Colorectal Cancer In Postmenopausal Women Research Articles

Incidence of IgA antibodies specific to benzo[a]pyrene and steroid hormones in women with colorectal cancer and breast cancer

Formation of DNA adducts of chemical carcinogens is a trigger for carcinogenesis. Adducts of benzo[a]pyrene metabolites and estradiol metabolites with DNA have been found in normal and tumor cells in healthy women and patients with breast and colorectal cancer. These low-weight compounds in macromolecular complexes induce the synthesis of specific antibodies. Previously, the presence of specific antibodies against benzo[a]pyrene (IgA-Bp), estradiol (IgA-Es) and progesterone (IgA-Pg) was revealed in breast cancer patients. The aim of this study is to identify the putative features of the IgA-Bp, IgA-Es, and IgA-Pg formation in postmenopausal women with colorectal cancer, in comparison with healthy and breast cancer patients. Using a noncompetitive enzyme-linked immunosorbent assay, the content of these antibodies was studied in the blood serum of healthy women (n = 401), patients with colorectal cancer (n = 219) and breast cancer (n = 1469) using conjugates of Bp, Es, and Pg with bovine serum albumin as adsorbed antigens. When compared with healthy people, the patients with colorectal cancer exhibited higher incidence of IgA-Bp 3 (75% vs 37%, p 0.0001, OR = 5.0), as well as more common levels of individual antibody ratios: IgA-Bp/IgA-Es 1 (82% vs 41%, p 0.0001, OR = 6.5); IgA-Bp/IgA-Pg 1.5 (77% vs 20%, p 0.0001, OR = 13.4); IgA-Es/IgA-Pg 1 (89% vs 48%, p 0.0001, OR = 8.7). In breast cancer patients, compared with healthy people, high IgA-Bp values ( 3) were more common (45% vs 37%, p 0.004, OR = 1.4), as well as increased IgA-Bp/IgA-Es ratio 1 (57% vs 41%, p 0.0001, OR = 1.9), IgA-Bp/IgA-Pg 1.1 (71% vs 36%, p 0.0001, OR = 4.4) and IgA-Es/IgA-Pg 1.1 (71% vs 41%, p 0.0001, OR = 3.5). In patients with colorectal cancer, compared with patients with breast cancer we have found higher incidence of increased IgA-Bp values ( 3) (75% vs 45%, p 0.0001), IgA-Es 3 (53% vs 39%, p 0, 0001), and of IgA-Pg 2 (52% vs 44%, p = 0.025), as well as IgA-Bp/IgA- Es 1 (82% vs 57%, p 0.0001, OR = 50.8 ); IgA-Bp/IgA-Pg 1.5 (77% vs 49%, p 0.0001); IgA-Es/IgA-Pg 1.1 (85% vs 71%, p 0.0001). The apparently high serum IgA-Bp levels reflect the formation of DNA-Bp adducts at large scale in target cells in colorectal cancer compared with healthy women and breast cancer patients, due to direct exposure of colon epithelium to Bp from food. Immunoassay for IgA-Bp, IgA-Es and IgA-Pg is proposed for assessing individual risk of colorectal cancer in postmenopausal women. The ratios of IgA Bp/IgA-Pg levels 1.5 represent the most informative marker of individual risk for colorectal cancer.

Plasma sex hormones and risk of conventional and serrated precursors of colorectal cancer in postmenopausal women

