Risk Of Cancer In Postmenopausal Women Research Articles

Nutrition and metabolic factors in cancer causation and prevention

EPIC represents a large and mature resource for epidemiological studies of cancer aetiology. Data can be integrated from studies on diet, physical activity, anthropometry and biomarker measurements to build a broad picture of the role of nutrition and metabolic factors in cancer causation. Since the initial baseline collection, cohort participants have been followed up to obtain information on changes in major dietary and lifestyle factors including a series of questions on whether the subjects had suffered from a number of common diseases and medical conditions. So far, over 60,000 newly incident cancer cases have been reported, including around 14,000 breast, 3,600 lung, 5,200 colorectal, 1,180 pancreatic, and 1,400 endometrial cancer cases, giving scope for well-powered studies on cancer causation. Some notable findings from EPIC research include the association between fibre consumption and a reduced risk in the development of colorectal cancer, red meat consumption and an increased risk of digestive tract cancers, positive associations with BMI and colon cancer in men, waist-hip ratio and the development of colon cancer in both men and women and a significant prediction between being overweight (expressed as BMI) and breast cancer risk in postmenopausal women not using HRT. It is clear that a number of chemical, physical and biological carcinogens have a major role in cancer causation and in some cases account for most of the variations in cancer incidence across the world. However, they cannot explain the global variations for a large number of cancers that represent a significant proportion of the world’s total cancer burden. Research conducted during past decades, and particularly those based on large prospective studies including EPIC, has found that diet, nutrition physical activity and anthropometry have major influences on population risk of cancer. From a scientific point of view, the unravelling of the mechanistic effects underlying the increased cancer risk associated with some components of current western diet and lifestyle is challenging. The effect may be due to fine modulation or modest dis-regulation of normal physiological processes rather than gross disruption, as may be the case for some strong exogenous carcinogens. From a public health point of view, these metabolic lifestyle factors are of great interest as they largely overlap with the major known risk factors of cardiovascular diseases and diabetes, therefore offering the opportunity of targeting the prevention of a number of non-communicable diseases with the same panel of public health interventions.

Urinary Levels of Melatonin and Risk of Postmenopausal Breast Cancer: Women's Health Initiative Observational Cohort

Results from prospective studies on the association between urinary levels of melatonin and risk of postmenopausal breast cancer have been mixed. Several although not all studies have found lower urinary levels of melatonin in women who developed breast cancer compared with cancer-free women. We examined the association between urinary levels of melatonin and breast cancer risk in postmenopausal women in a case-control study nested in the Women's Health Initiative Observational Cohort. Levels of 6-sulfatoxymelatonin were measured in first morning voids from 258 women who later developed breast cancer and from 515 matched controls. Multivariable conditional logistic regression was used to calculate ORs and 95% confidence intervals (CI). Fully adjusted risk estimates of breast cancer, relative to the lowest quartile level of creatinine-adjusted melatonin, were 1.07 (95% CI, 0.67-1.71), 1.26 (95% CI, 0.79-2.01), and 1.25 (95% CI, 0.78-2.02) for women in the second, third, and highest quartile (Ptrend = 0.27). Comparable results for cases diagnosed less than four years after urinary collection and matched controls were 1.0, 1.25 (95% CI, 0.51-3.06), 1.85 (95% CI, 0.75-4.57), and 1.94 (95% CI, 0.75-5.03; Ptrend = 0.11). Melatonin levels and breast cancer were not associated in cases diagnosed four or more years after urinary collection and matched controls (Ptrend = 0.89). We found no evidence that higher urinary levels of melatonin are inversely associated with breast cancer risk in postmenopausal women. Accumulating discrepancies in results across studies warrant further exploration.

