Iowa Women's Health Study Research Articles

WCRF/AICR recommendation adherence and breast cancer incidence among postmenopausal women with and without non-modifiable risk factors.

Taller height, family history of breast cancer, greater number of years of potential fertility and nulliparity are established non-modifiable risk factors for postmenopausal breast cancer. Greater adherence to the World Cancer Research Fund/American Institute for Cancer Research (WCRF/AICR) diet, physical activity and body weight recommendations has previously been shown to be associated with lower breast cancer risk. However, no prior studies have evaluated whether women with non-modifiable risk factors receive similar benefits from recommendation adherence compared to women without these risk factors. In the Iowa Women's Health Study prospective cohort, we investigated whether associations of WCRF/AICR recommendation adherence differed by the presence/absence of non-modifiable breast cancer risk factors. Baseline (1986) questionnaire data from 36,626 postmenopausal women were used to create adherence scores for the WCRF/AICR recommendations (maximum score = 8.0). Overall and single recommendation adherence in relation to breast cancer risk (n = 3,189 cases) across levels of non-modifiable risk factors were evaluated using proportional hazards regression. Mean adherence score was 5.0 points (range: 0.5-8.0). Higher adherence scores (score ≥ 6.0 vs. ≤ 3.5, HR = 0.76, 95% CI = 0.67-0.87), and adherence to the individual recommendations for body weight and alcohol intake were associated with a lower breast cancer incidence. While not statistically significant among women with more non-modifiable risk factors (score ≥ 6.0 vs. ≤ 3.5, HR = 0.76, 95% CI = 0.36-1.63), hazard ratios were comparable to women with the no non-modifiable risk factors (score ≥ 6.0 vs. ≤ 3.5, HR = 0.74, 95% CI = 0.49-0.93) (p-interaction = 0.57). WCRF/AICR recommendation adherence is associated with lower breast cancer risk, regardless of non-modifiable risk factor status.

Role of survivor bias in pancreatic cancer case-control studies

PurposeThe purpose of this study was to evaluate the impact of survivor bias on pancreatic cancer case-control studies. MethodsThe authors constructed five case-loss scenarios based on the Iowa Women's Health Study cohort to reflect how case recruitment in population-based studies varies by case survival time. Risk factors for disease incidence included smoking, body mass index (BMI), waist circumference, diabetes, and alcohol consumption. Odds ratios (ORs) were estimated by conditional logistic regression and quantitatively compared by the interactions between risk factors and 3-month survival time. Additionally, Kaplan–Meier estimates for overall survival were compared within the subset cohort of pancreatic cancer cases. ResultsBMI and waist circumference showed a significant inverse relationship with survival time. Decreasing trends in ORs for BMI and waist circumference were observed with increasing case survival time. The interaction between BMI and survival time based on a cutpoint of 3 months was significant (P < .01) as was the interaction between waist circumference and survival time (P < .01). ConclusionsThe findings suggested that case losses could result in survivor bias causing underestimated odds ratios for both BMI and waist circumference, whereas other risk factors were not significantly affected by case losses.

Association between inflammatory potential of diet and mortality in the Iowa Women's Health study.

Chronic diseases such as cancer and cardiovascular disease (CVD) are well-established causes of disability and premature deaths. Dietary components that are known to affect chronic inflammation have been implicated in the etiology and prognosis of these chronic diseases. We examined the ability of the dietary inflammatory index (DII) to predict overall, cancer and CVD mortality in the Iowa Women's Health study. The DII was computed from baseline dietary intake assessed in this cohort of 37,525 women, who were aged 55-69years when enrolled starting in 1986. During the follow-up period, through December 31, 2010, in a total of 17,793 deaths, 5044 cancer- and 6528 CVD-related deaths were identified through mortality record linkage. Cox proportional hazards regression was used to estimate hazard ratios (HR) with DII expressed both as a continuous variable and as quartiles. Comparing subjects in DII Quartile 4 versus Quartile 1, modest positive associations were noted for all-cause mortality (HRQ4vsQ1 1.07; 95% CI 1.01-1.13; p-trend=0.006), digestive cancer mortality (HRQ4vsQ1 1.19; 95% CI 1.00-1.43; p-trend=0.05), CVD mortality (HRQ4vsQ1 1.09; 95% CI 1.01-1.18; p-trend=0.08), non-cancer/non-CVD/non-acute mortality (HRQ4vsQ1 1.09; 95% CI 1.00-1.19; p-trend=0.19), coronary heart disease (CHD) mortality (HRQ4vsQ1 1.17; 95% CI 1.05-1.30; p-trend=0.001) and chronic obstructive pulmonary disease (COPD) mortality (HRQ4vsQ1 1.43; 95% CI 1.18-1.75; p-trend=0.0006). No substantial associations were observed for mortality from stroke, Alzheimer's disease or unspecified dementia. These results indicate that a pro-inflammatory diet, as evidenced by higher DII scores, may be associated with total mortality as well as mortality from digestive cancer, CVD, CHD and COPD.

