Anouk Pijpe

Exposure to diagnostic radiation and risk of breast cancer among carriers of BRCA1/2 mutations: retrospective cohort study (GENE-RAD-RISK)

Objective To estimate the risk of breast cancer associated with diagnostic radiation in carriers of BRCA1/2 mutations. Design Retrospective cohort study (GENE-RAD-RISK). Setting Three nationwide studies (GENEPSO, EMBRACE, HEBON) in France, United Kingdom, and the Netherlands, Participants 1993 female carriers of BRCA1/2 mutations recruited in 2006-09. Main outcome measure Risk of breast cancer estimated with a weighted Cox proportional hazards model with a time dependent individually estimated cumulative breast dose, based on nominal estimates of organ dose and frequency of self reported diagnostic procedures. To correct for potential survival bias, the analysis excluded carriers who were diagnosed more than five years before completion of the study questionnaire. Results In carriers of BRCA1/2 mutations any exposure to diagnostic radiation before the age of 30 was associated with an increased risk of breast cancer (hazard ratio 1.90, 95% confidence interval 1.20 to 3.00), with a dose-response pattern. The risks by quarter of estimated cumulative dose <0.0020 Gy, ≥0.0020-0.0065 Gy, ≥0.0066-0.0173 Gy, and ≥0.0174 Gy were 1.63 (0.96 to 2.77), 1.78 (0.88 to 3.58), 1.75 (0.72 to 4.25), and 3.84 (1.67 to 8.79), respectively. Analyses on the different types of diagnostic procedures showed a pattern of increasing risk with increasing number of radiographs before age 20 and before age 30 compared with no exposure. A history of mammography before age 30 was also associated with an increased risk of breast cancer (hazard ratio 1.43, 0.85 to 2.40). Sensitivity analysis showed that this finding was not caused by confounding by indication of family history. Conclusion In this large European study among carriers of BRCA1/2 mutations, exposure to diagnostic radiation before age 30 was associated with an increased risk of breast cancer at dose levels considerably lower than those at which increases have been found in other cohorts exposed to radiation. The results of this study support the use of non-ionising radiation imaging techniques (such as magnetic resonance imaging) as the main tool for surveillance in young women with BRCA1/2 mutations.

Higher usual dietary intake of phytoestrogens is associated with lower aortic stiffness in postmenopausal women

Objective—Phytoestrogens have been postulated to protect against cardiovascular diseases, but few studies have focused on the effect of Western dietary phytoestrogen intake. Methods and Results—Four hundred three women with natural menopause either between 1987 and 1989 or between 1969 and 1979 were selected from the baseline data of the PROSPECT study (n=17 395). Isoflavone and lignan intake was calculated from a food-frequency questionnaire. Aortic stiffness was noninvasively assessed by pulse-wave velocity measurement of the aorta. Linear regression analysis was used. After adjustment for age, body mass index, smoking, physical activity, mean arterial pressure, follow-up time, energy intake, dietary fiber intake, glucose, and high density lipoprotein cholesterol, increasing dietary isoflavone intake was associated with decreased aortic stiffness: −0.51 m/s (95% CI −1.00 to −0.03, fourth versus first quartile, P for trend=0.07). Increasing dietary intake of lignans was also associated with decreased aortic pulse-wave velocity: −0.42 m/s (95% CI −0.93 to 0.11, fourth versus first quartile, P for trend=0.06). Results were most pronounced in older women: for isoflavones, −0.94 m/s (95% CI −1.65 to −0.22, P for trend=0.02), and for lignans, −0.80 m/s (95% CI −1.85 to −0.05), fourth versus first quartile. Conclusions—The results of our study support the view that phytoestrogens have a protective effect on the risk of atherosclerosis and arterial degeneration through an effect on arterial walls, especially among older women.

Physical activity and survival of postmenopausal, hormone receptor-positive breast cancer patients: results of the Tamoxifen Exemestane Adjuvant Multicenter Lifestyle study.

