Papers in back-to-back issues of the Journal of the American Medical Association (JAMA) offer health professionals the first comprehensive survey of information about how to care for patients who carry genetic mutations that put them at high risk for colon, breast, and other cancers. In addition, the papers suggest a research agenda to help provide longer-term answers to unsolved questions about cancer surveilence, prevention and treatment in people whose disease arises from inherited changes in their DNA.
The two papers are products of the Cancer Genetics Studies Consortium (CGSC), a network of research studies funded three years ago by several components of the National Institutes of Health (NIH), and led by the National Human Genome Research Institute (NHGRI), to learn about the impact of genetic testing for inherited cancer risks on people and their health care providers. What are the options for monitoring or preventing the cancer? How well do they work? Do patients with inherited tendencies to develop cancer respond differently to standard treatments than do other patients?
The NIH components that contributed to the study include the National Cancer Institute, the National Institute of Mental Health, the National Institute on Nursing Research, and the Office of Research on Women's Health. These days, discovery of a disease-causing gene mutation is almost immediately translated into a clinical test able to detect the mutation in an individual's DNA. In some cases, there may not yet be a treatment for the disease. In others, specific information is lacking about what monitoring, prevention or treatment options work best in people whose disease arises from a gene mutation. It could be, for example, that breast cancer progresses differently in a person with a specific gene mutation than in someone who does not have that mutation.
"The ability to identify cancer-linked gene mutations in healthy people is so new, health professionals don t know how to incorporate the information into patient care," said Wylie Burke, M.D., Ph.D., associate professor of medicine at the University of Washington.
Burke led the CGSC task force in a comprehensive review of studies performed so far to seek out what is already known about cancer surveillance, prevention and treatment in people known to be at high risk for inherited colon or breast cancer. "These reports are a first step toward helping those patients now, and they identify research questions we hope will give us more complete answers in the long term," Burke said.
The authors note that the recommendations were developed for people who are known to carry specific mutations that put them at increased risk for colon or breast cancer. They may also apply to close relatives of individuals who have tested positive for those mutations, or for family members in which those diseases follow an inheritance pattern that indicate they are linked to a mutation. But, because even among family members, most breast and colon cancers do not arise from inherited mutations, the recommendations do not apply, the articles say, to the majority of individuals with a family history of colon, breast or ovarian cancer.
In every case, health care decisions based on genetic test results should be made between the patient and his or her health professional and should also address the emotional and social dimensions of decision-making about cancer risk.
In this week's JAMA, Burke and her coworkers look at disease monitoring strategies and their effects on individuals who carry mutations in the BRCA1 or BRCA2 genes, which place them at increased risk for breast cancer, ovarian cancer or both. For example, women who have a strong family history of breast cancer and who carry a BRCA1 mutations have an estimated 85 percent chance of developing breast cancer by the time they are 70. They also have a significantly increased risk of developing ovarian cancer. Men who carry a BRCA1 mutation are more likely to develop prostate cancer.
For women who are known to carry BRCA1 or BRCA2 mutations, the authors recommend monthly self-examination of breasts to begin between the ages of 18 and 21, annual or semi-annual breast examination by a health professional to begin between 25 and 35, and annual mammography to begin between 25 and 35. But, the article says, mammography exposure in young women who are BRCA mutation carriers could, theoretically increase cancer risk. Even so, many experts believe that the benefit of early cancer detection is likely to outweigh the risk for women with an inherited predisposition to breast cancer, even when mammography is initiated at an early age, the authors say.
For early detection of ovarian cancer, the group recommends that BRCA1 mutation carriers between the ages 25 and 35 start annual or semi-annual screening by ultrasound, along with monitoring blood levels of CA-125, a marker that indicates the presence of tumor cells. The increase in risk of ovarian cancer is much smaller for BRCA2 mutation carriers than for BRCA1 carriers, so the benefits of ovarian cancer surveillance in BRCA2 carriers are less.
Men with BRCA1 mutations may have an increased risk of developing prostate cancer. However, the authors found insufficient data to advise these individuals about whether to start early cancer screening.
Both male and female BRCA1 mutation carriers should be informed about a possible increase in their risk for colorectal cancer and encouraged to follow screening recommendations for the general population, including regular sigmoidoscopy and fecal blood tests starting at age 50.
Although healthy BRCA mutation carriers should be informed about the option of mastectomy and ovary removal, they must also be informed about cases of cancer occurring in individuals after these operations have been performed. At this time, the paper says, there is insufficient information available to make recommendations about this procedure.