Associations between Environmental Exposures and Incident Colorectal Cancer by ESR2 Protein Expression Level in a Population-Based Cohort of Older Women

Cigarette smoking (smoking), hormone therapy (MHT), and folate intake (folate) are each thought to influence colorectal cancer risk, but the underlying molecular mechanisms remain incompletely defined. Expression of estrogen receptor β (ESR2) has been associated with colorectal cancer stage and survival. In this prospective cohort study, we examined smoking, MHT, and folate-associated colorectal cancer risks by ESR2 protein expression level among participants in the Iowa Women's Health Study (IWHS). Self-reported exposure variables were assessed at baseline. Archived, paraffin-embedded colorectal cancer tissue specimens were collected and evaluated for ESR2 protein expression by IHC. Multivariate Cox regression models were fit to estimate relative risks (RR) and 95% confidence intervals (CI) for associations between smoking, MHT, or folate and ESR2-defined colorectal cancer subtypes. Informative environmental exposure and protein expression data were available for 491 incident colorectal cancer cases. Positive associations between ESR2-low and -high tumors and several smoking-related variables were noted, most prominently with average number of cigarettes per day (RR, 4.24; 95% CI, 1.81-9.91 for ESR2-low and RR, 2.15; 95% CI, 1.05-4.41 for ESR2-high for ≥40 cigarettes compared with nonsmokers). For MHT, a statistically significant association with ESR2-low tumors was observed with longer duration of exposure (RR, 0.54; 95% CI, 0.26-1.13 for >5 years compared with never use). No associations were found for folate. In this study, smoking and MHT were associated with ESR2 expression patterns. These data support possible heterogeneous effects from smoking and MHT on ERβ-related pathways of colorectal carcinogenesis in older women.

Risk factors for pancreatitis in older women: the Iowa Women's Health Study

PurposePancreatitis—an inflammation of pancreas—is a severe and costly disease. Although many risk factors for pancreatitis are known, many pancreatitis cases, especially in elderly women, are of unknown etiology. MethodsRisk factors for acute pancreatitis (AP) and chronic pancreatitis (CP) were assessed in a prospective cohort (n = 36,436 women, aged ≥ 65 years). Exposures were self-reported at baseline. Pancreatitis was ascertained by linkage to Medicare claims (1986–2004) categorized by a physician as follows: “AP”, one AP episode (n = 511) or “CP”, 2+ AP or 1+ CP episodes (n = 149). ResultsMultivariable odds ratios (ORs) and 95% confidence intervals for AP and CP were calculated using multinomial logistic regression. Alcohol use was not associated with AP or CP. Heavy smoking (40+ vs. 0 pack-years) was associated with a twofold increased OR for CP. For body mass index greater than or equal to 30 versus less than 25 kg/m2, the ORs were 1.35 (1.07–1.70) for AP (P trend = .009) and 0.59 (0.37–0.94) for CP (P trend = .01). ORs for AP and CP were increased for hormone replacement therapy use, heart disease, and hypertension. There were positive significant associations between protein and total fat intake for CP and AP. ConclusionsWe identified factors associated with AP and CP that may be specific to older women.

Nitrate and nitrite ingestion and risk of ovarian cancer among postmenopausal women in Iowa.

Nitrate and nitrite are precursors in the endogenous formation of N-nitroso compounds (NOC), potential human carcinogens. We evaluated the association of nitrate and nitrite ingestion with postmenopausal ovarian cancer risk in the Iowa Women's Health Study. Among 28,555 postmenopausal women, we identified 315 incident epithelial ovarian cancers from 1986 to 2010. Dietary nitrate and nitrite intakes were assessed at baseline using food frequency questionnaire data. Drinking water source at home was obtained in a 1989 follow-up survey. Nitrate-nitrogen (NO3 -N) and total trihalomethane (TTHM) levels for Iowa public water utilities were linked to residences and average levels were computed based on each woman's duration at the residence. We computed multivariable-adjusted hazard ratios (HR) and 95% confidence intervals (CI) using Cox proportional hazards regression. We tested interactions of nitrate with TTHMs and dietary factors known to influence NOC formation. Ovarian cancer risk was 2.03 times higher (CI = 1.22-3.38, ptrend = 0.003) in the highest quartile (≥2.98 mg/L) compared with the lowest quartile (≤0.47 mg/L; reference) of NO3 -N in public water, regardless of TTHM levels. Risk among private well users was also elevated (HR = 1.53, CI = 0.93-2.54) compared with the same reference group. Associations were stronger when vitamin C intake was <median (pinteraction = 0.01 and 0.33 for private well and public supplies, respectively). Dietary nitrate was inversely associated with ovarian cancer risk (ptrend = 0.02); whereas, dietary nitrite from processed meats was positively associated with the risk (ptrend = 0.04). Our findings indicate that high nitrate levels in public drinking water and private well use may increase ovarian cancer risk among postmenopausal women.

