Exposure to multiple sources of polycyclic aromatic hydrocarbons and breast cancer incidence.

BACKGROUND: Despite studies having consistently linked exposure to single-source polycyclic aromatic hydrocarbons (PAHs) to breast cancer, it is unclear whether single sources or specific groups of PAH sources should be targeted for breast cancer risk reduction. OBJECTIVES: This study considers the impact on breast cancer incidence from multiple PAH exposure sources in a single model, which better reflects exposure to these complex mixtures. METHODS: In a population-based case-control study conducted on Long Island, New York (N=1508 breast cancer cases/1556 controls), a Bayesian hierarchical regression approach was used to estimate adjusted posterior means and credible intervals (CrI) for the adjusted odds ratios (ORs) for PAH exposure sources, considered singly and as groups: active smoking; residential environmental tobacco smoke (ETS); indoor and outdoor air pollution; and grilled/smoked meat intake. RESULTS: Most women were exposed to PAHs from multiple sources, and the most common included active/passive smoking and grilled/smoked food intake. In multiple-PAH source models, breast cancer incidence was associated with residential ETS from a spouse (OR=1.20, 95%CrI=1.03, 1.40) and synthetic firelog burning (OR=1.29, 95%CrI=1.06, 1.57); these estimates are similar, but slightly attenuated, to those from single-source models. Additionally when we considered PAH exposure groups, the most pronounced significant associations included total indoor sources (active smoking, ETS from spouse, grilled/smoked meat intake, stove/fireplace use, OR=1.45, 95%CrI=1.02, 2.04). CONCLUSIONS: Groups of PAH sources, particularly indoor sources, were associated with a 30-50% increase in breast cancer incidence. PAH exposure is ubiquitous and a potentially modifiable breast cancer risk factor.

Polychlorinated biphenyls and their association with survival following breast cancer.

BACKGROUND: Polychlorinated biphenyls (PCBs) are hypothesised to influence breast carcinogenesis due to their persistence and potential to induce oestrogenic and anti-oestrogenic effects. Whether PCBs influence survival following breast cancer is unknown. METHODS: A population-based cohort of women diagnosed with first primary invasive or in situ breast cancer in 1996-1997 and with blood-measured PCBs (n=627) collected shortly after diagnosis was followed for vital status through 2011. After 5 and 15 years, we identified 54 and 187 deaths, respectively, of which 36 and 74 were breast cancer related. Using Cox regression, we estimated hazard ratios (HRs) and 95% confidence intervals (CIs) for mortality for baseline PCB concentrations, individually and as oestrogenic (ΣGroup 1B: PCB101, PCB174, PCB177, PCB187, and PCB199), anti-oestrogenic (ΣGroup 2A: PCB66, PCB74, PCB105, and PCB118; ΣGroup 2B: PCB138 and PCB170), and cytochrome P450 enzyme-inducing (ΣGroup 3: PCB99, PCB153, PCB180, PCB183, and PCB203) groups. RESULTS: The highest PCB174 tertile was associated with an increase in all-cause (HR=2.22, 95% CI: 1.14-4.30) and breast cancer-specific (HR=3.15, 95% CI: 1.23-8.09) mortalities within 5 years of diagnosis and remained associated with breast cancer-specific mortality (HR=1.88, 95% CI: 1.05-3.36) at 15 years. At 5 years, the highest tertile of PCB177 was positively associated with all-cause mortality (HR=2.12, 95% CI: 1.05-4.30). At 15 years, the highest tertiles of ΣGroup 2A congeners and PCB118 were inversely associated with all-cause mortality (HR=0.60, 95% CI: 0.39-0.83; HR=0.63, 95% CI: 0.43-0.92, respectively). CONCLUSIONS: In this first US study of PCBs and breast cancer survival, PCBs were associated with mortality in biologically plausible directions. The investigation of other, structurally similar, chemicals may be warranted.

Sources of polycyclic aromatic hydrocarbons are associated with gene-specific promoter methylation in women with breast cancer.

