The Ribbon Newsletter

Breast cancer is a complex disease and one that has been the focus of many research studies over the years. Scientists have not only tried to learn more about the nature of the disease itself, but have also studied why certain women get breast cancer and others do not. Central to this search is the role that inherited genes play in the occurrence or non-occurrence of breast cancer and, similarly, how family history affects a woman's risk.

As early as the 1700s, it has been recognized that certain families seem to have more cancer cases than other families. However, it is also noted that the general population has a relatively high frequency of cancer, and researchers have yet to fully determine whether the appearance of several cases in a family is due to inherited susceptibility, environmental factors, or to coincidence.

One study looking for these answers is the Family Studies of Cancer, conducted by Dr. Thomas Sellers and colleagues at the Mayo Clinic in Rochester, Minnesota. This long-standing study has been gathering data on breast cancer families since the 1940s to determine if the clustering of cancer is a result of factors shared by family members (such as eating habits) or a result of genes that are passed down from parents to their children.

The Family Studies of Cancer began in 1944 when Dr. V. Elving Anderson and colleagues from the Dight Institute for Human Genetics at the University of Minnesota wanted to examine the conditions which influenced the occurrence of breast cancer and how those conditions could affect the age at which the cancer occurs. 544 women who were diagnosed with breast cancer (cases) at the Tumor Clinic of the University of Minnesota Hospital between 1944 and 1952 were asked about the history of cancer in their parents, grandparents, aunts and uncles, brothers and sisters, sons and daughters, and nieces and nephews. These family members were then mailed questionnaires to gather further information on medical history and lifestyle factors. This initial investigation found a significant excess of breast cancer among relatives of cases compared to relatives of their spouses.

The original records for both the cases and comparative controls were maintained at the University of Minnesota, and original tumor blocks for most of the breast cancer cases were maintained in storage. These files were rediscovered in the late 1980s and became the basis for a second study, funded by the National Cancer Institute, which updated the original records and pedigrees. This follow-up study, conducted between 1991-1996, identified new family members resulting from births or marriages and noted any family members who were deceased. After the pedigrees were updated, all female relatives were interviewed to collect data on cancer history and risk factors for cancer. Specifically, these interviews asked questions about marital status, education, occupational class, medical history of conditions associated with reproductive dysfunction, benign or malignant breast disease, mammography, menstrual and pregnancy history, oral contraceptive use, physical activity, smoking, and alcohol intake. Family members were also mailed a 153-item Food Frequency Questionnaire which assessed usual dietary intake and a Body Measurement Questionnaire (and tape measure) which assessed current height and weight; relative weight at ages 12, 18, 30, 40 and 50; and circumference of the waist and hips. In all, 426 of the original 544 families identified by Dr. Anderson participated in this subsequent study which included over 9,000 family members.

Results from this study confirmed the significance of family history as a risk factor for breast cancer. Compared to women who married into the families (considered the controls), first degree relatives, such as sisters or daughters of the breast cancer patient, were at a 2-fold increased risk for breast cancer, and second degree relatives, such as nieces or granddaughters, were at a 1.5-fold increased risk. Data gathered from this study became the basis for another, more extensive study funded by the National Cancer Institute in July 2000 to look at how the interaction of genes and environment can affect breast cancer risk, especially as it relates to family history. This program project grant is actually four related studies, each of which is based on some or all members of the original 426 families.

Project 1: Factors that influence cancer risk of women who inherit alterations in BRCA1 or BRCA2. Several years ago, scientists identified the BRCA1 and BRCA2 genes that greatly increase risk of breast cancer (as well as ovarian and some less common cancers, too) when inherited in altered forms. Studies have shown that sometimes people who inherit these altered genes never get cancer. Furthermore, in some families, cancer can affect women in their twenties, yet other women carrying the same genetic alteration do not develop cancer until they are in their seventies or later. The purpose of this study is to identify why some people can inherit a gene that greatly increases risk of cancer, yet never get cancer.

By collecting blood specimens from the participating families, the researchers can test for this inherited gene and see how it's passed from parents to offspring. These results will be integrated with information gathered regarding breast cancer risk factors and breast cancer occurrences in certain families to identify factors that affect how cancer genes work. This knowledge could help identify ways to prevent cancer from ever occurring.

Project 2: Processing of hormones and breast cancer risk. There is strong evidence that estrogens influence risk of breast cancer. Estrogens are naturally occurring substances (called hormones) produced by the body that regulate normal body functions. Certain factors, like not having children or having children later in life (after age 30), have been shown to increase the risk of breast cancer. Most scientists believe that this is because pregnancy influences hormone levels.

Hormones have specific chemical structures. The body makes slight changes to the chemical structures in order to increase or decrease the function of the hormones; therefore, unusual hormone changes may influence cancer risk. There are many ways that hormone levels are controlled by the body. Some of the ways by which structural changes occur in estrogens is influenced by our genes.

