Person-directed, non-pharmacological interventions for sleepiness at work and sleep disturbances caused by shift work.

BACKGROUND: Shift work is often associated with sleepiness and sleep disorders. Person-directed, non-pharmacological interventions may positively influence the impact of shift work on sleep, thereby improving workers' well-being, safety, and health. OBJECTIVES: To assess the effects of person-directed, non-pharmacological interventions for reducing sleepiness at work and improving the length and quality of sleep between shifts for shift workers. SEARCH METHODS: We searched CENTRAL, MEDLINE Ovid, Embase, Web of Knowledge, ProQuest, PsycINFO, OpenGrey, and OSH-UPDATE from inception to August 2015. We also screened reference lists and conference proceedings and searched the World Health Organization (WHO) Trial register. We contacted experts to obtain unpublished data. SELECTION CRITERIA: Randomised controlled trials (RCTs) (including cross-over designs) that investigated the effect of any person-directed, non-pharmacological intervention on sleepiness on-shift or sleep length and sleep quality off-shift in shift workers who also work nights. DATA COLLECTION AND ANALYSIS: At least two authors screened titles and abstracts for relevant studies, extracted data, and assessed risk of bias. We contacted authors to obtain missing information. We conducted meta-analyses when pooling of studies was possible. MAIN RESULTS: We included 17 relevant trials (with 556 review-relevant participants) which we categorised into three types of interventions: (1) various exposures to bright light (n = 10); (2) various opportunities for napping (n = 4); and (3) other interventions, such as physical exercise or sleep education (n = 3). In most instances, the studies were too heterogeneous to pool. Most of the comparisons yielded low to very low quality evidence. Only one comparison provided moderate quality evidence. Overall, the included studies' results were inconclusive. We present the results regarding sleepiness below. Bright light Combining two comparable studies (with 184 participants altogether) that investigated the effect of bright light during the night on sleepiness during a shift, revealed a mean reduction 0.83 score points of sleepiness (measured via the Stanford Sleepiness Scale (SSS) (95% confidence interval (CI) -1.3 to -0.36, very low quality evidence). Another trial did not find a significant difference in overall sleepiness on another sleepiness scale (16 participants, low quality evidence).Bright light during the night plus sunglasses at dawn did not significantly influence sleepiness compared to normal light (1 study, 17 participants, assessment via reaction time, very low quality evidence).Bright light during the day shift did not significantly reduce sleepiness during the day compared to normal light (1 trial, 61 participants, subjective assessment, low quality evidence) or compared to normal light plus placebo capsule (1 trial, 12 participants, assessment via reaction time, very low quality evidence). Napping during the night shiftA meta-analysis on a single nap opportunity and the effect on the mean reaction time as a surrogate for sleepiness, resulted in a 11.87 ms reduction (95% CI 31.94 to -8.2, very low quality evidence). Two other studies also reported statistically non-significant decreases in reaction time (1 study seven participants; 1 study 49 participants, very low quality evidence).A two-nap opportunity resulted in a statistically non-significant increase of sleepiness (subjective assessment) in one study (mean difference (MD) 2.32, 95% CI -24.74 to 29.38, 1 study, 15 participants, low quality evidence). Other interventionsPhysical exercise and sleep education interventions showed promise, but sufficient data to draw conclusions are lacking. AUTHORS' CONCLUSIONS: Given the methodological diversity of the included studies, in terms of interventions, settings, and assessment tools, their limited reporting and the very low to low quality of the evidence they present, it is not possible to determine whether shift workers' sleepiness can be reduced or if their sleep length or quality can be improved with these interventions.We need better and adequately powered RCTs of the effect of bright light, and naps, either on their own or together and other non-pharmacological interventions that also consider shift workers' chronobiology on the investigated sleep parameters.

Perioperative chemo(radio)therapy versus primary surgery for resectable adenocarcinoma of the stomach, gastroesophageal junction, and lower esophagus.