BackgroundSex hormones have been suggested to play a role in colorectal cancer (CRC), but their influence on early initiation of CRC remains unknown.MethodsWe retrospectively examined the associations with risk of CRC precursors, including conventional adenomas and serrated polyps, for plasma estrone, estradiol, free estradiol, testosterone, free testosterone, sex hormone-binding globulin (SHBG), and the ratio of estradiol to testosterone among 5404 postmenopausal women from the Nurses’ Health Study I and II. Multivariable logistic regression was used to calculate the odds ratio (OR) and 95% confidence intervals (CI). Given multiple testing, P < 0.005 was considered statistically significant.ResultsDuring 20 years of follow-up, we documented 535 conventional adenoma cases and 402 serrated polyp cases. Higher concentrations of SHBG were associated with lower risk of conventional adenomas, particularly advanced adenomas (multivariable OR comparing the highest to the lowest quartile, 0.40, 95% CI 0.24–0.67, P for trend < 0.0001). A nominally significant association was found for SHBG with lower risk of large serrated polyps (≥ 10 mm) (OR, 0.47, 95% CI 0.17–1.35, P for trend = 0.02) as well as free estradiol and free testosterone with higher risk of conventional adenomas (OR, 1.54, 95% CI 1.02–2.31, P for trend = 0.03 and OR, 1.33, 95% CI 0.99–1.78, P for trend = 0.03, respectively).ConclusionsThe findings suggest a potential role of sex hormones, particularly SHBG, in early colorectal carcinogenesis.

Obesity Has a Stronger Relationship with Colorectal Cancer in Postmenopausal Women than Premenopausal Women.

To examine the relationship between obesity measured by waist circumference (WC) and body mass index (BMI) and the incidence of colorectal cancer in premenopausal and postmenopausal women. A total of 1,418,180 premenopausal and 4,854,187 postmenopausal women without cancer at baseline and ages over 40 were identified using the Korean National Health Insurance System Cohort during 2009 to 2014. The hazard ratio (HR) for colorectal cancer incidence was assessed according to menopausal state using Cox proportional hazards models. During a mean follow-up period of 7.2 years, 7,094 and 57,449 colorectal cancer cases occurred in premenopausal and postmenopausal women, respectively. Compared with the reference group (WC 65-75), the HRs [95% confidence interval (CI)] of colorectal cancer in WC <65, 75-85, 85-95, and >95 groups were 1.01 (0.91-1.11), 1.02 (0.97-1.07), 1.09 (1.00-1.18), and 1.31 (1.12-1.52), respectively, in premenopausal women and 1.01 (0.95-1.17), 1.09 (1.07-1.12), 1.19 (1.00-1.18), and 1.30 (1.25-1.35), respectively, in postmenopausal women. Compared with the reference group (BMI 18.5-22.9), HRs (95% CI) for colorectal cancer in BMI <18.5, 23-25, 25-30, and >30 groups were 0.99 (0.87-1.14), 0.99 (0.94-1.06), 0.98 (0.92-1.04), and 1.06 (0.92-1.20), respectively, in premenopausal women. In postmenopausal women, those values were 0.99 (0.93-1.05), 1.05 (1.03-1.08), 1.11 (1.09-1.13), and 1.20 (1.16-1.25), respectively. WC is associated with the risk of colorectal cancer in both groups of women, but this association was stronger in postmenopausal women than in premenopausal women. BMI increased the incidence of colorectal cancer only in postmenopausal women IMPACT: Obesity has a stronger relationship with colorectal cancer in postmenopausal women than in premenopausal women.

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

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. 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. 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. Our findings suggest that a predominance of putative anti- relative to pro-colorectal carcinogenic mineral intakes may be inversely associated with colorectal cancer risk. These results support further investigation of colorectal cancer etiology using composite mineral intake scores.

Colorectal tumor prevention by the progestin medroxyprogesterone acetate is critically dependent on postmenopausal status.

The large randomized placebo controlled trials of the Women’s Health Initiative have shown that the combination of estrogen and progestin medroxyprogesterone acetate (MPA) protects from colorectal cancer in postmenopausal women. No effect was observed in women treated with estrogen alone. This suggests that progesterone, or more specifically the progestin MPA may have chemopreventive activity. The effect of MPA on colorectal carcinogenesis has been difficult to study in animal models. Most models are not affected by either depleting female hormones by ovariectomy or treatment with MPA. Importantly, an ovariectomy fails to reproduce one of the hall marks of the postmenopausal state in women with intact ovaries. That is, the continued production of androgens by the atrophic postmenopausal ovaries. Here we show that adenoma incidence is increased in the vinyl cylcohexene diepoxide (VCD) mouse model of the menopause compared to age matched fertile female mice. Treatment with MPA protected VCD treated mice from adenomagenesis, but had no effect on adenoma numbers in age-matched fertile female mice. Our data show that the protective effect of MPA depends on the postmenopausal state and suggest that MPA monotherapy may be studied as a chemopreventive agent in postmenopausal women.