Effect of isoflavone soy protein supplementation on endometrial thickness, hyperplasia, and endometrial cancer risk in postmenopausal women

This study aims to determine whether long-term isoflavone soy protein (ISP) supplementation affects endometrial thickness and rates of endometrial hyperplasia and cancer in postmenopausal women. In this randomized, double-blind, placebo-controlled trial, 350 postmenopausal women aged 45 to 92 years were randomized to a total daily dose of 154 mg of ISP or a milk protein-matched placebo for a 3-year period. Women with a surgically absent uterus were excluded from the analysis (final study population, N = 224). The main outcome measures were as follows: mean change in endometrial thickness on transvaginal ultrasound from baseline until up to 36 months of follow-up and the incidence of endometrial sampling, endometrial hyperplasia, and endometrial cancer. A total of 666 visits among 224 participants were evaluated. Treatment groups did not significantly differ on the mean baseline or on-trial changes in endometrial thickness. Of the 103 placebo-treated participants, 7 (6.8%) underwent endometrial biopsy; 6 (85.7%) of these biopsies were benign. One woman in the placebo group was diagnosed with complex endometrial hyperplasia with atypia and underwent hysterectomy. The pathology result from this surgical operation was stage IB endometrial cancer. Of the 121 participants in the soy group, 9 (7.4%) underwent endometrial biopsy. The results were benign in all nine cases (100%). Although the rate of hyperplasia/malignancy was higher in the placebo group (14.3% vs 0%), the difference was not statistically significant. Three-year ISP supplementation has no effect on endometrial thickness or on the rates of endometrial hyperplasia and cancer in postmenopausal women.

Associations between Weight in Early Adulthood, Change in Weight, and Breast Cancer Risk in Postmenopausal Women

Adult weight is positively associated with postmenopausal breast cancer but few studies have investigated whether there are associations with weight and body mass index (BMI) in early adulthood, or subsequent weight change. A total of 14,441 postmenopausal women from the Melbourne Collaborative Cohort Study (MCCS) were followed for 16.5 years (mean) and 668 incident breast cancers were identified. Hazard ratios (HRs) were estimated using Cox regression. Weight and BMI at 18 to 21 years were not associated with risk of any type of breast cancer and there was no variation by age. Women with the greatest increase in weight and BMI had higher risk at older ages [HR per 5 kg/m(2) gain in BMI = 1.24; 95% confidence interval (CI), 1.11-1.40], although the test for homogeneity by age was not significant. At older ages, the association was stronger for progesterone (PR) positive disease compared with PR negative disease (HR per 5 kg/m(2) gain in BMI, 1.43; 95% CI, 1.23-1.66; test for homogeneity by PR status, P < 0.01) and for diseases that were positive for both estrogen (ER) and PR (HR per 5 kg/m(2) gain in BMI, 1.45; 95% CI, 1.24-1.69; test for homogeneity by ER/PR status, P = 0.02). HRs were also greater for HER2- and luminal A tumors, but the P values for homogeneity by tumor subgroups were not significant. Early adulthood weight is not associated with risk of postmenopausal breast cancer. Greater weight gain during adulthood might be associated with increased risk for older women (>69 years) and this association might vary by tumor hormone receptor status. Further studies need to investigate the impact of increase in weight during adulthood on postmenopausal breast cancer risk and the potential variation by age or tumor characteristics.

Effects of Dietary Weight Loss and Exercise on Insulin-Like Growth Factor-I and Insulin-Like Growth Factor-Binding Protein-3 in Postmenopausal Women: A Randomized Controlled Trial

