Candyce H. Kroenke

Night Work and Risk of Breast Cancer

Background: Melatonin shows potential oncostatic activity and is acutely suppressed by light exposure. Some evidence suggests an association between night work and breast cancer risk, possibly through the melatonin pathway. Methods: In a cohort of premenopausal nurses, we prospectively studied the relation between rotating night shift work and breast cancer risk. Total number of months during which the nurses worked rotating night shifts was first assessed at baseline in 1989 and periodically updated thereafter. We used Cox proportional hazards models to calculate relative risks (RRs) and 95% confidence intervals (CIs). Results: Among 115,022 women without cancer at baseline, 1,352 developed invasive breast cancer during 12 years of follow up. Women who reported more than 20 years of rotating night shift work experienced an elevated relative risk of breast cancer compared with women who did not report any rotating night shift work (multivariate RR = 1.79; 95% CI = 1.06–3.01). There was no increase in risk associated with fewer years of rotating night work. Conclusion: Our results suggest a modestly elevated risk of breast cancer after longer periods of rotating night work. Additional studies are warranted to rule out small sample size or uncontrolled sources for confounding as alternative explanations.

Analyses and comparisons of telomerase activity and telomere length in human T and B cells: Insights for epidemiology of telomere maintenance

Telomeres are the DNA-protein complexes that protect the ends of eukaryotic chromosomes. The cellular enzyme telomerase counteracts telomere shortening by adding telomeric DNA. A growing body of literature links shorter telomere length and lower telomerase activity with various age-related diseases and earlier mortality. Thus, leukocyte telomere length (LTL) and telomerase activity are emerging both as biomarkers and contributing factors for age-related diseases. However, no clinical study has directly examined telomerase activity and telomere length in different lymphocyte subtypes isolated from the same donors, which could offer insight into the summary measure of leukocyte telomere maintenance. We report the first quantitative data in humans examining both levels of telomerase activity and telomere length in four lymphocyte subpopulations from the same donors-CD4+, CD8+CD28+ and CD8+CD28- T cells and B cells, as well as total PBMCs-in a cohort of healthy women. We found that B cells had the highest telomerase activity and longest telomere length; CD4+ T cells had slightly higher telomerase activity than CD8+CD28+ T cells, and similar telomere length. Consistent with earlier reports that CD8+CD28- T cells are replicatively senescent cells, they had the lowest telomerase activity and shortest telomere length. In addition, a higher percentage of CD8+CD28- T cells correlated with shorter total PBMC TL (r=-0.26, p=0.05). Interestingly, telomerase activities of CD4+ and CD8+CD28+ T cells from the same individual were strongly correlated (r=0.55, r<0.001), indicating possible common mechanisms for telomerase activity regulation in these two cell subtypes. These data will facilitate the understanding of leukocyte aging and its relationship to human health.

PREDICT: A Simple Risk Score for Clinical Severity and Long-Term Prognosis After Hospitalization for Acute Myocardial Infarction or Unstable Angina The Minnesota Heart Survey

BACKGROUND We evaluated short- and long-term mortality risks in 30- to 74-year-old patients hospitalized for acute myocardial infarction or unstable angina and developed a new score called PREDICT. METHODS AND RESULTS PREDICT was based on information routinely collected in hospital. Predictors abstracted from hospital record items pertaining to the admission day, including shock, heart failure, ECG findings, cardiovascular disease history, kidney function, and age. Comorbidity was assessed from discharge diagnoses, and mortality was determined from death certificates. For 1985 and 1990 hospitalizations, the 6-year death rate in 6134 patients with 0 to 1 score points was 4%, increasing stepwise to 89% for >/=16 points. Score validity was established by only slightly attenuated mortality prediction in 3570 admissions in 1970 and 1980. When case severity was controlled for, 6-year risk declined 32% between 1970 and 1990. When PREDICT was held constant, 24% of those treated with thrombolysis died in 6 years compared with 31% of those not treated. CONCLUSIONS The simple PREDICT risk score was a powerful prognosticator of 6-year mortality after hospitalization.

