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From OncoLog, April 2013, Vol. 58, No. 4

Graphic: Compass: Quarterly discussion of cancer types for which there is no standard treatment or more than one standard treatment

Breast Cancer Risk Reduction

By Sunni Hosemann

Various 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.

Risk

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 mutations.

Risk assessment

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.

Genetic risk

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 descent.

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.

Graphic: Flowchart of options for breast cancer surveillance and risk reduction

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 follows testing.

Risk reduction

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 risk.

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

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 this surgery.”

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.

Chemoprevention

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 trial.

The next consideration is whether the woman is particularly susceptible to certain adverse effects or likely to benefit from other effects. For example:

  • 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 osteoporosis.

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 study.

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.

References

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, V1.2012 [PDF].

National Cancer Institute. Breast Cancer Risk Assessment Tool.

Susan G. Komen for the Cure. Breast Cancer Screening Recommendations for Women at Average Risk. 2013.

Contributing Faculty
The University of Texas MD Anderson Cancer Center

Photo: Dr. Banu K. Arun

Banu K. Arun, M.D.
Professor, Breast Medical Oncology, and Co-Medical Director, Clinical Cancer Genetics Program

Photo: Dr. Therese B. Bevers

Therese B. Bevers, M.D.
Professor, Clinical Cancer Prevention, and Medical Director, Cancer Prevention Center

Photo: Dr. Powel H. Brown 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.

Other articles in OncoLog, April 2013 issue:

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