Ovarian Cancer Screening Trial Cohort Research Articles

Prediagnostic whole blood cadmium and molybdenum associated with pancreatic cancer in an American cohort.

Environmental exposures such as cadmium might be contributing to the increasing incidence of pancreatic cancer. Few prospective studies have examined the association between trace elements and pancreatic ductal adenocarcinoma (PDAC). We conducted a nested case-control study in participants aged 55-74 years at baseline from the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial cohort to examine the association between 12 trace elements measured in predignostic whole blood and PDAC. From May 1998 through December 2014, 318 incident PDAC cases were identified during follow-up to 16.7 years. Two controls (n = 636) alive when each case was diagnosed were selected and matched by age (+ 5 years), sex, calendar date of blood draw (2-month blocks), and race and ethnic group. We used multivariable adjusted conditional logistic regression to calculate odds ratios (OR) and 95% confidence intervals (CI). Cadmium and molybdenum were associated with PDAC [highest compared to lowest quintile: cadmium OR=1.81; 95% CI: 01.12, 2.95; P-trend = 0.03; molybdenum OR=0.50; 95% CI: 0.32, 0.80; P-trend = 0.02]. The inverse molybdenum association was only observed among ever smokers (OR=0.31, 95% CI: 0.17, 0.58, P-trend= 0.003, P-interaction=0.03) with no association in never smokers. Lead, arsenic, and other trace elements were not associated with PDAC. Our results support that increasing prediagnostic whole blood cadmium increases while molybdenum reduces PDAC risk.

Fine Particulate Matter, Noise Pollution, and Greenspace and Prostate Cancer Risk in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial Cohort.

Greenspace is hypothesized as being protective against cancer, whereas noise pollution and fine particulate matter (<2.5 μm in diameter, PM2.5) are both potential risk factors. Findings from recent studies of greenspace and PM2.5 with prostate cancer are not conclusive and the association between noise exposure and cancer has not been evaluated in a U.S. study. We assessed PM2.5, noise, and greenspace exposure using spatiotemporal models and satellite-based estimates at enrollment addresses for N = 43,184 male participants of the prospective Prostate, Lung, Colorectal, and Ovarian Cancer (PLCO) Screening Trial cohort (enrolled 1994-2001). We used Cox regression models adjusted for age, race and ethnicity, study center, family history of prostate cancer, and Area Deprivation Index to estimate associations between ambient PM2.5 (μg/m3), greenspace (index range from -1 to 1), and noise pollution (loudest 10% of total existing sound, decibels) and incident prostate cancer risk through December 2017. A total of 6,327 cases of prostate cancer were diagnosed among male participants during follow-up. PM2.5 and noise exposures were moderately positively correlated (Spearman ρ = 0.46), and PM2.5 and greenspace were not correlated (ρ = 0.10); greenspace and noise were inversely correlated (ρ = -0.32). In single-pollutant and multipollutant models mutually adjusted for coexposures, we found no associations with prostate cancer risk. We did not find evidence that PM2.5, greenspace, and noise pollution were associated with prostate cancer risk in this large, geographically spread cohort. This study contributes to a small body of existing literature investigating these biologically plausible associations.

Associations of serum trimethylamine N-oxide and its precursors with colorectal cancer risk in the Prostate, Lung, Colorectal, Ovarian Cancer Screening Trial Cohort.

Dietary intake influences gut microbiome composition, which in turn may be associated with colorectal cancer (CRC). Associations of the gut microbiome with colorectal carcinogenesis may be mediated through bacterially regulated, metabolically active metabolites, including trimethylamine N-oxide (TMAO) and its precursors, choline, L-carnitine, and betaine. Prospective associations of circulating TMAO and its precursors with CRC risk were investigated. TMAO, choline, betaine, and L-carnitine were measured in baseline serum samples from 761 incident CRC cases and 1:1 individually matched controls in the prospective Prostate, Lung, Colorectal, Ovarian Cancer Screening Trial Cohort using targeted fully quantitative liquid chromatography tandem mass spectrometry panels. Prospective associations of the metabolites with CRC risk, using multivariable conditional logistic regression, were measured. Associations of a priori-selected dietary exposures with the four metabolites were also investigated. TMAO and its precursors were not associated with CRC risk overall, but TMAO and choline were positively associated with higher risk for distal CRC (continuous ORQ90 vs. Q10[95% CI] =1.90 [CI, 1.24-2.92; p=.003] and 1.26 [1.17-1.36; p<.0001], respectively). Conversely, choline was inversely associated with rectal cancer (ORQ90 vs. Q10 [95% CI]=0.77 [0.76-0.79; p<.001]). Red meat, which was previously associated with CRC risk in the Prostate, Lung, Colorectal, Ovarian Cancer Screening Trial Cohort , was positively associated with TMAO (Spearman rho=0.10; p=.0003). Serum TMAO and choline may be associated with higher risk of distal CRC, and red meat may be positively associated with serum TMAO. These findings provide insight into a potential microbially mediated mechanism underlying CRC etiology.