BACKGROUND: The outcome of patients with locally advanced gastroesophageal adenocarcinoma (adenocarcinoma of the esophagus, gastroesophageal (GE) junction, and stomach) is poor. There is conflicting evidence regarding the effects of perioperative chemotherapy on survival and other outcomes. OBJECTIVES: To assess the effect of perioperative chemotherapy for gastroesophageal adenocarcinoma on survival and other clinically relevant outcomes in the overall population of participants in randomized controlled trials (RCTs) and in prespecified subgroups. SEARCH METHODS: We performed computerized searches in the Cochrane Central Register of Controlled Trials (CENTRAL), Database of Abstracts of Review of Effectiveness (DARE), the Cochrane Database of Systematic Reviews (CDSR) from The Cochrane Library, MEDLINE (1966 to May 2011), EMBASE (1980 to May 2011), and LILACS (Literatura Latinoamericana y del Caribe en Ciencias de la Salud), combining the Cochrane highly sensitive search strategy with specific search terms. Moreover, we handsearched several online databases, conference proceedings, and reference lists of retrieved papers. SELECTION CRITERIA: We included RCTs which randomized patients with gastroesophageal adenocarcinoma, in the absence of distant metastases, to receive either chemotherapy with or without radiotherapy followed by surgery, or surgery alone. DATA COLLECTION AND ANALYSIS: Two independent review authors identified eligible trials. We solicited individual patient data (IPD) from all selected trials. We performed meta-analyses based on intention-to-treat populations using the two-stage method to combine IPD with aggregate data from RCTs for which IPD were unavailable. We combined data from all trials providing IPD in a Cox proportional hazards model to assess the effect of several covariables on overall survival. MAIN RESULTS: We identified 14 RCTs with 2422 eligible patients. For eight RCTs with 1049 patients (43.3%), we were able to obtain IPD. Perioperative chemotherapy was associated with significantly longer overall survival (hazard ratio (HR) 0.81; 95% confidence interval (CI) 0.73 to 0.89). This corresponds to a relative survival increase of 19% or an absolute survival increase of 9% at five years. This survival advantage was consistent across most subgroups. There was a trend towards a more pronounced treatment effect for tumors of the GE junction compared to other sites, and for combined chemoradiotherapy as compared to chemotherapy in tumors of the esophagus and GE junction. Resection with negative margins was a strong predictor of survival. Multivariable analysis showed that tumor site, performance status, and age have an independent significant effect on survival. Moreover, there was a significant interaction of the effect of perioperative chemotherapy with age (larger treatment effect in younger patients). Perioperative chemotherapy also showed a significant effect on several secondary outcomes. It was associated with longer disease-free survival, higher rates of R0 resection, and more favorable tumor stage upon resection, while there was no association with perioperative morbidity and mortality. AUTHORS' CONCLUSIONS: Perioperative chemotherapy for resectable gastroesophageal adenocarcinoma increases survival compared to surgery alone. It should thus be offered to all eligible patients. There is a trend to a larger survival advantage for tumors of the GE junction as compared to other sites and for chemoradiotherapy as compared to chemotherapy in esophageal and GE junction tumors. Likewise, there is an interaction between age and treatment effect, with younger patients having a larger survival advantage, and no survival advantage for elderly patients.

Menopausal hormone therapy and risk of clinical breast cancer subtypes.

BACKGROUND: Breast cancer is a heterogeneous disease with subtypes that may vary in their etiologies. Menopausal hormone therapy has been associated more strongly with lobular and tubular than ductal histologic types and with tumors that are smaller, hormone receptor-positive, and of lower grade. At the same time, correlations have been observed between histology and clinical characteristics. To identify those tumor subtypes most strongly associated with hormone therapy use, it is necessary to disentangle these interrelationships. METHODS: Based on 3,464 postmenopausal breast cancer cases and 6,657 controls from the population-based Mammary carcinoma Risk factor Investigation study, we used polytomous logistic regression to evaluate associations between hormone therapy use and risk of invasive breast cancer subtypes. We assessed variations in risk for selected tumor characteristics among histologic and hormone receptor subtypes, both overall and for specific hormone therapy regimens. RESULTS: Lobular and mixed types showed less variation by prognostic factors than did ductal tumors. Current hormone therapy use had the strongest associations with prognostic variables in estrogen receptor (ER)-positive and/or progesterone receptor (PR)-positive ductal tumors and in lobular tumors regardless of ER/PR status, with little effect on ER/PR-negative ductal tumors. The observed associations varied minimally by hormone therapy type or regimen. CONCLUSION: Current hormone therapy use was associated with more favorable breast cancer characteristics for ductal tumors but had less effect on prognostic characteristics in women with lobular tumors. Both histologic type and estrogen receptor/progesterone receptor status seem to be important in explaining the role of hormone therapy in the etiology of breast cancer subtypes.

