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Vol. 09 Issue 4, Fall 2004

Sister Study: Environmental and Genetic Risk Factors for Breast Cancer
The Ribbon 

"Family history" is known to be one of the most consistently demonstrated risk factors for breast cancer. The risk associated with family history is due to both shared genes and shared environment. By taking advantage of the fact that sisters of women who have had breast cancer are more likely to have genetic patterns and exposures that enhance their risk for breast cancer, "The Sister Study: Environmental and Genetic Risk Factors for Breast Cancer" will make enormous strides toward answering questions about the contributions of environmental exposures and genes to breast cancer risk. Its purpose is "to study the independent and joint effects of genetic susceptibility and environmental, biological, and lifestyle factors on risk for breast cancer and other diseases in a high risk, motivated cohort."

Why sisters?
50,000 sisters of women who have had breast cancer will be enrolled. Studying sisters has many key advantages for studying breast cancer risk, starting with the fact that sisters of women with breast cancer have about twice the risk of developing breast cancer themselves. This means that the study will have more statistical power than most, as twice as many participants on average will develop breast cancer during the course of the study, as would a similar sized cohort from the general population. It is expected that response rates and retention rates will be high, as the sisters of women with breast cancer are often especially motivated to join such a study, provide the information, and stay with it through the years. By focusing on this genetically susceptible group, a better understanding of the contributions of genetics and environment may be possible.

Not only will more of the participants develop breast cancer than in a group from the general population – increasing the statistical power for studying small effects or interactions – but more of the women in this study will have any genes or exposures that are relevant to breast cancer risk, since they will have some of these genes and exposures in common with their sister who developed breast cancer. To the extent that the genes they share are relevant to breast cancer, or the exposures they share contribute to the disease, the Sister Study stands a better chance of being able to link these genes and exposures to breast cancer, because of this higher proportion of participants who will have them.

Thinking broadly, over time
The design of this study is prospective, meaning that the exposures are measured in the present, and outcome is measured prospectively, over time. The study enrollees have not had breast cancer. For those that do develop the disease, information will have been collected before that diagnosis. Current hypotheses about risk factors and gene-environment interactions for breast cancer risk will be tested, but this study design also opens the way to addressing new hypotheses as they emerge. It even leaves open the possibility of developing and validating new methods for measuring exposures – a notorious challenge in environmental health studies.

Dr. Dale P. Sandler, of the National Institute of Environmental Health Sciences (NIEHS) of the National Institutes of Health (NIH), Department of Health and Human Services (DHHS), and principal investigator of the study says that "by collecting data on a wide range of potential risk factors, including novel exposures and exposures at potentially vulnerable time periods, along with environmental and biological samples, we hope to create a framework from which to think more broadly about environmental exposures and gene environment interactions."

Wide array of possible risk factors addressed
Notwithstanding the plan to incorporate new ideas and methodologies over the lifetime of the study, there are some current hypotheses that the study team plans to test. These include - among many others - questions about the role of the following diverse factors in breast cancer risk: prolactin, insulin-like growth factor-1 (IGF-1), and vitamin D. These are all examples of factors that need to be understood in women prior to a breast cancer diagnosis, because of the altered way in which they may be present after the disease occurs.

Special effort will go in to collecting information about occupational and environmental exposures. Many cohort studies have focused on factors such as hormone use, diet, exercise, and reproductive history. The Sister Study will collect data on these topics, too, but data collection will also include extensive efforts to understand participants’ occupational and environmental exposures. This will include data on exposures such as hair dyes, as well as cosmetics that may contain hormonally active compounds. Although there is currently no evidence to link these exposures to breast cancer risk, serious assessment of these hypothesized risks is important. By recruiting a diverse cohort, including women from throughout the US and of many different races and ethnicities, the ranges of exposures that women within the study will have had is increased. This too will improve the odds of the ability to detect associations.

Considering vulnerable time periods
The Sister Study is committed to improving information about exposures at potentially vulnerable time periods, such as in utero, around the time of menarche, and early reproductive years. Although enrollment begins at age 35, the Sister Study includes research strategies to help better understand the impact of exposures during these time periods of greatest breast tissue development. The investigators recognize that information on early life may be subject to poor reporting and that they cannot collect information about the past with the same level of detail as for the present. Questions about a participant’s mother’s exposures while pregnant with the participant obviously cannot be as complex as those about exposures in the past 12 months. But, it is important to try to collect this information as well as information on the childhood of participants. This information will be collected via a take-home questionnaire, which will enable participants to consult with their mothers and siblings. Currently there are few biological measures of exposures that occurred long in the past.

Many approaches to studying breast cancer risk
On Page X of this edition of The Ribbon Rachel Shakked explores some research themes and approaches in understanding gene-environment interaction and breast cancer risk, including an overview of some of the “twin studies.” Twin studies are ideal for identifying the extent to which inheritance contributes to breast cancer risk and finding clues regarding specific genes that might enhance risk. When the exposure or lifestyle of twins differs markedly, it is also possible to study the role of environment by, in effect, controlling for genetic differences. In contrast, Dr. Sandler explains:

The Sister Study is not designed to quantify the risk of breast cancer associated with having a sister with breast cancer, but it starts with the premise that the sisters are at increased risk, based on prior reports. We are not comparing participants directly with their sisters, but rather studying risk factors within this cohort of sisters who are more susceptible. Because sisters share genes and early life exposures and experiences –and may continue to share these – they will, as a group, have a higher frequency of any genes that prove to be involved in breast cancer risk, for example by affecting hormone levels or receptors, or affecting metabolism of chemicals or drugs. They may also have a higher frequency of exposures that may prove relevant to breast cancer risk and that may have contributed to the development of breast cancer in their sisters.  

Broad input to be collected over the life of the Study
The sponsors of this study are the National Institute of Environmental Health Sciences of the National Institutes of Health, Department of Health and Human Services, the Susan G. Komen Breast Cancer Foundation, and the Y-ME Breast Cancer Foundation. The Study has a Scientific Advisory Board made up of representatives of many pertinent academic and governmental organizations, plus the American Cancer Society. The role of this Board extends through the life of the study. Members of the Board reviewed the scientific protocol for the study before it was submitted for funding and their input led to changes that improved the proposal. Over the course of the study, the Board will meet annually to review progress, identify areas in need of improvement, and help decide on best practices and priorities. As the time gets closer to having a complete data repository, the Board will help establish guidelines for using the banked data and samples and will help evaluate individual requests to use Sister Study data. Dr. Suzanne Snedeker, Associate Director of Translational Research for BCERF, sits on this Board. There are also three Community Liaisons representing diverse regions of the country. Says Dr. Sandler, “the collective experience of the board – from a wide range of disciplines – will provide important insights that will help us monitor the study, stay abreast of the latest hypotheses and techniques, and prioritize our efforts.” Dr. Snedeker says of her involvement,

I have been very impressed with how forward-thinking the study scientists are in designing questionnaires which will help address a wide array of environmental factors that may influence breast cancer risk. And how well they will be prepared to answer emerging questions by collecting and storing a variety of biological samples. This flexibility to both ask the sisters questions to help evaluate current areas of concern, and being poised to answer questions scientists may have in the future, are two of the greatest strengths of the study.  Being on the advisory board is both an honor and exciting.”

BCERF fully intends to provide readers with updates and findings on this promising study as it progresses.

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Last Update 10.27.04