Association of physical activity and sitting time with incident colorectal cancer in postmenopausal women.

Findings from epidemiological studies have found that physical activity (PA) is associated with a lower risk of colorectal cancer (CRC). Recent studies have found an increased CRC risk with higher sitting time (ST); however, many studies did not include PA as a potential confounder. The objective of this project was to investigate the independent and combined associations of ST and PA with the risk of incident CRC, specifically colon and rectal cancer. Participants in the Women's Health Initiative Observational Study (n=74 870), 50-79 years of age self-reported ST and PA at baseline, years 3 and 6. Incident CRC was the primary outcome; colon and rectal cancers were the secondary outcomes, which were centrally adjudicated. Over a 13-year follow-up period, 1145 incident cases of CRC were documented. A positive age-adjusted association was found between higher ST (≥10 vs. <5 h/day) and CRC (P for trend=0.04) and colon cancer (P for trend=0.05); however, these associations were attenuated and no longer significant in multivariable-adjusted models. Compared with inactive women (≤1.7 MET-h/week), the multivariable risk of CRC in the high PA (>20 MET-h/week) group was 0.81 (95% confidence interval: 0.66-1.00; P for trend 0.04). Compared with inactive women with high ST (≥10 h/day), there was a trend toward reduced multivariable CRC risks with higher PA irrespective of ST level (interaction=0.64). We observed an inverse association between leisure time PA and the risk of CRC, particularly for rectal cancer. There was no association between ST and CRC in multivariable models.

Metabolic obesity phenotypes and risk of colorectal cancer in postmenopausal women

Obesity has been postulated to increase the risk of colorectal cancer by mechanisms involving insulin resistance and the metabolic syndrome. We examined the associations of body mass index (BMI), waist circumference, the metabolic syndrome, metabolic obesity phenotypes and homeostasis model-insulin resistance (HOMA-IR-a marker of insulin resistance) with risk of colorectal cancer in over 21,000 women in the Women's Health Initiative CVD Biomarkers subcohort. Women were cross-classified by BMI (18.5-<25.0, 25.0-<30.0 and ≥30.0 kg/m2 ) and presence of the metabolic syndrome into 6 phenotypes: metabolically healthy normal weight (MHNW), metabolically unhealthy normal weight (MUNW), metabolically healthy overweight (MHOW), metabolically unhealthy overweight (MUOW), metabolically healthy obese (MHO) and metabolically unhealthy obese (MUO). Neither BMI nor presence of the metabolic syndrome was associated with risk of colorectal cancer, whereas waist circumference showed a robust positive association. Relative to the MHNW phenotype, the MUNW phenotype was associated with increased risk, whereas no other phenotype showed an association. Furthermore, HOMA-IR was not associated with increased risk. Overall, our results do not support a direct role of metabolic dysregulation in the development of colorectal cancer; however, they do suggest that higher waist circumference is a risk factor, possibly reflecting the effects of increased levels of cytokines and hormones in visceral abdominal fat on colorectal carcinogenesis.