Cancer risk factors associated with insulin-like growth factor (IGF)-I and IGF-binding protein-3 levels in healthy women: effect modification by menopausal status.

Insulin-like growth factor-I (IGF-I) and IGF-binding protein-3 (IGFBP-3) appear to influence breast cancer risk and are hypothesized to mediate the effects of several cancer risk factors that depend on menopausal status. We investigated associations among cancer risk factors and plasma IGF-I and IGFBP-3 in 882 healthy control women (426 premenopausal, 456 postmenopausal) from two population-based breast cancer case­control studies. Interactions with menopausal status were statistically tested. We observed associations with non-modifiable (age, benign breast disease) and modifiable factors [body mass index (BMI), physical activity, smoking habits, alcohol consumption]. Furthermore, we demonstrated statistical interactions with menopausal status. Premenopausal IGFBP-3 levels increased and postmenopausal levels decreased with age (p-interaction = 0.001). Overweight postmenopausal women had higher IGF-I (p = 0.049) and IGFBP-3 (p = 0.005) levels than women with lower BMI. Postmenopausal IGF-I levels were positively associated with physical activity (p-trend = 0.012, p-interaction = 0.050). Postmenopausal current smokers had lower IGF-I (p = 0.014) and IGFBP-3 levels (p = 0.011). Increasing alcohol consumption was associated with lower premenopausal IGF-I (p-trend = 0.002, p-interaction = 0.004) and higher postmenopausal IGFBP-3 levels (p = 0.019). Benign breast disease was associated with higher premenopausal (p = 0.044) and postmenopausal (p = 0.002) IGF-I levels. IGF-I and/or IGFBP-3 potentially mediate changes in breast cancer risk associated with BMI, benign breast disease, and perhaps alcohol consumption. Other observed associations suggest that neither IGF-I nor IGFBP-3 alone acts as mediator. Consideration of menopausal status may help disentangle carcinogenic pathways involving IGF proteins.

Disease-free survival as a surrogate for overall survival in neoadjuvant trials of gastroesophageal adenocarcinoma: Pooled analysis of individual patient data from randomised controlled trials.

INTRODUCTION: Disease-free survival (DFS) is increasingly being used as surrogate end-point for overall survival (OS) in cancer trials. So far, there has been no validation of the surrogacy of DFS for OS for neoadjuvant treatment of gastroesophageal adenocarcinoma. METHODS: The study uses individual patient data (IPD) from eight randomised controlled trials (RCTs) (n = 1126 patients) comparing neoadjuvant therapy followed by surgery with surgery alone for gastroesophageal adenocarcinoma. Correlation between OS time and DFS time was calculated to evaluate individual-level surrogacy. For each trial, survival curves using the Kaplan-Meier method were plotted and hazard ratios (HRs) on the treatment effects were calculated for OS and DFS separately. Those HRs were pooled in a random-effects meta-analysis. Observed HRs were compared with predicted HRs for OS using results from an error-in-variables linear regression model accounting for the uncertainty about the estimated effect. The strength of the association was quantified by the coefficient of determination to assess trial-level surrogacy. The surrogate threshold effect was calculated to determine the minimum treatment effect on DFS necessary to predict a non-zero treatment effect on OS. RESULTS: A strong correlation between OS time and DFS time was observed, indicating a high individual-level surrogacy. For all RCTs, estimated HRs for OS and DFS were highly similar. In the meta-analysis, the overall HR for OS was virtually identical to that for DFS. The estimated coefficient of determination r2 for the association between HRs for OS and DFS was 0.912 (95% confidence interval: 0.75-1.0), indicating a very good fit of the regression model and thus a strong trial-level surrogacy between OS and DFS. The surrogate threshold effect based on the regression analysis was 0.79. DISCUSSION: Based on strong correlations between DFS and OS, as well as a strong correlation of the treatment effects of the two end-points in the error-in-variable regression, DFS seems an appropriate surrogate marker for OS in randomised trials of neoadjuvant chemotherapy or chemoradiotherapy for gastroesophageal adenocarcinoma.

Serum 25-hydroxyvitamin D and risk of post-menopausal breast cancer--results of a large case-control study.