BACKGROUND: Tobacco smoke, diet and indoor/outdoor air pollution, all major sources of polycyclic aromatic hydrocarbons (PAHs), have been associated with breast cancer. Aberrant methylation may be an early event in carcinogenesis, but whether PAHs influence the epigenome is unclear, particularly in breast tissue where methylation may be most relevant. We aimed to evaluate the role of methylation in the association between PAHs and breast cancer. METHODS: In a population-based case-control study, we measured promoter methylation of 13 breast cancer-related genes in breast tumor tissue (n=765-851 cases) and global methylation in peripheral blood (1055 cases/1101 controls). PAH sources (current active smoking, residential environmental tobacco smoke (ETS), vehicular traffic, synthetic log burning, and grilled/smoked meat intake) were evaluated separately. Logistic regression was used to estimate adjusted odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: When comparing methylated versus unmethylated genes, synthetic log use was associated with increased ORs for CDH1 (OR=2.26, 95%CI=1.06-4.79), HIN1 (OR=2.14, 95%CI=1.34-3.42) and RARß (OR=1.80, 95%CI=1.16-2.78) and decreased ORs for BRCA1 (OR=0.44, 95%CI=0.30-0.66). Residential ETS was associated with decreased ORs for ESR1 (OR=0.74, 95%CI=0.56-0.99) and CCND2 methylation (OR=0.65, 95%CI=0.44-0.96). Current smoking and vehicular traffic were associated with decreased ORs for DAPK (OR=0.53, 95%CI=0.28-0.99) and increased ORs for TWIST1 methylation (OR=2.79, 95%CI=1.24-6.30), respectively. In controls, synthetic log use was inversely associated with LINE-1 (OR=0.59, 95%CI=0.41-0.86). DISCUSSION: PAH sources were associated with hypo- and hypermethylation at multiple promoter regions in breast tumors and LINE-1 hypomethylation in blood of controls. Methylation may be a potential biologic mechanism for the associations between PAHs and breast cancer incidence.

Organochlorine insecticides DDT and chlordane in relation to survival following breast cancer.

Organochlorine insecticides have been studied extensively in relation to breast cancer incidence, and results from two meta-analyses have been null for late-life residues, possibly due to measurement error. Whether these compounds influence survival remains to be fully explored. We examined associations between organochlorine insecticides [p,p'-DDT (dichlorodiphenyltrichloroethane), its primary metabolite, p,p'-DDE, and chlordane] assessed shortly after diagnosis and survival among women with breast cancer. A population-based sample of women diagnosed with a first primary invasive or in situ breast cancer in 1996-1997 and with available organochlorine blood measures (n = 633) were followed for vital status through 2011. After follow-up of 5 and 15 years, we identified 55 and 189 deaths, of which 36 and 74, respectively, were breast cancer-related. Using Cox regression models, we estimated the multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for lipid-adjusted organochlorine concentrations with all-cause and breast cancer-specific mortality. At 5 years after diagnosis, the highest tertile of DDT concentration was associated with all-cause (HR = 2.19; 95% CI: 1.02, 4.67) and breast cancer-specific (HR = 2.72; 95% CI: 1.04, 7.13) mortality. At 15 years, middle tertile concentrations of DDT (HR = 1.42; 95% CI 0.99, 2.06) and chlordane (HR = 1.42; 95% CI: 0.94, 2.12) were modestly associated with all-cause and breast cancer-specific mortality. Third tertile DDE concentrations were inversely associated with 15-year all-cause mortality (HR = 0.66; 95% CI: 0.44, 0.99). This is the first population-based study in the United States to show that DDT may adversely impact survival following breast cancer diagnosis. Further studies are warranted given the high breast cancer burden and the ubiquity of these chemicals.

Gene-Specific Promoter Methylation Status in Hormone-Receptor-Positive Breast Cancer Associates with Postmenopausal Body Size and Recreational Physical Activity.

