Irene Andrulis - US grants

DESCRIPTION (provided by applicant): The identification of risk factors for breast cancer has tremendous clinical importance. One of the strongest risk factors is a family history of breast cancer. Most studies have focused on genetics and lifestyle factors in adult women. However, there is growing evidence that young girls may be particularly sensitive to exposures that either initiate or protect against breast cancer. These include ionizing radiation exposure, childhood and adolescent growth, body composition, and physical activity. It remains unknown whether effects of early life and childhood exposures are greater in individuals with a family history of breast cancer (BCFH). Studies on individuals with a family history of cancer have been of great value in the identification of genetic alterations that play a role in cancer, not only in the familial setting, but more generally in sporadic cancer as well;similarly, familial clustering is also likely associated with clustering of risk factors influenced by both genes and environment, as well as clustering of health-related behaviors, and may therefore be a powerful setting in which to identify factors important in both familial and sporadic breast cancer. We propose to establish a cohort of 450 girls aged 6-13 years who are the offspring of women enrolled in the Breast Cancer Family Registry (BCFR), and 450 girls from families without breast cancer. The youth cohort, named LEGACY (Lessons in Epidemiology and Genetics of Adult Cancer from Youth), will be followed prospectively, with repeated data and biospecimen collection at 6-month intervals. The objectives are to 1) study prospectively the association of pubertal development (onset and tempo of breast development), age at menarche, and breast tissue characteristics over time with childhood measures of body size, growth, lifestyle factors (physical activity, diet, vitamin D), built environment, and selected biomarkers of exposure, and to assess whether these associations are modified by BCFH;2) assess the association of childhood exposures with genomic DNA methylation and changes in genomic DNA methylation, and assess whether genomic DNA methylation levels are modified by BCFH;and 3) evaluate longitudinally how psychosocial adjustment and behaviors of girls from breast cancer families differ from those of girls from families without breast cancer. Unlike any other youth cohort, the LEGACY cohort is unique in that it will be enriched with girls at increased breast cancer risk, given their family history, and covering a wide spectrum of risk. It is currently not known how young girls at increased risk can lower their risk, how they adapt to their familial risk, and how such familial risk impacts their behaviors throughout development. Understanding these relations is necessary for the successful translation of early-life exposure information into health-promoting and breast cancer-preventing behaviors during childhood and adolescence. LEGACY will provide a rich resource for molecular and biomarker studies in young girls that will inform our understanding of when breast cancer susceptibility begins, whether it is influenced by modifiable determinants, and how it impacts psychosocial adjustment and behaviors. PUBLIC HEALTH RELEVANCE: Focusing on childhood and adolescence is particularly important for developing breast cancer prevention programs as we know that the interplay of modifiable factors such as nutrition, body size, and physical activity is apparent early in life, and that early life patterns have long lasting influence on adult patterns. Knowledge gained from the proposed study will not only be relevant for breast cancer prevention strategies for individuals with a family history of breast cancer families, but also for individuals without a family history. A thorough understanding of perceptions of risk and risk reduction interventions among children and adolescents is critical for the implementation of effective prevention programs that start early in life.