Aromatase inhibitors and the risk of colorectal cancer in postmenopausal women with breast cancer

BackgroundA large trial of postmenopausal women with breast cancer reported an imbalance in colorectal cancer events with aromatase inhibitors (AIs), compared with tamoxifen in the adjuvant setting. This unexpected signal was observed within 3years of randomization. To date, no observational studies have examined this important safety question in the natural setting of clinical practice. Thus, the objective of this study was to determine whether AIs, when compared with tamoxifen, are associated with increased risk of colorectal cancer in postmenopausal women with breast cancer. Patients and methodsUsing the UK Clinical Practice Research Datalink, we identified women, at least 55years of age, with breast cancer newly treated with either AIs or tamoxifen between 1 January 1996 and 30 September 2015, with follow-up until 30 September 2016. High-dimensional propensity score-adjusted Cox proportional hazards models were used to estimate hazard ratios (HRs) with 95% confidence intervals (CIs) of incident colorectal cancer associated with AIs when compared with tamoxifen overall, by cumulative duration of use, and time since initiation. All exposures were lagged by 1 year for latency considerations. ResultsA total of 9701 and 8893 patients initiated AIs and tamoxifen as first-line hormonal therapy (median follow-up of 2.4 and 2.9years, respectively). Compared with tamoxifen, AIs were not associated with an increased risk of colorectal cancer (incidence rates of 150 per 100000 person-years in both groups; adjusted HR: 0.90, 95% CI: 0.53–1.52). Similarly, there was no evidence of an association with cumulative duration of use (P-heterogeneity=0.54), and time since initiation (P-heterogeneity=0.66). ConclusionsIn this first population-based study, the use of AIs was not associated with an increased risk of colorectal cancer. These findings should provide reassurance to the concerned stakeholders.

Changes in the Inflammatory Potential of Diet Over Time and Risk of Colorectal Cancer in Postmenopausal Women.

We examined the associations between changes in dietary inflammatory potential and risk of colorectal cancer (CRC) in 87,042 postmenopausal women recruited from 1993-1998 by the Women's Health Initiative, conducted in the United States. Food frequency questionnaire data were used to compute patterns of change in dietary inflammatory index (DII) scores and cumulative average DII scores over 3 years. Cox regression models were used to estimate hazard ratios for CRC risk. After a median of 16.2 years of follow-up, 1,038 CRC cases were diagnosed. DII changes were not substantially associated with overall CRC, but proximal colon cancer risk was higher in the proinflammatory-change DII group than in the antiinflammatory-stable DII group (hazard ratio=1.32, 95% confidence interval: 1.01, 1.74). Among nonusers of nonsteroidal antiinflammatory drugs (NSAIDs) (Pinteraction=0.055), the proinflammatory-stable DII group was at increased risk of overall CRC and proximal colon cancer. Also among nonusers of NSAIDs, risks of overall CRC, colon cancer, and proximal colon cancer were higher in the highest quintile compared with the lowest cumulative average DII quintile (65%, 61%, and 91% higher risk, respectively). Dietary changes toward, or a history of, proinflammatory diets are associated with an elevated risk of colon cancer, particularly for proximal colon cancer and among nonusers of NSAIDs.

Longitudinal association of hemostatic factors with risk for cancers of the breast, colorectum, and lung among postmenopausal women.

The aim of this study was to examine whether hemostatic factors associated with coagulation and inflammation pathways are associated with cancer risk in postmenopausal women. We used data from the Women's Health Initiative study to examine the association of plasma fibrinogen levels, factor VII antigen activity, and factor VII concentration measured at baseline and during follow-up with the risk for cancers of the breast, colorectum, and lung. Among 5287 women who were followed up for a median of 11.4 years, 275 cases of breast cancer, 102 cases of colorectal cancer, and 90 cases of lung cancer were identified. Cox proportional hazards models were used to estimate hazard ratios and 95% confidence intervals for the association of hemostatic factors with each cancer. Hemostatic factors were not associated with breast cancer in either baseline or longitudinal analyses. Baseline hemostatic factors showed weak associations with colorectal cancer; however, no association was seen in longitudinal analyses. Fibrinogen was positively associated with lung cancer in both baseline and longitudinal analyses; the association was seen only in never and former smokers, not in current smokers. We found no evidence of an association between hemostatic factors and breast or colorectal cancer in postmenopausal women. The positive association of fibrinogen levels with lung cancer requires confirmation in larger studies.