Dietary Inflammatory Index and Risk of Colorectal Cancer in the Iowa Women's Health Study

Colorectal cancer, the third most common cancer in the United States, has a natural history that usually encompasses several decades. Dietary components have been implicated in the etiology of colorectal cancer, perhaps through their effect on inflammation. We examined the ability of the dietary inflammatory index (DII) to predict colorectal cancer in the Iowa Women's Health Study. The DII was computed based on dietary intake assessed by a 121-item food frequency questionnaire in this cohort of 34,703 women, ages 55 to 69 years, free of any self-reported prior malignancy at enrollment in 1986. Incident colorectal cancer cases were identified through linkage with the State Health Registry of Iowa (a Surveillance, Epidemiology, and End Results program member). Cox proportional hazards regression was used to estimate HRs. Through the end of 2010, 1,636 incident colorectal cancers were identified, including 1,329 colon and 325 rectal cancers. Multivariable analysis, adjusting for body mass index, smoking status, pack-years of smoking, hormone replacement therapy, education, diabetes, and total energy intake, revealed positive associations between higher DII and colorectal cancer risk [HR for DIIcontinuous: 1.07 per unit increase in DII (corresponding to 0.5 SD unit increase); 95% confidence interval (CI), 1.01-1.13; HR for DIIquintiles: Q5 vs. Q1 = 1.20; 95% CI, 1.01-1.43]. HRs for DII were similar for colon cancer and rectal cancer, though not statistically significant for rectal cancer. These results indicate that a proinflammatory diet, as indicated by higher DII scores, was associated with higher risk of developing colorectal cancer. Proinflammatory diets are associated with increased risk of colorectal cancer.

Abstract 2174: Association of diabetes and obesity with risk of esophageal and gastric adenocarcinoma in the Iowa Women's Health Study (IWHS)

Abstract Incidence rates of esophageal and gastric cancers have increased rapidly in developing countries during the past four decades. The rate of esophageal adenocarcinomas has approximately tripled among US whites and now exceeds that of esophageal squamous cell carcinomas. Incidence of gastric cardia adenocarcinomas has also risen significantly during this period, though to a lesser extent. These cancers often respond poorly to treatment, highlighting the importance of identifying modifiable risk factors with a view to prevention. The association between diabetes and gastroesophageal adenocarcinoma has been examined in only a few studies and findings are inconsistent. While obesity is a significant risk factor for esophageal and gastric adenocarcinomas, few analyses have been conducted in prospective cohorts. We examined the association between diabetes, BMI, and waist circumference and incidence of esophageal, non-cardia gastric and gastric cardia adenocarcinomas in a large prospective cohort of postmenopausal women. A mailed survey at baseline (1986) collected information on self-reported diabetes and anthropometric measures and included a detailed food-frequency questionnaire. The 34,466 initially cancer free women were followed for 24 years with annual cancer incidence obtained through the State Health Registry of Iowa, part of the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) Program; 83 women developed gastroesophageal adenocarcinoma. Associations were examined using proportional hazards regression models: hazard ratios (HR) and 95% confidence intervals (CI) were calculated. Significant associations were observed in age-adjusted models for diabetes (yes/no) [HR: 2.09, 95% CI: 1.01-4.34], body mass index (kg per meters squared) [HR: 1.09, 95% CI: 1.03-1.15], and waist circumference (cm) [HR: 1.24, 95% CI: 1.01-1.53]. Additionally, a positive association between diabetes and adenocarcinoma of the gastroesophageal junction was found in both age-adjusted [HR: 3.43, 95% CI: 1.32-8.90] and multivariate-adjusted models [HR: 3.00, 95% CI: 1.13-7.99]. An inverse association was found with increasing daily fiber intake (g/day) and all gastroesophageal adenocarcinomas [HR: 0.84, 95% CI: 0.73-0.96]. These findings support the view that diabetes, body mass index and waist circumference increase risk of gastroesophageal adenocarcinoma while increased fiber intake may decrease risk. Citation Format: Bryan P. LaBore, Anna E. Prizment, Frank G. Ondrey, Kristin E. Anderson. Association of diabetes and obesity with risk of esophageal and gastric adenocarcinoma in the Iowa Women's Health Study (IWHS). [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 2174. doi:10.1158/1538-7445.AM2014-2174

Allergic diseases and risk of hematopoietic malignancies in a cohort of postmenopausal women: a report from the Iowa Women's Health Study.

