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We investigated whether the relationship between diabetes and all-cause and CVD-related mortality differed between women with and without breast cancer among a cohort drawn from the same source population. We interviewed 1,363 women newly diagnosed with breast cancer in 1996–1997, and 1,358 age-matched women without breast cancer, to assess history of physician-diagnosed diabetes. All-cause (n = 631) and CVD-specific mortality (n = 234) was determined by the National Death Index through 2009. We estimated multivariable-adjusted hazard ratios (HRs) for the rates of all-cause and CVD-specific mortality and, to account for competing causes of death, and subdistribution HRs (sHRs) for risk of CVD-related death. Among women with and without breast cancer, respectively, diabetes was associated with: all-cause mortality [HR (95% CI) 1.52 (1.13, 2.05) and 2.17 (1.46, 3.22)]; CVD-specific deaths [1.74 (1.06, 2.84) and 2.06 (1.11, 3.84)]; and risk of CVD-related death [sHR 1.36 (0.81, 2.27) and 1.79 (0.94, 3.40)]. Differences in effect estimates between women with and without breast cancer did not reach statistical significance (p-interaction > 0.10). We found that the positive association between a history of physician-diagnosed diabetes and risk of all-cause and CVD-related mortality is of similar magnitude among a population-based cohort of women with or without breast cancer.

Whether aspirin or other nonsteroidal anti-inflammation drug (NSAID) use is associated with mortality following breast cancer remains unclear. Consideration of use patterns and interaction with obesity may help to clarify the inconsistent results. Pre-diagnosis NSAID use, weight, and height were assessed ~ 3 months after diagnosis through in-person interviews with a population-based cohort of 1,442 women with first primary breast cancer. Vital status was determined through the national death index after ~ 18 years of follow-up (N = 237/597 breast cancer-specific/all-cause deaths). We used Cox proportional hazards regression to estimate multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs). Multiplicative interaction by body mass index (BMI) was evaluated using the likelihood ratio test. Ever aspirin use was inversely associated with breast cancer-specific mortality (HR 0.87, 95% CI 0.59–1.29), but positively associated with all-cause mortality (HR 1.21, 95% CI 0.99–1.48); the CIs included the null values. The HRs, however, were more pronounced for the highest level of duration, frequency, regularity, and timing for all-cause, but not breast cancer-specific mortality. Interactions with BMI revealed no significant heterogeneity (pinteraction = 0.37 and pinteraction = 0.36, respectively). Pre-diagnosis aspirin use was not strongly associated with mortality following breast cancer. The all-cause mortality associations, however, were slightly stronger when we considered patterns of use.

Despite the overlap between the clinical symptoms/sequelae of polycystic ovarian syndrome (PCOS) and many known reproductive risk factors for breast cancer, the relationship between PCOS and breast cancer remains unclear, possibly because of the complex heterogeneity and challenges in diagnosing PCOS over time. We hypothesized that PCOS, specific PCOS-related symptoms/sequelae, or clusters of PCOS-related symptoms/sequelae may be differentially associated with pre- versus postmenopausal breast cancer risk. Cases were 1,508 women newly diagnosed with a first primary in situ or invasive breast, and the 1,556 population-based controls were frequency-matched by age. History of physician-diagnosed PCOS was reported by 2.2 % (n = 67), among whom oral contraceptive (OC) use, irregular menstruation, and infertility due to ovulatory dysfunction were common. Using unconditional logistic regression, adjusted odds ratios (95 % CI) for PCOS were increased for premenopausal [2.74 (1.13, 6.63)], but not postmenopausal breast cancer [0.87 (0.44, 1.71)]. We used cluster analysis to investigate whether risk among all women varied by PCOS-related symptoms/sequelae, such as reproductive irregularities, OC use, and components of insulin resistance. In the cluster analysis, odds ratios were elevated among premenopausal women who had a history of OC use and no ovulatory dysfunction [1.39 (1.03, 1.88)], compared to those with fewer number of PCOS-related symptoms/sequelae. PCOS and associated PCOS-related symptoms/sequelae including OC use may play a role in the development of premenopausal breast cancer. Our findings require confirmation in studies with a larger number of premenopausal women with systematically applied diagnostic criteria for PCOS.