Physical activity has been related to improved breast cancer outcomes. Especially in the older breast cancer population, physical activity may be important because old age is associated with comorbidities and decreased physical function. The purpose of this study was to investigate the relation between physical activity and overall survival, breast cancer–specific survival, and recurrence in several age groups of postmenopausal breast cancer patients.

Do BRCA1/2 mutation carriers have an earlier onset of natural menopause?

Objective:It has been hypothesized that BRCA1/2 mutation carriers have an earlier age at natural menopause (ANM), although to date findings are inconclusive. This study assessed the influence of BRCA mutation status on ANM, and aimed to explore the reasons of inconsistency in the literature. Methods:Cross-sectional assessment from an ongoing nationwide cohort study among members of BRCA1/2 mutated families. Information was obtained by a standardized questionnaire. Kaplan-Meier curves were constructed, and Cox regression was used to assess the association between BRCA1/2 mutation status and ANM. Adjustments were made for birth cohort, family, smoking, use of hormonal contraceptives, and parity. Results:A total of 1,208 BRCA1/2 mutation carriers and 2,211 proven noncarriers were included. Overall, no association was found between BRCA1/2 mutation status and ANM (adjusted hazard ratio [HR] = 1.06 [95% CI, 0.87-1.30]). We examined if the null finding was due to informative censoring by uptake of risk-reducing salpingo-oophorectomy. Indeed, within the oldest birth cohort, in which the percentage of surgical menopause events was lowest and comparable between carriers and noncarriers, the HR for earlier natural menopause in carriers was 1.45 (95% CI, 1.09-1.94). The second oldest birth cohort, however, demonstrated a decreased HR (0.67 [95% CI, 0.46-0.98]), and thus no trend over birth cohorts was found. Conclusions:Various types of selection bias hamper the comparison of ANM between BRCA1/2 mutation carriers and noncarriers, genetically tested in the clinic.

Physical activity and the risk of breast cancer in BRCA1/2 mutation carriers in the Netherlands.

CTRC-AACR San Antonio Breast Cancer Symposium: 2008 Abstracts Abstract #505 Background : Physical activity reduces the risk of breast cancer in the general population by 20-40%. Suggested biological mechanisms include a reduction of adipose tissue and decreased lifetime exposure to estrogens. This is one of the first studies that investigates the association between physical activity and breast cancer risk in BRCA1/2 mutation carriers (carriers). Patients and methods : We analyzed data from a nationwide retrospective cohort study (GEO-HEBON), including 1026 carriers, of which 465 had a history of breast cancer. We examined the association between breast cancer risk and average (METhr/wk) sports, walking/cycling, occupational, household, and total physical activity, lifetime and for age-periods below and above age 20, separately. All analyses were stratified for birth cohort and gene, clustered on family, and adjusted for confounders and other physical activity variables (when investigating separate components). Preliminary results : For adulthood sports activity we found a risk reduction for active carriers (low: Hazard Ratio (HR) = 0.72; 95% CI = 0.54-0.96; medium: HR = 0.64; 95% CI = 0.46-0.90; high: HR = 0.71; 95% CI = 0.48-1.06) when compared to carriers who had never engaged in sports. No risk change was found for sports activity before age 20. For lifetime (mainly adulthood) household activity we found a risk reduction of 0.74 (95% CI = 0.57-0.96) for the second versus the lowest quartile but for higher quartiles HRs were not significantly decreased, and a similar pattern for occupational activity (0.53 (0.35-0.82)). We found neither an effect for walking/cycling activity nor for total physical activity. Discussion : Our physical activity information was relatively extensive, and we used proxy-questionnaires to examine survival bias. Limitations include the retrospective character of the cohort and potential misclassification bias. In conclusion, these preliminary results suggest that physical activity may reduce the risk of breast cancer in carriers. The inverse associations were clearest for physical activity during adulthood. Time-dependent, weighted (for testing bias), and stratified (for example by menopausal status and Body Mass Index) analyses will be conducted. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 505.