INTRODUCTION: Breast cancer, the leading cancer diagnosis among American women, is positively associated with postmenopausal obesity and little or no recreational physical activity (RPA). However, the underlying mechanisms of these associations remain unresolved. Aberrant changes in DNA methylation may represent an early event in carcinogenesis, but few studies have investigated associations between obesity/RPA and gene methylation, particularly in postmenopausal breast tumors where these lifestyle factors are most relevant. METHODS: We used case-case unconditional logistic regression to estimate odds ratios (ORs) and 95% confidence intervals (CI) for the associations between body mass index (BMI=weight [kg]/height [m2]) in the year prior to diagnosis, or RPA (average hours/week), and methylation status (methylated vs. unmethylated) of 13 breast cancer-related genes in 532 postmenopausal breast tumor samples from the Long Island Breast Cancer Study Project. We also explored whether the association between BMI/RPA and estrogen/progesterone-receptor status (ER+PR+ vs. all others) was differential with respect to gene methylation status. Methylation-specific PCR and the MethyLight assay were used to assess gene methylation. RESULTS: BMI 25-29.9kg/m2, and perhaps BMI≥30kg/m2, was associated with methylated HIN1 in breast tumor tissue. Cases with BMI≥30kg/m2 were more likely to have ER+PR+ breast tumors in the presence of unmethylated ESR1 (OR=2.63, 95% CI 1.32-5.25) and women with high RPA were more likely to have ER+PR+ breast tumors with methylated GSTP1 (OR=2.33, 95% CI 0.79-6.84). DISCUSSION: While biologically plausible, our findings that BMI is associated with methylated HIN1 and BMI/RPA are associated with ER+PR+ breast tumors in the presence of unmethylated ESR1 and methylated GSTP1, respectively, warrant further investigation. Future studies would benefit from enrolling greater numbers of postmenopausal women and examining a larger panel of breast cancer-related genes.

Global DNA Methylation, Measured by the Luminometric Methylation Assay (LUMA), Associates with Postmenopausal Breast Cancer in Non-Obese and Physically Active Women.

INTRODUCTION: Little is known about how modifiable lifestyle factors interact with the epigenome to influence disease. Body mass index (BMI, weight kg/height m2) and physical activity are associated with postmenopausal breast cancer, but the mechanisms are not well-understood. We hypothesized that BMI or physical activity may modify the association between markers of global DNA methylation and postmenopausal breast cancer risk. METHODS: Resources from a population-based case-control study (~1300 postmenopausal women) were used to construct logistic regression models. We explored whether the association between breast cancer and global methylation, assessed using the luminometric methylation assay (LUMA) and long interspersed elements-1 (LINE-1) methylation in white blood cell DNA, was modified by BMI or recreational physical activity (RPA). RESULTS: The LUMA-breast cancer association was modified by BMI (multiplicative p=0.03) and RPA (p=0.004). Non-obese women in the highest quartile of LUMA experienced a greater than two-fold increased risk of postmenopausal breast cancer (BMI<25kg/m2: OR=2.16; 95% CI=1.35, 3.57 and BMI 25-29.9kg/m2: OR=2.96; 95% CI=1.69, 5.19) compared to women in the lowest LUMA quartile. Similar increases in the LUMA-breast cancer association were observed among women who were physically active (moderate RPA: OR=2.62; 95% CI=1.44, 4.75 and high RPA: OR=2.62; 95% CI=1.53, 4.49). Estimates among obese and inactive women were less pronounced and imprecise. Although we observed statistical interactions (p<0.05) between BMI and RPA with LINE-1, we were unable to discern any clear associations with breast cancer. CONCLUSIONS: The association between LUMA and postmenopausal breast cancer risk may be modified by postmenopausal body size and physical activity.

Genetic polymorphisms in DNA repair and oxidative stress pathways may modify the association between body size and postmenopausal breast cancer.

PURPOSE: Obesity is associated with increased bioavailability of estrogen, hyperinsulinemia, and chronic inflammation, all of which may promote tumor growth. Given DNA repair and oxidative stress pathways may work together with these mechanisms to influence carcinogenesis, we hypothesized that genetic variation in these pathways may modify the obesity-postmenopausal breast cancer (BC) association. METHODS: Resources from a population-based case-control study (990 cases and 970 controls) were used to construct logistic regression models. Body mass index (BMI, weight [kilogram]/height [square meter]) was assessed 1 year before reference date. We characterized interactions between BMI and 29 genetic polymorphisms in oxidative stress and DNA repair pathways. RESULTS: Age-adjusted odds ratios (95% confidence intervals) for postmenopausal BC were 1.24 (1.00-1.52) and 1.35 (1.09-1.71) for 25 ≥ BMI < 30 and BMI ≥ 30 kg/m(2), respectively. We observed multiplicative interactions (P ≤ .05) for eight gene polymorphisms in DNA repair and oxidative stress pathways. For example, among MPO variant allele carriers, obesity was associated with a twofold increased risk of postmenopausal BC (2.13 [1.35-3.36]); however, in wild-type homozygotes, the relationship was less pronounced (1.33 [0.93-1.89]). Our findings were no longer significant after Bonferroni correction. CONCLUSIONS: Obesity may be particularly deleterious for postmenopausal BC development in the presence of biologically plausible DNA repair or oxidative stress genotypes.

