Prevention of Cancer Trial

To present the results (to January 1996, the end of blinded treatment) of the Nutritional Prevention of Cancer (NPC) Trial, a randomized trial of selenium (200 µg daily) designed to test the hypothesis that selenium supplementation (SS) could reduce the risk of recurrent nonmelanoma skin cancer among 1312 residents of the Eastern USA.

A Pooled Analysis of Advanced Colorectal Neoplasia Diagnoses After Colonoscopic Polypectomy

BACKGROUND & AIMS Limited data exist regarding the actual risk of developing advanced adenomas and cancer after polypectomy or the factors that determine risk. METHODS We pooled individual data from 8 prospective studies comprising 9167 men and women aged 22 to 80 with previously resected colorectal adenomas to quantify their risk of developing subsequent advanced adenoma or cancer as well as identify factors associated with the development of advanced colorectal neoplasms during surveillance. RESULTS During a median follow-up period of 47.2 months, advanced colorectal neoplasia was diagnosed in 1082 (11.8%) of the patients, 58 of whom (0.6%) had invasive cancer. Risk of a metachronous advanced adenoma was higher among patients with 5 or more baseline adenomas (24.1%; standard error, 2.2) and those with an adenoma 20 mm in size or greater (19.3%; standard error, 1.5). Risk factor patterns were similar for advanced adenomas and invasive cancer. In multivariate analyses, older age (P < .0001 for trend) and male sex (odds ratio [OR], 1.40; 95% confidence interval [CI], 1.19-1.65) were associated significantly with an increased risk for metachronous advanced neoplasia, as were the number and size of prior adenomas (P < .0001 for trend), the presence of villous features (OR, 1.28; 95% CI, 1.07-1.52), and proximal location (OR, 1.68; 95% CI, 1.43-1.98). High-grade dysplasia was not associated independently with metachronous advanced neoplasia after adjustment for other adenoma characteristics. CONCLUSIONS Occurrence of advanced colorectal neoplasia is common after polypectomy. Factors that are associated most strongly with risk of advanced neoplasia are patient age and the number and size of prior adenomas.

Vitamin D with Calcium Reduces Mortality: Patient Level Pooled Analysis of 70,528 Patients from Eight Major Vitamin D Trials

INTRODUCTION Vitamin D may affect multiple health outcomes. If so, an effect on mortality is to be expected. Using pooled data from randomized controlled trials, we performed individual patient data (IPD) and trial level meta-analyses to assess mortality among participants randomized to either vitamin D alone or vitamin D with calcium. SUBJECTS AND METHODS Through a systematic literature search, we identified 24 randomized controlled trials reporting data on mortality in which vitamin D was given either alone or with calcium. From a total of 13 trials with more than 1000 participants each, eight trials were included in our IPD analysis. Using a stratified Cox regression model, we calculated risk of death during 3 yr of treatment in an intention-to-treat analysis. Also, we performed a trial level meta-analysis including data from all studies. RESULTS The IPD analysis yielded data on 70,528 randomized participants (86.8% females) with a median age of 70 (interquartile range, 62-77) yr. Vitamin D with or without calcium reduced mortality by 7% [hazard ratio, 0.93; 95% confidence interval (CI), 0.88-0.99]. However, vitamin D alone did not affect mortality, but risk of death was reduced if vitamin D was given with calcium (hazard ratio, 0.91; 95% CI, 0.84-0.98). The number needed to treat with vitamin D plus calcium for 3 yr to prevent one death was 151. Trial level meta-analysis (24 trials with 88,097 participants) showed similar results, i.e. mortality was reduced with vitamin D plus calcium (odds ratio, 0.94; 95% CI, 0.88-0.99), but not with vitamin D alone (odds ratio, 0.98; 95% CI, 0.91-1.06). CONCLUSION Vitamin D with calcium reduces mortality in the elderly, whereas available data do not support an effect of vitamin D alone.

Case–Control Study of Overweight, Obesity, and Colorectal Cancer Risk, Overall and by Tumor Microsatellite Instability Status