Allergic diseases signify immune dysregulation attributable to underlying genetics and environmental exposures. Associations between various allergies and hematopoietic cancers have been observed, albeit inconsistently; however, few prospective studies have examined the risk, and even fewer among older adults. We examined risk of incident hematopoietic cancers in those reporting allergic diseases in a population-based cohort of 22,601 older women (Iowa Women's Health Study). Self-reported allergic status, including asthma, hay fever, eczema, and/or other allergies, was determined via questionnaire in 1997 (mean age, 72 years; range, 63-81 years). Incident cancers were ascertained by linkage with the Iowa Cancer Registry from 1997 to 2011. Cox proportional hazards regression was performed to estimate multivariate-adjusted HR and 95% confidence intervals (CI) for myeloid (N = 177) and lymphoid (N = 437) malignancies, respectively. Allergic diseases were not associated with risk of myeloid (HR, 1.00; 95% CI, 0.72-1.37) or lymphoid (HR, 0.99; 95% CI, 0.81-1.22) malignancies overall, or for most allergic and malignant subtypes examined. Self-reported asthma was positively associated with development of myelodysplastic syndrome (MDS; HR, 2.00; 95% CI, 0.93-4.32). In addition, there was a 30% to 40% decrease in risk of both lymphoid and myeloid cancers in those reporting rural residences but no association in those reporting urban residences; the interaction between residence and allergy was statistically significant for lymphoid malignancies (Pinteraction = 0.05). These results suggest that asthma may contribute to the pathogenesis of MDS, a finding consistent with the chronic antigen stimulation hypothesis. Susceptibility differences by location of residence are concordant with the hygiene hypothesis and merit additional exploration.

Diet pattern and longevity: do simple rules suffice? A commentary

Nutritionism reduces dietary advice to statements about a few nutrients, with sometimes unintended implications for science, industry, and the public. Although reductionist questions about nutrition are legitimate scientifically, a nutrient focus in the public arena forces the food industry to compete with the use of nutrient statements. Consumers must interpret information that may not be correct or relevant. The theory of food synergy, which postulates that the many constituents of individual foods and dietary patterns act together on health, leads to the idea that dietary policy would be clearer if it focused on foods. To illustrate this method, the food-based A Priori Diet Quality Score was described in the Iowa Women's Health Study; a substantial total mortality reduction for increasing quartiles of the score was found. The simple food-based rules implied in this a priori score support minimizing meat, salt, added sugar, and heavily processed foods while emphasizing phytochemical-rich foods. These principles could help improve nutrition policy, help industry to supply better food, and help to focus future scientific research. Although an understanding of what foods are best for health is a step forward in nutrition, other major challenges remain, including getting high-quality food to the masses and food sustainability.

The Association between Postdiagnosis Dietary Supplement Use and Total Mortality Differs by Diet Quality among Older Female Cancer Survivors

Dietary supplements are widely used by cancer survivors. However, health effects among older cancer survivors are unclear. We used the Iowa Women's Health Study, a prospective cohort study with 2,118 postmenopausal women with a confirmed cancer diagnosis (1986-2002), to evaluate the association between postdiagnosis dietary supplement use assessed in 2004 and subsequent all-cause mortality. Risk of death was evaluated using multivariable-adjusted Cox proportional hazards regression. We performed stratified analyses by diet quality score, dietary micronutrient intake, and perceived general health. Through 2010, 608 deaths were identified. Approximately 85% of the cancer survivors used dietary supplements. Overall supplement use and multivitamin use were not associated with mortality. Iron supplement use was associated with 39% higher risk of death [95% confidence interval (CI), 1.09-1.77]. This association was stronger among survivors with deteriorating general health. Folic acid supplement use was associated with higher risk of death, only among survivors reporting low-quality diets (HR, 2.33; 95% CI, 1.33-4.08; P interaction = 0.006). Multivitamin use and using a greater number of supplements was associated with a trend towards higher mortality only among those with poor diet quality. Using vitamin E supplements in combination with multivitamin was associated with lower risk of death only among survivors with higher dietary vitamin E intake (HR, 0.61; 95% CI, 0.39-0.94; P interaction = 0.02). Postdiagnosis supplement use was associated with higher mortality among older female cancer survivors with poor general health and/or poor dietary intake. The association between postdiagnosis dietary supplement use and mortality may differ by diet quality and health status among older female cancer survivors.

Physical Activity and Quality of Life among Elderly Cancer Survivors Compared to Women without Cancer: The Iowa Women's Health Study

Abstract Few studies have examined lifestyle factors and health-related quality of life (QOL) in elderly, long-term cancer survivors compared to a cancer-free comparison group. We examined the degree to which physical inactivity is associated with poor QOL among elderly, female cancer survivors compared to similar-aged women without cancer. Methods: Subjects included women enrolled in the Iowa Women's Health Study in 1986 who completed the 2004 questionnaire (at ages 71–89 years) and were alive through 2005. The 2004 questionnaire asked participants about recreational physical activity and included the Medical Outcomes Study Short Form-36 (SF36) QOL assessment. Physical inactivity was defined as moderate or vigorous activity less than once per week. Logistic regression was used to compute the odds of poor QOL for each SF36 subscale (&amp;lt;0.5 SD below the mean score of women without cancer) associated with physical inactivity between 4 groups based on the cross-classification of cancer history (no/yes) and physical inactivity (no/yes) (referent group = No/No). Results: Analyses included 12,067 women without a history of cancer and 1,707 women diagnosed with cancer between 1986 and 2002. Inactive cancer survivors were significantly more likely to report poor QOL for each SF36 subscale compared to the referent group (Odds Ratios (OR) 1.7 to 4.5), independent of age, comorbidity, BMI, and diet quality. Compared with the other 3 groups, inactive cancer survivors had the greatest odds of poor Physical Function (inactive cancer survivors [OR = 4.5, 95% CI 3.9–5.3], inactive women without cancer [OR = 3.8, 95% CI 3.5–4.2], active cancer survivors [OR = 1.0,95% CI 0.8–1.2]) and poor General Health (inactive cancer survivors [OR = 3.2, 95% CI 2.7–3.8], inactive women without cancer [OR = 2.8, 95% CI 2.5–3.0), active cancer survivors [OR = 1.2, 95% CI 0.98–1.4]). Among physically active women, cancer survivors had similar QOL as women without a cancer history. Conclusions: Physical inactivity was more strongly associated with poor General Health and Physical Function in elderly, long-term cancer survivors compared to women without cancer. These findings support the need for interventions to help older women maintain or regain a physically active lifestyle after a cancer diagnosis.

