The burden of breast and ovarian cancer in the United States
One in eight (12%) of U.S. women aged 90 years or younger will develop
breast cancer sometime during her lifetime (1). One in 70 (1.4%) will develop ovarian cancer (2).
About 200,000 U.S. women and 1500 men develop breast cancer each year (3).
About 23,000 U.S. women develop ovarian cancer each year (3).
Female sex, increasing age, and family history of breast and/or ovarian cancer are the three greatest risk factors for both breast cancer and ovarian cancer (2).
What are BRCA-1 and BRCA-2?
BRCA-1 stands for breast cancer gene number one because it was the first
breast/ovarian cancer-related gene discovered. BRCA-2 was the second breast/ovarian cancer-related gene
discovered. Some changes
(mutations) in these genes increase the risk for breast and ovarian
cancer.
Inherited mutations in genes other than BRCA-1 and BRCA-2 have been shown or are
suspected to increase susceptibility for developing breast and other
forms of cancer. Testing is available for some of these mutations. Mutations in these genes (such as TP53 and PTEN) are much less
common than mutations in BRCA-1 or BRCA-2 (2).
The genetics of hereditary breast cancer susceptibility due to BRCA-1 or
BRCA-2
About 5%-10% of women in whom breast or ovarian cancer is diagnosed have
a hereditary form of cancer due to mutations in the BRCA-1 or BRCA-2
genes (2).
BRCA-1 and BRCA-2 mutations can be inherited from either the mother or the
father.
Testing is available that will determine if there are mutations in the BRCA-1 or
the BRCA-2 genes (4).
A genetic counselor or physician who specializes in genetics or oncology
can provide the most complete information about genetic testing for BRCA
mutations and the most complete answers about the options for cancer
prevention and early detection.
Prevalence of BRCA-1 and BRCA-2 mutations
About 1 in 800 persons in the general population carry a mutation in
BRCA-1 that may result in an increased risk for breast and/or ovarian
cancer (2, 5).
The prevalence in the general population of BRCA-2 mutations associated with
an increased risk of cancer is unknown (10).
About 1 in 40 (2.5%) of Ashkenazi Jewish descent carry one of three common
mutations that may result in an increased risk for breast and/or ovarian
cancer. Two of these mutations are in BRCA-1 (del185AG and 5382insC) and one mutation is in
BRCA-2 (6174delT)(6).
Who is most likely to have a BRCA-1 or BRCA-2 mutation?
Most women do not have a mutation in the BRCA-1 or BRCA-2 gene. The National Cancer Institute has stated (2)
that some factors, that may be independent of each other, increase the
likelihood that a person carries an inherited BRCA mutation. They include:
- A family history of several (three or more) close blood relatives
(sisters, daughters, mother, grandmothers, aunts) affected with
breast cancer, ovarian cancer, or both.
- A family history of early onset (before 50 or before menopause) breast
or ovarian cancer in one or more close blood relatives (sisters,
daughters, mother, grandmothers, or aunts).
- A family history of one or more close blood relatives (sisters,
daughters, mother, grandmothers, aunts) with two or more primary
tumors of the breast or bilateral breast cancer.
- A family history of one or more close male blood relatives (father,
sons, brothers, uncles, grandfathers) who have developed breast
cancer.
- Ashkenazi (Eastern European) Jewish ancestry and a family history of breast
and/or ovarian cancer.
However, even when one or more of these identified risk factors are present, most
women will not have a mutation in BRCA 1 or BRCA 2 (7).
Overall, the likelihood of detecting a mutation in BRCA1/2 in relation
to these risk factors is about 17% (7).
Remember, both maternal and paternal family history is relevant for determining a
person’s risk for breast/ovarian cancer. Women who meet one or more of the above criteria can contact
their primary health providers for referral for genetic counseling and
cancer risk assessment to discuss their risks for breast and/or ovarian
cancer and whether BRCA testing is clinically appropriate for their
situation.
Eligibility for BRCA-1 and BRCA-2 testing
Guidelines for assessment, counseling and testing for genetic susceptibility for
breast and ovarian cancer have been developed by the American College of
Medical Genetics and the New York Department of Health (11)
The CDC has not established testing guidelines. These guidelines describe the process for assessing cancer risk(11).
Most often, the first person that is tested in a family for BRCA-1 and
BRCA-2 mutations is one who developed breast or ovarian cancer since
this determines if the cancer in the family is associated with a BRCA
mutation. If a mutation is found, it becomes a simple matter to
test other blood relatives for the same mutation. If a mutation is not found in the family member who has or had
cancer, the test is not informative and would not provide helpful
information to other family members. If no family members with cancer are living or available for testing,
testing options are generally considered on a case-by-case basis for
each family.