We previously reported an inverse association between flavonoid intake and breast cancer incidence, which has been confirmed by others, but no studies have considered simultaneously potential interactions of flavonoids with multiple genetic polymorphisms involved in biologically relevant pathways (oxidative stress, carcinogen metabolism, DNA repair, and one-carbon metabolism). To estimate interaction effects between flavonoids and 13 polymorphisms in these four pathways on breast cancer risk, we used population-based data (n = 875 cases and 903 controls) and several statistical approaches, including conventional logistic regression and semi-Bayesian hierarchical modeling (incorporating prior information on the possible biologic functions of genes), which also provides biologic pathway-specific effect estimates. Compared to the standard multivariate model, the results from the hierarchical model indicate that gene-by-flavonoid interaction estimates are attenuated, but more precise. In the hierarchical model, the average effect of the deleterious versus beneficial gene, controlling for average flavonoid intake in the DNA repair pathway, and adjusted for the three other biologically relevant pathways (oxidative stress, carcinogen metabolism, and one-carbon metabolism), resulted in a 27 % increase risk for breast cancer [odds ratio = 1.27; 95 % confidence interval (CI) = 0.70, 2.29]. However, the CI was wide. Based on results from the semi-Bayesian model, breast cancer risk may be influenced jointly by flavonoid intake and genes involved in DNA repair, but our findings require confirmation.

The mechanisms driving the physical activity-breast cancer association are unclear. Exercise both increases reactive oxygen species production, which may transform normal epithelium to a malignant phenotype, and enhances antioxidant capacity, which could protect against subsequent oxidative insult. Given the paradoxical effects of physical activity, the oxidative stress pathway is of interest. Genetic variation in CAT or antioxidant-related polymorphisms may mediate the physical activity-breast cancer association.We investigated the main and joint effects of three previously unreported polymorphisms in CAT on breast cancer risk. We also estimated interactions between recreational physical activity (RPA) and 13 polymorphisms in oxidative stress-related genes. Data were from the Long Island Breast Cancer Study Project, with interview and biomarker data available on 1,053 cases and 1,102 controls.Women with ≥1 variant allele in CAT rs4756146 had a 23 % reduced risk of postmenopausal breast cancer compared with women with the common TT genotype (OR = 0.77; 95 % CI = 0.59-0.99). We observed two statistical interactions between RPA and genes in the antioxidant pathway (p = 0.043 and 0.006 for CAT and GSTP1, respectively). Highly active women harboring variant alleles in CAT rs1001179 were at increased risk of breast cancer compared with women with the common CC genotype (OR = 1.61; 95 % CI, 1.06-2.45). Risk reductions were observed among moderately active women carrying variant alleles in GSTP1 compared with women homozygous for the major allele (OR = 0.56; 95 % CI, 0.38-0.84).Breast cancer risk may be jointly influenced by RPA and genes involved in the antioxidant pathway, but our findings require confirmation.

To examine the relationship between obesity and mammography use in a large population of black and white women.Baseline data from 18,756 black and 6,304 white women enrolled in the Southern Community Cohort Study were used to examine the association between body mass index categories (healthy weight: 18.5-24.9 kg/m(2), overweight: 25-29.9 kg/m(2), and obesity classes I: 30-34.9 kg/m(2), II: 35-39.9 kg/m(2), and III: 40+ kg/m(2)) and mammogram use in the past two years. Cross-sectional analyses were conducted using logistic regression controlling for socioeconomic measures, medical conditions, insurance coverage, and lifestyle factors.Among white women, obesity class III was associated with a reduced likelihood of recent mammography compared to healthy weight women (OR = 0.70, 95% CI 0.56-0.87) that appeared unrelated to income and insurance coverage. A deterring effect of obesity was not evident among black women; instead, overweight and obesity were associated with small elevations in mammography use compared to healthy weight.In light of rising obesity rates and known associations between obesity and breast cancer risk and prognosis, a deterring effect of extreme obesity on mammography screening for white women is a concern that should be addressed by screening programs and by further directed research into the factors underlying this association.