Various studies suggest that vitamin D may reduce breast cancer risk. Most studies assessed the effects of dietary intake only, although endogenous production is an important source of vitamin D. Therefore, the measurement of serum 25-hydroxyvitamin D [25(OH)D] better indicates overall vitamin D status. To assess the association of 25(OH)D serum concentrations with post-menopausal breast cancer risk, we used a population-based case-control study in Germany, which recruited incident breast cancer patients aged 50-74 between 2002 and 2005. Information on sociodemographic and breast cancer risk factors was collected by personal interview. For this analysis, we included 1394 cases and 1365 controls, matched on year of birth and time of blood collection. Conditional logistic regression was used to calculate odds ratios (ORs) for breast cancer adjusted for potential confounders. Serum 25(OH)D concentration was significantly inversely associated with post-menopausal breast cancer risk. Compared with the lowest category (<30 nM), OR [95% confidence intervals (CI)] for the higher categories of 25(OH)D (30-45, 45-60, 60-75 and >/=75 nM) were 0.57 (0.45-0.73), 0.49 (0.38-0.64), 0.43 (0.32-0.57) and 0.31 (0.24-0.42), respectively (P(trend) < 0.0001). Analysis using fractional polynomials indicated a non-linear association. The association was stronger in women never using menopausal hormone therapy (HT) compared with past and current users (P(interaction) < 0.0001). Our findings strongly suggest a protective effect for post-menopausal breast cancer through a better vitamin D supply as characterized by serum 25(OH)D measurement, with a stronger inverse association in women with low serum 25(OH)D concentrations (<50 nM).

Vitamin D receptor gene polymorphisms and haplotypes and postmenopausal breast cancer risk.

INTRODUCTION: Vitamin D receptor (VDR) genotypes may influence breast cancer risk by altering potential anticarcinogenic effects of vitamin D, but epidemiological studies have been inconsistent. Effect modification by serum 25-hydroxyvitamin D (25 [OH]D), the biomarker for vitamin D status in humans, has rarely been examined. METHODS: We assessed the effects of two frequently analyzed polymorphisms (FokI and TaqI) and two potentially functional variants (VDR-5132 and Cdx2) in the VDR gene, which thus far have not been analyzed with respect to breast cancer risk, on postmenopausal breast cancer risk in a population-based, case-control study including 1,408 patients (cases) and 2,612 control individuals (controls) matched for year of birth. Odds ratios (ORs) for breast cancer adjusted for potential confounders were calculated for genotypes and estimated haplotypes. RESULTS: No differences in serum 25(OD)D concentrations by VDR genotype were observed. None of the analyzed polymorphisms was associated with overall risk for postmenopausal breast cancer. However, the TaqI polymorphism was associated with a significantly increased risk for oestrogen receptor positive tumours (OR = 1.18, 95% confidence interval [CI] = 1.00 to 1.38, comparing t allele carriers with noncarriers) but not for oestrogen receptor negative tumours (OR = 0.88, 95% CI = 0.69 to 1.13; P for interaction = 0.04). Haplotype analysis revealed the haplotype FtCA (FokI F, TaqI t, VDR-5132 C, Cdx2 A), which contains the TaqI t allele, to be associated with a significantly greater breast cancer risk as compared with the most frequent haplotype FTCG (OR = 1.43, 95% CI = 1.00 to 2.05). No significant interaction between VDR genotypes or haplotypes and 25(OH)D was observed. CONCLUSION: Our results support potential effects of VDR polymorphisms on postmenopausal breast cancer risk and possible differential effects of receptor status of the tumour. However, further studies focusing on the influence of polymorphisms and haplotypes on VDR functionality, activity and concentration are needed.

Risk of different histological types of postmenopausal breast cancer by type and regimen of menopausal hormone therapy.

In a large population-based case-control study in Germany, including 3,464 breast cancer cases aged 50-74 at diagnosis and 6,657 population based and frequency matched controls, we investigated the effects of menopausal hormone therapy (HT) by type, regimen, timing and progestagenic constituent on postmenopausal breast cancer risk overall and according to histological type. Data were collected by face-to-face interviews. Logistic and polytomous logistic regression analysis were used to estimate odds ratios (OR) and 95%-confidence intervals (95% CI). Risk of invasive breast cancer was significantly elevated in current users (OR, 1.73, 95% CI, 1.55-1.94) and heterogeneous by histological type (p < 0.01), being more than 2-fold higher for lobular and tubular than for ductal cancer. Risks for current users varied significantly by type and regimen of HT, with ORs per year of use of 1.05 (95% CI, 1.04-1.06) for continuous combined estrogen-progestagen, 1.03 (95% CI, 1.02-1.04) for cyclical EP and 1.01 (95% CI, 1.00-1.03) for estrogen-only therapy. No statistically significant increase in risk was observed after 5 years of cessation of HT use for any histological type. Analyses of progestagenic content by regimen revealed a significantly higher risk for continuously administered norethisterone- or levonorgestrel-derived progestagens than for continuously administered progesterone-derived progestagens (OR, 2.27, 95% CI, 1.98-2.62 vs. 1.47, 95% CI, 1.12-1.93, respectively, p = 0.003), which may be explained by dose rather than type of progestagen. These data suggest that the risks associated with menopausal HT differ by type and regimen of HT and histological type of breast cancer and may vary by progestagenic component, depending on the effective dose.

