w/ risk of Breast Cancer

Several important medical decisions may

be affected by a woman's underlying risk
of breast cancer. These decisions include
when to use postmenopausal hormone replacement
therapy.
At what age to begin mammography screening
When to use tamoxifen to prevent breast cancer.
When to perform prophylactic mastectomy to prevent
breast cancer.
 Postmenopausal hormone
replacement
Postmenopausal hormone replacement therapy
reduces the risk of coronary artery disease and
osteoporosis by 50%, but increases the risk of
breast cancer by less than 30%.
Because the average woman's risk of dying from
coronary artery disease is much greater than her risk
of dying from breast cancer, it may be argued that
the benefits of hormone replacement therapy
outweigh the risks.
Mammography
 Mammography
Routine use of screening mammography in women age 50 years and
older reduces mortality from breast cancer by 33%.
This reduction comes without substantial risks and at an acceptable
economic cost.
However, the use of screening mammography is more controversial in
women younger than age 50 years for several reasons:
(1) breast density is greater and screening mammography is less likely to detect
early breast cancer.
(2) screening mammography results in more false-positive tests, resulting in
unnecessary biopsies.
(3) younger women are less likely to have breast cancer so fewer young women
will benefit from screening.
However, on a population basis, the benefits of screening
mammography in women between the ages of 40 and 49 years still
appear to outweigh the risks in a woman with a family history of
breast cancer.
 Tamoxifen
Tamoxifen, a selective estrogen receptor
modulator, was the first drug shown to reduce
the incidence of breast cancer in healthy
women. It is currently the only drug approved by
the Food and Drug Administration for reducing
the risk of breast cancer, in women w/ high risk
for breast cancer.
Adverse effect:
Deep venous thrombosis occurs 1.6 times
Pulmonary emboli 3.0 times,
Endometrial cancer 2.5 times
Cataract surgery 2 times
Tamoxifen currently is only recommended for women who
have a Gail relative risk of 1.70 or greater.
 Prophylactic mastectomy
Women at high risk for breast cancer
(BRCA mutation) found that prophylactic
mastectomy reduced their risk by more
than 90%.
For women with an estimated lifetime risk
of 40%, prophylactic mastectomy added
almost 3 years of life, whereas for women
with an estimated lifetime risk of 85%,
prophylactic mastectomy added more
than 5 years of life.
 BRCA Mutations
BRCA-1
BRCA-2
Identifying BRCA Mutation Carriers
BRCA Mutation Testing
Cancer Prevention for BRCA Mutation
Carriers
 BRCA-1
5 to 10% of breast cancers are caused by
inheritance of germline mutations such as
BRCA-1 and BRCA-2, which are inherited
in an autosomal dominant fashion with
varying penetrance.
BRCA-1 is located on chromosome 17q, spans a genomic
region of about 100 kb of DNA, and contains 22 coding
exons. The full-length mRNA is 7.8 kb and encodes a
protein of 1863 amino acids.

Both BRCA-1 and BRCA-2 function as tumor-suppressor

genes, and for each gene, loss of both alleles is required
for the initiation of cancer.

The BRCA-1 gene suggest a role in transcription, cell-cycle

control, and DNA damage repair pathways.

Germline mutations in BRCA-1 represent a predisposing

genetic factor in as many as 45% of hereditary breast
cancers and in at least 80% of hereditary ovarian cancers.
Female mutation carriers have up to
a 90% lifetime risk for developing
breast cancer and up to a 40%
lifetime risk for developing ovarian
cancer. Breast cancer in these
families appears as an autosomal
dominant trait with high penetrance.
Approximately 50% of children of
carriers inherit the trait.
 BRCA-1 associated breast cancers have
a number of distinguishing clinical
features, such as :
Early age of onset when compared with
sporadic cases;
Higher prevalence of bilateral breast cancer;
The presence of associated cancers in some
affected individuals, specifically ovarian
cancer and possibly colon and prostate
cancers.
 Analysis of germline mutations in Jewish
and non-Jewish women with early-onset
breast cancer indicates that 20% of
Jewish women who develop breast
cancer before age 40 years carry the
185delAG mutation.
 BRCA-2
BRCA-2 is located on chromosome 13q and spans a
genomic region of about 70 kb of DNA. The 11.2-kb
coding region contains 26 coding exons. It encodes a
protein of 3418 amino acids.
 The breast cancer risk for BRCA-2
mutation carriers is close to 85% and the
lifetime ovarian cancer risk, while lower
than for BRCA-1, is still estimated to be
close to 20%.
Breast cancer in BRCA-2 families is an
autosomal dominant trait and has a high
penetrance.
Approximately 50% of children of carriers
inherit the trait.
 BRCA-2associated breast cancer has a
number of distinguishing clinical features,
such as
An early age of onset compared with
sporadic cases.
Higher prevalence of bilateral breast cancer;
and the presence of associated cancers in
some affected individuals, specifically
ovarian, colon, prostate, pancreas,
gallbladder, bile duct, and stomach cancers,
as well as melanoma.
 A number of founder mutations have
been identified in BRCA-2. The 6174delT
mutation is found in Ashkenazi Jews with
a prevalence of 1.2%.
Another BRCA-2 founder mutation,
999del5, is observed in Icelandic and
Finnish populations.
 Identifying BRCA Mutation Carriers