Completed and attempted suicides among 18,154 subjects with schizophrenia included in a large simple trial.

OBJECTIVE: To characterize subgroups of subjects with schizophrenia from the Ziprasidone Observational Study of Cardiac Outcomes (ZODIAC) trial who either completed or attempted suicide and those who did not. METHOD: The ZODIAC, conducted between February 2002 and March 2007, was an open-label, randomized, large simple trial of patients with schizophrenia (N = 18,154) followed up for 1 year by unblinded investigators providing usual care in 18 countries; the primary outcome measure was nonsuicide mortality. Every report on a completed or attempted suicide was independently adjudicated using a predefined algorithm. Primary analysis for the current report examined the association between completed or attempted suicides and the baseline variables using descriptive statistics and multivariate logistic regression models. Usage of "hard" or "soft" methods for attempted or completed suicide and distribution of suicide-related events by geographical region were also summarized. RESULTS: Overall incidences of subjects who either completed (35/18,154) or attempted (108/18,154) suicide were low, as were rates per person-time on assigned treatment analysis (0.24 for completed and 0.74 for attempted suicides per 100 person-years of exposure). The highest suicide-related mortality was seen among subjects recently diagnosed with schizophrenia. Among all potential baseline risk factors for completed suicide examined, the variables most associated with completed suicide were history of suicide attempts (OR = 2.6; 95% CI, 1.33-5.12) and usage of antidepressant medication (OR = 3.5; 95% CI, 0.84-14.85). History of > 5 hospitalizations in the past (OR = 2.1; 95% CI, 1.35-3.31) and history of suicide attempts (OR = 5.0; 95% CI, 3.21-7.76) were the variables most associated with attempted suicide among potential baseline risk factors for suicide attempts. CONCLUSIONS: Our results, obtained in a large prospective randomized study, confirm current clinical understanding regarding completed or attempted suicide in schizophrenia and the associated risk factors. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00418171.

Polymorphisms in DNA repair genes, recreational physical activity and breast cancer risk.

The mechanisms driving the inverse association between recreational physical activity (RPA) and breast cancer risk are complex. While exercise is associated with increased reactive oxygen species production it may also improve damage repair systems, particularly those that operate on single-strand breaks including base excision repair (BER), nucleotide excision repair (NER) and mismatch repair (MMR). Of these repair pathways, the role of MMR in breast carcinogenesis is least investigated. Polymorphisms in MMR or other DNA repair gene variants may modify the association between RPA and breast cancer incidence. We investigated the individual and joint effects of variants in three MMR pathway genes (MSH3, MLH1 and MSH2) on breast cancer occurrence using resources from the Long Island Breast Cancer Study Project. We additionally characterized interactions between RPA and genetic polymorphisms in MMR, BER and NER pathways. We found statistically significant multiplicative interactions (p < 0.05) between MSH2 and MLH1, as well as between postmenopausal RPA and four variants in DNA repair (XPC-Ala499Val, XPF-Arg415Gln, XPG-Asp1104His and MLH1-lle219Val). Significant risk reductions were observed among highly active women with the common genotype for XPC (OR = 0.54; 95% CI, 0.36-0.81) and XPF (OR = 0.62; 95% CI, 0.44-0.87), as well as among active women who carried at least one variant allele in XPG (OR = 0.46; 95% CI, 0.29-0.77) and MLH1 (OR = 0.46; 95% CI, 0.30-0.71). Our data show that women with minor alleles in both MSH2 and MLH1 could be at increased breast cancer risk. RPA may be modified by genes in the DNA repair pathway, and merit further investigation.

Lessons learned in the conduct of a global, large simple trial of treatments indicated for schizophrenia.