Association between magnesium intake and risk of colorectal cancer among postmenopausal women.

Data relating to magnesium intake and colorectal cancer (CRC) risk in postmenopausal women are incomplete. We investigated the association between total magnesium intake and the risk of CRC in an ethnically diverse cohort of postmenopausal women enrolled in the Women's Health Initiative. Self-reported dietary and supplemental magnesium were combined to form total magnesium intake. Invasive incident CRC was the primary outcome. Cox proportional hazard models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CI). During an average follow-up of 13 years (1,832,319 person-years), of the 140,601 women included for analysis, 2,381 women were diagnosed with CRC (1,982 colon cancer and 438 rectal cancer). After adjustment for potential confounding variables, an inverse association was observed in the highest quintile of total magnesium intake compared to the lowest quintile for risk of CRC (HR 0.79, 95% CI 0.67, 0.94, p trend < 0.0001) and colon cancer (HR 0.80, 95% CI 0.66, 0.97, p trend < 0.0001). A borderline significant inverse association was detected in the highest versus the lowest quintile of total magnesium intake for rectal cancer (HR 0.76, 95% CI 0.51, 1.13, p trend < 0.001). Findings from this study support the hypothesis that magnesium intake around 400 mg/day from both dietary and supplemental sources is associated with a lower incidence of CRC in postmenopausal women.

The association between dietary inflammatory index and risk of colorectal cancer among postmenopausal women: results from the Women's Health Initiative.

Inflammation is a process central to carcinogenesis and in particular to colorectal cancer (CRC). Previously, we developed a dietary inflammatory index (DII) from extensive literature review to assess the inflammatory potential of diet. In the current study, we utilized this novel index in the Women's Health Initiative to prospectively evaluate its association with risk of CRC in postmenopausal women. The DII was calculated from baseline food frequency questionnaires administered to 152,536 women aged 50-79years without CRC at baseline between 1993 and 1998 and followed through 30 September 2010. Incident CRC cases were ascertained through a central physician adjudication process. Multiple covariate-adjusted Cox proportional hazards regression models were used to estimate hazard ratios (HR) and 95% confidence intervals (95% CI) for colorectal, colon (proximal/distal locations), and rectal cancer risk, by DII quintiles (Q). During an average 11.3years of follow-up, a total of 1,920 cases of CRC (1,559 colon and 361 rectal) were identified. Higher DII scores (representing a more pro-inflammatory diet) were associated with an increased incidence ofCRC (HRQ5-Q1 1.22; 95% CI 1.05, 1.43; p trend=0.02) and colon cancer, specifically proximal colon cancer (HRQ5-Q1 1.35; 95% CI 1.05, 1.67; p trend=0.01) but not distal colon cancer (HRQ5-Q1 0.84; 95% CI 0.61, 1.18; p trend=0.63) or rectal cancer (HRQ5-Q1 1.20; 95% CI 0.84, 1.72; p trend=0.65). Consumption of pro-inflammatory diets is associated with an increased risk of CRC, especially cancers located in the proximal colon. The absence of a significant association for distal colon cancer and rectal cancer may be due to the small number of incident cases for these sites. Interventions that may reduce the inflammatory potential of the diet are warranted to test our findings, thus providing more information for colon cancer prevention.

Visceral fat accumulation is associated with colorectal cancer in postmenopausal women.