Correlates of use of different types of complementary and alternative medicine by breast cancer survivors in the nurses' health study

PurposeAmong breast cancer survivors, we identified the prevalence and correlates of use of different types of complementary and alternative medicine (CAM).Patients and methodsWe included 2,022 women diagnosed with breast cancer 1998–2003 who responded to a survey about CAM use. We performed logistic regression to determine demographic and disease factors associated with use of different CAM therapies (including relaxation/imagery, spiritual healing, yoga, energy healing, acupuncture, massage, chiropractic, high-dose vitamins, herbs, and homeopathy). We also measured quality of life (QoL) using the SF36 and optimism using LOT-R and fit linear regression models to compare mean scores among CAM users and nonusers.ResultsSixty-two percent of respondents used CAM. Younger age was the most consistent correlate of CAM use, but factors associated with CAM use varied by type of CAM. Chemotherapy was associated with use of relaxation/imagery (OR 1.3 95%CI 1.1–1.7). Radiotherapy was associated with use of high-dose vitamins (OR 1.5 95% CI 1.2–2.0). Tamoxifen or anastrozole treatment was associated with use of homeopathy (OR 0.5 95%CI 0.3–0.9). Users of most types of CAM had worse QoL scores than nonusers, but better QoL was found among users of yoga. The lowest QoL scores were associated with the use of energy healing. Optimism was higher among users of relaxation/imagery.ConclusionsFactors associated with CAM use varied according to type of CAM. Our finding of worse QoL among women using energy healing and better QoL among women using yoga suggests the need for longitudinal studies to determine the temporal relationships between these therapies and QoL.

Urinary 6-sulfatoxymelatonin levels and their correlations with lifestyle factors and steroid hormone levels

Abstract:  Exposure to light at night, as experienced by rotating night shift workers, has been related to lower circulating levels of melatonin, a hormone with recognized cancer protective properties. However, little is known about the relationship of other lifestyle factors or endogenous sex steroid hormones with melatonin levels. We examined cross‐sectional associations of age, reproductive and menopausal factors, body mass index (BMI), alcohol consumption, smoking history, night shift work, as well as several other breast cancer risk factors, and circulating sex steroid hormone levels with creatinine‐adjusted morning urinary melatonin (6‐sulfatoxymelatonin, aMT6s) levels. Participants were 459 healthy, primarily premenopausal (age range 33–50 yr) women from the Nurses’ Health Study II (NHS II). Using multiple linear regression, we computed least‐square mean hormone levels across categories of lifestyle factors. Age was inversely related to aMT6s levels, particularly before menopause (premenopausal women, ≤39 yr versus ≥49 yr; aMT6s, 20.8 ng/mg versus 11.8 ng/mg creatinine; P for trend, 0.02). In multivariate analyses, BMI was significantly and inversely associated with aMT6s levels (P for trend, <0.01). Higher pack‐years of smoking were associated with significantly lower aMT6s levels (never smoker versus 15+ pack‐years, aMT6s = 17.4 ng/mg versus 12.3 ng/mg creatinine; P for trend, 0.04). We also observed a positive association between parity and aMT6s levels (P for trend, <0.01), but no other reproductive factors nor any of the sex hormones (estradiol, progesterone, estrone, estrone sulfate, dehydroepiandrostenedione, dehydroepiandrostenedione sulfate, testosterone, and androstenedione), as measured either in the luteal or the follicular phase of the menstrual cycle, were significantly associated with aMT6s. In conclusion, higher age, BMI, and heavy smoking were significantly related to lower levels of melatonin, whereas parity was significantly associated with higher aMT6s levels. Melatonin levels may be one mechanism through which these factors influence the development of cancer, but more studies are needed to elucidate these mechanisms definitively.

Weight Change and Survival after Breast Cancer in the After Breast Cancer Pooling Project