High levels of insulin-like growth factor (IGF)-I may increase the risk of common cancers in humans. We hypothesized that weight loss induced by diet and/or exercise would reduce IGF-I in postmenopausal women. Four hundred and thirty nine overweight or obese [body mass index (BMI) ≥ 25 kg/m(2)] women (50-75 years) were randomly assigned to: (i) exercise (N = 117), (ii) dietary weight loss (N = 118), (iii) diet + exercise (N = 117), or (iv) control (N = 87). The diet intervention was a group-based program with a 10% weight loss goal. The exercise intervention was 45 minutes/day, 5 days/week of moderate-to-vigorous intensity activity. Fasting serum IGF-I and IGF-binding protein (IGFBP)-3 were measured at baseline and 12 months by radioimmunoassay. Higher baseline BMI was associated with lower IGF-I and IGF-I/IGFBP-3 molar ratio. Although no significant changes in either IGF-I or IGFBP-3 were detected in any intervention arm compared with control, the IGF-I/IGFBP-3 ratio increased significantly in the diet (+5.0%, P < 0.01) and diet + exercise (+5.4%, P < 0.01) groups compared with control. Greater weight loss was positively associated with change in both IGF-I (P(trend) = 0.017) and IGF-I/IGFBP-3 ratio (P(trend) < 0.001) in the diet group, but inversely with change in IGFBP-3 in the diet + exercise group (P(trend) = 0.01). No consistent interaction effects with baseline BMI were detected. Modified IGF-I bioavailability is unlikely to be a mechanism through which caloric restriction reduces cancer risk in postmenopausal women.

Adipocytokines, Inflammation, and Breast Cancer Risk in Postmenopausal Women: A Prospective Study

Obesity is a known risk factor for postmenopausal breast cancer; it has been postulated that adipocytokines may mediate this association. We explored the relationship between three markers altered by obesity: leptin, adiponectin, and soluble tumor necrosis factor receptor 2 (sTNF-R2), an inflammatory marker, with breast cancer risk in postmenopausal women. A nested case-control study of postmenopausal women was conducted within CLUE II, a prospective population-based cohort. Baseline plasma levels of leptin, adiponectin, and sTNF-R2 were assayed in 272 female breast cancer cases and 272 controls matched on age, date, and hour of blood draw. Conditional logistic regression was used to estimate matched odds ratios (OR) and 95% confidence intervals (CI). sTNF-R2 and leptin were independently positively associated with breast cancer risk in adjusted models. The OR for breast cancer comparing the highest to lowest tertile was 2.44 (95% CI: 1.30-4.58) for sTNF-R2 and 1.98 (95% CI: 1.20-3.29) for leptin. While higher levels of adiponectin were protective (OR for the lowest tertile = 1.63; 95% CI: 1.02-2.60), there was no dose response. A 20% reduction in the breast cancer risk associated with overweight/obesity was observed when sTNF-R2 alone was included in multivariable models. Including both sTNF-R2 and adiponectin in the models resulted in a 29% reduction in the OR. Adipocytokines and sTNF-R2 are important factors in the etiology of postmenopausal breast cancer due to adiposity. This study informs our understanding of the relationship between obesity, inflammation, and postmenopausal breast cancer and identifies potential biomarkers.

Endometrial profile of bazedoxifene acetate alone and in combination with conjugated equine estrogens in a primate model

Concerns of breast cancer risk in postmenopausal women taking combined estrogen + progestin therapy have generated interest in the use of selective estrogen receptor modulators (SERMs) as potential progestin alternatives. Endometrial proliferation and cancer risk are major concerns, however, for estrogens and certain types of SERMs when given alone. The primary aim of this study was to evaluate the endometrial profile of bazedoxifene acetate (BZA), a third-generation SERM, alone and in combination with conjugated equine estrogens (CEE) in a postmenopausal primate model. Ninety-eight ovariectomized cynomolgus monkeys (Macaca fascicularis) were randomized to receive no hormone treatment (controls), BZA 20 mg, CEE 0.45 mg, or the combination of BZA 20 mg + CEE 0.45 mg once daily for 20 months in a parallel-arm study design. The primary outcome measure was endometrial epithelial proliferation. BZA + CEE and BZA treatment resulted in significantly less endometrial epithelial area and Ki67 expression compared with CEE (P < 0.001 for all). The prevalence of endometrial hyperplasia and other estrogen-induced morphologic changes in the BZA + CEE and BZA groups was not significantly different from controls. The addition of BZA to CEE completely inhibited the expression of estrogen receptor-α-regulated genes (TFF1 and PGR), whereas BZA alone had no effect. BZA + CEE and BZA treatment also resulted in lower estrogen receptor-α protein expression in the endometrium compared with the control and CEE groups (P < 0.05 for all). BZA given at a clinically relevant dose inhibits estrogen effects on the endometrium and lacks uterotropic effects when given alone.