Associations between Cigarette Smoking, Hormone Therapy, and Folate Intake with Incident Colorectal Cancer by TP53 Protein Expression Level in a Population-Based Cohort of Older Women

Cigarette smoking (CS), hormone therapy (HT), and folate intake (FI) are each thought to influence colorectal cancer risk, but the underlying molecular mechanisms remain incompletely defined. The TP53 (p53) protein, encoded by the TP53 tumor-suppressor gene that is commonly mutated in colorectal cancer, can be readily assessed to differentiate biologically distinct colorectal cancer subtypes. In this prospective cohort study, we examined CS-, HT-, and FI-associated colorectal cancer risks by TP53 protein expression level among Iowa Women's Health Study (IWHS) participants. The IWHS recruited 41,836 randomly selected Iowa women, ages 55 to 69 years, with a valid driver's license at study entry in 1986. Self-reported exposure variables were assessed at baseline. Incident colorectal cancer cases were ascertained by annual linkage with the Iowa Cancer Registry. Archived, paraffin-embedded tissue specimens were collected and evaluated for TP53 protein expression by immunohistochemistry. Multivariate Cox regression models were fit to estimate relative risks (RR) and 95% confidence intervals (CI) for associations between CS, HT, or FI and TP53-defined colorectal cancer subtypes. Informative environmental exposure and protein expression data were available for 492 incident colorectal cancer cases: 222 (45.1%) TP53 negative, 72 (14.6%) TP53 low, and 198 (40.2%) TP53 high. Longer duration (>5 years) of HT was inversely associated with TP53 high colorectal cancers (RR, 0.50; 95% CI, 0.27-0.94). No other statistically significant associations were observed. These data support possible heterogeneous effects from HT on TP53-related pathways of colorectal carcinogenesis in older women.

Sugar-Sweetened Beverage Intake and the Risk of Type I and Type II Endometrial Cancer among Postmenopausal Women

Sugar-sweetened beverage (SSB) intake has been associated with an increased risk of obesity and type II diabetes. However, its association with endometrial cancer is unclear. We evaluated dietary intake of SSB, fruit juice, sugar-free beverages, sweets/baked goods, starch, and sugars among 23,039 postmenopausal women in the Iowa Women's Health Study. Incident estrogen-dependent type I and estrogen-independent type II endometrial cancers were identified via linkage with the Surveillance Epidemiology and End Results Registry. Risks of type I and type II endometrial cancers were separately compared by energy-adjusted dietary intake in Cox proportional hazards regression models. From 1986 to 2010, 506 type I and 89 type II incident endometrial cancers were identified. An increased risk of type I endometrial cancer was observed with increasing SSB intake after adjustment for body mass index (BMI) and other cofounders (Ptrend = 0.0005). Compared with nondrinkers of SSB, the risk was 78% higher [95% confidence intervals (CI), 1.32-2.40] among women in the highest quintile of SSB intake. The observed association was not modified by BMI, physical activity, history of diabetes, or cigarette smoking. Higher risk of type I endometrial cancer was also observed with higher intake of sugars. None of the dietary items included in the analysis was associated with type II endometrial cancer risk. Higher intake of SSB and sugars was associated with an increased risk of type I, but not type II, endometrial cancer. SSB intake may be a risk factor for type I endometrial cancer regardless of other lifestyle factors.

Abstract A44: Coffee consumption and colorectal cancer risk by molecularly defined subtypes in a prospective cohort study of older women