Background: Weight change after a breast cancer diagnosis has been linked to lower survival. To further understand effects of postdiagnostic weight variation on survival, we examined the relationship by comorbid status and initial body mass index (BMI). Methods: The current analysis included 12,915 patients with breast cancer diagnosed between 1990 and 2006 with stage I–III tumors from four prospective cohorts in the United States and China. HRs and 95% confidence intervals (CI) representing the associations of five weight change categories [within <5% (reference); 5%–<10% and ≥10% loss and gain] with mortality were estimated using Cox proportional hazards models. Results: Mean weight change was 1.6 kg. About 14.7% women lost and 34.7% gained weight. Weight stability in the early years postdiagnosis was associated with the lowest overall mortality risk. Weight loss ≥10% was related to a 40% increased risk of death (HR, 1.41; 95% CI, 1.14–1.75) in the United States and over three times the risk of death (HR, 3.25; 95% CI: 2.24, 4.73) in Shanghai. This association varied by prediagnosis BMI, and in the United States, lower survival was seen for women who lost weight and had comorbid conditions. Weight gain ≥10% was associated with a nonsignificant increased risk of death. Conclusions: Prevention of excessive weight gain is a valid public health goal for breast cancer survivors. Although intentionality of weight loss could not be determined, women with comorbid conditions may be particularly at risk of weight loss and mortality. Impact: Weight control strategies for breast cancer survivors should be personalized to the individuals medical history. Cancer Epidemiol Biomarkers Prev; 21(8); 1260–71. ©2012 AACR.

Autonomic and adrenocortical reactivity and buccal cell telomere length in kindergarten children.

Objective: To examine associations between autonomic nervous system and adrenocortical reactivity to laboratory stressors and buccal cell telomere length (BTL) in children. Methods: The study sample comprised 78 children, aged 5 to 6 years, from a longitudinal cohort study of kindergarten social hierarchies, biologic responses to adversity, and child health. Buccal cell samples and reactivity measures were collected in the spring of the kindergarten year. BTL was measured by real-time polymerase chain reaction, as the telomere-to-single-copy gene ratio. Parents provided demographic information; parents and teachers reported childrens internalizing and externalizing behavior problems. Components of childrens autonomic (heart rate, respiratory sinus arrhythmia [RSA], and preejection period [PEP]) and adrenocortical (salivary cortisol) responses were monitored during standardized laboratory challenges. We examined relationships between reactivity, internalizing and externalizing behaviors, and BTL, adjusted for age, race, and sex. Results: Heart rate and cortisol reactivity were inversely related to BTL, PEP was positively related to BTL, and RSA was unrelated to BTL. Internalizing behaviors were also inversely related to BTL (standardized &bgr; = −0.33, p =.004). Split at the median of reactivity parameters, children with high sympathetic activation (decreasing PEP), and parasympathetic withdrawal (decreasing RSA) did not differ with regard to BTL. However, children with both this profile and high cortisol reactivity (n = 12) had significantly shorter BTL (0.80 versus 1.00; &khgr;2 = 7.6, p =.006), compared with other children. Conclusions: The combination of autonomic and adrenocortical reactivity was associated with shorter BTL in children. These data suggest that psychophysiological processes may influence, and that BTL may be a useful marker of, early biologic aging.DNA = deoxyribonucleic acid; BTL = buccal cell telomere length; ANS = autonomic nervous system; HPA = hypothalamic-pituitary-adrenal; HR = heart rate; SNS = sympathetic nervous system; PNS = parasympathetic nervous system; PEP = preejection period; RSA = respiratory sinus arrhythmia; PAWS = Peers and Wellness Study; BMI = body mass index; T/S = telomere repeat copy number to single-copy gene copy number; ECG = electrocardiograph; SES = socioeconomic status.

Greater endogenous estrogen exposure is associated with longer telomeres in postmenopausal women at risk for cognitive decline.

Longer duration of reproductive years of life and thus greater exposure to endogenous estrogen may be associated with a lower risk of age-related diseases in women. The present study examined the relationship between estimated endogenous estrogen exposure and telomere length (TL) and telomerase activity, two biomarkers of cellular aging, in a sample of postmenopausal women at risk for cognitive decline. Telomere length was measured using a quantitative PCR method and telomerase activity by TRAP (Telomere-Repeats Amplification Protocol) assay in peripheral blood mononuclear cells (PBMCs). Study subjects were 53 postmenopausal women (35 with natural and 18 with surgical menopause) receiving hormone therapy (HT) for at least one year or longer. Length of reproductive years of life, computed as the difference between age at menopause and age at menarche, was used as a proxy of duration of exposure to endogenous estrogen. Length of time on HT was the measure used for duration of exogenous estrogen exposure. We found that longer endogenous estrogen exposure was associated with greater TL (standardized β=0.06, Wald χ(2)=3.7, p=0.04) and with lower telomerase activity (standardized β=-0.09, Wald χ(2)=5.0, p=0.03). Length of reproductive years was also inversely associated with the combination of short TL and high telomerase (OR=0.78, 95% CI: 0.63, 0.97, p=0.02). Length of HT use was not associated with TL or telomerase activity in this study. The results suggest that the endogenous estrogens may be associated with deceleration of cellular aging. This is the first study to examine associations between endogenous estrogens, telomere length and telomerase activity.

