From OncoLog, April 2013, Vol. 58,
Compass: Breast Cancer Risk Reduction
By Sunni Hosemann
interventions and strategies can reduce a woman’s chances of developing
breast cancer. Some of these strategies—dietary and lifestyle changes,
for example—come with the difficulty and inconvenience of change but do
not pose additional disadvantages or health risks. At the other end of
the spectrum, risk-reducing surgeries—bilateral mastectomy and
salpingo-oophorectomy—have inherent risks. Before discussing these
options with a woman, a physician must first conduct an accurate,
personalized risk assessment.
This discussion addresses strategies for reducing the risk of breast
cancer in women. Although men also can develop breast cancers, these
cancers are rare, and the same risk models and risk-reduction
strategies do not apply.
Cancer risk is an estimate of the chance of developing a particular
type of cancer over the course of a lifetime for members of a
particular group. According to the American Cancer Society, a woman in
the United States has a 1 in 8 chance of developing breast cancer at
some time in her life.
While such estimates reflect how widespread the disease is in a
population, they are not particularly helpful for determining the
cancer risk for a given individual. In the area of breast cancer
prevention, current efforts are aimed at identifying individual women’s
short-term risks of developing the disease. The main risk factors
considered in such assessments are age, family history, personal
history of premalignant breast lesions (such as ductal or lobular
atypical hyperplasia or carcinoma in situ), menstrual and childbearing
history, previous radiation therapy, breast density, and genetic
According to Therese Bevers, M.D., a professor in the Department of
Clinical Cancer Prevention and medical director of the Cancer
Prevention Center at The University of Texas MD Anderson Cancer Center,
various tools are available to assess breast cancer risk. The modified
Gail model is a standard and commonly used tool developed by the U.S.
National Cancer Institute. Others in regular use are the Claus and
Tyrer-Cuzick models. None of these tools applies to all women, and each
represents one part of an overall risk assessment.
The tools most commonly used to assess whether a woman is a candidate
for genetic testing are the Breast and Ovarian Analysis of Disease
Incidence and Carrier Estimation Algorithm and the BRCAPRO model.
Five to ten percent of breast cancers are hereditary, and women who
have a strong family history of breast cancer have a significantly
increased risk of developing the disease.
BRCA1 and BRCA2 gene mutations are linked specifically to hereditary
breast and ovarian cancers. Women with a BRCA1 or BRCA2 mutation have a
50%–60% lifetime risk of developing breast cancer. Also associated with
higher breast cancer risk are mutations in the TP53, PTEN, CDH1, ATM,
CHEK2, CDH1, and STK11 genes, which are linked to hereditary cancer
syndromes such as Li-Fraumeni, Cowden, hereditary diffuse gastric
cancer, and Peutz-Jaegers syndromes. Mutations in these and the BRCA
genes are considered high-penetrance mutations, meaning that a high
proportion of individuals with the genotype develop breast cancer.
The family history characteristics that should raise suspicion of
identifiable genetic mutations and prompt further investigation include
having at least one first-degree relative who was diagnosed with breast
cancer at a young age (<40 years), having more than one close
relative with breast or ovarian cancer, having a first-degree relative
diagnosed with breast and ovarian cancer or bilateral breast cancer,
having a male relative with breast cancer, or being of Ashkenazi Jewish
Genetic counseling and testing
According to Banu Arun, M.D., a professor in the Department of Breast
Medical Oncology and co-chair of the Clinical Cancer Genetics Program,
genetic testing is not a general screening tool and should be
considered only when a relevant mutation is strongly suspected. Genetic
testing is expensive and, if not undertaken carefully, may produce
results that are not useful. For example, she said, there are more than
2,000 variants of BRCA mutations, and no single test identifies them
all. “It is crucial to use the right test and to test the right
person,” Dr. Arun said.
When one or more family members are concerned about hereditary cancer,
testing should begin on the cancer patient to identify a specific
mutation to target for any additional testing of unaffected relatives
thought to be at high risk. If a relative with cancer cannot be tested,
then—in addition to clinical judgment—risk-assessment models that
calculate the risk of carrying a BRCA mutation can be used to help
determine whether a healthy woman should undergo genetic testing.