Vegetarian diets and risk of all-cause mortality in a population-based prospective study in the United States

The popularity of vegetarian diets has increased the need for studies on long-term health outcomes. A limited number of studies, including only one study from a non-vegetarian population, investigated the risk of mortality with self-identified vegetarianism and reported inconsistent results. This study evaluated prospective associations between vegetarian diets and all-cause mortality among 117,673 participants from the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial cohort study. Vegetarian diet status was self-identified on the questionnaire. Deaths were ascertained from follow-up questionnaires and the National Death Index database. Multivariable Cox regression models were used to estimate the risk of all-cause mortality in hazard ratio (HR) and 95% confidence intervals (CI). By diet group, there were 116,894 omnivores (whose diet does not exclude animal products), 329 lacto- and/or ovo-vegetarians (whose diet excludes meat, but includes dairy and/or eggs), 310 pesco-vegetarians (whose diet excludes meat except for fish and seafood) and 140 vegans (whose diet excludes all animal products). After an average follow-up of 18 years, 39,763 participants were deceased. The risk of all-cause mortality did not statistically significantly differ among the four diet groups. Comparing with the omnivore group, the HR (95% CI) were 0.81 (0.64–1.03) for pesco-vegetarian group, 0.99 (0.80–1.22) for lacto- and/or ovo-vegetarian group and 1.27 (0.99–1.63) for vegan group, respectively. Similarly, mortality risk did not differ when comparing lacto- and/or ovo-vegetarians plus vegans with meat/fish eaters (omnivores and pesco-vegetarians) (HR [95% CI] = 1.09 [0.93–1.28]). As this study is one of the two studies of vegetarianism and mortality in non-vegetarian populations, further investigation is warranted.

SAT-LB005 Association of Serum Estrogens and Estrogen Metabolites with Use of Non-Steroidal Anti-Inflammatory Drugs in Postmenopausal Women

Background: In several recent studies of postmenopausal women, the use of non-steroidal anti-inflammatory drugs (NSAIDs) has been associated with lower circulating estrogens. These analgesics have also been studied in association with breast cancer risks with inconsistent findings. Cross-talk between immune and endocrine factors may play important roles in the development of breast cancer. Methods: We conducted a study of postmenopausal women drawn from the Prostate, Lung, Colon and Ovarian Cancer Screening Trial cohort (PLCO). At study baseline, participants reported their frequency of use for aspirin, non-aspirin NSAIDs via questionnaire. High-performance liquid chromatography-tandem mass spectrometry was used to measure estrogens and estrogen metabolites (EM) in baseline serum samples from 354 women who went on to get breast cancer during study follow-up, and 423 women who remained healthy. All selected participants reported no use of menopausal hormones at study baseline. General linear models were used to estimate multivariable-adjusted mean EM by self-reported use of analgesics (daily, weekly, or less than weekly) in all participants, while adjusting for continuous age, baseline BMI and breast cancer outcome. Results: In comparison to women who reported that they did not use any NSAIDs on a daily basis, those reporting daily use of aspirin only, daily use of non-aspirin NSAIDs only and daily use of both aspirin and non-aspirin NSAIDs had lower multivariable adjusted serum concentrations of unconjugated estradiol (Pdiff<0.02). Greater frequency of non-aspirin NSAID use was associated with trends towards lower concentrations of total EM (Ptrend=.004), estrone (Ptrend=.004), and unconjugated estradiol (Ptrend=.04), and higher ratios of 2- and 4- hydroxylated EM to the parent estrogens (Ptrend=.02 and .04). Associations were similar in women who did and did not go on to have breast cancer. Discussion: In this sample of postmenopausal women, more frequent use of NSAIDs was associated with lower circulating estrogens and with patterns of estrogen metabolism that may be more favorable with respect to breast cancer risk. These results require independent confirmation in additional well-designed studies. Unless otherwise noted, all abstracts presented at ENDO are embargoed until the date and time of presentation. For oral presentations, the abstracts are embargoed until the session begins. s presented at a news conference are embargoed until the date and time of the news conference. The Endocrine Society reserves the right to lift the embargo on specific abstracts that are selected for promotion prior to or during ENDO.