BACKGROUND Being overweight or obese is an established risk factor for colorectal cancer, more so for men than for women. Approximately 10%-20% of colorectal tumors display microsatellite instability (MSI), defined as the expansion or contraction of small repeated sequences in the DNA of tumor tissue relative to nearby normal tissue. We evaluated associations between overweight or obesity and colorectal cancer risk, overall and by tumor MSI status. METHODS The study included 1794 case subjects with incident colorectal cancer who were identified through population-based cancer registries and 2684 of their unaffected sex-matched siblings as control subjects. Recent body mass index (BMI), BMI at age 20 years, and adult weight change were derived from self-reports of height and weight. Tumor MSI status, assessed at as many as 10 markers, was obtained for 69.7% of the case subjects and classified as microsatellite (MS)-stable (0% of markers unstable; n = 913), MSI-low (>0% but <30% of markers unstable; n = 149), or MSI-high (> or =30% of markers unstable; n = 188). Multivariable conditional logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (95% CIs). All statistical tests were two-sided. RESULTS Recent BMI, modeled in 5 kg/m(2) increments, was positively associated with risk of colorectal cancer for men and women combined (OR = 1.24; 95% CI = 1.15 to 1.34), for women only (OR = 1.20; 95% CI = 1.10 to 1.32), and for men only (OR = 1.30; 95% CI = 1.15 to 1.47). There was no interaction with sex (P = .22). Recent BMI, per 5 kg/m(2), was positively associated with the risk of MS-stable (OR = 1.38; 95% CI = 1.24 to 1.54) and MSI-low (OR = 1.33; 95% CI = 1.04 to 1.72) colorectal tumors, but not with the risk of MSI-high tumors (OR = 1.05; 95% CI = 0.84 to 1.31). CONCLUSION The increased risk of colorectal cancer associated with a high BMI might be largely restricted to tumors that display the more common MS-stable phenotype, suggesting further that colorectal cancer etiology differs by tumor MSI status.

The Nutritional Prevention of Cancer: 400 Mcg Per Day Selenium Treatment

Nonexperimental studies suggest that individuals with higher selenium (Se) status are at decreased risk of cancer. The Nutritional Prevention of Cancer (NPC) study randomized 1,312 high-risk dermatology patients to 200-mcg/day of Se in selenized yeast or a matched placebo; selenium supplementation decreased the risk of lung, colon, prostate, and total cancers but increased the risk of nonmelanoma skin cancer. In this article, we report on a small substudy in Macon, GA, which began in 1989 and randomized 424 patients to 400-mcg/day of Se or to matched placebo. The subjects from both arms had similar baseline Se levels to those treated by 200 mcg, and those treated with 400-mcg attained plasma Se levels much higher than subjects treated with 200 mcg. The 200-mcg/day Se treatment decreased total cancer incidence by a statistically significant 25%; however, 400-mcg/day of Se had no effect on total cancer incidence.

Plasma levels of 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D and the risk of prostate cancer

In the US, prostate cancer (PCa) has the highest incidence rate of all cancers in males, with few known modifiable risk factors. Some studies support an association between the Vitamin D metabolites, 1,25-dihydroxyvitamin D (1alpha,25(OH)(2)D(3)) and/or 25-hydroxyvitamin D (25(OH)D(3)), and prostate cancer, while others have yielded conflicting results. 1alpha,25(OH)(2)D(3) has anti-proliferative and pro-differentiating effects in prostate cancer cell lines, and levels of circulating 25(OH)D(3) may be important as PCa cells possess 1-alpha-hydroxylase activity. Using a nested case-control design, we evaluated whether plasma levels of 25(OH)D(3) and 1alpha,25(OH)(2)D(3) were associated with prostate cancer risk in participants from the Nutritional Prevention of Cancer (NPC) trial. With 83 cases and 166 matched controls, we calculated the adjusted odds ratios for increasing plasma levels of 25(OH)D(3) and 1alpha,25(OH)(2)D(3). Compared to the lowest tertile of plasma 25(OH)D(3) levels, the adjusted odds ratios were 1.71 (0.68-4.34) and 0.75 (0.29-1.91); the corresponding odds ratios for 1alpha,25(OH)(2)D(3) were 1.44 (0.59-3.52) and 1.06 (0.42-2.66). Given the pivotal effects of the Vitamin D receptor on gene transcription, it is likely that the anti-carcinogenic effects of Vitamin D that have previously been described are related to the activity and expression of the Vitamin D receptor and should be investigated further.

Association Between Body Mass Index and Colorectal Neoplasia at Follow-Up Colonoscopy: A Pooling Study

A direct relation between body mass index (BMI) and risk of colorectal adenomas and cancer has been reported, but few studies have had adequate sample size for conducting stratified analyses by sex, family history, colorectal subsite, or features of metachronous lesions. Data from 8,213 participants in 7 prospective studies of metachronous colorectal adenomas were pooled to assess whether the association between BMI and metachronous neoplasia varied by these factors. A statistically significant direct association between BMI and the odds of nonadvanced adenomas (P(trend) < 0.001) was observed, while the relation for advanced adenomas was of marginal significance (P(trend) < 0.07). In sex-stratified analyses, obesity was statistically significantly associated with the odds of any metachronous lesion among men (odds ratio = 1.36, 95% confidence interval: 1.17, 1.58) but not among women (odds ratio = 1.10, 95% confidence interval: 0.89, 1.37). The associations with BMI appeared to be limited to proximal neoplasia, with statistically significant results for BMI and proximal (P(trend) < 0.001), but not distal (P(trend) < 0.85), neoplasia. Exploratory analyses indicated that BMI was significantly related to most histologic characteristics of metachronous adenomas among men but not among women. Our results provide further support for the association between BMI and metachronous colorectal adenomas, particularly among men, thereby indicating that body size may affect colorectal carcinogenesis at comparatively early stages.

