Reproductive risk factors for incident bladder cancer: Iowa Women's Health Study

We studied the association between reproductive factors and bladder cancer incidence in a prospective cohort study of 37,459 Iowa women aged 55-69 years and initially free from cancer in 1986. Women reported reproductive history and were followed prospectively through 2003. After adjusting for age and smoking, there was an inverse association between age at menopause and incident bladder cancer (n = 192). Compared with menopause at age > or =48, the hazard ratio (HR) of bladder cancer was 1.32 (95% CI; 0.90-1.94) for menopause at 43-47, and 1.60 (95% CI; 1.06-2.39) for < or =42 (p-trend = 0.02). The associations were similar for ages at natural and surgical menopause. In addition, women with a history of bilateral oophorectomy had an increased risk of bladder cancer compared with those who did not undergo bilateral oophorectomy: HR = 1.58 (95% CI; 1.12, 2.22). Finally, there was an indication of a positive association between bladder cancer and shorter lifetime years of ovulation (p-trend = 0.09). There were no associations between incident bladder cancer and age at first birth, number of births, age at menarche, use of hormone replacement therapy or any other reproductive characteristics. This study provides evidence that increased risk of bladder cancer is associated with earlier age at menopause in postmenopausal women.     

Diet and risk of leukemia in the Iowa Women's Health Study.

Nearly 30,000 individuals ages over 21 years are diagnosed with leukemia each year in the United States. Other than benzene, radiation, and chemotherapy, which account for a small proportion of cases, there are few identified risk factors for adult leukemia. Although recent data from animal studies indicate a potentially protective role for dietary restriction in leukemogenesis, few data exist on dietary relationships in adult leukemia. Food frequency data collected at baseline (1986) were analyzed from the prospective Iowa Women's Health Study to begin to address the role of diet in adult leukemia. Data from 35,221 women ages 55-69 years were analyzed. A total of 138 women developed leukemia during the 14-year follow-up period of 1986 to 1999. With the exception of an inverse association (P trend = 0.08) with increasing consumption of all vegetables (relative risk, 0.56 and 95% confidence interval, 0.36-0.88; relative risk, 0.69 and 95% confidence interval, 0.44-1.07 for medium and high consumption, respectively), there was little evidence of an important role for other dietary factors in leukemogenesis. Analyses that excluded cases diagnosed in the first 2 years from baseline did not notably alter the results. Leukemia subgroups, including acute myeloid leukemia and chronic lymphoblastic leukemia, were also analyzed, but no statistically significant associations with dietary factors were revealed. This study provides evidence that increased vegetable consumption may decrease the risk of adult leukemia. However, given that our study focused on older women from a defined geographical area, analyses of prospective studies in other populations are needed to confirm or refute these results.     

Prospective evaluation of trans-fatty acid intake and colorectal cancer risk in the Iowa Women's Health Study

Concerns regarding the safety of dietary trans-fatty acids (tFAs) have generated recent public interest, scientific discussion and legislative action. Although most widely recognized as a risk factor for cardiovascular disease, associations between tFA intake and incident cancer have also been proposed. With respect to colorectal cancer (CRC), existing observational data remain limited and inconclusive. Therefore, we conducted a prospective evaluation of tFA intake and CRC risk, overall and by anatomic subsite, among participants in the Iowa Women's Health Study (IWHS), a population-based cohort of older women (ages 55-69 years at enrollment). Exposure data were collected at baseline using a semiquantitative food-frequency questionnaire. Incident CRC cases were identified through annual linkage to the Iowa Cancer Registry. CRC risks were estimated using Cox proportional hazards regression models. In total, 35,216 women met our inclusion criteria and 1,229 CRC cases (631 proximal, 571 distal, 27 site not specified) were observed through 18 years of follow-up. Adjusting for age and total energy consumption, tFA intake in the 4th versus 1st quartile was not significantly associated with overall CRC risk [relative risk (RR) = 1.12; 95% confidence interval (CI) = 0.96-1.32]. Similarly, risk estimates based on proximal (RR = 1.09; 95% CI = 0.87-1.37) and distal (RR = 1.18; 95% CI = 0.93-1.49) CRC subsites did not differ from unity. Multivariable adjustment yielded slightly attenuated risk estimates, but the observed associations were not meaningfully altered. Given these findings, tFA intake does not appear to be a major CRC risk factor, at least among older women.     