Racial Disparities in Posttraumatic Stress After Diagnosis of Localized Breast Cancer: The BQUAL Study

BACKGROUND Little is known about the development of posttraumatic stress disorder (PTSD) over time among women diagnosed with breast cancer. This study examines changes in PTSD symptoms in the first 6 months after diagnosis and assesses racial/ethnic differences in PTSD symptomatology over time. METHODS We recruited women with newly diagnosed breast cancer, stages I to III, from three sites in the United States. Three telephone interviews were conducted: baseline at about 2 to 3 months after diagnosis, first follow-up at 4 months after diagnosis, and second follow-up at 6 months after diagnosis. We measured traumatic stress in each interview using the Impact of Events Scale; recorded sociodemographic, tumor, and treatment factors; and used generalized estimating equations and polytomous logistic regression modeling to examine the associations between variables of interest and PTSD. RESULTS Of 1139 participants, 23% reported symptoms consistent with a diagnosis of PTSD at baseline, 16.5% at first follow-up, and 12.6% at the second follow-up. Persistent PTSD was observed among 12.1% participants, as defined by having PTSD at two consecutive interviews. Among participants without PTSD at baseline, 6.6% developed PTSD at the first follow-up interview. Younger age at diagnosis, being black (odds ratio [OR] = 1.48 vs white, 95% confidence interval [CI] =1.04 to 2.10), and being Asian (OR = 1.69 vs white, 95% CI = 1.10 to 2.59) were associated with PTSD. CONCLUSIONS Nearly one-quarter of women newly diagnosed with breast cancer reported symptoms consistent with PTSD shortly after diagnosis, with increased risk among black and Asian women. Early identification of PTSD may present an opportunity to provide interventions to manage symptoms.

High- and Low-Fat Dairy Intake, Recurrence, and Mortality After Breast Cancer Diagnosis

BACKGROUND Dietary fat in dairy is a source of estrogenic hormones and may be related to worse breast cancer survival. We evaluated associations between high- and low-fat dairy intake, recurrence, and mortality after breast cancer diagnosis. METHODS We included 1893 women from the Life After Cancer Epidemiology study diagnosed with early-stage invasive breast cancer from 1997 to 2000, who completed the Fred Hutchinson Cancer Research Center Food Frequency Questionnaire after diagnosis. A total of 349 women had a recurrence and 372 died during a median follow-up of 11.8 years, with 189 deaths from breast cancer. We used delayed entry Cox proportional hazards regression to evaluate associations between categories of the cumulative average of dairy fat at baseline and at follow-up 5 to 6 years later and subsequent outcomes. Tests of statistical significance were two-sided. RESULTS In multivariable-adjusted analyses, overall dairy intake was unrelated to breast cancer-specific outcomes, although it was positively related to overall mortality. Low-fat dairy intake was unrelated to recurrence or survival. However, high-fat dairy intake was positively associated with outcomes. Compared with the reference (0 to <0.5 servings/day), those consuming larger amounts of high-fat dairy had higher breast cancer mortality (0.5 to <1.0 servings/day: hazard ratio [HR] = 1.20, 95% confidence interval [CI] = 0.82 to 1.77; and ≥1.0 servings/day: HR = 1.49, 95% CI = 1.00 to 2.24, P trend = .05), higher all-cause mortality (P trend < .001), and higher non-breast cancer mortality (P trend = .007); the relationship with breast cancer recurrence was positive but not statistically significant. The higher risk appeared consistent across different types of high-fat dairy products. CONCLUSIONS Intake of high-fat dairy, but not low-fat dairy, was related to a higher risk of mortality after breast cancer diagnosis.