BackgroundObesity is a known risk factor for colorectal cancer (CRC), and emerging data suggest that this association is mediated by visceral fat rather than total body fat. However, there is a lack of studies evaluating the association between visceral fat area and the prevalence of CRC.MethodsTo investigate the relationship between visceral adiposity and prevalence of CRC, data of 497 women diagnosed with CRC and 318 apparently healthy women were analysed and data of well-balanced 191 pairs of women with CRC and healthy women matched based on propensity scores were additionally analysed. Diagnosis of CRC was confirmed by colonoscopy and histology. Metabolic parameters were assessed, along with body composition, using computed tomography.ResultsThe median visceral fat area was significantly higher in the CRC group compared with the control group before and after matching. The prevalence of CRC increased significantly with increasing visceral fat tertiles after matching (p for trend <0.01). A multivariate analysis showed that mean visceral fat area of individuals in the 67th percentile or greater group was associated with an increased prevalence of CRC (adjusted odds ratio: 1.80; 95% confidence interval: 1.12–2.91 before matching and adjusted odds ratio: 2.96; 95% confidence interval: 1.38–6.33) compared with that of individuals in the 33th percentile or lower group.ConclusionThus, we conclude that visceral fat area is positively associated with the prevalence of CRC. Although we could not determine the causality, visceral adiposity may be associated with the risk of CRC. Further prospective studies are required to determine the benefits of controlling visceral obesity for reducing CRC risk.

Abstract 256: Periodontal disease severity and incident cancer in postmenopausal women: the Buffalo OsteoPerio Study

Abstract Background: Periodontal disease has an infectious etiology and there is growing evidence that it may be positively associated with cancer occurrence. Potential mechanisms may involve the host inflammatory response to oral infection and the potential mobility of the oral microbiome to extra-oral sites. However, few studies have focused on older postmenopausal women who are susceptible to both periodontal disease and cancer and where comprehensive periodontal assessments have been made. This study aims to determine whether loss of alveolar crestal bone height (ACH) in the oral cavity, a measure of chronic periodontitis, is associated with incident cancer in a well-characterized cohort of postmenopausal women. Methods: We prospectively followed a cohort of 1,337 postmenopausal women (aged 53-85 years at baseline; 3% current smokers) who participated in the Buffalo OsteoPerio Study, an ancillary study of the Women's Health Initiative. Whole mouth mean and worst site ACH (mm of loss) were assessed from oral radiographs. Incident cancer was ascertained from annual health updates and confirmed using medical records by physician adjudicators. Cox proportional hazard regression was used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for associations of ACH with total and site-specific cancer risk in multivariate-adjusted models. Results: During an average follow-up of 9.6 years (SD=2.7), there were 170 confirmed incident cancer cases. The most common sites were breast (N=77), lung (N=15), colorectum (N=14), and endometrium (N=12), accounting for 69% of all cancers. When analyzed as a continuous exposure and after adjusting for age, education, and pack-years of smoking, worst site ACH was not associated with total cancer risk (HR=1.04 per 1mm loss, 95% CI=0.94-1.15). However, there was a statistically significant increased risk of lung (HR=1.49, 95% CI=1.18-1.89) and colorectal cancer (HR=1.35, 95% CI=1.04-1.74). No associations were found for worst site ACH with breast (HR=0.91, 95% CI=0.77-1.09) or endometrial cancer (HR=0.77, 95% CI=0.46-1.30). Whole mouth mean ACH was also significantly associated with incident lung cancer (HR=2.05 per 1mm loss, 95% CI=1.40-3.01), but not with total cancer (HR=1.09, 95% CI=0.89-1.33), or with colorectal (HR=1.45, 95% CI=0.91-2.33), breast (HR=0.83, 95% CI=0.57-1.20) or endometrial (HR=0.62, 95% CI=0.21-1.85) cancers in multivariate-adjusted models. These estimates did not change appreciably after further adjustments. Conclusions: This study provides evidence that chronic periodontitis is positively associated with risk of lung and colorectal cancer in postmenopausal women. These results need to be interpreted cautiously given the small number of incident cancer cases. Further research utilizing a larger sample is warranted to confirm these results. Citation Format: Xiaodan Mai, Jo L. Freudenheim, Michael J. LaMonte, Kathleen M. Hovey, Christopher A. Andrews, Robert J. Genco, Jean Wactawski-Wende. Periodontal disease severity and incident cancer in postmenopausal women: the Buffalo OsteoPerio Study. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 256. doi:10.1158/1538-7445.AM2014-256