Physical activity and postmenopausal breast cancer: effect modification by breast cancer subtypes and effective periods in life.

Physical activity (PA) has been inversely associated with postmenopausal breast cancer risk. However, it is unclear how and in which life periods PA may be effective to reduce breast cancer risk. Moreover, the evidence is still not judged as 'convincing' as there is some heterogeneity among study results. Most studies regarded breast cancer as a single disease, at best separated by menopausal status. Yet, breast cancers are heterogeneous and likely have different etiologies. Therefore, we analyzed the association of PA with different breast cancer subtypes in 3,414 postmenopausal cases and 6,569 controls from a case-control study on breast cancer conducted 2002-2005 in Germany (MARIE study). PA in the age periods 30-49 and 50+ years was assessed, including leisure-time PA (sports, cycling, walking) and non-recreational PA (occupational and household activities). There was a significant protective effect of leisure-time PA for ER+/PR+ carcinomas (adjusted odds ratio = 0.71, 95% confidence interval: 0.60, 0.85; trend P = 0.0001), but no effect for ER-/PR- carcinomas. Moreover, looking at physical activity pattern over time, the effect of PA after menopause on reducing breast cancer risk was more pronounced than the effect of PA before menopause. Overall, effects of PA were independent from adult weight gain, body mass index, and energy intake. These findings suggest that leisure-time PA after menopause may reduce postmenopausal breast cancer risk at least in part via hormonal pathways and not solely by changing body composition. Inactive postmenopausal women should be encouraged to become physically active even later in life.

The Gc2 allele of the vitamin D binding protein is associated with a decreased postmenopausal breast cancer risk, independent of the vitamin D status.

Vitamin D pathway gene polymorphisms may influence breast cancer risk by altering potential anticarcinogenic effects of vitamin D. The association between polymorphisms in the vitamin D binding protein (Gc) and postmenopausal breast cancer risk, with additional focus on the influence of serum 25-hydroxyvitamin D [25(OH)D], the biomarker for vitamin D status in humans, has not been examined thus far. We assessed the combined effects of two known functional polymorphisms in the Gc gene (rs4588 and rs7041), composing the phenotypic alleles Gc1s, Gc1f (combined: Gc1), and Gc2, on postmenopausal breast cancer risk and potential effect modification by 25(OH)D status in a population-based case-control study including 1,402 cases and 2,608 matched controls. Odds ratios (OR) for breast cancer risk adjusted for potential confounders were calculated for Gc genotypes. ANOVA was used to compare geometric means of serum 25(OH)D across Gc genotypes. Serum 25(OH)D concentrations in the control group significantly differed by Gc genotype, being lowest in Gc2 allele carriers. The geometric means of 25(OH)D were 53.0, 47.8, and 40.4 nmol/L for Gc1-1, Gc2-1, and Gc2-2 genotypes, respectively (P(trend) < 0.0001). Gc2-2 genotype was associated with a significantly decreased risk of postmenopausal breast cancer with an odds ratio (95% confidence interval) of 0.72 (0.54-0.96), compared with homozygote Gc1s allele carriers. No interaction between 25(OH)D status and Gc genotype was observed, nor did the association change considerably after adjustment for 25(OH)D status. Our results provide evidence for a serum 25(OH)D-independent effect of Gc2 allele carrier status in postmenopausal breast cancer.

Test-retest reliability of self-reported reproductive and lifestyle data in the context of a German case-control study on breast cancer and postmenopausal hormone therapy.