Risk factors for lymphedema in breast cancer survivors, the Iowa Women's Health Study

Risk factors for lymphedema and related arm symptoms in breast cancer (BC) survivors have not been examined using a large prospective population-based cohort. The Iowa Women’s Health Study (IWHS) collected self-reported data for diagnosed lymphedema in 2004, and data for cancer diagnosis, treatment, behavioral and health characteristics between 1986 and 2003. We studied 1,287 women, aged 55–69 at baseline, who developed unilateral BC: n = 104 (8%) with diagnosed lymphedema, n = 475 (37%) with arm symptoms but without diagnosed lymphedema, and n = 708 without lymphedema. Age- and multivariate-adjusted logistic regression models examined risk factors for lymphedema and related arm symptoms (OR [95% confidence interval]). The mean time between BC and the 2004 survey was 8.1 ± 5.0 (mean ± SD) years. After multivariate adjustment, the following cancer characteristics were positively associated with lymphedema: tumor stage (regional vs. in situ: 3.92 [1.61–9.54]), number of excised nodes (highest vs. lowest quintile: 3.52 [1.32–9.34], P _trend = 0.003), tumor-positive nodes (yes vs. no 2.12 [1.19, 3.79]), and adjuvant chemotherapy (yes vs. no: 3.05 [1.75–5.30]). Several health characteristics were positively associated with lymphedema: baseline body mass index (highest vs. lowest tertile: 3.24 [1.70–6.21]), waist and hip circumference, and general health (fair/poor vs. excellent: 3.44 [1.30–9.06]). Positive associations with arm symptoms were number of excised nodes (highest vs. lowest quintile: 2.38 [1.41–4.03], P _trend = 0.007), axillary radiation (yes vs. no: 1.72 [1.15–2.57]), and baseline general health (fair/poor vs. excellent: 4.27 [2.60–7.00]). In the IWHS, obesity, poorer general health, and markers of more advanced cancer were risk factors for lymphedema and related arm symptoms in BC survivors.     

Diabetes mellitus and subsite-specific colorectal cancer risks in the Iowa Women's Health Study.

OBJECTIVE: Controversy remains regarding the association between type 2 diabetes mellitus (DM) and colorectal cancer (CRC) risk. To clarify and extend the existing data, we prospectively evaluated the association between self-reported type 2 DM (onset at >30 years of age) and incident CRC, overall and by anatomic subsite, among postmenopausal women in the Iowa Women's Health Study (n = 35,230).METHODS: After 14 years of follow-up, a total of 870 incident CRC cases were identified through annual linkage to the Iowa Cancer Registry. DM was analyzed as reported at baseline and as a time-dependent variable using information obtained during follow-up. CRC risks were estimated using Cox proportional hazards regression models.RESULTS: After adjusting for age, body mass index and other potential confounding variables, the relative risk (RR) for women with DM versus women without DM was modestly increased at 1.4 [95% confidence interval (95% CI), 1.1-1.8]. By anatomic subsite, the RR for proximal colon cancer was statistically significantly increased (RR, 1.9; 95% CI, 1.3-2.6), whereas the RRs for distal colon (RR, 1.1; 95% CI, 0.6-1.8) and rectal cancer (RR, 0.8; 95% CI, 0.4-1.6) were not statistically different from unity. Analyses that included DM ascertained at baseline and follow-up yielded similar results.CONCLUSION: In this large, prospective study of postmenopausal women, the association between DM and incident CRC was found to be subsite specific. If confirmed by others, this finding implies that CRC prevention strategies among type 2 DM patients should include examination of the proximal colon.     

Alcohol consumption and postmenopausal endometrial cancer: results from the Iowa Women's Health Study

At least three case-control studies have examined the association between alcohol consumption and endometrial cancer; two studies showed inverse associations, and a third a positive association. To our knowledge, no prospective studies of this association have been reported. The association between alcohol and endometrial cancer was examined in the Iowa Women's Health Study (United States), a prospective study of postmenopausal women. Information on alcohol consumption and other variables was obtained through a mailed questionnaire in January 1986. Through December 1990, 167 incident endometrial cancer cases occurred in the at-risk cohort of 25,170 women. Multivariate-adjusted relative risks (RR) and 95 percent confidence intervals (CI) were computed using Cox proportional hazards regression controlling for age, body mass index (BMI), parity, age at menopause, and noncontraceptive estrogen use, and to determine multiplicative interactions. The RRs of endometrial cancer associated with <4.0 and 4.0 g of alcohol per day compared with abstainers were 0.7 (CI=0.5–1.1) and 1.0 (CI=0.7–1.6), respectively. No statistically significant association between endometrial cancer and consumption of either beer, wine, or liquor was observed. There was no interaction between alcohol and any other endometrial cancer risk factors, including BMI or noncontraceptive estrogen use. These data do not support an association between alcohol and endometrial cancer among postmenopausal women.This project was supported by grant RO1-CA39742 to Dr Folsom from the US National Cancer Institute; the contents are solely the responsibility of the authors and do not necessarily represent the official views of the National Cancer Institute. Dr Gapstur was supported by NIH training grant T32-CA09607 to Dr Potter.     

