T H E   N I H   C A T A L Y S T     J A N U A R Y  –  F E B R U A R Y  2008



by Eddy Ball, NIEHS
Sister Researchers: Clarice Weinberg (left), co-investigator, and Dale Sandler, principal investigator, in studies to plumb the underpinnings of breast cancer

For the past three years, scientists in the NIEHS Epidemiology Branch have championed a nationwide campaign to recruit sisters of women with breast cancer for what they believe is the largest effort of its kind ever attempted—a study involving a cohort of more than 50,000 sisters who will be followed prospectively for 10 years or more.

What the study promises other investigators at NIH and elsewhere is a mother lode for data mining in future explorations of breast cancer and other diseases.

Launched in October 2004 and known as the Sister Study, the study has already recruited more than 46,000 women, but it still needs to increase the number of participants from targeted demographic groups (see "Recruitment Call . . . " ).

The investigation is being led by NIEHS Epidemiology Branch Chief and Principal Investigator Dale Sandler in partnership with Biostatistics Branch Chief and Co-Investigator Clarice Weinberg.

The researchers view the effort as their "life’s work" and characterize the Sister Study as a pioneering initiative that "in many ways feeds into the [NIH] Roadmap for multidisciplinary studies and encourages collaborations across divisions."

The project is a prospective study of the etiology of breast cancer using a risk-based sampling approach. In a recent paper,* Weinberg and Sandler described the strategy as one offering investigators several significant benefits, including "a sizable increase in the rate of accrual of newly incident cases, enrichment for risk factors that are known or even unknown, and a high level of motivation among participants."

"Basically, the idea is to enrich for genes that are related to risk and to also enrich for exposures. The same kind of strategy could be followed in studying something like autism," Weinberg elaborated.

"One of the things about the Sister Study, like other prospective studies, such as the Nurses’ Health Study," Sandler explained, "is that what we’ve built is a resource for the future. . . . We are already designing into the study opportunities to look at . . . respiratory disease, osteoporosis, and a host of other conditions."

The study aims to uncover the links between genetics and the environment in the development of breast cancer using epidemiological analysis and biochemical investigations of a cohort with about twice the risk of other women for developing breast cancer. The volunteers are at increased risk because they have a sister with the disease.

Laboratory data from samples now being archived will be analyzed, along with information collected at enrollment and during annual interviews to track the volunteers’ ongoing medical histories and everyday lives. The investigators will search for correlations between outcomes and the genetic makeup, diet, and environmental exposures of the volunteers.

The Sister Study is a massive undertaking, with banked samples of whole blood, cryopreserved lymphocytes, plasma, serum, urine, toenail clippings, buccal cells, and household dust.

Should a woman develop breast cancer—or any other cancer—"down the road," Sandler added, tumor tissue will be requested and then added to the sample bank.

The study’s prospective design allows investigators to assess exposures before the onset of disease and to avoid biases common to retrospective studies, while creating a framework for testing new hypotheses.

Sandler and Weinberg anticipate about 1,500 cases of incident breast cancer to develop in the cohort during the next five years. Beyond that, as the volunteers age, there may be as many as 3,000 new cases to analyze, Weinberg said.

The Two Sister Study: Targeting
Young-Onset and Survival Issues

In an effort to glean additional insights from the Sister Study cohort, Sandler and Weinberg have secured a commitment for three years of funding from the Susan G. Komen for the Cure foundation for a family-based study.

Called the Two Sister Study, its aim is to investigate the genetic and environmental factors that influence young-onset breast cancer—breast cancer developed before age 50.

The study will include about 2,000 of the 50,000 women with breast cancer whose sisters enrolled in the Sister Study, along with their unaffected sister and genetic data from any parents who are still living.

According to Weinberg, criteria for enrollment in the Two Sister Study include the development of breast cancer before the age of 50 and during the past three years. Participants will provide saliva and household dust samples, information about family and lifestyle, and details of their breast cancer diagnosis and treatment.

The affected sisters will also be asked to give permission for release of medical records and tumor tissue blocks.

If they have living parents who are willing to provide saliva samples for extraction of DNA, their parents will also be included.

The plan is to genotype more than 1,500 markers on about 150 candidate genes to identify genetic variants that tend to be transmitted to offspring who develop breast cancer.

Looking to the future, Weinberg said, "I’m hoping that we’ll be able to afford to do a genome-wide association study for Two Sisters, where we look at maybe 500,000 SNP markers across the genome."

The archived DNA will serve as a resource for future tests of new candidate genes uncovered in ongoing whole-genome scans and could potentially be employed in studies of gene-gene interactions and epigenetic modifications.

Exposures related to risk will be identifiable from the comparison of the affected and unaffected sisters. The family structure will then provide a powerful basis for characterizing the combined effects of genetic and nongenetic risk factors.

The young-onset cases enrolled in the Two Sister Study will be merged with the incident cases diagnosed in the larger Sister Study during follow-up. Together, they will form a cohort of cancer survivors.

The investigators hope to secure funding to follow these survivors for up to 10 years to identify factors that influence prognosis following treatment.

* C. R. Weinberg, D. L. Shore, D. M. Umbach, and D. P. Sandler, "Using risk-based sampling to enrich cohorts for endpoints, genes,and exposures," Am. J. Epidemiol. 166. 447 (2007).



The Sister Study has been on track in meeting enrollment goals in terms of total numbers. However, co-investigators Dale Sandler and Clarice Weinberg are still striving to build a cohort that reflects the diversity of American and Puerto Rican women in terms of age and geographic distribution, race and ethnic background, and education and occupation.

Cohort diversity is particularly important, they say, in light of the fact that different populations of women may experience the disease very differently.

African American women, for example, are 10 percent less likely to be diagnosed with breast cancer, but 35 percent more likely to die from it—a statistic that underscores the need for the study to be as inclusive as possible.

The investigators seek to double the number of women enrolled from several target groups, including:

Racial and ethnic minorities

Women aged 65 to 74

Women with less than a college education

Women in underrepresented occupations, especially in trades and industry

Visit the bilingual (Spanish and English) Sister Study website:

Recruiters may be contacted by e-mail or called toll free at 1-877-474-7837 (1-866-889-4747 for deaf or hard of hearing).

The Sister Study is funded by NIEHS and has received additional financial support from a sister IC, the National Center on Minority Health and Health Disparities, for targeted recruitment of minorities.

The study has also received nonfinancial support from the American Cancer Society, the Susan G. Komen for the Cure foundation, the Intercultural Cancer Council, the Sisters Network, and the Y-ME National Breast Cancer Organization.

The women in the study themselves have also provided additional support, Sandler said. "They really care about the research and about their sisters. . . . They even help us recruit."

Eddy Ball


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