Descriptive profile of PIK3CA-mutated colorectal cancer in postmenopausal women

Approximately 10-30 % of colorectal cancers exhibit somatic mutations in the phosphoinositide-3-kinase, catalytic, alpha polypeptide gene (PIK3CA). We evaluated the relationship between PIK3CA mutation status and demographic factors, lifestyle factors, and other tumor characteristics and the relationship between PIK3CA mutation status and colorectal cancer survival. The population-based study included postmenopausal women with invasive colorectal cancer diagnosed between 1998 and 2002 in Western Washington State. Participants were interviewed, and tumor specimens were tested for PIK3CA mutations in exons 9 and 20 hotspots, KRAS exon 2 mutations, BRAF p.V600E mutation, and microsatellite instability. We used Cox regression to evaluate the association between PIK3CA mutation status and disease-specific and overall survival. Stratified analyses were conducted by KRAS mutation status. PIK3CA mutations were evident in approximately 13 % of cases (N = 35). Women with PIK3CA-mutated colorectal cancer were significantly more likely than those with PIK3CA wild-type disease to be non-white, to have proximal colon cancer, and to have KRAS-mutated tumors (p < 0.05). In Cox proportional hazards regression analyses, overall survival was poorer, although not statistically significantly so, for women with PIK3CA-mutated versus wild-type colorectal cancer (hazard ratio = 1.74, 95 % confidence interval 0.86-3.50). This association between PIK3CA mutation status and survival was evident only when analyses were restricted to cases without somatic KRAS mutations (hazard ratio = 2.94, 95 % confidence interval 1.12-7.73). PIK3CA-mutated colorectal cancer appears to have a distinct epidemiologic profile that is of clinical significance. Women with PIK3CA-mutated colorectal cancer experience a poorer prognosis than those with PIK3CA wild-type disease.

B vitamin intakes and incidence of colorectal cancer: results from the Women’s Health Initiative Observational Study cohort

The role of one-carbon metabolism nutrients in colorectal carcinogenesis is not fully understood. Associations might be modified by mandated folic acid (FA) fortification or alcohol intake. We investigated associations between intakes of folate, riboflavin, vitamin B-6, and vitamin B-12 and colorectal cancer (CRC) in the Women's Health Initiative Observational Study, stratified by time exposed to FA fortification and alcohol intake. A total of 88,045 postmenopausal women were recruited during 1993-1998; 1003 incident CRC cases were ascertained as of 2009. Quartiles of dietary intakes were compared; HRs and 95% CIs were estimated by Cox proportional hazards models. Dietary and total intakes of vitamin B-6 in quartile 4 compared with quartile 1 (HR: 0.80; 95% CI: 0.66, 0.97 and HR: 0.80; 95% CI: 0.66, 0.99, respectively) and total intakes of riboflavin (HR: 0.81; 95% CI: 0.66, 0.99) were associated with reduced risk of CRC overall and of regionally spread disease. In current drinkers who consumed <1 drink (13 g alcohol)/wk, B vitamin intakes were inversely associated with CRC risk (P-interaction < 0.05). Dietary folate intake was positively associated with CRC risk among women who had experienced the initiation of FA fortification for 3 to <9 y (P-interaction < 0.01). Vitamin B-6 and riboflavin intakes from diet and supplements were associated with a decreased risk of CRC in postmenopausal women. Associations of B vitamin intake were particularly strong for regional disease and among women drinkers who consumed alcohol infrequently. Our study provides new evidence that the increased folate intake during the early postfortification period may have been associated with a transient increase in CRC risk.

