Environmental and Genetic Risk Factors For Breast Cancer: The Sister Study

National Institute Of Environmental Health Sciences

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Abstract

We are following 50,844 US and Puerto Rican women who were between the ages of 35 and 74 and had a sister with breast cancer but did not have breast cancer themselves when they joined the study between 2003 and 2009. At enrollment, data on potential risk factors and current health status were collected using computer assisted telephone interviews and mailed questionnaires. Blood, urine, and environmental samples were collected in a home visit and banked for future use in nested studies of women who develop breast cancer (or other diseases) and a sample of those who don't. The cohort is tracked annually for changes in vital status and major health outcomes. Detailed follow-up questionnaires on health outcomes, environmental and lifestyle exposures, and special topics are completed every 2-3 years. Medical records and tumor tissue (for breast cancer cases) are retrieved for those who develop cancer or other conditions of interest. The first Sister Study follow-up survey was completed in June 2012; responses were obtained from 48,090 women for a response rate of 95%. The second (January 2012 to July 2014) and third (September 2014 to August 2016) detailed follow-up surveys was completed with better than 92% response. A new follow-up effort is scheduled to begin in late fall 2017. In 2014-2015 we repeated the collection of biological and environmental samples from women diagnosed with breast cancer since enrollment and a random sample of the cohort. Of approximately 3,800 participants invited, samples were collected from 2,436 (63%) including 1,229 women who had been diagnosed with breast cancer. Repeat samples will allow us to explore changes in biomarkers and exposures over time and in relation to breast cancer diagnosis and treatment. In summer 2017 we began contacting participants to obtain comprehensive updates on family history of cancers relevant to breast cancer risk prediction. More than 2,500 women have reported a diagnosis of breast cancer or DCIS/LCIS. As expected, women in the cohort have, on average, more than twice the breast cancer risk as other US women. The ratio of observed to expected cases is greatest for women who also have a mother with breast cancer and for those whose sisters were younger at diagnosis. Breast cancer and ovarian cancer cases through 2014 and a random sample of the cohort have been genotyped as part of the multi-study Oncoarray project. We also generated data on 450,000 CpGs for the same 2000 breast cancer cases and 2000 noncases to evaluate methylation patterns in relation to breast cancer and in relation to exposures of interest. Sister Study data have been included in several collaborative analyses (pooling projects) from the oncoarray project whose findings on potentially novel loci in ovarian cancer, estrogen receptor negative breast cancer, and overall breast cancer have been accepted for publication. DNA have also been extracted for more recently diagnosed cancer cases (breast, ovarian, and other sites). The Sister Study also participates in the NCI-sponsored Cohort Consortium and has contributed to studies of head and neck, gallbladder, thyroid, and ovarian cancers, allowing us to contribute to research on conditions we are not able to address on our own due to sample size constraints. We are leading a new Consortium project premenopausal breast cancer The Premenopausal Breast Cancer Collaboration- with primary collaborators Hazel Nichols (University of North Carolina) and Anthony Swerdlow and Minouk Schoemaker from the Institute for Cancer Research in the UK. To date more than 20 cohorts have joined this effort. A paper describing this consortium has been published and manuscripts on motivating hypotheses, including the short-term rise in breast cancer risk following a pregnancy are being drafted. Our collaboration with researchers from the Division of Cancer Prevention and Control at the Centers for Disease Control and Prevention (CDC) to study quality of life in breast cancer survivors continues. A survey of approximately 20,000 Sister Study participants in 2012 focused on the impact of having a sister with breast cancer. A second survey, completed in May 2013, involved women diagnosed with breast cancer and included topics that are of interest to younger women such as body image, work-life balance, and fertility as well as questions related to breast cancer care and quality of life. In view of increasing rates of contralateral prophylactic mastectomy (CPM), we evaluated satisfaction with surgical decisions among breast cancer survivors. Although women reported satisfaction with their mastectomy decision, including those with CPM, body image scores were significantly worse among women who underwent CPM, especially without reconstruction, than among those who had breast conserving surgeries. We have also reported on lifestyle behavior changes among survivors. A paper currently in review addresses a question that motivated our CDC collaboration, namely communication between mothers and daughters about breast cancer risk. Three extramural collaborators have received grant funding for work building on the Sister Study. Joel Kaufman, University of Washington, is leading research on air pollution and cardiovascular disease that includes data from our cohort. Honglei Chen, former NIEHS investigator now at Michigan State University, is investigating air pollution and loss of sense of smell. Parisa Tehranifar and Mary Beth Terry from Columbia University are collecting mammograms from Sister Study participants to evaluate change in breast density in improved risk prediction models. This will enable future work on environmental contributors to breast density, a marker of increased breast cancer risk. Recent findings from the Sister Study concern early life and more recent environmental and lifestyle exposures. For example, we reported that regular physical activity in early life is associated with reduced breast cancer risk even after considering adult physical activity. Childhood residence on or near heavily travelled roads was associated with a small increase in breast cancer risk as was childhood exposure to environmental tobacco smoke. We also reported that regular use of wood stoves or fireplaces at the enrollment address of participants was associated with increased breast risk. Several novel measures of poor sleep such as not getting as much sleep as you need and sleeping in a lighted room were also associated with increased breast cancer risk. In work with collaborators Weinberg, Shi, and OBrien, we reported that previous GWAS hits associated with breast cancer at all ages were associated with young onset disease and reported several novel associations. We also found that higher levels of serum vitamin D were associated with decreased risk for breast cancer within five years and reported several single nucleotide polymorphisms in vitamin-D genes that may modify vitamin D-breast cancer associations. In other work, we reported that urinary levels of a prostaglandin E2 metabolite and estrogen were independently associated with breast cancer risk, suggesting that the increased breast cancer risk associated with this prostaglandin metabolite might not be fully explained by the estrogen-cancer association alone, but may also reflect additional effects related to inflammation. We also reported a possible inverse association between oxidative stress and premenopausal breast cancer risk and found that oxidative stress was lower in women with higher consumption of fruits and vegetables. Breast cancer and diabetes share common lifestyle risk factors, and overweight and obesity are associated with postmenopausal breast cancer risk. Using Sister Study data, we found that multiple episodes of gestational diabetes were associated with increased breast cancer risk, suggesting that