Some 200,000 women in the United States are diagnosed with breast cancer each year. Among them, 15% to 20% have a family history of breast cancer and/or other cancers, and an additional 5% to 10% have a hereditary form of the disease.1 Although great strides are being taken in the early detection and treatment of breast cancer, this disease remains the second leading cause of cancer deaths among women.
Equally important to early detection and improved treatment options is an understanding of factors that increase women’s risk for breast cancer, and the identification and management of women at increased risk—as well as identifying women who should be referred for high-risk evaluation and management. Interventions that limit the risk, whether offered by the primary care provider or a breast cancer specialist, can ultimately prevent some breast cancers from developing.
Risk assessment for breast cancer and an overview of high-risk evaluation and management provide the basis for this article.
A variety of factors—some modifiable, some not—increase a woman’s risk for breast cancer (see Table 12). Factors associated with particularly increased risk include:
• Family history of breast cancer in a first-degree relative or of breast or ovarian cancer in two or more close relatives1-3
• Prior breast biopsy findings that revealed atypical ductal hyperplasia (ADH), atypical lobular hyperplasia (ALH), or lobular carcinoma in situ (LCIS)
• Personal or family history of a BRCA1 or BRCA2 mutation
• Having undergone radiation to the chest wall between ages 10 and 30
• Personal or family history of other rare hereditary breast cancer syndromes,4 such as Cowden syndrome, Li-Fraumeni syndrome, or Peutz-Jeghers syndrome.5-7
To understand high-risk factors in the overall context of breast cancer, it is important to understand the differences between sporadic, familial, and hereditary cancers. The majority of breast cancers, approximately 70%, occur sporadically.8 Sporadic cancers may be caused by random events occurring among or within cells, radiation exposure, or environmental or other unknown factors.
Among breast cancers, 15% to 20% are familial8,9—ie, a recognized pattern of cancers occurs in the patient’s family, but affected members have tested negative for known genetic mutations. Familial cancers may be influenced by not-yet-identified genetic mutations or by environmental factors. As families usually share the same environment, dietary habits, and lifestyles, there may be an association between those factors and families with a cancer history.
Anyone who has a personal or family history of a mutation in either of the breast or ovarian cancer susceptibility genes, BRCA1 and BRCA2, has a significant risk for breast cancer. These are hereditary autosomal dominant mutations, inherited from an affected parent. Hereditary cancer syndromes, such as those associated with BRCA1 or BRCA2, are relatively rare. Only 5% to 10% of breast cancers are considered hereditary; of those, approximately 80% are related to mutations in BRCA1 or BRCA2.10
Several “red flags” suggest the possibility of a hereditary type of breast cancer syndrome. Genetic risk is primarily identified through thorough history taking, which must address both the maternal and paternal sides of the family—over three generations, if possible.10 Table 210-14 identifies these red flags.
Atypical cells identified on breast biopsy also increase breast cancer risk. The presence of ADH or ALH increases a woman’s risk four to five times higher than the average.2 LCIS is associated with a 10-fold increase in breast cancer risk.9 The overall incidence of breast cancer in women with LCIS is estimated at 22.3%.3
Radiation exposure to the chest wall, particularly when administered between ages 10 and 30, also increases the risk for breast cancer. This usually occurs in female patients who have undergone mantle-field radiation treatment for another cancer, such as Hodgkin’s disease or non-Hodgkin’s lymphoma.15,16 Risk associated with this type of treatment can be as great as 12 times the normal risk. Patients treated before or during adolescence appear to be at highest risk.2 Persons exposed to other types of radiation (eg, survivors of atomic weapons) also have increased breast cancer risk.1
Rare genetic syndromes not associated with BRCA1 or BRCA2 have been associated with breast cancer as well. Cowden, Li-Fraumeni, and Peutz-Jeghers syndromes are all known hereditary breast cancer syndromes.4-7 Although these syndromes account for less than 1% of all breast cancers,10 it is important to be able to identify a patient who is at risk for harboring a genetic mutation that causes one of these syndromes—and to understand how to manage a woman who is already affected.
