National Institute of Nursing Research
National Cancer Institute
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 to learn about the problems
encountered by both health care providers and their patients when genetic
tests show the patient will likely develop cancer. 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?
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
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
"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 a CGSC task force in a
comprehensive review of studies performed so far to seek out what is
already known about cancer 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," she
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 the mutations. But, because even among family members,
most breast and colons 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
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
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. Women who carry a BRCA1 mutations have an
estimated 85 percent chance of developing breast cancer by the time they
are 70 and a significantly increased risk of developing ovarian cancer.
Men who carry a BRCA1 mutation are more likely to develop prostate cancer.
BRCA2 mutations appear to confer a similar breast cancer risk on women,
but have a smaller effect on the development of ovarian cancer.
For women who are known to carry BRCA1 or BRCA2
mutations, the authors recommend monthly self-examination of breasts to begin by age
18-21, annual or semi-annual breast examination by a health professional to
begin by age 25-35, and annual mammography to begin by age 25-35. 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 25-35 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 author 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 of both preventive 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 JAMA's 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 5-10 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 20's. People with HNPCC mutations are
also more likely to develop endometrial and ovarian cancer, and cancer of
the small bowel, stomach, and ureters.
Because HNPCC can occur throughout the colon, the authors
recommend full colonoscopy every one to three years beginning at age 20-25
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
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
picks up as much as 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 those
individuals. 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 in these components 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 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.
This work was funded by the National Human Genome Research Institute, the
National Cancer Institute, the National Institute of Mental Health, and the
National Institute of Nursing Research, which are components of the
National Institutes of Health, the federal government's primary biomedical
research agency, located in Bethesda, Maryland.
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.