Identifying hereditary risk for breast

cancer is a four-step process that
includes:
Obtaining a complete, multigenerational
family history
Assessing the appropriateness of genetic
testing for a particular patient
Counseling the patient
Interpreting the results of testing.
A hereditary risk of breast
cancer is considered if a
family includes two or more
women who developed
ovarian cancer or breast
cancer before age 50 years.
BRCA Mutation Testing
Appropriate counseling for the individual
being tested is strongly recommended,
and documentation of informed consent
is required.
The test that is clinically available for
analyzing BRCA mutation is gene
sequence analysis.
 In a family with a history suggestive of hereditary breast
cancer and no previously tested member, the most
First informative strategy is to first test an affected family member.

This person undergoes complete sequence analysis of both

the BRCA-1 and BRCA-2 genes.
Second

If a mutation is identified, relatives are usually only tested for

that specific mutation.
Third

The false-negative rate for BRCA mutation testing is less than

5%

A woman who carries a deleterious mutation has a
breast cancer risk of up to 85%, as well as a greatly
increased risk of ovarian cancer.

If the mutation is not present, the woman

may be reassured that her risk of breast or
ovarian cancer is no greater than that of
the general population, regardless of family
history, and no BRCA mutation can be
passed on to the woman's children. In the
absence of a previously identified
mutation, a negative test result in an
affected individual generally indicates that
a BRCA mutation is not responsible for the
familial cancer.
 Cancer Prevention for BRCA Mutation Carriers

Risk management strategies for

BRCA-1 and BRCA-2 carriers include:
1. Prophylactic mastectomy and
reconstruction.
2. Prophylactic oophorectomy and
hormone replacement therapy.
3. Intensive surveillance for breast and
ovarian cancer.
4. Chemoprevention.
Prophylactic mastectomy and
reconstruction
Although removal of breast tissue will
reduce the likelihood of BRCA-1 and
BRCA-2 carriers developing breast
cancer, mastectomy does not remove all
breast tissue and women continue to be
at risk, because a germline mutation is
present in any remaining breast tissue.
 For postmenopausal BRCA-1 and BRCA-2
carriers who have not had a
mastectomy, it may be advisable to
avoid hormone replacement therapy.
 Because breast cancers in BRCA
mutation carriers have the same
mammography appearance as breast
cancers in noncarriers, a screening
mammogram is likely to be effective in
BRCA mutation carriers, provided it is
performed and interpreted with a high
level of suspicion by an experienced
radiologist.
 Present screening recommendations for
BRCA mutation carriers who do not
undergo prophylactic mastectomy include
clinical breast exam every 6 months and
mammography every 12 months beginning
at age 25 years, because the risk of breast
cancer in BRCA mutation carriers increases
after age 30 years.
Prophylactic oophorectomy and
hormone replacement therapy
The risk of ovarian cancer in BRCA-1 and BRCA-2
carriers ranges from 20 to 40%, which is 10 times
higher than that for the general population.

The American College of Obstetrics and

Gynecology recommends that women with a
documented BRCA-1 or BRCA-2 mutation
consider prophylactic oophorectomy at the
completion of childbearing or at the time of
menopause.
 Intensive surveillance for
breast and ovarian cancer

The Cancer Genetics Studies Consortium

recommended yearly transvaginal
ultrasound timed to avoid ovulation and
yearly serum CA 125 levels beginning at
age 25 years as the best screening
modalities for ovarian carcinoma in
BRCA mutation carriers who have opted
to defer prophylactic oophorectomy.