Vitamin D–binding protein and pancreatic cancer: a nested case-control study

Vitamin D-binding protein (DBP) is the primary carrier of 25-hydroxyvitamin D [25(OH)D] in the circulation. One prospective study in male smokers found a protective association between DBP and pancreatic cancer, particularly among men with higher 25(OH)D concentrations. The objective was to examine the association between DBP and pancreatic cancer risk in an American population. We conducted a nested case-control study in the Prostate, Lung, Colorectal, and Ovarian Cancer screening trial cohort of men and women aged 55-74 y at baseline. Between 1993 and 2010, 295 incident pancreatic adenocarcinoma cases were reported (follow-up to 15.1 y). Two controls (n = 590) were matched to each case by age, race, sex, and month of blood draw. We calculated smoking- and diabetes-adjusted ORs and 95% CIs with the use of conditional logistic regression. DBP concentration was not significantly associated with pancreatic cancer overall [highest (≥7149.4 nmol/L) vs. lowest (<3670.4 nmol/L) quintile; OR: 1.75; 95% CI: 0.91, 3.37; P-trend = 0.25]. For serum 25(OH)D compared with the referent (50 to <75 nmol/L), individuals in the highest group had a significantly higher risk (≥100 nmol/L; OR: 3.23; 95% CI: 1.24, 8.44), whereas those in the lowest group had no significant association (<25 nmol/L; OR: 2.50; 95% CI: 0.92, 6.81). Further adjustment for DBP did not alter this association. Our results do not support the hypothesis that serum DBP or 25(OH)D plays a protective role in pancreatic cancer. This trial was registered at clinicaltrials.gov as NCT00339495.

Polybrominated Diphenyl Ethers and Thyroid Cancer Risk in the Prostate, Colorectal, Lung, and Ovarian Cancer Screening Trial Cohort

Polybrominated diphenyl ethers (PBDEs) alter thyroid hormone homeostasis, but their relationship with thyroid cancer is unknown. To investigate whether serum concentrations of PBDE were associated with thyroid cancer, we conducted a nested, case-control study in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial, a large multicenter clinical trial in the United States. Cases with thyroid cancer (n = 104) were recruited from 1992 to 2001 and diagnosed through 2009, and controls (n = 208) were individually matched (2:1) to cases by race, sex, birth date (within 1 year), center, and blood collection date (within 15 days). We used gas chromatography isotope dilution high-resolution mass spectrometry to measure 10 tri- to heptabrominated diphenyl eithers in serum samples. Odds ratios and 95% confidence intervals were calculated using conditional logistic regression for lipid-adjusted PBDE levels detected in more than 50% of controls and for the sum of these BDEs (∑PBDEs). We observed no significant differences between cases and controls in lipid-adjusted concentrations of ∑PBDEs (for cases, median = 12.8 ng/g lipid (interquartile range, 6.2-42.1); for controls, median = 19.4 ng/g lipid (interquartile range, 7.6-50.2)) or for individual congeners. Increasing quartiles of ∑PBDEs and 4 BDE congeners were not associated with risk of thyroid cancer (for the fourth vs. first quartile of ∑PBDEs, adjusted odd ratio = 0.62, 95% confidence interval: 0.29, 1.30; P for trend = 0.56). Our study does not support an association between exposure to PBDEs and thyroid cancer.

Sex steroid hormone metabolism in relation to risk of aggressive prostate cancer.