So far, no drug or other agent to reduce cancer risk in an individual with a genetic predisposition has been identified. Nevertheless, there are several promising agents being evaluated. These and other anti-cancer agents have risks and side effects that should be considered.
In the JAMA March 19 issue, Burke and her coworkers identified and evaluated options for monitoring and reducing risk of disease in people known to carry mutations for a type of colon cancer known as HNPCC (hereditary non-polyposis colon cancer). Mutations in at least four genes are linked to HNPCC, and an estimated 5 to10 percent of colon cancer cases are believed to result from HNPCC mutations. The cancer is usually diagnosed in people around age 45, much earlier than are non-inherited forms of colon cancer, and can occur in people in their 20s. People with HNPCC mutations are also more likely to develop endometrial and ovarian cancer, and cancer of the small bowel, stomach and uterus.
Because HNPCC can occur throughout the colon, the authors recommend full colonoscopy every one to three years beginning between the ages of 20 and 25 for individuals who carry HNPCC-associated mutations or who have family histories that indicate the disease follows a tell-tale inheritance pattern. The procedure detects polyps in the colon before they become cancerous and at a time when they are easiest to remove. However, the studies so far do not confirm whether colonoscopy and removal of polyps significantly reduces colon cancer incidence. Further, the report says, there have been no randomized control trials to demonstrate that colonoscopy decreases mortality or the incidence of colon cancer in HNPCC mutation carriers.
For early detection of HNPCC-related endometrial cancer, the authors recommend annual screening exams beginning between the ages of 25 and 35, either by sampling endometrial tissue or by ultrasound. These methods pick up 82 to 98 percent of endometrial cancers in women after menopause, but their effectiveness in younger women is uncertain.
Removal of the colon may be an option for mutation carriers with polyps because of the known progression of the polyps into malignant tumors, which may be more rapid in people with HNPCC mutations. However, there is not enough evidence to recommend this procedure to HNPCC mutation carriers. Similarly, there is not enough evidence to recommend hysterectomy or ovary removal to healthy women who have HNPCC mutations, although the authors say those women should be made aware of this option. These surgeries are recommended for women who have developed cancer, although their effectiveness in women whose cancer is linked to HNPCC mutations is not yet known.
As for lifestyle features such as diet, exercise and certain toxic exposures, the authors say there is no information yet to determine if modifications influence the development of BRCA- or HNPCC-related cancers. Still, the overall health benefits of good diet and exercise and reduced exposure to potential carcinogens warrant inclusion in any health-maintenance strategy.
These provisional recommendations form the basis of an interim policy that is the first step towards finding improved surveillance, treatment and prevention of these cancers in the future. However, the authors say, prospective studies are needed to identify optimal screening and follow-up regimens, and to identify the best measures to prevent cancer development in people identified as being high risk. Burke and her coworkers call for the establishment of registries of mutation carriers to aid in long-term surveillance and follow-up, and to stimulate research on the clinical and population characteristics of hereditary cancers.
Without firm data on these aspects of patient care, the authors recommend genetic testing take place within a research protocol, where individuals can receive appropriate counseling and research information can be collected. The proposed Cancer Genetics Network sponsored by the National Cancer Institute represents a promising mechanism for accomplishing these objectives, they conclude.
Recommendations for Follow-Up Care of Individuals with an Inherited Susceptibility to Cancer. 1: HNPCC. JAMA. Vol. 277 (11): 915-919, March 19, 1997, and, Recommendations for Follow-Up Care of Individuals with an Inherited Susceptibility to Cancer.2: BRCA1 and BRCA2 Mutations, JAMA. Vol. 277 (12): 997-1003, March 26, 1997. The authors of both articles are: Wylie Burke, M.D., Ph.D., University of Washington; Gloria Petersen, Ph.D., The Johns Hopkins University; Patrick Lynch, M.D., J.D., University of Texas; Jeffrey Botkin, M.D., M.P.H., University of Utah; Mary Daly, M.D., Ph.D., Fox Chase Cancer Center; Judy Garber, M.D., M.P.H., Dana-Farber Cancer Institute; Mary Jo Ellis Kahn, National Breast Cancer Coalition; Anne McTiernan, M.D., Ph.D., Fred Hutchinson Cancer Research Center; Kenneth Offit, M.D., M.P.H., Memorial Sloan-Kettering Cancer Center, Elizabeth Thomson, M.S., R.N., National Human Genome Research Institute; and, Claudette Varricchio, D.S.N, R.N, National Cancer Institute, for the Cancer Genetics Studies Consortium, Ethical, Legal, and Social Implications Research Program, National Human Genome Research Institute.
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Last Reviewed: September 2006