Abstract Background: Different molecules within coffee may be pro-carcinogenic, while others may have anti-oxidant and anti-neoplastic effects. Hence, it can be hypothesized that coffee may have differing risk associations with specific colorectal cancer (CRC) subtypes. The aim of this study was to evaluate associations between coffee consumption and incident CRC overall, by anatomic subsite, and by molecularly defined tumor subtypes, in the population-based Iowa Women's Health Study (IWHS). Methods: IWHS participants, ages 55-69 years, provided dietary intake estimates using self-reported food frequency questionnaires at baseline (1986). From 35,216 women included the final analysis, 1298 developed CRC (673 with proximal CRC, 597 with distal CRC) through December 31, 2002 (end of the IWHS molecular epidemiology project study period). Archived, paraffin-embedded tissue specimens for 732 representative CRC cases were collected and analyzed to determine if coffee consumption (none or &amp;lt;1 cup/month, &amp;lt;1 cup/week, 1 cup/day, 2-3 cups/day and ≥4 cups/day) was associated with microsatellite instability (MSI-L/MSS or MSI-H), CpG island methylator phenotype (CIMP-negative or CIMP-positive), BRAF mutation status (BRAF-wildtype or BRAF-mutated), KRAS mutation status (KRAS-wildtype and KRAS-mutated), p53 protein expression level (p53 absent, low or high) and estrogen receptor β protein expression level (ERβ absent, low or high). Multivariable Cox regression models were fit to estimate relative risks (RR) and 95% confidence intervals (CI) with adjustment for age, smoking, alcohol use, diabetes, body mass index and waist-hip ratio, physical activity, estrogen use, dietary intake of fat, calcium, vitamin E, sucrose, red meat and methionine. P-values were not adjusted for multiple testing. Results: There was no significant difference in the risk of overall (RR, 1.05; 95% CI, 0.85-1.29; Ptrend=0.50), proximal (RR, 0.91; 95% CI, 0.68-1.21; Ptrend=0.57) or distal CRC (RR, 1.18; 95% CI, 0.86-1.64; Ptrend=0.19) in women who consumed ≥4 cups of coffee/day (caffeinated or decaffeinated), as compared to non-consumers. By CRC molecular subtypes for these same two exposure groups, women with ≥4 cups of coffee/day were more likely to develop ERβ-low CRC (RR, 2.98; 95% CI, 1.04-8.51; Ptrend=0.06), though no significant associations were observed for caffeinated or decaffeinated coffee specifically. In contrast, women who consumed ≥4 cups of decaffeinated coffee/day were less likely to develop MSI-L/MSS (RR, 0.57; 95% CI, 0.36-0.92; Ptrend=0.04) and BRAF-WT (RR, 0.69; 95% CI, 0.44-1.06; Ptrend=0.06) CRCs than non-consumers. Women who consumed ≥4 cups of caffeinated coffee/day were also less likely to develop p53-low CRCs (RR, 0.53; 95% CI, 0.24-1.15; Ptrend=0.02). Null associations were observed between decaffeinated coffee consumption and risk of CIMP-, KRAS- and p53- defined CRC subtypes, as well as between caffeinated coffee consumption and risk of MSI-, BRAF-, CIMP- or KRAS-defined CRC subtypes. Conclusion: In this prospective cohort study of older women, though coffee consumption was not associated with risk of overall or site-specific CRC, unique associations were observed with molecularly defined CRC subtypes, supporting a need for further investigation of the potential pro- and anti-carcinogenic effects of coffee constituents on biologic targets involved in colorectal carcinogenesis. Citation Format: Siddharth Singh, Robert Vierkant, Lori Tillmans, Alice Wang, Daniel Weisenberger, Peter Laird, Maki Inoue-Choi, Andrea Mariani, Charles Lynch, Kristin Anderson, Amy French, Robert Haile, Lisa Harnack, John Potter, Susan Slager, Thomas Smyrk, Stephen Thibodeau, James Cerhan, Paul Limburg. Coffee consumption and colorectal cancer risk by molecularly defined subtypes in a prospective cohort study of older women. [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 A44.

Abstract CN06-02: Insight into colorectal cancer etiology through MPE: Unmasking the links with obesity and smoking