Difficulty becoming pregnant and family history as interactive risk factors for postmenopausal breast cancer: the Iowa Women's Health Study

We recently provided data from a prospective cohort study of postmenopausal women which suggested that a first livebirth at age 30 or older (cf before age 20) was associated with a twofold increased risk of breast cancer in women without a family history, but a 5.8-fold higher risk in women with a positive family history. To address the question of whether these observations reflect difficulty becoming pregnant or maintaining a pregnancy, we performed additional analyses in which the outcome of each pregnancy was considered. During five years of follow-up, 620 incident cases of breast cancer were identified in the 37,105 women at risk. There was little evidence for an increased risk associated with a history of spontaneous abortion (relative risk [RR]=1.1; 95 percent confidence interval [CI]=0.9–1.4), nor was the risk higher among women who reported two or more spontaneous abortions in consecutive pregnancies (RR=1.0, CI=0.7–1.4). Although women who reported that they had tried unsuccessfully to become pregnant had only slightly and nonsignificantly elevated risks of breast cancer (RR=1.1, CI=0.9–1.3), a more pronounced and statistically significant association was noted in women with a positive family history (RR=2.0, CI=1.4–3.2). There was a strong inverse association between failure to become pregnant and parity (P<0.0001); nearly 50 percent of the nulliparous married women reported having tried and failed to become pregnant, whereas the frequency was only 6.8 percent among married women with five or more livebirths. Thus, difficulties in becoming pregnant may characterize a subset of women at increased risk of breast cancer, especially in the presence of a family history.The authors are with the Division of Epidemiology, School of Public Health, University of Minnesota, Minneapolis, MN, USA. Dr Sellers is also affiliated with the Institute of Human Genetics, University of Minnesota School of Medicine. Address correspondence to Dr Sellers, Division of Epidemiology, Suite 300, 1300 South Second Street, Minneapolis, MN 55454-1015. This publication was supported by a grant (RO1 CA39742) from the US National Cancer Institute. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the National Cancer Institute.     

No association between XRCC1 and XRCC3 gene polymorphisms and breast cancer risk: Iowa Women's Health Study

BACKGROUND: Genetic variation in DNA repair may contribute to differences in the susceptibility of several cancers. We evaluated two polymorphisms in the base excision repair pathway (BER) (XRCC1; Arg194Trp and Arg399Gln) and one polymorphism in the double strand DNA repair pathway (XRCC3; Thr241Met) for their association with breast cancer risk. METHODS: The association was analyzed in a nested case control study of 460 breast cancer cases and 324 cancer-free controls within the Iowa Women's Health Cohort. DNA was obtained from blood samples or paraffin embedded tissues (PET) and all samples were genotyped by one of three genotyping platforms-PCR-RFLP, PCR-INVADER, or Sequenom. RESULTS: None of the three polymorphisms studied were significantly associated with breast cancer risk (XRCC1: Arg194Trp (OR=1.21, 95% CI: 0.78-1.88); Arg399Gln (OR=1.20, 95% CI: 0.80-1.79); XRCC3: Thr241Met (OR=1.04, 95% CI: 0.76-1.41). CONCLUSIONS: These results suggest that independently these polymorphisms of XRCC1 and XRCC3 genes do not contribute significantly to the genetic susceptibility of breast cancer.     

BRCA1 susceptibility markers and postmenopausal breast cancer: the Iowa Women's Health Study.

Much research on early-onset breast cancer families has been performed and has shown that breast cancer in many of these families is linked to either BRCA1 or BRCA2. Fewer studies have examined the role of genetic predisposition in postmenopausal breast cancer. A nested case-control family study of breast cancer was conducted within the Iowa Women's Health Study, a population-based prospective study of 41,836 postmenopausal women. Probands were 251 incident cases diagnosed between 1988 and 1989. Three-generation pedigrees were developed through mailed questionnaires. From this collection of pedigrees, thirteen were identified for more detailed genetic analysis. Sibling-pair linkage analyses were performed using polymorphic markers in candidate regions in these 13 families with multiple cases of breast and other cancers. Four of the DNA markers are located on chromosome 17, and two of these (D17S579 and THRA1) flank the BRCA1 locus. Significant evidence for linkage to D17S579 was obtained in the total sample, in a model without inclusion of covariates or age at onset (P = 0.005), and in a model adjusted for five measured covariates and for variable age at onset (P = 0.008). Complete sequencing of the BRCA1 gene in these families, including all intron/exon boundaries, failed to reveal any mutations in 24 women with breast cancer from the 13 families. These data suggest that in some families identified by postmenopausal breast cancer cases, breast cancer risk may be mediated by a gene (or genes) in the BRCA1 region, but not BRCA1 itself.     