PURPOSE: Studies using survey questionnaires to collect epidemiologic data rely on the accuracy of participants' self-reporting. As part of the quality control protocol for a large population-based case-control study of the association between postmenopausal hormone therapy (HT) and breast cancer in German women (the Mammakarzinom-Risikofaktoren-Erhebung [MARIE] study), the authors used test-retest to evaluate the reliability of women's self-reporting of a number of putative breast cancer risk factors, including HT, reproductive history, family history, and lifestyle. METHODS: Of those women interviewed between November 2002 and July 2003, 62 cases and 61 controls were re-interviewed an average of 10 months later, using a shortened version of the original study questionnaire. RESULTS: Agreement between the first and second interviews was assessed using Cohen's kappa and proportion of agreement. There was very good overall agreement between the two questionnaires for HT ever/never use (kappa = 0.90), type of therapy (kappa = 0.83), and form of application (kappa = 0.73) and good agreement for duration of use (kappa = 0.60). Agreement for other factors ranged from kappa = 1.00 for age at first birth to kappa = 0.43 for weekend bicycle riding. Agreement was nondifferential by disease status. CONCLUSIONS: These findings indicate that the MARIE survey instrument was of good quality and had a low likelihood of misclassification.

Preoperative chemo(radio)therapy versus primary surgery for gastroesophageal adenocarcinoma: systematic review with meta-analysis combining individual patient and aggregate data.

BACKGROUND: The prognosis of patients with gastroesophageal adenocarcinoma is poor. There is conflicting evidence regarding effects of preoperative chemotherapy on survival and other outcomes. METHODS: We conducted a meta-analysis with aggregate and individual patient data (IPD) to assess the effect of preoperative chemotherapy for gastroesophageal adenocarcinoma on survival and other outcomes. Two independent reviewers identified eligible randomised controlled trials (RCTs) comparing chemotherapy+/-radiotherapy followed by surgery with surgery alone for gastroesophageal adenocarcinoma. IPD was solicited from all trials. Meta-analyses were performed using the two stage method. RESULTS: We identified 14 RCTs (2422 patients). For eight RCTs (1049 patients; 43.3%) we obtained IPD. Preoperative chemotherapy was associated with longer overall survival (hazard ratio [HR] 0.81; 95% confidence interval [CI] 0.73-0.89; p<0.0001). There were larger treatment effects in tumours of the gastroesophageal junction and for chemoradiotherapy compared to chemotherapy, but the tests for subgroup differences were not statistically significant. Preoperative chemotherapy was associated with longer disease-free survival, higher likelihood of R0 resection and more favourable post-treatment tumour stage, but not perioperative complications. CONCLUSION: Preoperative chemotherapy for locoregional gastroesophageal adenocarcinoma increases survival compared to surgery alone. It should be offered to all eligible patients. There appear to be larger survival advantages in tumours of the gastroesophageal junction and for chemoradiotherapy, but these findings require prospective confirmation.

The use of herbal preparations to alleviate climacteric disorders and risk of postmenopausal breast cancer in a German case-control study.

BACKGROUND: The use of herbal preparations (HEP) to alleviate climacteric disorders is expected to increase as women seek alternatives to menopausal hormone therapy to avoid the associated breast cancer risk. Data are sparse on the long-term effects of HEP containing phytoestrogens and black cohosh on breast cancer risk. METHODS: Within a German case-control study, associations between patterns of HEP use and incident breast cancer were investigated in 10,121 postmenopausal women (3,464 cases, 6,657 controls). Information on HEP use was collected in face-to-face interviews supported by a list of brand names. Multivariate logistic and polytomous regression analyses were done. FINDINGS: Ever use of HEP (9.9%) was inversely associated with invasive breast cancer [odds ratio (OR), 0.74; 95% confidence interval (CI), 0.63-0.87] in a dose-dependent manner (OR, 0.96 per year of use; P = 0.03). Classes of HEP did not differ significantly (P(heterogeneity) = 0.81). Risks for invasive ductal (OR, 0.72; 95% CI, 0.60-0.87) and combined lobular/mixed/tubular tumors (OR, 0.76; 95% CI, 0.58-1.01) were similarly reduced by any HEP use but not for in situ carcinomas (1.34; 95% CI, 0.86-2.09). There were no substantial differences in associations of HEP use by estrogen receptor status (ER(+) OR, 0.74; 95% CI, 0.62-0.89; ER- OR, 0.68, 95% CI, 0.50-0.93) and progesterone receptor status of the tumor. INTERPRETATION: Our findings support the hypothesis that HEP use protects from invasive breast cancer in postmenopausal women. Among conceivable modes of action, those independent of estrogen receptor-mediated pathways seem to be involved (i.e., cytotoxicity, apoptosis).