Association between Urinary Prostaglandin E2 Metabolite and Breast Cancer Risk: A Prospective, Case–Cohort Study of Postmenopausal Women

Overweight or obese women are at increased risk of developing and dying from breast cancer. Obesity-driven inflammation may stimulate prostaglandin E2 (PGE2)-mediated aromatase activation and estrogen biosynthesis in breast tissues. We hypothesized that increased production of PGE2 would contribute to elevated breast cancer risk in postmenopausal women. We carried out a case-cohort study with 307 incident breast cancer cases and 300 subcohort members from the Sister Study cohort. HRs and 95% confidence intervals (CI) were estimated for the association between urinary levels of a major PGE2 metabolite (PGE-M) and breast cancer risk using Prentice's pseudo-likelihood approach. Several lifestyle factors were associated with urinary levels of PGE-M: smoking, high-saturated fat diet, and obesity increased urinary PGE-M, and use of nonsteroidal antiinflammatory drugs (NSAID) decreased urinary PGE-M. Although there was no association between urinary PGE-M and postmenopausal breast cancer risk in the overall analysis or among regular users of NSAIDs, there was a positive association among postmenopausal women who did not regularly use NSAIDs with HRs of 2.1 [95% confidence interval (CI): 1.0-4.3]; 2.0 (95% CI: 1.0-3.9); and 2.2 (95% CI: 1.1-4.3) for the second, third, and highest quartiles of PGE-M. Our findings suggest a link between systemic PGE2 formation and postmenopausal breast cancer, and a possible modification of the association by lifestyle and pharmacologic interventions. If confirmed in larger studies, these results may have useful implications for the development of preventive strategies.

Update on Raloxifene

Raloxifene is the only selective estrogen receptor modulator approved for long-term treatment in the prevention of osteoporotic fractures and for the reduction of invasive breast cancer risk in post-menopausal women. The demonstrated beneficial effects on bone and mammalian tissue led clinical and molecular research to focus mainly on these organs, giving less attention to all other systemic effects. The aim of this review was to evaluate all described systemic effects of raloxifene, investigating its molecular and tissutal mechanism of action. A literature research was carried out in electronic databases MEDLINE, EMBASE, ScienceDirect, and the Cochrane Library in interval time between 2000 and 2012. Outcomes were considered in relation to positive/adverse effects concerning bone metabolism, lipid metabolism, coagulation pattern, menopausal symptoms, breast cancer onset, and endometrial cancer onset. Raloxifene acts as an estrogen agonist or antagonist depending on the tissue. This feature is related to specific actions on at least 2 distinct estrogen receptors, whose proportions vary according to tissue type. Raloxifene is a drug for the treatment of osteoporosis and for the prevention of estrogen receptor-positive breast cancer because it guarantees a safety profile on the endometrium. Raloxifene is furthermore an effective therapy in women with increased levels of plasma cholesterol. Raloxifene treatment shifts the coagulation pattern toward prothrombosis, and the patients should be exhaustively informed about the risks associated with therapy. Raloxifene does not show to affect memory and cognition. Finally, it is noteworthy that quality-of-life studies demonstrated some favorable effects of raloxifene.

Urinary PGE-M: A Promising Cancer Biomarker

Cancer prevention, early diagnosis, and targeted therapies are the keys to success in better cancer control and treatment. A big challenge remains to identify biomarkers for predicting who may have higher cancer risk and are able to respond to certain chemopreventive agents as well as for assessing a patient's response during treatment. Although a large body of evidence indicates that chronic inflammation is a risk factor for cancer, it is unclear whether inflammatory biomarkers can be used to predict cancer risk, progression, and death. Considering the importance of the proinflammatory COX-2-derived prostaglandin E2 (PGE2) in inflammation and cancer, Morris and colleagues found that urinary PGE-M is positively associated with obesity, smoking, and lung metastases in patients with breast cancer (4). Along the same lines, Kim and colleagues showed a potential association between urinary PGE-M and breast cancer risk in postmenopausal women (beginning on page 511). In agreement with previous reports, their findings indicate that urinary PGE-M may serve as a promising biomarker for prognosticating cancer risk and disease progression.