History of allergy and reduced incidence of colorectal cancer, Iowa Women's Health Study.

Previous epidemiologic studies have reported that a history of allergy is associated with reduced risk of colorectal cancer and other malignancies. We studied the association between allergy history and incident colorectal cancer (n=410) prospectively in 21,292 Iowa women followed for 8 years. Allergy was defined from four self-reported questions about physician-diagnosed asthma (a), hay fever (b), eczema or allergy of the skin (c), and other allergic conditions (d). A history of any allergy was inversely associated with incident colorectal cancer: after multivariate adjustment, the hazard ratio (HR) was 0.74 [95% confidence interval (95% CI), 0.59-0.94]. Compared with women with no allergy, women reporting only one of the four types of allergy and women reporting two or more types had HRs of 0.75 (95% CI, 0.56-1.01) and 0.58 (95% CI, 0.37-0.90), respectively (P trend=0.02). The inverse association persisted in analyses restricted to any type of nonasthmatic allergy (HR, 0.73; 95% CI, 0.56-0.95). HRs were similar for rectal and colon cancers as well as for colon subsites: proximal and distal (HRs for any allergy ranged from 0.63 to 0.78 across these end points). Allergy history, which may reflect enhanced immunosurveillance, is associated with a reduced risk of colorectal cancer.     

Dietary glycemic load and risk of colorectal cancer in the Women's Health Study

Although diet is believed to influence colorectal cancer risk, the long-term effects of a diet with a high glycemic load are unclear. The growing recognition that colorectal cancer may be promoted by hyperinsulinemia and insulin resistance suggests that a diet inducing high blood glucose levels and an elevated insulin response may contribute to a metabolic environment conducive to tumor growth. We prospectively followed a cohort of 38 451 women for an average of 7.9 years and identified 174 with incident colorectal cancer. We used baseline dietary intake measurements, assessed with a semiquantitative food-frequency questionnaire, to examine the associations of dietary glycemic load, overall dietary glycemic index, carbohydrate, fiber, nonfiber carbohydrate, sucrose, and fructose with the subsequent development of colorectal cancer. Cox proportional hazards models were used to estimate relative risks (RRs). Dietary glycemic load was statistically significantly associated with an increased risk of colorectal cancer (adjusted RR = 2.85, 95% confidence interval [CI] = 1.40 to 5.80, comparing extreme quintiles of dietary glycemic load; P(trend) =.004) and was associated, although not statistically significantly, with overall glycemic index (corresponding RR = 1.71, 95% CI = 0.98 to 2.98; P(trend) =.04). Total carbohydrate (adjusted RR = 2.41, 95% CI = 1.10 to 5.27, comparing extreme quintiles of carbohydrate; P(trend) =.02), nonfiber carbohydrate (corresponding RR = 2.60, 95% CI = 1.22 to 5.54; P(trend) =.02), and fructose (corresponding RR = 2.09, 95% CI = 1.13 to 3.87; P(trend) =.08) were also statistically significantly associated with increased risk. Thus, our data indicate that a diet with a high dietary glycemic load may increase the risk of colorectal cancer in women.     

Dietary glycemic load and breast cancer risk in the Women's Health Study.

A diet with a high glycemic load (GL) may contribute to a metabolic environment that enhances tumorigenesis. Little is known, however, about whether high glycemic diets increase breast cancer risk in women. We examined the associations between baseline measurements of dietary GL and overall glycemic index (GI) and subsequent breast cancer in a cohort of 39,876 women, ages 45 years or older, participating in the Women's Health Study. During a mean of 6.8 years of follow-up there were 946 confirmed cases of breast cancer. We found no association between dietary GL [multivariable-adjusted relative risk (RR), 1.01; confidence interval (CI), 0.76-1.35, comparing extreme quintiles; P for trend = 0.96] or overall GI (corresponding RR, 1.03; CI, 0.84-1.28; P for trend = 0.66) and breast cancer risk in the cohort as a whole. Exploratory analyses stratified by baseline measurements of menopausal status, physical activity, smoking history, alcohol use, and history of diabetes mellitus, hypertension, or hypercholesterolemia showed no significant associations, except in the subgroup of women who were premenopausal and reported low levels of physical activity (GL multivariable-adjusted RR, 2.35; CI, 1.03-5.37; P for trend = 0.07; GI multivariable-adjusted RR, 1.56; CI, 0.88-2.78; P for trend = 0.02, comparing extreme quintiles). Although we did not find evidence that a high glycemic diet increases overall breast cancer risk, the increase in risk in premenopausal women with low levels of physical activity suggests the possibility that the effects of a high glycemic diet may be modified by lifestyle and hormonal factors. Prospective studies of a larger sample size and longer duration are warranted to confirm our findings.     

