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:
Women with the BRCA1 or BRCA2 mutation had a 20 percent chance of developing breast cancer by age 40, a 55 percent chance by age 60, and more than 80 percent by age 80. Overall, they had an 82 percent chance of developing cancer in their lifetime. (The overall risk for all women is about 10 percent.)
The cancer rate varies depending on whether the women were born before or after 1940, the median birth year in the study. This suggests that even when there is a strong genetic risk present, environmental factors play a vital role in determining when cancer occurs. Women born before 1940 had a 24 percent chance of developing breast cancer by age 50; women born after 1940 had a 67 percent chance.
Regardless of what year a woman was born, if she exercised during her teenage years, she was likely to develop cancer later in life than women who did not exercise. That was also true for weight: women who were not obese during their teenage years developed cancer at similar rates, but later in life.
Half the women in the study who carried BRCA1 or BRCA2 mutations and developed cancer did not have a family history of breast cancer. In most cases, that’s because they inherited the mutation from their fathers. 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 Estée 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 Ovarian Cancer Prevention Program in the UW School of Medicine and affiliate investigator at Fred Hutchinson. At the Seattle Cancer Care Alliance, Gralow is a breast cancer oncologist and Swisher is a gynecological oncologist.
Both physicians stressed that the findings of the paper are important, but for context it is important to realize that only a small proportion of women in the population have inherited mutations in the BRCA1 or BRCA2 genes. The direct findings of the paper apply only to those women with BRCA1 and BRCA2 mutations.
Most women have a much lower risk of developing breast and ovarian cancer than the women in the study. Most breast and ovarian cancers apparently arise from a complex combination of genetic, lifestyle and environmental factors. Women with BRCA1 and BRCA2 mutations often are diagnosed with breast cancer at a young age, and have a family history of breast and/or ovarian cancer.
This paper shows that women with BRCA mutations have a very high lifetime risk of breast cancer (more than 80 percent) and ovarian cancer (54 percent for BRCA1 mutations and 23 percent for BRCA2 mutations) even when the woman did not have many family members with cancer. This very high cancer risk makes it important to identify those women who have BRCA1 and BRCA2 mutations so preventive measures can be offered, Swisher said.
This is the first time a study has shown that exercise and weight control can influence the onset of cancer in women who have a genetic predisposition to cancer. “Living a healthy lifestyle, getting regular physical activity and maintaining a healthy body weight are important for all aspects of health and well-being in all women, but it is reassuring to know that a healthy lifestyle can help postpone cancer onset in women with a strong inherited predisposition to this disease,” Gralow said.
Another finding of the paper is that many of the women did not necessarily have the strong family history of cancer that tips a woman off that she is high risk. In many of these cases, the mutation came from the father. “There is a misperception out there, even among physicians, that the mutation is always passed down by the mother, but it can also come from the father,” Gralow said.
“It’s very important that a woman try to get as much information as she can about her father’s side of the family when gathering a medical history,” Swisher said. “It’s wise for a woman to ask all her older relatives if they remember anyone in the family with cancer. These questions are becoming more challenging because in the United States, people are now having smaller families, so there are fewer relatives to provide any warning of the mutation.”
Any woman with a family history of two or more breast or ovarian cancers is advised to consult a health-care provider for a thorough evaluation and careful discussion of all options, Swisher said. At places such as the University of Washington/Seattle Cancer Care Alliance Breast and Ovarian Cancer Prevention Program, staff help examine the person’s individual risk assessment, along with lifestyle factors, to determine a prevention and screening plan.
A team of health-care providers – a gynecologic oncologist, surgeon, genetic counselor, medical geneticist, and medical oncologist – may meet with a patient first one-on-one and then all together as a group.
“A multidisciplinary team like this can help each woman develop a plan to lower and manage her risk for breast or ovarian cancer,” Swisher said.
There are a number of ways that women with a genetic risk of breast and ovarian cancer can decrease cancer risk. Women may participate in aggressive monitoring programs that try to detect any cancer as soon as possible. A number of medications to prevent cancer (such as tamoxifen) are being evaluated in high-risk women. Surgery to remove the ovaries can reduce the risk of both breast and ovarian cancer. Risk-reducing prophylactic breast surgery is another option for women at extremely high risk of breast cancer.
AUTHORS OF THE PAPER
The New York Breast Cancer Study Group includes Dr. King, other University of Washington researchers and co-authors Joan H. Marks and Jessica B. Mandell of the Sarah Lawrence College Graduate Program in Human Genetics. The study team also included physicians, surgeons, and genetic counselors from Albert Einstein College of Medicine/Montefiore Medical Center; Beth Israel Medical Center; Columbia Presbyterian Medical Center, Columbia University; Englewood Hospital and Medical Center; Greenwich Hospital, Yale Cancer Center; Hackensack University Medical Center; Memorial Sloan-Kettering Cancer Center; New York University Medical Center; North Shore University Hospital; Sarah Lawrence College; Stamford Hospital, Bennett Cancer Center; Strang Cancer Prevention Center; White Plains Hospital Center; and private practitioners.
More than 100 genetics counseling graduate students also worked on the project.
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