The combined action of androgens and estrogens-specifically their balance-may play a role in prostate carcinogenesis, but existing evidence is sparse and inconsistent. We investigated associations between serum sex steroid hormones, including estrogen metabolites, and risk of aggressive prostate cancer. In a case-control study nested within the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial cohort, we measured serum estrone, estradiol, and 13 estrogen metabolites, in the 2-, 4-, or 16-hydroxylation pathways, using an LC/MS-MS assay. Cases (n = 195) were non-Hispanic white men ages 55 to 70 years when diagnosed with aggressive prostate cancer (stage III or IV and/or Gleason ≥7). Controls (n = 195) were non-Hispanic white men without prostate cancer who were frequency matched to cases by age and year at blood draw, and time since baseline screen. Only men with serum testosterone and sex hormone-binding globulin measured previously were eligible. Logistic regression models were used to estimate ORs and 95% confidence intervals (95% CI). Risk of aggressive prostate cancer was strongly inversely associated with estradiol:testosterone ratio (OR4th quartile vs. 1st = 0.27; 95% CI, 0.12-0.59, Ptrend = 0.003) and positively associated with 2:16α-hydroxyestrone ratio (OR4th quartile vs. 1st = 2.44; 95% CI, 1.34-4.45, Ptrend = 0.001). Individual estrogen metabolites were unrelated to risk. Our findings suggest that sex steroid hormones, specifically the estrogen-androgen balance, may be important in the development of aggressive prostate cancer. Improved understanding of the hormonal etiology of prostate cancer is critical for prevention and therapeutic interventions.

Alcohol and risk of breast cancer in postmenopausal women: an analysis of etiological heterogeneity by multiple tumor characteristics.

Alcohol consumption is an established risk factor for breast cancer. Whether associations vary by specific tumor characteristics independent of other characteristics is unclear. We evaluated the association between alcohol consumption and breast cancer risk in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial cohort (54,562 women aged 55-74 years recruited at 10 US screening centers between 1993 and 2001; median follow-up, 8.9 years; 1,905 invasive breast cancer cases). Hazard ratios and 95% confidence intervals for subtypes defined by histological type and estrogen receptor (ER)/progesterone receptor (PR) status were calculated with standard Cox models. A novel 2-stage Cox model assessed heterogeneity in risk for individual tumor characteristics while adjusting for others. Significant trends across categories of alcohol consumption were observed, with hazard ratios for those consuming 7 or more drinks per week versus never drinkers as follows: for estrogen receptor-positive (ER+) cancer, 1.48 (95% confidence interval (CI): 1.19, 1.83); for progesterone receptor-positive (PR+) cancer, 1.64 (95% CI: 1.31, 2.06); for ER+/PR+ cancer, 1.63 (95% CI: 1.30, 2.05); and for mixed ductal/lobular cancer, 2.51 (95% CI: 1.20, 5.24). For ER+ and PR+ cancers, trends were significant for ductal and mixed ductal/lobular types. PR status explained the positive association with ER status (for ER status, Pheterogeneity=0.70 after adjustment for PR status). Alcohol consumption was not associated with all breast cancer subtypes. Future work should emphasize large collaborative studies, precise definition of subtypes, and adjustment for correlated tumor characteristics.

Abstract B61: Vitamin D-binding protein and pancreatic cancer: A nested case-control study