Large, "practical" or streamlined trials (LSTs) are used to study the effectiveness and/or safety of medicines in real world settings with minimal study imposed interventions. While LSTs have benefits over traditional randomized clinical trials and observational studies, there are inherent challenges to their conduct. Enrollment and follow-up of a large study sample of patients with mental illness pose a particular difficulty. To assist in overcoming operational barriers in future LSTs in psychiatry, this paper describes the recruitment and observational follow-up strategies used for the ZODIAC study, an international, open-label LST, which followed 18,239 persons randomly assigned to one of two treatments indicated for schizophrenia for 1 year. ZODIAC enrolled patients in 18 countries in North America, South America, Europe, and Asia using broad study entry criteria and required minimal clinical care intervention. Recruitment of adequate numbers and continued engagement of both study centers and subjects were significant challenges. Strategies implemented to mitigate these in ZODIAC include global study expansion, study branding, field coordinator and site relations programs, monthly site newsletters, collection of alternate contact information, conduct of national death index (NDI) searches, and frequent sponsor, contract research organization (CRO) and site interaction to share best practices and address recruitment challenges quickly. We conclude that conduct of large LSTs in psychiatric patient populations is feasible, but importantly, realistic site recruitment goals and maintaining site engagement are key factors that need to be considered in early study planning and conduct.

Polymorphisms in oxidative stress genes, physical activity, and breast cancer risk.

PURPOSE: 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. METHODS: 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. RESULTS: 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). CONCLUSIONS: Breast cancer risk may be jointly influenced by RPA and genes involved in the antioxidant pathway, but our findings require confirmation.

Fat or fit: the joint effects of physical activity, weight gain, and body size on breast cancer risk.

BACKGROUND: Although physical activity reduces breast cancer risk, issues critical to providing clear public health messages remain to be elucidated. These include the minimum duration and intensity necessary for risk reduction and the optimal time period for occurrence, as well as subgroup effects, particularly with regard to tumor heterogeneity and body size. METHODS: This study investigated the relationship between recreational physical activity (RPA) and breast cancer risk, in addition to characterizing the joint effects of activity level, weight gain, and body size, through use of a population-based sample of 1504 cases (N = 233 in situ, N = 1271 invasive) and 1555 controls (aged 20-98 years) from the Long Island Breast Cancer Study Project, in Long Island, New York. RESULTS: A nonlinear dose-response association was observed between breast cancer risk and RPA during the reproductive period and after menopause. Women in the third quartile of activity experienced the greatest benefit with an approximate 30% risk reduction for reproductive (odds ratio = 0.67; 95% confidence interval = 0.48-0.94) and postmenopausal activity (odds ratio = 0.70; 95% confidence interval = 0.52-0.95). Little to no difference was observed regarding intensity of activity or hormone receptor status. Joint assessment of RPA, weight gain, and body size revealed that women with unfavorable energy balance profiles were at increased breast cancer risk. A significant multiplicative interaction was observed between RPA and adult weight gain (P = .033). CONCLUSIONS: RPA at any intensity level during the reproductive and postmenopausal years have the greatest benefit for reducing breast cancer risk. Substantial postmenopausal weight gain may eliminate the benefits of regular activity.

Influence of prediagnostic recreational physical activity on survival from breast cancer.

Recreational physical activity (RPA) is associated with a reduced risk of developing breast cancer, but there is limited research on whether prediagnostic RPA influences survival after breast cancer diagnosis or not. We evaluated the association between prediagnostic RPA and risk of death in 1508 women with a first breast cancer diagnosis during 1996 and 1997 in the population-based Long Island Breast Cancer Study Project. A 5-year mortality, through the end of 2002, was assessed using the National Death Index (N=196). An in-person interview was completed shortly after diagnosis to obtain information on lifetime RPA, which was expressed as metabolic equivalent task hours per week (MET-h/week). A lower risk of all-cause death was observed for women who engaged in an average of 9 or more MET-h/week of RPA from menarche to diagnosis compared with women who did not exercise [age-adjusted and BMI adjusted hazard ratio (HR)=0.57; 95% confidence interval (CI)=0.39-0.83], an association that was similar when evaluated according to menopausal status. Compared with women who did not engage in moderate RPA, those who engaged in any moderate intensity lifetime RPA (>0 MET-h/week) were found to have lower all-cause mortality (HR=0.62; 95% CI=0.46-0.84) and breast cancer-specific mortality (HR=0.64; 95% CI=0.43-0.93). Among postmenopausal women, RPA that took place after menopause resulted in a decrease in overall mortality, whereas no association was observed for RPA which took place prior to menopause (for >0 MET-h/week of RPA vs. no RPA, the HR=0.61; 95% CI=0.39-0.94 and HR=1.00; 95% CI=0.65-1.54, respectively). This study provides support that RPA prior to breast cancer diagnosis improves survival.