Abstract Colorectal cancer is a leading cause of cancer morbidity and mortality worldwide. Epidemiologic studies have identified a host of genetic, lifestyle and demographic factors associated with colorectal cancer incidence, including high body mass index (BMI) and, perhaps less convincingly, cigarette smoking. Epidemiologic studies have often considered colorectal cancer as a singular disease outcome, ignoring potential disease heterogeneity; more recently, however, studies have further investigated whether risk and prognostic factors for colorectal cancer differ by tumor molecular phenotype, including microsatellite instability (MSI) status. MSI is the result of defective DNA mismatch repair capacity and it is a distinct tumor phenotype whereby short repetitive DNA sequences undergo a change in repeat length. Approximately 15% of colorectal tumors display MSI, usually the result of epigenetic modification of MLH1, a gene that encodes a mismatch repair protein, or less often, because the affected individual has a germline mutation in a DNA mismatch repair gene, consistent with Lynch syndrome. The majority of colorectal tumors develop despite having competent mismatch repair; these tumors, known as microsatellite (MS)-stable, arise through chromosomal instability and do not display marked gains or losses in MS regions. Other important molecular phenotypes for colorectal cancer include CpG island methylator phenotype (CIMP), and presence or absence of somatic mutations in the KRAS and BRAF genes. While BMI is a consistent and convincing risk factor for colorectal cancer overall (odds ratios and relative risks in the range of 1.3 to 1.5 are common for an obese BMI relative to a normal BMI), recent studies have suggested the associations are higher, or even restricted to, tumors that are MS-stable. Using the Colon Cancer Family Registry, our group showed that an obese BMI (&amp;gt;30 kg/m^2) relative to a normal BMI (BMI: 18.5-24.99 kg/m^2) was associated with an approximate 2-fold increased risk of MS-stable colorectal cancer while the association with MSI-high colorectal cancer was null. Other recent studies have shown a similar pattern, and other groups have shown that these results might be corroborated with FASN. Current work in the Colon Cancer Family Registry is seeking to address whether the prognostic (i.e., survival) benefit of MSI-high compared to MS-stable tumors further differs by level of obesity. The link between colorectal cancer and cigarette smoking has been more equivocal, with studies generally showing null associations or only modestly higher risks among smokers compared to non-smokers. Herein, tumor molecular phenotype data have been particularly revealing. Data from the Colon Cancer Family Registry showed a null association between ever smoking and colorectal cancer risk overall; however, when stratified by MSI status, risk of MSI-high cancer was about 2-fold higher among long-duration smokers relative to never smokers. Similar findings were reported in the prospective Iowa Women's Health Study where doubling in risks of MSI-high, CIMP-positive and BRAF mutation-positive colorectal cancers were reported for ever smoking while null associations were shown for tumors that lacked these molecular phenotypes. Additional work from one study center involved in the Colon Cancer Family Registry has suggested that the adverse impact of smoking on colorectal cancer survival is limited to patients diagnosed with MSI-high tumors. In addition to presenting published and unpublished results on associations of BMI and smoking with colorectal cancer incidence and survival, this presentation will also share recent experiences with collecting tumor blocks from a prospective cohort study, the American Cancer Society's Cancer Prevention Study-II. Citation Format: Peter T. Campbell. Insight into colorectal cancer etiology through MPE: Unmasking the links with obesity and smoking. [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 CN06-02.

Abstract A42: Intake of vitamins A, C, E, and folate and risk of ovarian cancer in a pooled analysis of 10 cohort studies

Abstract Vitamins A, C, E and folate have properties, such as modulation of DNA synthesis and repair, control of cellular differentiation and proliferation, as well as antioxidation, which are potentially cancer preventive. In a 2007 international panel review of the epidemiological literature published through 2006, the available data on the associations between intake of these vitamins and ovarian cancer risk were judged to be limited and inconclusive. Relatively few studies had been published and statistical power may have been limited in most studies. Among subsequent studies, sample sizes have been large in some though results remain inconsistent. In this project, we examined vitamin intakes from food only (dietary) and from food and supplements together (total) in relation to ovarian cancer risk by pooling the primary data from the following studies: Breast Cancer Detection Demonstration Project Follow-up Study, Canadian National Breast Screening Study, Cancer Prevention Study II Nutrition Cohort, Iowa Women's Health Study, Netherlands Cohort Study, New York State Cohort, New York University Women's Health Study, Nurses' Health Study, Nurses' Health Study II, and Swedish Mammography Cohort. Vitamin intakes were ascertained from a validated food frequency questionnaire administered at baseline in each study. Study-specific relative risks (RR) were estimated using the Cox proportional hazards model, and then combined using a random-effects model. Multivariate models included total energy intake and other potential ovarian cancer risk factors. Among 501,857 women, 1,973 cases of ovarian cancer occurred during a maximum follow-up of 7 to 22 years across studies. When analyzed as continuous variables the RRs for dietary and total intakes of each of the vitamins were not significantly associated with ovarian cancer. For increments of intake defined by the mean of the standard deviation of the mean intake across studies, the pooled multivariate RRs (95% CI) for total intake of each vitamin were 1.02 (0.97-1.07) for each 1300 mcg/day increase in vitamin A, 1.01 (0.99-1.04) for each 400 mg/day increase in vitamin C, 1.02 (0.97-1.06) for each 130 mg/day increase in vitamin E and 1.01 (0.96-1.07) for each 250 mcg/day increase in folate. When vitamin intakes were analyzed as categorical variables defined by study-specific quintiles of intake, the results were consistent with the continuous analyses and indicated no significant association. There was no evidence of statistically significant heterogeneity between studies in any of the analyses. Also, the pooled RRs did not vary greatly by levels of parity, oral contraceptive use, postmenopausal hormone use, smoking status or alcohol consumption, nor did associations greatly differ by histological type. We also examined use of specific vitamin supplements and multivitamins and did not observe a significant association with risk of ovarian cancer overall; the pooled multivariate RR (95% CI) for multivitamin use versus non-use was 1.00 (0.89-1.12). This large pooled analysis suggests that vitamins A, C, E and folate are not associated with the risk of ovarian cancer. Citation Format: Anita Koushik, Stephanie A. Smith-Warner. Intake of vitamins A, C, E, and folate and risk of ovarian cancer in a pooled analysis of 10 cohort studies. [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 A42.