Excessive oxidative stress may induce and promote breast carcinogenesis. Manganese superoxide dismutase (MnSOD) is critical to management of oxidative stress by catalyzing the formation of hydrogen peroxide from two superoxide anions. To examine the relationship between MnSOD Val-9Ala polymorphism, breast cancer and potential modifiers, we analyzed data from a large population-based case-control study. Study participants completed an in-home interviewer-administered questionnaire, and self-completed a Block food frequency questionnaire. Age-adjusted unconditional logistic models included 1034 cases and 1084 controls. As compared with Val/Val genotype, we found no association between MnSOD Ala/Val (OR = 0.98, 95% CI: 0.79–1.21) and Ala/Ala (OR = 1.00, 95% CI: 0.79–1.28) genotypes and breast cancer. Results did not differ by menopausal status, stage of tumor, or estrogen and progesterone receptor status. No discernable patterns of interaction were found between this MnSOD variant and anti-oxidative exposures, including fruit and vegetable intake or NSAID use, or pro-oxidant exposures, including smoking and alcohol. This study provides little evidence that variation in Val-9Ala polymorphism of MnSOD alone or through substantial interaction with key exposures believed to be pro- or anti-oxidant properties influences breast cancer risk.

To examine the relation between breast cancer risk and job history among women 20-44 years of age who participated in a multi-center, population-based, case-control study.Participants consisted of women newly diagnosed with breast cancer (1642) and controls identified by random-digit dialing (1494). Details about the three longest jobs were collected and coded by an industrial hygienist. Odds ratios and 95% confidence intervals were calculated and adjusted for age, study site, and other breast cancer risk factors.Several occupational and industrial categories were found to influence breast cancer risk. Stratification of the study population by parity revealed differences in breast cancer risk between the two groups for several occupational categories, including teachers, librarians or counselors (increased risk only among parous women) and natural scientists and mathematicians (decreased risk only among nulliparous women).This is among the first population-based case-control studies to examine occupational history and breast cancer risk in young women, with the ability to consider a wide array of potential confounders, including reproductive characteristics. This study provides further evidence of an increased breast cancer risk for several occupations and industries. Other findings were not as strongly supported by previous investigations.

To assess risk factors for breast cancer among very young compared to older premenopausal women.Between 1990 and 1992 a population-based case-control study conducted in Atlanta, GA, Seattle/Puget Sound, WA, and central NJ interviewed 3307 premenopausal women aged 20-54 years. Logistic regression models estimated adjusted relative risks (RR) and 95% confidence intervals (CI) for each of three 10-year age groups.Among the youngest age group (35 years, n = 545), significant predictors of risk included African-American race (RR = 2.66: 95% CI 1.4-4.9) and recent use of oral contraceptives (RR = 2.26; 95% CI 1.4-3.6). Although these relationships were strongest for estrogen receptor-negative (ER-) tumors (RRs of 3.30 for race and 3.56 for recent oral contraceptive use), these associations were also apparent for young women with ER+ tumors. Delayed childbearing was a risk factor for ER+ tumors among the older premenopausal women (Ptrend0.01), but not for women35 years in whom early childbearing was associated with an increased risk, reflecting a short-term increase in risk immediately following a birth. Family history of early-onset breast cancer was more strongly associated with risk among women35 years (RR = 3.22) than those 45-54 years (RR = 1.51). Risk factors for premenopausal breast cancer not significantly modified by age at diagnosis included early age at menarche, low body mass index, and heavy alcohol consumption.These findings suggest the possibility that women who develop breast cancers at very young ages may be etiologically as well as clinically distinct.

A population-based case-control study of breast cancer with a focus on premenopausal women under 45 years of age, conducted in three geographic regions of the United States, enabled the evaluation of risk in relation to varying breastfeeding practices. Among premenopausal parous women (1,211 cases, 1,120 random-digit-dialing controls), a history of breastfeeding for two or more weeks was associated with a relative risk (RR) of 0.87 (95 percent confidence interval [CI] = 0.7-1.0). This relationship was not altered substantially by removing from the reference group women who had problems with breastfeeding in the first two weeks, including those with insufficient milk production. Risk was not related substantially to number of children breastfed or length of breastfeeding, although a relatively low risk was observed among those breastfeeding for the longest duration examined (RR = 0.67, CI = 0.4-1.1 for an average period per child of 72 or more weeks). Women who began to breastfeed at a young age (< 22 years) experienced the greatest reduction in risk, but other timing parameters (e.g., interval since first or last breastfeeding) were not predictive of risk. Risks were not modified substantially by age or menopause status, although the number of menopausal subjects examined was limited. Use of medications to stop breast milk was unrelated to risk (RR = 1.04). The results of this study do not support the notion that breastfeeding substantially reduces breast cancer risk; however, this may reflect the fact that most of our study subjects breastfed only for limited periods of time (average breastfeeding per child of 30 weeks). Further studies are needed to clarify the relationship of breastfeeding to breast cancer risk, and to determine possible etiologic mechanisms underlying any observed associations.