Is the large simple trial design used for comparative, post-approval safety research? A review of a clinical trials registry and the published literature.

Post-approval, observational drug safety studies face well known difficulties in controlling for confounding, particularly confounding by indication for drug use. A study design that addresses confounding by indication is the large simple trial (LST). LSTs are characterized by large sample sizes, often in the thousands; broad entry criteria consistent with the approved medication label; randomization based on equipoise, i.e. neither physician nor patient believes that one treatment option is superior; minimal, streamlined data collection requirements; objectively-measured endpoints (e.g. death, hospitalization); and follow-up that minimizes interventions or interference with normal clinical practice. In theory then, the LST is a preferred study design for drug and vaccine safety research because it controls for biases inherent to observational research while still providing results that are generalizable to 'real-world' use. To evaluate whether LSTs are used for comparative safety evaluation and if the design is, in fact, advantageous compared with other designs, we conducted a review of the published literature (1949 through 31 December 2010) and the ClinicalTrials.gov registry (2000 through 31 December 2010). Thirteen ongoing or completed safety LSTs were identified. The design has rarely been used in comparative drug safety research, which is due to the operational, financial and scientific hurdles of implementing the design. The studies that have been completed addressed important clinical questions and, in some cases, led to re-evaluation of medical practice. We conclude the design has demonstrated utility for comparative safety research of medicines and vaccines if the necessary scientific and operational conditions for its use are met.

Comparative mortality associated with ziprasidone and olanzapine in real-world use among 18,154 patients with schizophrenia: The Ziprasidone Observational Study of Cardiac Outcomes (ZODIAC).

OBJECTIVE: The authors compared 1-year mortality rates associated with ziprasidone and olanzapine in real-world use. METHOD: The Ziprasidone Observational Study of Cardiac Outcomes (ZODIAC) was an open-label, randomized, postmarketing large simple trial that enrolled patients with schizophrenia (N=18,154) in naturalistic practice in 18 countries. The primary outcome measure was nonsuicide mortality in the year after initiation of assigned treatment. Patients were randomly assigned to receive treatment with either ziprasidone or olanzapine and followed for 1 year by unblinded investigators providing usual care. A physician-administered questionnaire was used to collect baseline demographic information, medical and psychiatric history, and concomitant medication use. Follow-up information on hospitalizations and emergency department visits, patients' vital status, and current antipsychotic drug status was collected and reported by treating psychiatrists. Post hoc analyses of sudden death, a secondary endpoint, were also conducted. RESULTS: The incidence of nonsuicide mortality within 1 year of initiating pharmacotherapy was 0.91 for ziprasidone (N=9,077) and 0.90 for olanzapine (N=9,077). The relative risk was 1.02 (95% CI=0.76-1.39). This finding was confirmed in numerous secondary and sensitivity analyses. CONCLUSIONS: Despite the known risk of QTc prolongation with ziprasidone treatment, the findings of this study failed to show that ziprasidone is associated with an elevated risk of nonsuicidal mortality relative to olanzapine in real-world use; the study excludes a relative risk larger than 1.39 with a high probability. However, the study was neither powered nor designed to examine the risk of rare events like torsade de pointes.

Associations between polycyclic aromatic hydrocarbon-related exposures and p53 mutations in breast tumors.

