Women who carry inherited mutations in the genes BRCA1 or BRCA2 have a lifetime risk of breast cancer of more than 80 percent, as well as a high risk of ovarian cancer, according to the most comprehensive study to date of these women and their families.
The study, published by The New York Breast Cancer Study Group in the Oct. 24 edition of Science, also found that many women with these inherited mutations come from families with few if any reports of breast or ovarian cancer.
The good news from the study is that even among women at very high risk, exercise and healthy weight as an adolescent delayed the onset of breast cancer.
“It was a surprise, but a source of hope, to learn that factors over which we have some control made a difference in the age at which these highest-risk women developed breast cancer,” said the lead author, Mary-Claire King, Ph.D. King is American Cancer Society Professor of Genome Sciences and Medicine in the University of Washington School of Medicine in Seattle and a pioneer in the study of the link between inherited genetic alterations and disease. “Women with inherited mutations were at extremely high risk, but exercise and appropriate weight during their adolescent years clearly delayed the onset of breast cancer.”
“The possibility that lifestyle changes such as increased exercise and weight control could modify the impact of genetic risk has very intriguing implications, not only for BRCA-related cancers but for other breast cancers as well,” said Dr. Larry Norton, head of the Division of Solid Tumor Oncology and Norna S. Serafim Chair in Clinical Oncology at Memorial Sloan-Kettering Cancer Center.
The research was conducted with financial support from The Breast Cancer Research Foundation of New York.
Previous studies had suggested widely varying estimates of breast cancer risk — ranging from 25 percent to 80 percent — among women with BRCA1 and BRCA2 mutations. In order to resolve these discrepancies and accurately calculate risk, the team determined the BRCA1 and BRCA2 genotypes of more than 2,000 people from families each identified through one woman with breast cancer, in the most extensive study of its kind.
What they learned:
The study involved more than 1,000 women with invasive breast cancer recruited at 12 major cancer centers in the New York City area between 1996 and 2000. The women were Ashkenazi Jewish patients, because the historical demography of this population led to a limited number of different mutations in BRCA1 and BRCA2, facilitating the analysis.
Of the 1,008 index cases with breast cancer, 104 had a mutation in BRCA1 or BRCA2. Exactly 50 percent of these 104 women did not have a history of breast cancer in their immediate family. In nearly all those 52 cases, the mutation had come from the father. “Mutations in BRCA1 and BRCA2 are inherited from fathers as often as from mothers, although fathers are rarely affected with breast cancer. So if a family is small, there may be no warning that a mutation is present,” King said.
“It is appropriate for health-care providers to consider referring breast or ovarian cancer patients for genetic counseling, even if the patient does not have an extensive family history of cancer and particularly if the cancer arises early in life,” said Jessica Mandell, certified genetic counselor and the research coordinator of the study. “Genetic counselors can draw upon the results of this study to help women make medical decisions that best suit their and their families’ needs related to cancer risk assessment and cancer prevention.”
All patients were provided genetic counseling at no cost to them during the study. Co-author Joan H. Marks of the Human Genetics Program at Sarah Lawrence College said the study was unique because “it combined the most current approaches to decoding the information in our genes with the most advanced concepts of psychological counseling and sensitivity toward patients at risk of carrying a breast cancer gene.”
The researchers determined the genotypes of adult female relatives of the original breast cancer patients with mutations. The researchers also queried women about environmental factors that might have influenced their breast cancer risk. Of those factors, the ones that appeared protective were normal weight during adolescence as well as exercise (sports, dance, or simply walking a lot). King said researchers should continue to study how environmental factors can modify powerful genetic predispositions toward cancer.
BACKGROUND ON THE BRCA MUTATIONS AND CANCER
Women have about a 10 percent chance of developing breast cancer during their life. Women have about a 1.8 percent risk of developing ovarian cancer, but it’s one of the most deadly cancers.
Between 5 and 10 percent of women who develop breast cancer have inherited a genetic mutation in BRCA1 or BRCA2 that predisposes them to the condition. It’s believed that when BRCA1 and BRCA2 are functioning properly, they help to repair cell damage and prevent cancer. Women whose BRCA1 or BRCA2 genes are affected by mutation thus have an impaired repair mechanism against cancer.
Any woman with a family history of breast cancer is advised to consult a health care provider for a thorough evaluation and careful discussion of all options. Not all women with a family history of breast cancer have an increased risk of developing the condition.
THE BREAST CANCER RESEARCH FOUNDATION
Founded in 1993 by Evelyn H. Lauder, senior corporate vice president of The Est?Lauder Companies, The Breast Cancer Research Foundation is the first and largest organization dedicated to funding clinical and genetic research on breast cancer. Since its inception, the foundation has raised over $70 million for research and awareness. In October 2003, the foundation awarded more than $14.5 million in research grants to 80 scientists at medical institutions across the United States and abroad. More information is available at http://www.bcrfcure.org/.
The following comments on the clinical implications of the Science paper are from Dr. Julie Gralow, associate professor of medicine in the Division of Medical Oncology at the University of Washington and associate member at Fred Hutchinson Cancer Research Center, and Dr. Elizabeth Swisher, assistant professor of medicine in the Department of Obstetrics and Gynecology, director of the Breast and Ovaria