Abstract Research examining the association between vitamin D and pancreatic cancer is inconsistent, with some studies showing an elevated risk with increased vitamin D (Stolzenberg-Solomon, 2006, 2009, 2010) and another showing an inverse association. (Wolpin, 2012) This counterintuitive finding has led researchers to investigate levels of vitamin D-binding protein (DBP) as a possible explanation. DBP serves several important functions in the body, including acting as the primary carrier of vitamin D in the bloodstream. (Speeckaert, 2006) Previous research in the Alpha-Tocopherol, Beta-Carotene Study found an inverse trend for DBP and pancreatic cancer in male Finnish smokers, with higher compared to lower DBP concentrations showing a protective association with pancreatic cancer. (Weinstein, 2012) We conducted a nested case-control study in the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial cohort of men and women aged 55-74 at baseline. Between 1993 and 2010, 295 incident cases of pancreatic adenocarcinoma were reported (follow-up to 15.1 years). Two controls (n = 590) who were alive at the time the case was diagnosed were selected for each case and were matched by age, race, sex, month of blood draw. We calculated odds ratios (ORs) and 95% confidence intervals (CIs) using conditional logistic regression, adjusting for smoking status and diabetes mellitus. DBP concentration was not significantly associated with pancreatic cancer overall (highest vs. lowest quintile, ≥7149.4 vs.&amp;lt;3670.4 nmol/L: OR=1.75, 95% CI 0.91-3.37, p-trend=0.32). However, we observed a significantly elevated pancreatic cancer risk among cases diagnosed &amp;gt;5 years after baseline (n = 214 cases, highest vs. lowest quintile, OR=2.12, 95% CI 1.01-4.43, p-value=0.047). We did not confirm the protective association seen previously. Our results do not support the hypothesis that DBP plays a protective role in pancreatic cancer. Funded by NCI Contract No. HHSN261200800001E. Citation Format: Marina R. Piper, William Kopp, Helen Rager, Ronald L. Horst, Rachael Z. Stolzenberg-Solomon. Vitamin D-binding protein and pancreatic cancer: A nested case-control study. [abstract]. In: Proceedings of the Twelfth Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2013 Oct 27-30; National Harbor, MD. Philadelphia (PA): AACR; Can Prev Res 2013;6(11 Suppl): Abstract nr B61.

Alcohol and breast cancer risk in postmenopausal women: The PLCO experience.

1521 Background: Moderate alcohol consumption is an established breast cancer (BC) risk factor. Invasive BC is a heterogeneous disease comprised of several histological subtypes with distinct biological features that suggest etiologic differences. Several studies show the alcohol link may be stronger for estrogen receptor-positive tumors (ER+/PR+ and ER+/PR-) and for lobular BC. Few have evaluated the role of alcohol consumption by BC histology and hormone receptor status combined. Methods: We evaluated the risk of BC by baseline alcohol consumption in the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial cohort (54649 participants, 1786 incident invasive breast cancers) by histology and hormone receptor status. Histologic subtype-specific associations were evaluated using a recently developed Cox proportional hazards model to calculate multivariate hazards ratios (HR) and 95% confidence intervals (CI). Results: 1444 ductal (81%), 233 lobular (13%) and 109 mixed ductal lobular (6%) cases were identified. The majority were ER+/PR+ (ductal: 959 ER+/PR+, 136 ER+/PR-, 229 ER-/PR-; lobular: 179 ER+/PR+, 37 ER+/PR-, 6 ER-/PR-; mixed ductal/lobular: 88 ER+/PR+, 6 ER+/PR-, 5 ER-/PR-). For ductal and lobular BC, risks for alcohol consumption were modestly elevated; compared to never drinkers, women consuming 7-14 drinks/week had a 40% increase in HR in both histologic subtypes. Risks for mixed ductal lobular cancer were significantly higher, particularly for women consuming 7-14 drinks per week (HR=3.0; 95% CI=1.5, 6.1). For all histologies combined, alcohol risks were confined to ER+/PR+ cancers with HR=1. 6 (95% CI=1.3, 2.1) for women consuming 7-14 drinks/ week; p trend=0.0005. Similarly, for each histologic subtype, the risk for alcohol consumption was limited to ER+/PR+ tumors, and notably, very few cases with pure lobular or mixed ductal lobular cancer were either ER+/PR- or ER-/PR-. Conclusions: Moderate alcohol consumption is associated with risk of ER+/PR+ BC in each of the predominant histologic subtypes, but not with hormone receptor-negative cancer. Unlike other studies, we did not find a link between alcohol consumption and ER+/PR- BC.