Dr. Arun stressed the importance of meeting with women before they
undergo genetic testing to discuss the possible test results and their
implications and meeting with women after genetic testing to discuss
the actual test results. A negative result is considered uninformative;
it may be a false negative result, and it does not eliminate the
possibility that the woman has gene mutations other than the ones
tested for. A positive result verifies that the person has a mutation
and therefore is at increased risk, but it does not predict whether the
person will actually develop cancer. For these reasons, it is important
to carefully select candidates for genetic testing, to select the
appropriate test, and to ensure that genetic counseling precedes and
According to Powel Brown, M.D., Ph.D., chair of the Department of
Clinical Cancer Prevention, the current strategies for managing breast
cancer risk consist of enhanced surveillance, lifestyle modifications,
chemoprevention, and prophylactic surgery. The benefits and associated
risks or side effects of these options vary. A woman’s preferences,
risk tolerance, and attitudes toward cancer and medical interventions
all play important roles in her choice of strategy.
Increased surveillance and lifestyle modifications
Recommendations on screening and surveillance for women at all levels
of breast cancer risk are available through the National Comprehensive
Cancer Network, the American Cancer Society, the U.S. Preventive
Services Task Force, and other sources. Recommendations for women who
have a high risk of breast cancer include undergoing breast examination
and mammography (plus magnetic resonance imaging in some cases) more
frequently or at earlier ages than recommended for women at average
According to Dr. Brown, women who have a BRCA mutation should also
undergo transvaginal ultrasonography and laboratory tests for cancer
antigen 125 levels to screen for ovarian cancers. Such women should
also be monitored by a gynecologist who is familiar with hereditary
breast and ovarian cancers.
Dr. Brown said that counseling for women at any risk level should
include a discussion of the benefits of diet, physical exercise, and
weight control and the increased breast cancer risks associated with
alcohol use and hormone replacement therapy. These factors are not
trivial—the National Cancer Institute estimates that regular physical
exercise alone can lower breast cancer risk by 20%–40%.
Risk-reducing surgery usually is considered only for women at very high
risk of breast cancer, particularly women with a BRCA mutation. Women
with BRCA1 mutations are more likely to have triple-negative breast
cancer than those with BRCA2 mutations.
Retrospective studies have found that bilateral salpingooophorectomy
reduces the risk of ovarian cancer associated with BRCA mutations by as
much as 80% and the risk of breast cancer by approximately 50% in women
younger than 50 years. Salpingo-oophorectomy should be performed by a
gynecologic or surgical oncologist. The surgeon will perform peritoneal
washings and lymph node evaluation, submitting removed tissue for
intra-operative pathologic analysis. “Experience has shown that there
is an 8%–12% chance of an occult ovarian cancer already being present,”
Dr. Brown said.
Studies have also shown that prophylactic bilateral total mastectomy
reduces breast cancer risk by 90% or more. “Prophylactic bilateral
mastectomy is an elective surgery, but it greatly reduces an
individual’s chance of developing breast cancer in the future,” Dr.
Brown said. “When appropriate, I support the patient’s decision to have
Risk-reducing surgery should never be undertaken without appropriate
counseling. The patient must be fully aware of all her options,
including surgery. According to Dr. Arun, the women most likely to
choose risk-reducing surgery are those who have known BRCA mutations or
have had a close relative who had ovarian cancer.
Tamoxifen and raloxifene are the only drugs currently approved by the
U.S. Food and Drug Administration for breast cancer risk reduction.
Both drugs are selective estrogen receptor modulators, but they differ
in their effects on tissues and organs as well as their side effects.
For breast cancer risk reduction, either drug is prescribed for 5
years. According to Dr. Bevers, data from a large clinical trial
indicated that the two drugs equally reduced the risk of invasive
breast cancers during the course of treatment—cutting risk
approximately in half—but longer follow-up showed that the benefits of
raloxifene tapered off with time while the preventive effect of
tamoxifen was more durable. On the other hand, tamoxifen has more
serious side effects than raloxifene. Dr. Bevers said that women with
atypical hyperplasia obtain an 86% reduction in breast cancer risk with
tamoxifen or raloxifene.
A third drug currently in use for breast cancer risk reduction is the
aromatase inhibitor exemestane. Aromatase inhibitors have not been
compared directly with tamoxifen or raloxifene in large primary cancer
prevention trials and are not currently approved for this use. However,
exemestane and other drugs in the same class have shown promise for the
prevention of secondary cancers when given as an adjuvant treatment in
women who have already had an invasive breast cancer.
Dr. Bevers said that tamoxifen, raloxifene, and exemestane each have
advantages and disadvantages. “Choosing which agent to use is a matter
of weighing all of the potential benefits against risks,” she said.