Interpreting a positive BRCA-1 or BRCA-2 test result: the basics
A positive result means that a mutation in BRCA-1 or BRCA-2 has been
detected.
Mutations in BRCA-1 or BRCA-2 are associated with lifetime risks for breast cancer
of 36% - 85% and with lifetime risk for ovarian cancer of 16% - 60%, depending on the population studied (2). Many women who have a mutation in BRCA-1 or BRCA-2 will not
develop breast cancer.
The highest published risk (85%) for breast and/or ovarian cancer associated
with BRCA-1 or BRCA-2 mutations has been found in studies of families
that have three or more blood relatives affected with breast and/or
ovarian cancer (6).
The lowest published risk (36%) for breast cancer associated with BRCA-1 or
BRCA-2 mutations was reported from a study of Ashkenazi Jewish women
with breast cancer who were tested for two mutations in BRCA-1 (185delAG
and 5382insC) and one mutation in BRCA-2 (6174delT) (8).
The lowest published risk (15%) for ovarian cancer associated with BRCA-1 or
BRCA-2 mutations was reported from a population-based study of 5000 well Ashkenazi Jewish women and their family members (9).
Mutations in BRCA-1 and BRCA-2 also have been associated with an increased risk of
male breast cancer (especially BRCA-2 mutations) and prostate cancer. Some evidence suggests that other cancers also may be increased
in mutation carriers.
Interpreting a negative BRCA-1 or BRCA-2 test result: the basics
A negative test result means that no mutation was detected in the BRCA-1 or BRCA-2 gene. The meaning of a negative test result depends on whether a mutation in BRCA-1 or
BRCA-2 was identified in a family member with cancer.
For families in which a BRCA-1 or BRCA-2 mutation has been documented, a
negative test result for an unaffected blood relative means that the
lifetime risk of breast cancer is the same as women without a family
history of breast cancer (one in eight).
For
women from families in which a BRCA-1 or BRCA-2 mutation has not been
documented in a blood relative, a negative test result probably will not
provide helpful information for assessing the risk of cancer for a
member of that family. In
other words, the test will be uninformative. In this situation, cancer risk will be estimated on the basis of
family and medical history and environmental and lifestyle factors. (9)
Test results of uncertain clinical significance
Sometimes BRCA-1 or BRCA-2 test results reveal mutations of unknown significance. Information about these mutations is insufficient to
determine whether they are associated with an increased risk for breast
cancer or are normal variations (polymorphisms). One study reported finding variants of unknown significance in
13% of patients tested (7).
Clinical utility of BRCA-1 and BRCA-2 test results: the basics
The risks associated with mutations in BRCA-1 and BRCA-2 mutations cannot be
quantified precisely. Information
is limited on how other non-genetic factors influence the risks
associated with these mutations.
However, results from BRCA genetic testing may be useful as an additional piece
of information in determining appropriate clinical management strategies
for prevention and early detection of breast and ovarian cancers in
high-risk women, according to the American College of Medical Genetics (9,
11).
For people who have a BRCA mutation, clinical management choices may include
increased or more intensive monitoring, chemoprevention, or prophylactic
surgery to remove at-risk organs. Although
some of these options may reduce the risk for developing breast and/or
ovarian cancer, no option totally eliminates this risk (2).
Ethical, legal, and social implications associated with BRCA-1 and BRCA-2 testing
Any woman who seeks this testing must be well informed about the risks and
benefits of the testing. This is best accomplished through a genetic risk evaluation that includes
informed consent and genetic counseling, according to the American
College of Medical Genetics (11).
A positive BRCA genetic test result in one person may mean that an entire
at-risk family has been identified. Issues related to communicating with other family members who may
or may not wish to have this information need to be considered when
making a testing decision.
Receiving BRCA test results, either positive or negative, may affect emotional
health and self esteem. People should consider the possible emotional reactions before being tested.
Genetic test results that uncover a genetic susceptibility for breast and/or
ovarian cancer may put the tested person at risk for discrimination by
health insurance providers, employers, and others according the American
College of Medical Genetics (11). Although genetic discrimination related to cancer susceptibility
testing has not been commonly observed, it should be considered as a
possibility when making a testing decision.
References
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JP, Hartge P, Wacholder S, et al.: The risk of cancer associated
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