Body Fat and Breast Cancer Risk in Postmenopausal Women: A Longitudinal Study

Associations between anthropometric indices of obesity and breast cancer risk may fail to capture the true relationship between excess body fat and risk. We used dual-energy-X-ray-absorptiometry- (DXA-) derived measures of body fat obtained in the Women's Health Initiative to examine the association between body fat and breast cancer risk; we compared these risk estimates with those for conventional anthropometric measurements. The study included 10,960 postmenopausal women aged 50–79 years at recruitment, with baseline DXA measurements and no history of breast cancer. During followup (median: 12.9 years), 503 incident breast cancer cases were diagnosed. Hazard ratios (HR) and 95% confidence intervals (CI) were estimated using Cox proportional hazards models. All baseline DXA-derived body fat measures showed strong positive associations with breast cancer risk. The multivariable-adjusted HR for the uppermost quintile level (versus lowest) ranged from 1.53 (95% CI 1.14–2.07) for fat mass of the right leg to 2.05 (1.50–2.79) for fat mass of the trunk. Anthropometric indices (categorized by quintiles) of obesity (BMI (1.97, 1.45–2.68), waist circumference (1.97, 1.46–2.65), and waist : hip ratio (1.91, 1.41–2.58)) were all strongly, positively associated with risk and did not differ from DXA-derived measures in prediction of risk.

Contribution of catechol-O-methyltransferase Val158Met polymorphism to endometrial cancer risk in postmenopausal women: a meta-analysis

Catechol-O-methyltransferase (COMT) is a critical enzyme to detoxify the carcinogenic catechol estrogen and the Val158Met polymorphism of COMT could influence its enzymatic activity. Recent epidemiological studies have investigated the correlation of COMT Val158Met polymorphism with endometrial cancer risk; however, the results are inconsistent. To better evaluate the role of COMT Val158Met in endometrial carcinogenesis, we performed this meta-analysis, considering menopausal status, study quality, ethnicity, and source of controls. Eight eligible studies including 5109 subjects were collected from PubMed, CNKI, and Chinese Biomedicine Database (updated until September 21, 2012). Although no obvious associations were detected between COMT Val158Met and endometrial cancer susceptibility in the pooled analysis, we noted significantly decreased endometrial cancer risk for Val/Met versus Val/Val, and Met/Met + Val/Met versus Val/Val genetic models in the postmenopausal female (OR = 0.795, 95%CI = 0.656-0.962, P = 0.019; and OR = 0.819, 95%CI = 0.683-0.983, P = 0.032; respectively), and similar results existed in high-quality studies (OR = 0.835, 95%CI = 0.726-0.961, P = 0.012; and OR = 0.853, 95%CI = 0.747-0.974, P = 0.019; respectively). However, no evidence of association was noted in different ethnic groups and sources of controls. In conclusion, our results suggested that the COMT Val/Val genotype might act as a potential endometrial cancer risk factor in postmenopausal women. Further studies are needed to investigate the interactions between COMT Val158Met polymorphism and endometrial cancer in a specific population.

Abstract P3-08-03: Urinary levels of prostaglandin E2 metabolite and postmenopausal breast cancer