Sleep duration and incidence of colorectal cancer in postmenopausal women

Background:Sleep duration is dependent on circadian rhythm that controls a variety of key cellular functions. Circadian disruption has been implicated in colorectal tumorigenesis in experimental studies. We prospectively examined the association between sleep duration and risk of colorectal cancer (CRC).Methods:In the Women’s Health Initiative Observational Study, 75 828 postmenopausal women reported habitual sleep duration at baseline 1993–1998. We used Cox proportional hazards regression model to estimate the hazard ratio (HR) of CRC and its associated 95% confidence interval (CI).Results:We ascertained 851 incident cases of CRC through 2010, with an average 11.3 years of follow-up. Compared with 7 h of sleep, the HRs were 1.36 (95% CI 1.06–1.74) and 1.47 (95% CI 1.10–1.96) for short (⩽5 h) and long (⩾9 h) sleep duration, respectively, after adjusting for age, ethnicity, fatigue, hormone replacement therapy (HRT), physical activity, and waist to hip ratio. The association was modified by the use of HRT (P-interaction=0.03).Conclusion:Both extreme short and long sleep durations were associated with a moderate increase in the risk of CRC in postmenopausal women. Sleep duration may be a novel, independent, and potentially modifiable risk factor for CRC.

Association Between Sex Hormones and Colorectal Cancer Risk in Men and Women

There is observational and clinical evidence that indicates that sex hormones affect development of colorectal cancer in men and women. However, the relationship between endogenous sex hormone levels and colorectal cancer is unclear. We collected data on lifestyle, medical history, and diet (through 2008), along with blood samples, from the Nurses' Health Study, the Women's Health Study, the Health Professional Follow-up Study, and the Physicians' Health Study II. We measured plasma levels of estrone, estradiol, testosterone, sex hormone binding globulin (SHBG), and C-peptide among 730 women (293 cases of colorectal cancer and 437 healthy individuals as controls) and 1158 men (439 colorectal cancer cases and 719 controls) and used unconditional logistic regression to estimate relative risks (RRs) and 95% confidence intervals. All statistical tests were 2-sided. Total testosterone, SHBG, and the ratio of estradiol to testosterone were associated with colorectal cancer in men after adjustments for matching and risk factors for colorectal cancer, including body mass index and plasma levels of C-peptide. The RRs in the highest relative to the lowest quartile were 0.62 for testosterone (95% confidence interval, 0.40-0.96), 0.65 for SHBG (95% confidence interval, 0.42-0.99), and 2.63 for the ratio (95% confidence interval, 1.58-4.36) (P values for trend ≤ .02). However, in women, only the ratio of estradiol to testosterone was (inversely) associated with colorectal cancer after adjustments for all factors (RR, 0.43; 95% confidence interval, 0.22-0.84; P value for trend = .03). On the basis of combined data from 4 population studies, there appears to be an association between levels of sex hormones and colorectal cancer risk in men. There also appears to be an inverse association between the ratio of estradiol to testosterone and colorectal cancer in postmenopausal women.

A longitudinal study of the metabolic syndrome and risk of colorectal cancer in postmenopausal women.

The metabolic syndrome is associated with increased risk of diabetes and coronary heart disease. Although higher BMI and other related factors have been frequently associated with colorectal cancer, whether the metabolic syndrome is associated with the risk of colorectal cancer is unclear. We therefore assessed the association of the metabolic syndrome with the risk of colorectal cancer in a subsample of participants of the Women's Health Initiative who had repeated measurements of the components of the syndrome at baseline and during follow-up. Women with diabetes at baseline enrollment were excluded. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (95% CI) at baseline and in time-dependent analyses. Among 4862 eligible women, 81 incident cases of colorectal cancer were identified over a median follow-up of 12 years. Presence of the metabolic syndrome at baseline was associated with increased risk of colorectal cancer (HR 2.15, 95% CI 1.30-3.53) and colon cancer (HR 2.28, 95% CI 1.31-3.98). These associations were largely explained by positive associations of serum glucose and systolic blood pressure with both outcomes. Time-dependent covariate analyses supported the baseline findings. Our results suggest that the positive association of the metabolic syndrome with risk of colorectal cancer is largely accounted for by serum glucose levels and systolic blood pressure. The biological mechanism underlying these associations remains to be clarified.

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.