Association of a common AKAP9 variant with breast cancer risk: a collaborative analysis.

Data from several studies have suggested that polymorphisms in A-kinase anchoring proteins (AKAPs), which are key components of signal transduction, contribute to carcinogenesis. To evaluate the impact of AKAP variants on breast cancer risk, we genotyped six nonsynonymous single-nucleotide polymorphisms that were predicted to be deleterious and found two (M463I, 1389G>T and N2792S, 8375A>G) to be associated with an allele dose-dependent increase in risk of familial breast cancer in a German population. We extended the analysis of AKAP9 M463I, which is in strong linkage disequilibrium with AKAP9 N2792S, to 9523 breast cancer patients and 13770 healthy control subjects from seven independent European and Australian breast cancer studies. All statistical tests were two-sided. The collaborative analysis confirmed the association of M463I with increased breast cancer risk. Among all breast cancer patients, the combined adjusted odds ratio (OR) of breast cancer for individuals homozygous for the rare allele TT (frequency = 0.19) compared with GG homozygotes was 1.17 (95% confidence interval [CI] = 1.08 to 1.27, P = .0003), and the OR for TT homozygotes plus GT heterozygotes compared with GG homozygotes was 1.10 (95% CI = 1.04 to 1.17, P = .001). Among the combined subset of 2795 familial breast cancer patients, the respective ORs were 1.27 (95% CI = 1.12 to 1.45, P = .0003) and 1.16 (95% CI = 1.06 to 1.27, P = .001).

Manganese superoxide dismutase Ala-9Val polymorphism, environmental modifiers, and risk of breast cancer in a German population.

OBJECTIVE: A functional polymorphism at codon 16 (Alanine-to-Valine) of manganese superoxide dismutase (MnSOD) has been hypothesized to increase the risk of breast cancer and to modify the effects of oxidative stress. However, study findings have been inconsistent and sample sizes often small. METHODS: We used a large population-based age-matched case-control study in German Caucasian women up to age 50 to assess breast cancer risk associated with this polymorphism and to investigate interaction with other known risk factors related to oxidative stress, including alcohol intake, cigarette smoking, and diet. Data on a total of 614 cases and 1,080 controls were evaluated using multivariate conditional logistic models. RESULTS: No main effect between genotype and breast cancer was observed. However, risk was significantly increased for Ala carriers who consumed > or =19 g of alcohol per day, compared to women homozygous for the Val allele who did not drink (OR 2.1, 95% CI 1.1-3.9; p = 0.13 for interaction). No significant effect modification was observed for smoking or diet. CONCLUSIONS: The MnSOD Ala-9Val polymorphism may contribute to an increase in breast cancer risk in the context of high alcohol consumption, however the polymorphism is not an overall risk factor for breast cancer in this primarily premenopausal population.

Evaluation of a short retrospective questionnaire for physical activity in women.

Physical activity (PA) is discussed as a preventive factor for many chronic diseases. Thus, in epidemiological studies it often is an important covariate. Due to frequently long latency periods, long-term PA in the past is of greater interest than current PA. However, there is a lack of retrospective questionnaires that are validated for long-term PA, including occupational, household, and leisure activities. We therefore evaluated a short questionnaire for the comprehensive assessment of usual PA in distant age periods, administered with cognitive interviewing techniques. From an ongoing study on postmenopausal breast cancer 110 cases and 101 controls, age 50-74 years, were randomly selected. Our questionnaire was administered in a telephone interview more than two months after the main study interview, which included a detailed questionnaire on PA performed in the age periods 30-49 years and 50+ years. Total PA scores were derived from both interviews as MET-hours per week. Degree of agreement was assessed using Bland-Altman analyses. Further, potential sources of systematic and random error were investigated. The mean difference between both questionnaires was 3 MET hours/week, and 53.6% of absolute differences were below 35 MET hours/week, i.e. showing good agreement. Further 28.9% of differences could be considered acceptable agreement. Measurement errors seem to be non-differential with respect to cancer status. The median interviewing time was 10 min. Overall, this short questionnaire appears to be a useful and valid tool to distinguish between high and low levels of women's physical activity in the distant past.