Abstract Estrogens are considered a key player in the mammary carcinogenesis. In postmenopausal women, peripheral aromatization of androgens is the predominant source of estrogens. Given that prostaglandin E2 (PGE2) is a potent activator of aromatase expression, we hypothesized that endogenous level of PGE2 would influence estrogen bioavailability and subsequent breast cancer risk in postmenopausal women. In addition, because PGE2 synthesis is suppressed by treatment of non-steroidal anti-inflammatory drugs (NSAIDs) via inhibition of cyclooxygenase enzyme activity, we further hypothesized that regular use of NSAIDs may modify the association between PGE2 and postmenopausal breast cancer risk. We carried out a case-cohort analysis within the NIEHS Sister Study, a prospective cohort study of 50,884 women. Postmenopausal women who were aged 50 or older and did not report current use of hormones were eligible for the present analysis (N = 11,338). Urinary levels of a major PGE2 metabolite (PGE-M), which is generally accepted as the most accurate index of endogenous PGE2 formation, were quantified using liquid chromatography/tandem mass spectrometry in 302 incident breast cancer cases and 305 subcohort members who were randomly selected by frequency matching for age among cases. Hazard ratios (HR) and 95% confidence intervals (95% CI) were estimated using Prentice's pseudo-likelihood approach with Barlow's weighting scheme. Several factors were associated with higher levels of urinary PGE-M in the multivariable analysis, including current smoking, obesity, high caloric intake from saturated fat and surgical menopause. No associations were observed for dietary intake of omega 3 fatty acids, use of vitamin supplements and physical activity. Overall, there was no association between urinary PGE-M and postmenopausal breast cancer risk. After including the interaction terms between NSAID use and urinary levels of PGE-M in the model, however, high levels of urinary PGE-M were associated with an increased risk of breast cancer in postmenopausal women who did not regularly use NSAIDs (likelihood ratio test p &amp;lt;0.01). Taking into account use of NSAIDs 1 day prior to urine collection did not change results. NSAID use may modify the conversion of androgens to estrogen and thereby lower breast cancer risk. Expected data on estrogen and estrogen metabolites will help us better understand these findings. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P3-08-03.

Abstract P6-02-08: Molecular drivers of adipogenotoxicosis in breast tumor-associated adipose

Abstract Background: Having long been thought to function only as an inert energy storage depot, the role of adipose tissue in tumorigenesis has been largely ignored; however, adipose is an active endocrine organ that can directly influence tumor growth. Improved understanding of the role of adipose in tumorigenesis is crucial given the association between obesity and breast cancer risk in post-menopausal women, increasing rates of obesity and use of autologous fat transfer in breast reconstruction. Methods: Adipose, adjacent to and distant from (&amp;gt;3 cm from the closest tumor margin) invasive breast tumors, was laser microdissected from 20 post-menopausal women, and from 22 post-menopausal women with non-malignant breast disease. Gene expression data were generated using U133A 2.0 microarrays. Data were analyzed to identify significant patterns of differential expression between adipose classes at the individual gene and molecular pathway level. Gene expression differences were validated using qRT-PCR in an additional set of 29 specimens. Results: SPP1, RRM2, MMP9 and PLA2G7 were expressed at &amp;gt;3-fold (P &amp;lt; 0.01) higher levels in adjacent adipose compared to distant adipose from the same breast. A number of immune response genes including MARCO, FABP7, ELF5, MYBPC1, MMP7, CLDN8, HLA-DQB1 and HLA-DQA1 were differentially expressed in distant adipose compared to adipose from non-malignant breasts. The most significant gene expression differences were detected between tumor-adjacent and non-malignant adipose with &amp;gt;3-fold higher expression of EGFL6 and ITGB2 and &amp;gt;3-fold lower levels of PIP, which are involved in growth, proliferation, and cellular adhesion in adjacent compared to non-malignant adipose. Pathway analysis revealed that immune response differs between non-malignant, distant and tumor-adjacent adipose with an enhanced B- and T-cell response detected in adjacent compared to distant or non-malignant adipose. Inflammatory response as well as DNA transcription and replication pathways were differentially expressed in distant compared to non-malignant adipose. Conclusions: Gene expression levels differ in breast adipose depending on presence of and proximity to tumor cells. Adipose adjacent to the tumor demonstrated the largest immune response, supporting the idea of adipogenotoxicosis, which through pro-inflammatory and genotoxic responses, promotes tumor development. In addition, genes involved in cellular proliferation, degradation of the extracellular matrix and angiogenesis are differentially expressed in adjacent compared to distant or non-malignant adipose, thus tumor-adjacent adipose may be contributing to the growth and invasion of the primary tumor. These data thus suggest that adipose is not an inert component of the breast microenvironment but plays an active role in tumorigenesis. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P6-02-08.