Serum IGF-I, IGF-II, IGFBP-3, and IGF-I/IGFBP-3 Molar Ratio and Risk of Pancreatic Cancer in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial

Experimental evidence suggests that an overexpression of insulin-like growth factor (IGF)-I is implicated in human pancreatic tumors. Increased IGF-II and decreased IGF binding protein (IGFBP)-3 serum concentrations have been linked to a number of other cancers. We conducted a nested case-control study in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial cohort of men and women 55 to 74 years of age at baseline to test whether prediagnostic circulating IGF-I, IGF-II, IGFBP-3, and IGF-I/IGFBP-3 molar ratio concentrations were associated with exocrine pancreatic cancer risk. Between 1994 and 2006, 187 incident cases of pancreatic adenocarcinoma occurred (follow-up of up to 11.7 years). Two controls (n = 374), who were alive at the time the case was diagnosed, were selected for each case and matched by age, race, sex, and date of blood draw. We calculated odds ratios (OR) and 95% confidence intervals (95% CI) with the use of conditional logistic regression, adjusting for smoking. IGF-I, IGF-II, and IGFBP-3 concentrations were not significantly associated with pancreatic cancer (highest compared with lowest quartile: OR, 1.58; 95% CI, 0.91-2.76; and P-trend = 0.25; OR, 0.86; 95% CI, 0.49-1.50; and P-trend = 0.31; and OR, 0.88; 95% CI, 0.51-1.51; and P-trend = 0.47, respectively). However, a significant positive trend was observed with high IGF-I/IGFBP-3 molar ratio levels (highest compared with lowest quartile: OR, 1.54; 95% CI, 0.89-2.66; P-trend = 0.04). A higher IGF-I/IGFBP-3 molar ratio represents increased free IGF-I, which may be a risk factor for pancreatic cancer. Our results highlight the importance of this biomarker for further investigation in large prospective cohort studies and pooled analysis with other prospective cohorts.

Abstract 2795: Serum IGF-I, IGF-II, IGFBP-3, and IGF-I/IGFBP-3 molar ratio and risk of pancreatic cancer in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial

Abstract Experimental evidence suggests that an overexpression of insulin-like growth factor-I (IGF-I) is implicated in human pancreatic tumors. Moreover, increased IGF-II and decreased insulin-like growth factor binding protein-3 (IGFBP-3) concentrations are found in a number of cancers. We conducted a nested case-control study in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial cohort of men and women 55-74 years of age at baseline, to test whether pre-diagnostic circulating IGF-I, IGF-II, IGFBP-3, and IGF-I/IGFBP-3 molar ratio concentrations were associated with exocrine pancreatic cancer risk. Between 1994 and 2006, 187 incident cases of pancreatic adenocarcinoma occurred (follow-up to 11.7 years). Two controls (n=374),who were alive at the time the case was diagnosed, were selected for each case and matched by age, race, sex and date of blood draw. We calculated odds ratios (ORs) and 95% confidence intervals (CIs) using conditional logistic regression, adjusting for smoking. In the multivariable adjusted model, IGF-I, IGF-II, and IGFBP-3 concentrations were not associated with pancreatic cancer (highest compared with lowest quintile, OR=1.23, 95% CI 0.67-2.25, p-trend=0.12; OR=0.98, 95% CI 0.52-1.85, p-trend=0.52; and OR=1.15, 95% CI 0.62-2.16, p-trend=0.90). However, a significant positive trend was observed with high IGF-I/IGFBP-3 molar ratio levels in the smoking-adjusted model (OR=1.46, 95% CI 0.78-2.74, p-trend=0.04). A higher IGF-I/IGFBP-3 molar ratio may represent increased free IGF-I and be a risk factor for pancreatic cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2795.

Circulating insulin-like growth factor (IGF)-I and IGF binding protein (IGFBP)-3 levels and postmenopausal breast cancer risk in the prostate, lung, colorectal, and ovarian cancer screening trial (PLCO) cohort.