Cowden syndrome is an autosomal dominant disorder caused by a mutation in the PTEN gene.4,17 This syndrome carries a 25% to 50% risk for breast cancer.18 Other findings associated with Cowden syndrome include facial or buccal lesions, fibrocystic breast disease, benign thyroid conditions (eg, goiter), nonmedullary thyroid cancer, endometrial cancer, macrocephaly, uterine fibroids, and gastrointestinal hamartomas.3,10
Li-Fraumeni syndrome is a highly penetrant, autosomal dominant disorder caused by a mutation in the TP53 gene.4,6,19,20 Affected women’s overall cancer risk is 50% by age 35 and 90% lifelong. Breast cancer risk is estimated at 50% by age 50.3 Multiple primary cancers, including early-onset breast cancer (ie, before age 40), sarcoma, leukemia, childhood brain tumors, and adrenocortical carcinoma, are all associated with Li-Fraumeni.6,10,19,21
Peutz-Jeghers syndrome is also an autosomal dominant condition, caused by a mutation in the STK11 gene.3,22,23 The mean age of breast cancer diagnosis in affected women is 44. Hallmark features of Peutz-Jeghers include gastrointestinal hamartomas (often discovered during childhood24) and cancers of the colon, small bowel, pancreas, uterus, thyroid, lung, and breast. The most commonly reported malignancies in patients with Peutz-Jeghers syndrome are breast cancer and colon cancer. Associated phenotypic features include pigmented spots on the lips, buccal mucosa, and skin.10,24
Risk Assessment Tools
Women with any of the identified high-risk factors should be referred to a provider experienced in high-risk breast cancer assessment and management. Many comprehensive breast centers are adding high-risk programs to their array of services. Researching those programs in your area will facilitate the process of referral for women in your practice who are identified as high risk.
In efforts to identify patients at high risk for breast cancer, the importance of thorough history taking cannot be overstated. It is imperative that both the maternal and paternal sides of the family be assessed, as genetic mutations can be acquired through the patient’s mother or father.10
A variety of tools to assess breast cancer risk are available. The one most commonly used is the Gail risk assessment model,25 which was developed at the National Cancer Institute. A modified version, validated during the Breast Cancer Prevention Trial,26 calculates five-year and lifetime risk based on the following criteria:
• Current age
• Age at menarche
• Age at first live birth
• Number of first-degree relatives with a history of breast cancer
• Number of previous breast biopsies
• History of atypical cells on previous breast biopsy.
The Gail model has certain limitations. It cannot be used to assess women younger than 3527 or older than 85. Also, age at breast cancer diagnosis, non–first-degree relatives with breast cancer, paternal cancer history, ovarian cancer history, and ethnicity are not included among its considerations.3
The Claus model28 assesses risk in women with a family history of breast cancer more accurately than the Gail model, but it does not incorporate male breast cancer, ovarian cancer, or ethnicity.9
Several models are available to predict the risk for carrying a BRCA1 or BRCA2 mutation. The Myriad Genetic Laboratories database,29 the BRCAPRO model,30,31 the Manchester scoring system,32,33 the Tyrer-Duffy-Cuzick (IBIS) model,34 and the BOADICEA model35 all provide probability data, but each has its limitations. Breast specialists who provide high-risk assessment services calculate risk using a variety of models and choosing the most appropriate model(s) for each patient.36,37 Women with a high probability of carrying a mutation, based on history and findings from the risk assessment model, are referred for genetics counseling and testing.