The Breast Cancer Family Registry (BCFR) Cohort is a large and well-characterized international cohort of multi-generational families that has been created for interdisciplinary collaborative research. Established in 1995 at six sites across the US, Canada and Australia, we recruited and followed 40,029 individuals (33,037 women and 6,992 men) from 15,056 families across the full spectrum of familial risk and/or genetic predisposition. Through recruitment of multiple family members across generations, the BCFR Cohort is unique from other cohorts of unrelated individuals, and has a wide range of absolute breast cancer risk, which enables investigation of factors that modify breast cancer susceptibility and outcomes after diagnosis across the spectrum of risk. The BCFR Cohort is also unique for its comprehensive biospecimen resources, including cell lines for many participants complementing standard stored DNA, plasma and tissue samples. We have followed individuals who were unaffected (n=27,671) and affected (n=12,358) with breast cancer at baseline for up to 25 years (average length of follow-up = 15.2 and 16.1 years, respectively) and prospectively ascertained 879 incident breast cancers and 863 second breast events, respectively. The overarching goal of this application is to enrich the BCFR Cohort by building upon and enhancing the core infrastructure using long-term prospective data collection and measurement of key markers to address novel hypotheses in cancer etiology, survival and survivorship. We aim to answer questions on the role of life course accumulation of risk, critical windows of exposure, and the factors underling the increase in breast cancer incidence in young women. We propose to continue a systematic and coordinated approach across all six sites over the next five years to: 1) enhance the BCFR Cohort by enrolling young women aged 18?39 years who are relatives of enrolled family members and collecting detailed data on menstrual cycles, hormone exposure and physical activity using mobile app technology; 2) retain and follow currently enrolled members of the BCFR Cohort through another wave of follow-up questionnaires, and linkages to cancer and death registries; 3) create a big data repository of multiple ?omics? datasets (e.g., whole genome, serial digital mammograms); and 4) expand the biospecimen resources, including collection of tissue and repeat blood samples. These activities will include collection and updating of detailed risk factor, biospecimen, clinical, and outcome data through novel approaches and technology (e.g., mobile app technologies, optical spectroscopy) and big data approaches. With the addition of these components, we will continue to provide the research community an important and unique family cohort to address cutting-edge research questions of clinical importance on cancer susceptibility, survival and survivorship (e.g., risk assessment, identification of early detection markers, knowledge and perception of risk). Through this resource, we envision a large platform for translational research that will provide rigorous evidence on complex questions related to primary, secondary and tertiary prevention efforts.

The Breast Cancer Family Registry (BCFR) Cohort is a large and well-characterized international cohort of multi-generational families that has been created for interdisciplinary collaborative research. Established in 1995 at six sites across the US, Canada and Australia, we recruited and followed 40,029 individuals (33,037 women and 6,992 men) from 15,056 families across the full spectrum of familial risk and/or genetic predisposition. Through recruitment of multiple family members across generations, the BCFR Cohort is unique from other cohorts of unrelated individuals, and has a wide range of absolute breast cancer risk, which enables investigation of factors that modify breast cancer susceptibility and outcomes after diagnosis across the spectrum of risk. The BCFR Cohort is also unique for its comprehensive biospecimen resources, including cell lines for many participants complementing standard stored DNA, plasma and tissue samples. We have followed individuals who were unaffected (n=27,671) and affected (n=12,358) with breast cancer at baseline for up to 25 years (average length of follow-up = 15.2 and 16.1 years, respectively) and prospectively ascertained 879 incident breast cancers and 863 second breast events, respectively. The overarching goal of this application is to enrich the BCFR Cohort by building upon and enhancing the core infrastructure using long-term prospective data collection and measurement of key markers to address novel hypotheses in cancer etiology, survival and survivorship. We aim to answer questions on the role of life course accumulation of risk, critical windows of exposure, and the factors underling the increase in breast cancer incidence in young women. We propose to continue a systematic and coordinated approach across all six sites over the next five years to: 1) enhance the BCFR Cohort by enrolling young women aged 18?39 years who are relatives of enrolled family members and collecting detailed data on menstrual cycles, hormone exposure and physical activity using mobile app technology; 2) retain and follow currently enrolled members of the BCFR Cohort through another wave of follow-up questionnaires, and linkages to cancer and death registries; 3) create a big data repository of multiple ?omics? datasets (e.g., whole genome, serial digital mammograms); and 4) expand the biospecimen resources, including collection of tissue and repeat blood samples. These activities will include collection and updating of detailed risk factor, biospecimen, clinical, and outcome data through novel approaches and technology (e.g., mobile app technologies, optical spectroscopy) and big data approaches. With the addition of these components, we will continue to provide the research community an important and unique family cohort to address cutting-edge research questions of clinical importance on cancer susceptibility, survival and survivorship (e.g., risk assessment, identification of early detection markers, knowledge and perception of risk). Through this resource, we envision a large platform for translational research that will provide rigorous evidence on complex questions related to primary, secondary and tertiary prevention efforts.