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/m²; 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.     

Heme iron, zinc, alcohol consumption, and colon cancer: Iowa Women's Health Study

We examined associations among colon cancer incidence and dietary intake of heme iron, a possible prooxidant, zinc, a possible antioxidant, and alcohol, a disruptor of iron homeostasis. During 15 years of follow-up, 34 708 postmenopausal women, aged 55-69 years at baseline who completed a food-frequency questionnaire for the Iowa Women's Health Study, were followed for incident colon cancer. After adjusting for each micronutrient, the relative risks for proximal colon cancer increased more than twofold across categories of heme iron intake (P(trend) =.01) and the corresponding relative risks decreased more than 50% across categories for zinc intake (P(trend) =.01). The positive association with heme iron and the inverse association with zinc intake were stronger among women who consumed alcohol than among those who did not. Zinc intake was also associated with a decreased risk of distal colon cancer (P(trend) =.03), regardless of alcohol or heme iron consumption. Our results suggest that intake of dietary heme iron is associated with an increased risk of proximal colon cancer, especially among women who drink, but that intake of dietary zinc is associated with a decreased risk of both proximal and distal colon cancer.     

Dietary catechins and cancer incidence among postmenopausal women: the Iowa Women's Health Study (United States)

Objective: Catechins are bioactive flavonoids present in tea, fruits, and vegetables. Previous epidemiological studies regarding tea and cancer risk were inconclusive, possibly because catechins are also present in other plant foods. We investigated whether a high intake of catechins are associated with cancer incidence among postmenopausal women. Methods: A cohort of 34,651 postmenopausal cancer-free women aged 55–69 years were followed from 1986 to 1998. At baseline, data on diet, medical history, and lifestyle were collected. Incident cancers were obtained through linkage with a cancer registry. Cox proportional hazards analysis was used to estimate risk ratios. Results: After adjustment for potential confounders, catechin intake was inversely associated with rectal cancer incidence only (risk ratios from lowest to highest quartile: 1.00, 0.93, 0.73, and 0.55; p for trend 0.02). Non-significant inverse trends were found for cancer of the upper digestive tract, pancreas, and for hematopoietic cancers. Catechins derived primarily from fruits, (+)-catechin and (–)-epicatechin, tended to be inversely associated with upper digestive tract cancer, whereas catechins derived from tea were inversely associated with rectal cancer. Conclusions: Among several cancers studied, our data suggest that catechin intake may protect against rectal cancer. The distinct effects found for catechins derived from solid foods (fruits) and beverages (tea) may be due to differences in bioavailability or metabolism of the catechins, or to their interactions with other dietary components.     

Menstrual and reproductive factors and risk of non-Hodgkin lymphoma: the Iowa Women's Health Study (United States)

Background: Endogenous sex hormones, particularly estrogens, modulate the immune system, and non-Hodgkin lymphoma (NHL) is a tumor that is related to immunologic status. Methods: Self-reported menstrual and reproductive history and risk of NHL were evaluated in a cohort of 37,934 Iowa women who were aged 55–69 years when first enrolled in 1986. Through 1998, 261 cases of NHL were identified by linkage to the Iowa SEER Cancer Registry. Results: After multivariate adjustment there was no association between NHL incidence and age at menarche, age at menopause, type of menopause, history of infertility, number of miscarriages, or history of induced abortion, while there were suggestive inverse associations with nulliparity (RR = 0.65; 95% CI 0.36–1.16) and years of ovulation (RR = 0.76 for 37 compared to <28 ovulatory years; p-trend = 0.07). Among parous women there was no association with number of livebirths or age at first livebirth, but there was an inverse association with number of children who were breast-fed (RR = 0.52 for breast-feeding >2 children versus none; 95% CI 0.33–0.82). Conclusions: Overall, menstrual and reproductive factors were not strongly related to NHL incidence. The inverse association with breast-feeding is novel but requires confirmation in other studies.