DHEA metabolites activate estrogen receptors alpha and beta

Dehydroepiandrosterone (DHEA) levels were reported to associate with increased breast cancer risk in postmenopausal women, but some carcinogen-induced rat mammary tumor studies question this claim. The purpose of this study was to determine how DHEA and its metabolites affect estrogen receptors α or β (ERα or ERβ)-regulated gene transcription and cell proliferation. In transiently transfected HEK-293 cells, androstenediol, DHEA, and DHEA-S activated ERα. In ERβ transfected HepG2 cells, androstenedione, DHEA, androstenediol, and 7-oxo DHEA stimulated reporter activity. ER antagonists ICI 182,780 (fulvestrant) and 4-hydroxytamoxifen, general P450 inhibitor miconazole, and aromatase inhibitor exemestane inhibited activation by DHEA or metabolites in transfected cells. ERβ-selective antagonist R,R-THC (R,R-cis-diethyl tetrahydrochrysene) inhibited DHEA and DHEA metabolite transcriptional activity in ERβ-transfected cells. Expression of endogenous estrogen-regulated genes: pS2, progesterone receptor, cathepsin D1, and nuclear respiratory factor-1 was increased by DHEA and its metabolites in an ER-subtype, gene, and cell-specific manner. DHEA metabolites, but not DHEA, competed with 17β-estradiol for ERα and ERβ binding and stimulated MCF-7 cell proliferation, demonstrating that DHEA metabolites interact directly with ERα and ERβin vitro, modulating estrogen target genes in vivo.

Migraine history, nonsteroidal anti-inflammatory drug use, and risk of postmenopausal endometrial cancer.

Endometrial cancer is primarily a hormonally mediated disease. As such, factors that mediate or reflect exposure to estrogens, or that mediate response to such exposure, may plausibly be associated with endometrial cancer risk. History of migraines, another hormonally mediated condition, has recently been associated with a reduced risk of hormone receptor-positive breast cancer; however, the relationship between migraines and endometrial cancer has not previously been explored. We evaluated the relationship between migraine history and endometrial cancer risk in postmenopausal women, considering also the potential impact of nonsteroidal anti-inflammatory drug (NSAID) use, given the relationship of NSAIDs to hormones and to migraine history. We identified 93,384 women participating in the Women's Health Initiative prospective cohort who had an intact uterus at the time of study entry. Using Cox proportional hazards regression, we assessed risk of endometrial cancer during study follow-up according to history of migraines and according to current NSAID use at the time of study entry, adjusting for age, study arm, race, and hormone therapy use. We also evaluated interaction in these associations by body mass index. Having a history of migraines was not associated with endometrial cancer risk [hazard ratio (HR) = 0.91, 95% confidence interval (CI) = 0.75-1.11], regardless of body mass index (BMI) or NSAID use status. Similarly, current NSAID use was not associated with endometrial cancer risk (HR = 1.01, 95% CI = 0.88-1.16), regardless of BMI. Migraine history and NSAID use do not appear to be associated with risk of endometrial cancer.