Anthropometric, medical history and lifestyle risk factors for myeloproliferative neoplasms in The Iowa Women's Health Study cohort

Classical myeloproliferative neoplasms (MPNs) are composed of essential thrombocythemia (ET), polycythemia vera (PV) and myelofibrosis (MF), the etiology of which is largely unknown. We investigated the role of anthropometric, medical and lifestyle factors with risk of MPN in a prospective cohort of 27,370 women aged 55-69 years at enrollment. After >250,000 person-years of follow-up, 257 cases of MPN were identified (172 ET, 64 PV, 21 MF). Risk factor profiles were mostly unique for the two most common types, ET and PV. ET was associated with energy balance factors including body mass index (RR = 1.52 for >29.3 vs. <23.4 kg/m(2) ; p-trend = 0.042), physical activity (RR = 0.66 for high vs. low; p-trend = 0.04) and adult onset diabetes (RR = 1.82; p = 0.009), while PV was not. PV was associated with current smoking (RR = 2.83; p-trend = 0.016), while ET was not. Regular use of aspirin was associated with lower risk of ET (RR = 0.68; p = 0.017). These results broadly held in multivariate models. Our results suggest distinct etiologies for these MPN subtypes and raise mechanistic hypotheses related to obesity-related inflammatory pathways for ET and smoking-related carcinogenic pathways for PV. Regular aspirin use may lower risk for ET.

Diet quality indexes and mortality in postmenopausal women: the Iowa Women’s Health Study

A priori diet scores such as the Alternative Healthy Eating Index (AHEI) and the food-based a priori diet quality score predict chronic disease risk. We compared the AHEI and a priori diet quality score relative to mortality. Postmenopausal women who were free of diabetes, cardiovascular disease (CVD), and cancer in the Iowa Women's Health Study (in 1986, n = 29,634 with a mean 6 SD age of 61.4 6 4.2 y; in 2004, n = 15,076 with a mean 6 SD age of 79.7 6 4.0 y). A food-frequency questionnaire was used. Through 31 December 2008, 10,343 total, 3646 CVD, 3207 cancer, and 2888 inflammatory-related deaths were identified through record linkage. HRs were computed for quartiles of each diet score at baseline and 2004. To compare scores, the residual of each score given the other score was computed by using linear regression. At baseline, indexes had a correlation of 0.65. For the AHEI, the multivariable-adjusted HRs (95% CIs) for total, CVD, cancer, and inflammatory-related mortality were 0.82 (0.77, 0.87), 0.79 (0.72, 0.88), 0.88 (0.79, 0.98), and 0.76 (0.68, 0.84), respectively. The a priori score had corresponding HRs of 0.80 (0.76, 0.85), 0.79 (0.72, 0.88), 0.86 (0.77, 0.95), and 0.75 (0.67, 0.84), respectively. Each score added information to the other score for total, CVD mortality, and inflammatory-related mortality. In 2004, both scores predicted total, CVD, and inflammatory-related mortality, and the a priori score also predicted cancer mortality. The a priori score added independent information for all outcomes except cancer, whereas the AHEI added information only for total mortality. Two correlated diet quality scores predicted total and disease-specific mortality, but their residuals also predicted complementarily.

Duration of diabetes and pancreatic cancer in a case-control study in the Midwest and the Iowa Women's Health Study (IWHS) cohort.

Studies have shown a relationship between history of diabetes and the risk of pancreatic cancer; however, the temporal relation between diabetes and pancreatic cancer is not clearly established. Diabetes and diabetes duration were examined in relation to pancreatic cancer in a population-based case-control study and prospective cohort. Case-control study: pancreatic cancer cases (n=200) from the Midwest were frequency matched by age and sex to population controls (n=673). Logistic regression yielded odds ratios (ORs) and 95% confidence intervals (95% CI). Iowa Women's Health Study (IWHS) cohort: 292 incident pancreatic cancer cases occurred between 1986-2008 among 36,084 post-menopausal, initially cancer-free women. Diabetes status and diagnosis age were ascertained at baseline and follow-ups. Proportional hazards regression yielded hazard ratios (HR, 95% CI) for pancreatic cancer in relation to baseline diabetes. Time-dependent analyses accounted for diabetes diagnosed after baseline. A nested-case control analysis assessed diabetes duration as a risk factor. In the case-control study, compared to participants without diabetes, the multivariate ORs (95% CI) for pancreatic cancer were 2.35 (1.24-4.47) for those with diabetes and 4.00 (0.94-16.9), 2.79 (0.97-8.04), and 2.40 (0.97-5.98) for diabetes durations of 2-5 years, 5.1-10 years, and more than 10 years, respectively. In IWHS, compared to no diabetes, multivariate-adjusted HRs for pancreatic cancer were 1.86 (1.23-2.83) for baseline diabetes and 1.94 (1.40-2.69) adding diabetes during follow-up. In an IWHS nested case-control analysis, ORs were 1.70 (0.78-3.67), 2.62 (1.48-4.65), and 2.10 (1.36-3.24) for diabetes durations of 2-5 years, 5.1-10 years and more than 10 years, respectively, versus no diabetes. Diabetes is associated with pancreatic cancer risk and this is similar across different duration categories.