BACKGROUND: Previous studies have suggested that polycyclic aromatic hydrocarbons (PAHs) may be associated with breast cancer. However, the carcinogenicity of PAHs on the human breast remains unclear. Certain carcinogens may be associated with specific mutation patterns in the p53 tumor suppressor gene, thereby contributing information about disease etiology. OBJECTIVES: We hypothesized that associations of PAH-related exposures with breast cancer would differ according to tumor p53 mutation status, effect, type, and number. METHODS: We examined this possibility in a population-based case-control study using polytomous logistic regression. As previously reported, 151 p53 mutations among 859 tumors were identified using Surveyor nuclease and confirmed by sequencing. RESULTS: We found that participants with p53 mutations were less likely to be exposed to PAHs (assessed by smoking status in 859 cases and 1,556 controls, grilled/smoked meat intake in 822 cases and 1,475 controls, and PAH-DNA adducts in peripheral mononuclear cells in 487 cases and 941 controls) than participants without p53 mutations. For example, active and passive smoking was associated with p53 mutation-negative [odds ratio (OR) = 1.55; 95% confidence interval (CI), 1.11-2.15] but not p53 mutation-positive (OR = 0.77; 95% CI, 0.43-1.38) cancer (ratio of the ORs = 0.50, p < 0.05). However, frameshift mutations, mutation number, G:C-->A:T transitions at CpG sites, and insertions/deletions were consistently elevated among exposed subjects. CONCLUSIONS: These findings suggest that PAHs may be associated with specific breast tumor p53 mutation subgroups rather than with overall p53 mutations and may also be related to breast cancer through mechanisms other than p53 mutation.

Common genetic variations in the LEP and LEPR genes, obesity and breast cancer incidence and survival.

Obesity is a strong risk factor for breast cancer in postmenopausal women and adverse prognostic indicator regardless of menopausal status. Leptin is an important regulator of adipose tissue mass and has been associated with tumor cell growth. Leptin exerts its effects through interaction with the leptin receptor (LEPR). We investigated whether genetic variations in the leptin (LEP) and LEPR genes are associated with risk of breast cancer, or once diagnosed, with survival. The polymorphisms LEP G-2548A and LEPR Q223R were characterized in population-based study consisting of mostly European-American women. The study examined 1,065 women diagnosed with first, primary invasive breast cancer between 1996 and 1997. Controls were 1,108 women frequency matched to the cases by 5-year age group. A modest increase in risk of developing breast cancer was associated with the LEP -2548AA genotype when compared to the LEP -2548GG genotype (age-adjusted OR = 1.30; 95% CI = 1.01-1.66). This association was stronger among postmenopausal women who were obese (OR = 1.86; 95% CI = 0.95-3.64) although the interaction was of borderline statistical significance (P = 0.07). We found no evidence of an association with polymorphisms of either LEP or LEPR in relation to all-cause or breast cancer-specific mortality among women with breast cancer (mean follow-up time = 66.7 months). The effects of these genotypes on breast cancer risk and mortality did not vary significantly when stratified by menopausal status. In summary, our results show that a common variant in LEP may be associated with the risk of developing breast cancer supporting the hypothesis that leptin is involved in breast carcinogenesis.

PAH-DNA adducts, cigarette smoking, GST polymorphisms, and breast cancer risk.

BACKGROUND: Polycyclic aromatic hydrocarbons (PAHs) may increase breast cancer risk, and the association may be modified by inherited differences in deactivation of PAH intermediates by glutathione S-transferases (GSTs). Few breast cancer studies have investigated the joint effects of multiple GSTs and a PAH biomarker. OBJECTIVE: We estimated the breast cancer risk associated with multiple polymorphisms in the GST gene (GSTA1, GSTM1, GSTP1, and GSTT1) and the interaction with PAH-DNA adducts and cigarette smoking. METHODS: We conducted unconditional logistic regression using data from a population-based sample of women (cases/controls, respectively): GST polymorphisms were genotyped using polymerase chain reaction and matrix-assisted laser desorption/ionization time-of-flight assays (n = 926 of 916), PAH-DNA adduct blood levels were measured by competitive enzyme-linked immunosorbent assay (n = 873 of 941), and smoking status was assessed by in-person questionnaires (n = 943 of 973). RESULTS: Odds ratios for joint effects on breast cancer risk among women with at least three variant alleles were 1.56 [95% confidence interval (CI), 1.13-2.16] for detectable PAH-DNA adducts and 0.93 (95% CI, 0.56-1.56) for no detectable adducts; corresponding odds ratios for three or more variants were 1.18 (95% CI, 0.82-1.69) for ever smokers and 1.44 (95% CI, 0.97-2.14) for never smokers. Neither interaction was statistically significant (p = 0.43 and 0.62, respectively). CONCLUSION: We found little statistical evidence that PAHs interacted with GSTT1, GSTM1, GSTP1, and GSTA1 polymorphisms to further increase breast cancer risk.