Adipokines Linking Obesity with Colorectal Cancer Risk in Postmenopausal Women

Mechanistic associations between obesity and colorectal cancer remain unclear. In this study, we investigated whether adipokines are risk factors for colorectal cancer and whether they may mediate its association with obesity. In a case-cohort study nested within the Women's Health Initiative cohort of postmenopausal women, baseline plasma samples from 457 colorectal cancer cases and 841 subcohort subjects were assayed for seven adipokines-adiponectin, leptin, plasminogen activator inhibitor-1 (PAI-1), resistin, hepatocyte growth factor, interleukin-6 (IL-6), and TNF-α. Serum insulin and estradiol values measured previously were also available for data analysis. After adjusting for age, race, smoking, colonoscopy history, and estrogen level, a low level of anti-inflammatory adiponectin and high levels of proinflammatory leptin, PAI-1, and IL-6 were associated with increased colorectal cancer risk, though only leptin remained significant after further adjustment for insulin [HRs comparing extreme quartiles (HR(Q4-Q1)), 1.84; 95% CI, 1.17-2.90]. Mediation analyses showed that leptin and insulin partially explained the association between waist circumference and colorectal cancer and attenuated it by 25% and 37%, respectively, with insulin being a significant mediator (P = 0.041). Our findings support the conclusion that adipokines involved in inflammation are associated with colorectal cancer risk, but that their effects may be mediated mostly by insulin, with leptin exerting an independent effect. Hyperinsulinemia and hyperleptinemia may therefore partially explain the adiposity association with colorectal cancer in postmenopausal women.

Diabetes and lung cancer among postmenopausal women.

OBJECTIVEEpidemiological evidence of diabetes as a lung cancer risk factor is limited and conflicting. Therefore, we assessed associations among diabetes, diabetes therapy, and lung cancer risk in postmenopausal women participating in the Women’s Health Initiative (WHI) study.RESEARCH DESIGN AND METHODSPostmenopausal women (n = 145,765), ages 50–79 years, including 8,154 women with diabetes at study entry were followed for a mean of 11 years with 2,257 lung cancers diagnosed. Information on diabetes therapy was collected via two methods (self-reported information on treatment history collected on a questionnaire at baseline and a face-to-face review of current medication containers that participants brought to the baseline visit). Lung cancers were confirmed by central medical record and pathology report review. Cox proportional hazards regression models adjusted for lung cancer risk factors were used to estimate hazard ratios (HRs) (95% CI) for diagnosis of diabetes and treatment of disease as risk factors for lung cancer.RESULTSCompared with women without diabetes, women with self-reported treated diabetes had a significantly higher risk of lung cancer (HR 1.27 [95% CI 1.02–1.59]), with risks increasing for women with diabetes requiring insulin treatment (1.71 [1.15–2.53]). However, we did not observe a significant association between lung cancer risk and diabetes not treated with medication or with duration of diabetes.CONCLUSIONSPostmenopausal women with treated diabetes, especially those using insulin, have a significantly higher risk of lung cancer. The influence of diabetes severity and specific classes of therapy for diabetes on lung cancer risk require future study.

Diabetes, Metformin, and Breast Cancer: Lilac Time?

Diabetes, Metformin, and Breast Cancer: Lilac Time?

Postmenopausal endometrial cancer risk and body size in early life and middle age: prospective cohort study

Background:Greater adiposity in early life has been linked to increased endometrial cancer risk in later life, but the extent to which this association is mediated through adiposity in later life is unclear.Methods:Among postmenopausal women who had never used menopausal hormone therapies and reported not having had a hysterectomy, adjusted relative risks (RRs) of endometrial cancer were estimated using Cox regression.Results:Among 249 791 postmenopausal women with 7.3 years of follow-up on average (1.8 million person-years), endometrial cancer risk (n=1410 cases) was strongly associated with current body mass index (BMI) at baseline (RR=1.87 per 5 kg m−2 increase in BMI, 95% confidence interval (CI): 1.77–1.96). Compared with women thinner than average at age 10, the increased risk among women plumper at age 10 (RR=1.27, 95% CI: 1.09–1.49) disappeared after adjustment for current BMI (RR=0.90, 95% CI: 0.77–1.06). Similarly, compared with women with clothes size 12 or less at age 20, the increased risk among women with clothes size 16 or larger (RR=1.87, 95% CI: 1.61–2.18) was not significant after adjustment for current BMI (RR=1.03, 95% CI: 0.88–1.22).Conclusion:Among women who have never used hormone therapy for menopause, the association between body size in early life and endometrial cancer risk in postmenopausal women can be largely explained by women’s current BMI.