Reducing the Risk
Risk reduction is an integral component of high-risk breast cancer management, and several strategies are currently recommended, including these:
• Exercise for 45 to 60 minutes at least five times per week.2,38 In women who engage in at least five hours of vigorous exercise each week, a 0.62 relative risk for breast cancer has been reported.38,39
• Limit alcohol intake to fewer than one to two drinks per day. A number of studies have documented a 30% to 50% increase in the incidence of breast cancer among women who consume alcohol in greater quantities.38,40
• Avoid obesity. Compared with women who have maintained their weight since age 18, those who gain 55 lb or more by menopause onset have a 1.45 relative risk for breast cancer.38,41
• Breastfeed infants. Lactation for two years or longer decreases the lifetime risk for breast cancer by 50%.3
• Follow a low-fat, high-fiber diet, rich in fresh fruits and vegetables. Increasing fruit and vegetable intake by even one serving per day has been associated with a 9% decrease in breast cancer incidence.38,42
Chemoprevention for At-Risk Women
Another risk reduction strategy for women at particularly high risk for breast cancer is chemoprevention. Currently, two medications, tamoxifen and raloxifene, are FDA approved for breast cancer risk reduction in women at high risk. These agents are offered to women with specific high-risk factors, including:
• Findings of LCIS, ADH, or ALH on previous breast biopsy
• A five-year probability of breast cancer exceeding 1.7%, based on a validated risk assessment model (eg, the Gail model, BRCAPRO)
• Presence of the BRCA1 or BRCA2 mutation.
Tamoxifen is a selective estrogen receptor modulator (SERM) that blocks the effects of estrogen on breast tissue.43 Often referred to as an “antiestrogen,” it is approved for use in both premenopausal and postmenopausal women. In the Breast Cancer Prevention Trial,44 women at high risk for breast cancer who took tamoxifen for five years had about a 50% risk reduction for invasive breast cancer and a 30% risk reduction in noninvasive breast cancer. The usual dose of tamoxifen is 20 mg/d.
Adverse effects associated with tamoxifen use, however, include blood clots, stroke, and uterine cancer. Women should not take tamoxifen if they have a history of cataracts, are current hormone therapy users, are planning a pregnancy or have the potential for becoming pregnant, or have a history of stroke, deep venous thrombosis, or pulmonary embolus. Less serious adverse effects include menopausal symptoms, menstrual irregularities, headache, fatigue, nausea, and skin irritation.43
Raloxifene, though more commonly prescribed to prevent and treat osteoporosis, has been shown to reduce the risk for invasive breast cancer by 56% to 72%, compared with placebo45,46; it exerts estrogenic effects on bone and antiestrogenic effects on breast and endometrial tissue.47 This SERM is approved for breast cancer risk reduction only in postmenopausal women.48 Recommended use is 60 mg/d for five years.
Although raloxifene provides a risk reduction benefit comparable to that of tamoxifen against invasive breast cancer (ie, incidence rates of 4.4 and 4.3, respectively, per 1,000 women per year49), it does not appear to reduce the risk for noninvasive breast cancer (ie, ductal carcinoma in situ).50 Potential major complications attributed to raloxifene use include blood clots, stroke, and uterine cancer, although the risk for uterine cancer is lower than with tamoxifen use.49 Minor adverse effects include leg cramps, menopausal symptoms, edema of the extremities, and flulike symptoms. Contraindications are comparable to those associated with tamoxifen.48
Combined with mammography and breast ultrasound, the use of MRI to screen high-risk women is now being recommended, according to guidelines published in March 2007 by the American Cancer Society.20 Patient factors suggesting greatest benefit from annual MRI screening (combined with mammography) are listed in Table 3.4,20,51-55
In addition to patient-driven reduction strategies and the provider-initiated interventions for surveillance and management, monthly breast self-examination is encouraged, as are clinical breast examinations every six months.
Even with the most aggressive risk reduction program, not all breast cancers can be prevented. A key objective of high-risk screening and management is to identify patients with breast cancer at the earliest possible stage so that a cure is more likely to be achieved.
Identifying and screening women at high risk for breast cancer are essential skills for all primary care providers. Maintaining a comprehensive list of referral sources for high-risk management and genetic counseling services in your area will allow you to partner with other professionals to provide patients with the best possible care. Women feel empowered by education, particularly the newly acquired knowledge about breast cancer risk reduction—and reassured, knowing that their providers are interested and well informed in this complex area of women’s health.
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