Vitamin D and breast cancer recurrence in the Women's Healthy Eating and Living (WHEL) Study

BACKGROUND There is a paucity of research evaluating the relation between vitamin D and recurrence of breast cancer after treatment. OBJECTIVE This study was designed to evaluate the associations between circulating concentrations of 25-hydroxyvitamin D [25(OH)D] and dietary, supplemental, and total intake of vitamin D and recurrent or new breast cancer events within the Womens Healthy Eating and Living (WHEL) Study. DESIGN A prospective cohort study design (n = 3085) was used to evaluate the relation between dietary, supplemental, and total vitamin D intake and recurrent breast cancer, and a nested case-control study with 512 matched pairs was used for analysis of the association between 25(OH)D and breast cancer recurrence. RESULTS No relation between 25(OH)D and breast cancer recurrence was observed. Compared with women with serum concentrations of 25(OH)D ≥ 30 ng/mL, adjusted odds ratios (95% CI) for breast cancer recurrence were 1.14 (0.57, 2.31) for those with concentrations < 10 ng/mL, 1.00 (0.68-1.48) for concentrations ≥ 10 and < 20 ng/mL, and 1.05 (0.76, 1.47) for concentrations ≥ 20 and < 30 ng/mL. No significant associations were observed when analyses were stratified by pre- and postmenopausal status or for local, regional, or distant recurrence or death. Vitamin D intake was not related to breast cancer recurrence overall, although for premenopausal women there was a significant inverse association between dietary vitamin D intake and recurrence (P for trend = 0.02). CONCLUSION These results do not provide support for a relation between concentrations of 25(OH)D after treatment and the recurrence of breast cancer. This trial is registered at clinicaltrials.gov for the WHEL Study as NCT00003787.

Folate fortification, plasma folate, homocysteine and colorectal adenoma recurrence.

In 1996, the US Food and Drug Administration mandated the fortification of grain products with folic acid, a nutrient that has been associated with lower risk of colorectal neoplasia. We assessed the relation of plasma folate and homocysteine and colorectal adenoma recurrence separately in 2 studies: the first involved an intervention of a cereal supplement that contained folic acid, wheat bran fiber (WBF), and the second was conducted primarily during postfortification of the food supply using ursodeoxycholic acid (UDCA). Analyses were stratified for multivitamin use. Results show that plasma folate and homocysteine concentrations were associated with adenoma recurrence among nonusers of multivitamins only. Among nonmultivitamin users, the odds ratio [OR] (95% confidence interval [CI]) for those in the highest versus the lowest folate quartile was 0.65 (0.40–1.06) for the WBF study and 0.56 (0.31–1.02) for the UDCA; likewise, individuals in the highest versus the lowest quartile of homocysteine had higher odds of adenoma recurrence, in both the WBF (OR = 2.25; 95% CI = 1.38–3.66) and UDCA (OR = 1.93; 95% CI = 1.07–3.49) populations. Analyses comparing multivitamin users to different plasma folate concentrations among nonusers show that odds of recurrence for supplement users was lower only when compared to nonusers who had lower concentrations. Our results show that higher plasma folate or lower homocysteine levels are associated with lower odds of recurrence among nonusers of multivitamins in both studies. Our finding, suggesting that multivitamins or supplemental folate only benefit individuals with lower plasma folate concentrations, should be taken into consideration when designing and interpreting results of intervention studies.

Dietary Supplements and Cancer Prevention: Balancing Potential Benefits Against Proven Harms

Nutritional supplementation is now a multibillion-dollar industry, and about half of all US adults take supplements. Supplement use is fueled in part by the belief that nutritional supplements can ward off chronic disease, including cancer, although several expert committees and organizations have concluded that there is little to no scientific evidence that supplements reduce cancer risk. To the contrary, there is now evidence that high doses of some supplements increase cancer risk. Despite this evidence, marketing claims by the supplement industry continue to imply anticancer benefits. Insufficient government regulation of the marketing of dietary supplement products may continue to result in unsound advice to consumers. Both the scientific community and government regulators need to provide clear guidance to the public about the use of dietary supplements to lower cancer risk.