Polycyclic aromatic hydrocarbon-DNA adducts and survival among women with breast cancer.

Polycyclic aromatic hydrocarbons (PAH) are mammary carcinogens in animal studies, and a few epidemiologic studies have suggested a link between elevated levels of PAH-DNA adducts and breast cancer incidence. An association between PAH-DNA adducts and survival among breast cancer cases has not been previously reported. We conducted a survival analysis among women with newly diagnosed invasive breast cancer between 1996 and 1997, enrolled in the Long Island Breast Cancer Study Project. DNA was isolated from blood samples that were obtained from cases shortly after diagnosis and assayed for PAH-DNA adducts using ELISA. Among the 722 cases with PAH-DNA adduct measurements, 97 deaths (13.4%) from all causes and 54 deaths (7.5%) due to breast cancer were reported to the National Death Index (NDI) by December 31, 2002. Using Cox proportional hazards models and controlling for age at diagnosis, we did not find evidence that all-cause mortality (hazard ratio (HR)=0.88; 95% confidence interval (CI): 0.57-1.37), or breast cancer mortality (HR=1.20; 95% CI: 0.63-2.28) was strongly associated with detectable PAH-DNA adduct levels compared with non-detectable adducts; additionally, no dose-response association was observed. Among a subgroup with treatment data (n=520), adducts were associated with over a two-fold higher mortality among those receiving radiation, but mortality for adducts was reduced among hormone therapy users. Results from this large population-based study do not provide strong support for an association between detectable PAH-DNA adducts and survival among women with breast cancer, except perhaps among those receiving radiation treatment.

The Ziprasidone Observational Study of Cardiac Outcomes (ZODIAC): design and baseline subject characteristics.

BACKGROUND: Ziprasidone has been used to treat schizophrenia since 2000. It is unknown whether its modest QTc-prolonging effect increases cardiovascular event risk. PURPOSE: To describe the study design of the Ziprasidone Observational Study of Cardiac Outcomes (ZODIAC). METHOD: The study was conducted between February 2002 and February 2006. One-year follow-up for the primary endpoint of nonsuicide death ended in April 2007. ZODIAC is an open-label, randomized, postmarketing study enrolling patients with schizophrenia in naturalistic practice in 18 countries. The primary outcome measure was the rate of nonsuicide mortality in the year after initial recommendation for therapy. Subjects were randomly assigned to either ziprasidone or olanzapine, after which follow-up was conducted by investigators aware of the assigned exposure. A physician-administered questionnaire collected baseline information on patients' demographics, medical and psychiatric history, and concomitant medication use. Data were self-reported by patients or reported by enrolling physicians. RESULTS: ZODIAC enrolled 18,240 patients with schizophrenia. Most (73.0%) were from the United States or Brazil. Patients' baseline mean age was 41.6 years, 55.1% were male, and 60.0% were white. At baseline, approximately 18% had hypertension, 14.8% had hyperlipidemia, 46.5% currently smoked, 28.9% had a body mass index >or= 30 kg/m(2), and 7.7% had diabetes. Mean time from schizophrenia diagnosis to study enrollment was 10.4 years and mean Clinical Global Impressions scale score was 5.2 (range: 1-8). Nearly one third of patients had ever attempted suicide. Seventy-one percent were using antipsychotics at baseline. Almost 80% were using concomitant medications, with 29.5% using antidepressants, 25.4% using anxiolytics, and 19.0% using mood stabilizers. Less than 3% were using antihypertensives or statins. CONCLUSIONS: ZODIAC is a uniquely designed study with an initial randomization to ziprasidone or olanzapine and follow-up largely consistent with usual practice (i.e., many characteristics of a nonexperimental study). Baseline data suggest this study population has a substantial prevalence of cardiovascular risk factors. Concomitant medications were used frequently, although hyperlipidemia and hypertension may be undertreated. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00174447.