Cohort profile: LIFEWORK, a prospective cohort study on occupational and environmental risk factors and health in the Netherlands.

Purpose LIFEWORK is a large federated prospective cohort established in the Netherlands to quantify the health effects of occupational and environmental exposures. This cohort is also the Dutch contribution to the international Cohort Study of Mobile Phone Use and Health (COSMOS). In this paper, we describe the study design, ongoing data collection, baseline characteristics of participants and the repeatability of key questionnaire items. Participants 88 466 participants were enrolled in three cohort studies in 2011–2012. Exposure information was collected by a harmonised core questionnaire, or modelled based on occupational and residential histories; domains include air pollution (eg, nitrogen dioxide (NO2), particulate matter with diameter ≤2.5 µm (PM2.5)), noise, electromagnetic fields (EMF), mobile phone use, shift work and occupational chemical exposures. Chronic and subacute health outcomes are assessed by self-report and through linkage with health registries. Findings to date Participants had a median age of 51 years at baseline (range 19–87), and the majority are female (90%), with nurses being over-represented. Median exposure levels of NO2, PM2.5, EMF from base stations and noise at the participants’ home addresses at baseline were 22.9 µg/m3, 16.6 µg/m3, 0.003 mWm2 and 53.1 dB, respectively. Twenty-two per cent of participants reported to have started using a mobile phone more than 10 years prior to baseline. Repeatability for self-reported exposures was moderate to high (weighted kappa range: 0.69–1) for a subset of participants (n=237) who completed the questionnaire twice. Future plans We are actively and passively observing participants; we plan to administer a follow-up questionnaire every 4–5 years—the first follow-up will be completed in 2018—and linkage to cause-of-death and cancer registries occurs on a (bi)annual basis. This prospective cohort offers a unique, large and rich resource for research on contemporary occupational and environmental health risks and will contribute to the large international COSMOS study on mobile phone use and health.

P1-46 Diagnostic radiation exposure and breast cancer risk in BRCA1/2 mutation carriers in the gene-rad-risk study

Introduction BRCA1/2 mutation carriers might be more sensitive to ionising radiation due to impaired DNA repair mechanisms. Methods A retrospective European collaborative cohort study (GENE-RAD-RISK) of 1993 female BRCA1/2 mutation carriers was performed using self-reported exposure to diagnostic radiation. Risk of breast cancer was estimated using a weighted Cox proportional hazards model with cumulative radiation exposure from diagnostic procedures as a time-dependent variable lagged by 5 years. Results are not presented in the abstract due to a publication embargo.

P2-246 The Nightingale Study: a prospective cohort study on shift work and breast cancer among nurses in the Netherlands

A new prospective cohort study (the Nightingale Study) among nurses in the Netherlands was initiated in collaboration with the Institute for Risk Assessment Sciences (IRAS, Utrecht University) and the nationwide register of healthcare professionals (BIG-register of the Ministry of Health, Welfare and Sport, The Hague). Exposure to light-at-night has been suggested as a contributing cause of breast cancer (IARC classification “probable human carcinogen, 2A”). Since shift- and night-time work is prevalent and increasing in modern societies, this exposure may contribute to the continuing elevation in breast cancer risk and may be of public health concern. This study will provide insight into, among others, the potential association between occupational exposures (eg, shift work, electromagnetic fields) and the risk of cancer and other diseases, and on potential biological mechanisms. The total projected study population is 50 000 women. Through the BIG-register, women with a nurse diploma and who are younger than 60 years, will be asked to complete a (web-based or paper) questionnaire, sign an informed consent, and donate toenails for DNA analyses (eg, clock genes). In the spring of 2011, a pilot study (N=800) will be conducted of which the results will be presented. Specific attention will be directed to potential shift-work related selection.

Early radiation exposures and BRCA1-associated breast cancer in young women from Poland

1525 Background: Ionizing radiation is an established risk factor for breast cancer in young women. There is concern that early radiation exposure might pose a risk to women who are genetically pre...