“And each woman has a unique mix of variables that can tip the scales
in favor of one approach over the other.”
The first deciding factor is menopausal status. While all three agents
are appropriate for postmenopausal women, neither raloxifene nor
exemestane has been studied in premenopausal women (and exemestane may
actually increase estrogen production in women whose ovaries are still
producing it). So for now, the choices for premenopausal women who wish
to use a chemopreventive agent are tamoxifen or an appropriate clinical
The next consideration is whether the woman is particularly susceptible
to certain adverse effects or likely to benefit from other effects. For
- Tamoxifen carries an increased risk of endometrial
cancer that is not associated with the other agents, so whether a woman
has had a previous hysterectomy is a factor to consider.
- Raloxifene is approved for the treatment and
prevention of osteoporosis and thus would provide additional benefit
for women affected by or at risk for osteoporosis. For women with
osteoporosis, it may be reasonable to continue raloxifene beyond the 5
years recommended for breast cancer risk reduction.
- Both tamoxifen and raloxifene carry the risk of
thrombotic vascular events (including stroke, pulmonary embolism, and
deep vein thrombosis) and therefore are contraindicated in women who
have a history of thrombosis. Exemestane does not carry these risks and
thus is a better choice for such women and possibly for those who have
other risk factors for thrombotic events (e.g., smoking, diabetes,
atrial fibrillation, or cardiovascular disease).
- Exemestane has been associated with bone loss and
so is not appropriate for women who have or are at risk of
According to Dr. Bevers, women with proliferative breast lesions are
the most likely to opt for chemoprevention. As with risk-reducing
surgery, chemoprevention is an elective treatment, so considerable
discussion and counseling are necessary to help patients make
decisions. “We are developing materials that help advance these
discussions—educational videos and written materials. Some of these are
already available to our patients,” Dr. Bevers said.
Clearly, there is a need for chemopreventive agents that are effective
but do not have toxicities. “The drugs we have at the present time have
side effects that are serious enough to discourage women from taking
them. Only 20% of women who are thought to be at high risk of breast
cancer opt to take tamoxifen, for example,” Dr. Arun said, “and we do
not have agents to use to reduce the risk of developing estrogen
receptor–negative breast cancers.”
To that end, several studies are under way to identify agents that
could reduce risk without side effects that diminish quality of life.
Dr. Bevers is currently enrolling women in studies evaluating vitamin D
as an agent for breast cancer risk reduction. Likewise, Dr. Arun and
colleagues are enrolling patients in a phase II trial to study the
risk-reducing effects of curcumin (one of the compounds in turmeric),
which has anti-inflammatory properties and has been shown to exert an
inhibitory effect on at least four molecular pathways that affect the
proliferation of breast cancer cells in the laboratory. “Some potential
risk-reducing agents are things that many of my patients like to take
anyway, such as green tea and curcumin,” Dr. Arun said, “but these may
need to be specially formulated to increase bioavailability.” A
nanoparticle formulation of curcumin is being used in the phase II
Celecoxib, metformin, anastrozole, and lapatinib are other agents being
studied for breast cancer risk reduction. Thus, women who are at high
risk for breast cancer but find currently approved risk reduction
strategies unacceptable may look to clinical trials for other options.
National Comprehensive Cancer Network. Clinical Practice Guidelines in
Oncology, Breast Cancer Risk Reduction, V1.2012 [PDF].
National Comprehensive Cancer Network. Clinical Practice Guidelines in
Oncology, Breast Cancer Screening and Diagnosis, V1.2012 [PDF].
National Comprehensive Cancer Network. Clinical Practice Guidelines in
Oncology, Genetic/Familial High-Risk Assessment: Breast and Ovarian,
National Cancer Institute. Breast Cancer Risk Assessment Tool.
Susan G. Komen for the Cure. Breast Cancer Screening Recommendations
for Women at Average Risk. 2013.
The University of Texas MD Anderson Cancer Center
Banu K. Arun, M.D.
Professor, Breast Medical Oncology, and Co-Medical Director, Clinical Cancer Genetics Program
Therese B. Bevers, M.D.
Professor, Clinical Cancer Prevention, and Medical Director, Cancer Prevention Center
|Powel H. Brown, M.D., Ph.D.
Professor and Chair, Clinical Cancer Prevention
For more information, talk to your physician, visit www.mdanderson.org, or call askMDAnderson at 877-632-6789.
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