Early prospective studies suggested circulating insulin-like growth factor (IGF)-I was positively associated with risk of premenopausal, but not postmenopausal, breast cancer; however, a recent, large analysis reported a statistically significant positive association with postmenopausal disease. Therefore, we conducted a large study nested within the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial cohort to assess the association between circulating IGF-I and IGF binding protein (IGFBP)-3 levels and subsequent postmenopausal breast cancer risk. We included 389 breast cancer cases and 470 controls, aged 55-74, not using exogenous hormones at blood draw, and matched by age at and date of serum collection. Mean follow-up was 8.5 years; mean time between serum collection and diagnosis was 4.0 years. We used Cox proportional hazards regression models to obtain hazard ratios (HRs) and 95% confidence intervals (95% CIs). Multivariate HRs for IGF-I, IGFBP-3, and the molar ratio IGF-I/IGFBP-3, comparing the highest quintile to the lowest, were 1.28 (95% CI, 0.67-2.44), 1.12 (95% 0.55-2.27), and 1.25 (95% 0.72-2.15), respectively. Multivariate HRs per one quintile increase were 1.07 (95% 0.92-1.25) for IGF-I, 1.01 (95% 0.86-1.18) for IGFBP-3, and 1.10 (95% 0.98-1.24) for the molar ratio. These models included accepted breast cancer risk factors and height, along with baseline BMI and serum estradiol, both of which increased the risk associated with IGF-I and the molar ratio. IGF-I and the IGF-I/IGFBP-3 molar ratio were positively, although not statistically significantly, associated with postmenopausal breast cancer risk. Further research should emphasize larger studies, including pooled analyses, analyses by cancer subtype, improved exposure assessment, and possible mechanisms.

Energy Intake and Risk of Postmenopausal Breast Cancer: An Expanded Analysis in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO) Cohort

Although animal experiments have consistently shown a positive relationship between breast cancer and energy intake, evidence from human studies remains inconclusive. In the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial cohort, 29,170 women, ages 55 to 75 years, who successfully completed a food frequency questionnaire (FFQ) at entry (1993-2001), were followed through 2007, and 1,319 incident breast cancers were ascertained (median time from FFQ completion to diagnosis, 4.4 years). Women in the highest quartile of energy intake, relative to the lowest, had modestly, but significantly, increased breast cancer risk [multivariate relative risk (RR), 1.21; 95% confidence interval (95% CI), 1.03-1.42; P(trend) = 0.03]. The inclusion of body mass index and physical activity in the model reduced risk slightly (RR, 1.18; 95% CI, 1.00-1.39; P(trend) = 0.07). However, in similar analyses using energy intake from a FFQ administered approximately five years after entry (27,428 women; 806 incident breast cancers; median time from FFQ completion to diagnosis, 2.7 years), women in the highest and lowest quartiles of energy intake had similar risk. When follow-up time after the first FFQ was divided into three 4-year periods, the multivariate RRs for high versus low energy intake increased from 1.21 to 1.37 to 1.55 with increasing time since dietary assessment. Although the divergent results for the two FFQs could be due to subtle questionnaire differences, our findings suggest a modest positive association between energy intake and postmenopausal breast cancer that strengthens with time since dietary assessment.

Folate intake, alcohol use, and postmenopausal breast cancer risk in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial

Several epidemiologic studies suggest that higher folate intakes are associated with lower breast cancer risk, particularly in women with moderate alcohol consumption. We investigated the association between dietary folate, alcohol consumption, and postmenopausal breast cancer in women from the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial cohort. Dietary data were collected at study enrollment between 1993 and 2001. Folate content was assigned on the basis of prefortification (ie, pre-1998) databases. Of the 25 400 women participants with a baseline age of 55-74 y and with complete dietary and multivitamin information, 691 developed breast cancer between September 1993 and May 2003. We used Cox proportional hazard models with age as the underlying time metric to generate hazard ratios (HRs) and 95% CIs. The adjusted HRs were 1.19 (95% CI: 1.01, 1.41; P for trend = 0.04) for women reporting supplemental folic acid intake >/=400 mug/d compared with subjects reporting no supplemental intake. Comparison of the highest with the lowest quintile gave adjusted HRs of 1.04 (95% CI: 0.83, 1.31; P for trend = 0.56) and 1.32 (95% CI: 1.04, 1.68; P for trend = 0.03) for food and total folate intake, respectively. Alcohol consumption was positively associated with breast cancer risk (highest compared with lowest quintile: HR = 1.37; 95% CI: 1.08, 1.76; P for trend = 0.02); the risk was greatest in women with lower total folate intake. Our results do not support the hypothesis that high folate intake reduces breast cancer risk; instead, they suggest that a high intake, generally attributable to supplemental folic acid, may increase the risk in postmenopausal women. However, our results confirm previous studies showing positive associations between moderate alcohol consumption and breast cancer.