This study compares women with and without a history of breast cancer to see if there are differences in the frequency of inherited variations in any of nine different genes that influence how the body processes estrogen. This information could be very important in the efforts to identify women at greatest risk so that appropriate screening strategies can be determined.

Project 3: Genetic study of mammographic breast density. When a doctor looks at a mammogram, he or she sees portions of the breast that are white (dense tissue) and portions that are dark (fat tissue). Recent studies have shown that women who have a greater percentage of dense tissue have a three- to five-fold increased risk of breast cancer. However, it is not yet understood why this occurs or why women differ from each other in the amount of dense tissue in their breasts.

This study is built on earlier research that a woman's genetic makeup may influence the amount of dense tissue visible in her mammogram. Previous studies have shown that women with a high percentage of dense tissue in their breasts are at greater risk of breast cancer than women with a low percentage of dense tissue. The purpose of this study is to identify the gene (or genes) that influence breast density and thereby provide significant insights into the causes of breast cancer and possible prevention strategies.

Project 4: Early life exposures and breast cancer risk. There is some evidence that exposures occurring as early as before birth may affect a woman's future risk of breast cancer. For example, women whose mothers had pre-eclampsia/eclampsia, an indicator of decreased estrogen exposure, may have a decreased risk of breast cancer. Scientists have also looked at factors related to nutrition and growth, including birthweight, growth rates, and diet and physical activity during adolescence.

The purpose of this study is to examine those factors surrounding the intrauterine environment, early childhood, and adolescence and their influence on the occurrence of breast cancer in families. Information is also being collected on suspected risk factors such as smoking habits, alcohol consumption, physical activity, and environmental exposures. It is hoped that by gathering this information along with updated health histories, the researchers can identify those women more likely to get the disease which can, in turn, determine better screening and prevention strategies.

The four studies described above tie together seamlessly as data gathered for one project are used collectively to answer distinct, but related questions. For example, as described earlier, Project 4 seeks to identify new risk factors for breast cancer, primarily in adolescent growth, physical activity, and diet. If these factors are found to be associated with breast cancer risk, the researchers can then examine them as factors that influence the age at onset of breast cancer in members of Project 1 families who have known BRCA1 or BRCA2 mutations. Similarly, Project 1 can use data collected from Project 3 which seeks to identify a gene for mammographic breast density. If successful, this new genetic marker might influence the age at onset of breast cancer among those family members with BRCA1 or BRCA2.

Such sharing of data and results form the premise and build the strength of the Family Studies of Cancer. In fact, since 1991, the study has collected almost 13,000 questionnaires and surveys, 1800 DNA samples, and almost 25,000 mammogram films. Although the current study is still in its early stages collecting data, some results have already been found, such as the correlation between early formulations of birth controls pills and an increased risk of breast cancer for those women with a strong family history of the disease (see related story).

Today, the Family Studies of Cancer includes more than 28,000 individuals and spans over five generations. This resource cultivated since the 1940s is invaluable to teaching us more about the nature of breast cancer. It is hoped that by learning more about how breast cancer affects certain families and family members, we can understand how cancer occurs and can better predict who is at greatest risk. Only through this knowledge can better screening and treatment options be determined and, in doing so, make significant strides in the fight against breast cancer.

Oral Contraceptives and Breast Cancer Risk
Birth control pills have long been thought to slightly increase women's risk of breast cancer, though recent research has suggested the risk disappears after women stop taking them. The data have been less clear on the pill's effect on women with a strong family history of the disease.
Dr. Thomas Sellers and colleagues at the Mayo Clinic in Rochester, MN, conducted the first multigenerational study to address this question. This study included 3,396 blood relatives of 426 women diagnosed with breast cancer between 1944 and 1952. Women were mailed questionnaires to gather information on medical history and risk factor information, including oral contraceptive use.
Findings suggested that those women with a strong family history of breast cancer who used oral contraceptives, particularly those introduced prior to 1975, may have a further elevated risk of breast cancer. Among sisters and daughters of breast cancer patients, the risk of breast cancer was three times greater for those who had used oral contraceptives compared to those who had not. In families in which five or more blood relatives had been diagnosed with breast or ovarian cancer, the risk was even greater: sisters and daughters of breast cancer patients were 11 times more likely to have developed breast cancer if they had taken oral contraceptives. The risk of breast cancer among granddaughters and nieces of breast cancer patients as well as for women who married into the families did not appear to be influenced by oral contraceptive use.
Earlier formulations of oral contraceptives contained higher levels of estrogen and progestins than formulations in use today. Because of the relatively small number of breast cancer cases among women who had used more recent formulations, the researchers were unable to draw definitive conclusions about their effect on breast cancer risk. However, the current trends provide no indication that there may be an elevated breast cancer risk from their use.

Family Studies on Breast Cancer at the Mayo Clinic The Ribbon

Family Studies on Breast Cancer at the Mayo Clinic
The Ribbon