SYMPOSIUM ON BREAST CANCER

Assessing breast cancer risk

Genetic factors are not the whole story

Larissa A. Korde, MD, MPH; Kathleen A. Calzone, RN, MSN, APNG; JoAnne Zujewski, MD

VOL 116 / NO 4 / OCTOBER 2004 / POSTGRADUATE MEDICINE

CME learning objectives

• To learn how to identify and quantify risk factors for breast cancer
• To understand and know where to find breast cancer quantitative risk-assessment tools
• To become familiar with several breast cancer risk-management strategies and how to identify appropriate candidates for risk reduction

The authors disclose no financial interests in this article. They disclose unlabeled uses of aromatase inhibitors, nonsteroidal anti-inflammatory drugs, raloxifene, and retinoids.

Preview: Genetic syndromes that convey a significant risk of breast cancer are responsible for a small but significant percentage of these cancers. However, the vast majority of breast cancers occur in women with no family history of the disease. Nongenetic risk factors include age, previous breast disease, breast tissue density, radiation exposure, and lifestyle factors, such as weight, exercise, and alcohol consumption. In this article, the authors outline genetic and other risk factors for breast cancer, explore risk-reduction strategies, and encourage primary care physicians to assess breast cancer risk in all their patients.
Korde LA, Calzone KA, Zujewski J. Assessing breast cancer risk: genetic factors are not the whole story. Postgrad Med 2004;116(4):6-20, 34

In the United States, it is estimated that 215,990 new cases of invasive breast cancer will be diagnosed in women in 2004, and 40,110 women will die of the disease (1). In women, breast cancer is the leading cause of cancer and is second only to lung cancer in cancer deaths. Because breast cancer is such an important public health issue, it is critical that in primary care, patients' risk of breast cancer is assessed and appropriate risk-management strategies are recommended.

Women at average risk for breast cancer have about a 10% to 14% chance of having this disease by age 90 years. At increased risk are women with a strong family history of breast cancer, those with a known or suspected genetic predisposition for breast cancer, those with a history of thoracic irradiation, those with previous breast disease, and those with a 5-year Gail model risk of 1.67% or greater. (For risk factors included in the Gail model, see table 1.) Risk-reduction strategies should be tailored to each patient's lifetime breast cancer risk, balance of risk and benefits, and personal preference.

Table 1. Gail model risk factors

Age (model valid only for ages >35 yr) Age at menarche Age at first live birth Number of first-degree relatives with breast cancer Number of previous breast biopsies Atypical hyperplasia on any previous breast biopsy Race* *Projections for women of African American, Hispanic, and other racial and ethnic descent are subject to greater uncertainty than those for white women.

About 5% to 10% of breast cancers occur in women with an inherited susceptibility to cancer (2). The majority of these are women with hereditary breast and ovarian cancer syndrome, which is explained by deleterious mutations in the BRCA1 and BRCA2 genes. These mutations are transmitted in an autosomal dominant pattern. According to estimates, mutations in these two genes are responsible for cancer in most families with both breast and ovarian cancer and in close to half of families with breast cancer only (3). Features suggestive of hereditary breast and ovarian cancer syndrome are listed in table 2. Other autosomal dominant syndromes that carry an increased risk of breast cancer include Li-Fraumeni syndrome, Cowden disease, and Peutz-Jeghers syndrome (4-8) (table 3).

Table 2. Features suggestive of hereditary breast and ovarian cancer syndrome

Early-onset breast cancer (age <40 yr, or age <50 yr if Ashkenazi Jewish heritage) Ovarian cancer in a woman with family history of breast or ovarian cancer Breast and ovarian cancer in the same woman Bilateral breast cancer Breast cancer in a male patient Ashkenazi Jewish heritage and family history of breast cancer Information from National Comprehensive Cancer Network. Genetic/familial high-risk assessment: breast and ovarian. NCCN clinical practice guidelines in oncology, version 1.2004. Available at: http://www.nccn.org/professional/physician_gls/default.asp. Accessed Aug 13, 2004.

Another 15% to 20% of breast cancers occur in women with a family history of the disease but no readily identifiable inheritance pattern. These cancers are likely due to a combination of genetic and environmental factors or to genes that have yet to be identified (2). Despite the existence of these genetic susceptibilities, however, it is important to appreciate that the vast majority of breast cancers occur in women with no family history of the disease.

Risk factors

A number of factors are known to increase the risk of breast cancer in women without a genetic predisposition (9-15) (table 4). As with other cancers, age is one of the strongest risk factors. Breast cancer is extremely uncommon in women younger than 30 years. The incidence rate begins to increase between ages 35 and 39 years and plateaus at age 80 years (16). Breast cancer incidence is also influenced by race. In the United States, breast cancer risk is slightly higher in whites than in African Americans, although the incidence of early-onset cancers is higher in African Americans. Incidence rates are markedly lower in other racial and ethnic groups (16). Figure 1 shows breast cancer incidence for various races by age at diagnosis.

Reproductive and hormonal factors
Multiple hormonal and reproductive factors have been shown to influence the development of breast cancer (9). Breast cancer risk may be related to the total number of ovulatory menstrual cycles a woman experiences in her lifetime. Risk is inversely related to age at menarche and is increased with a late age at menopause. Risk is drastically reduced by a young age at first live birth and increased by nulliparity. The effects of these reproductive and menstrual factors are likely related to hormonal pathways. High levels of serum estrogens, particularly estradiol, have been shown in multiple studies to increase the risk of breast cancer in postmenopausal women (17).

Exogenous hormones also increase breast cancer risk. Combined hormone replacement therapy (with estrogen and progestin) was recently shown in the Women's Health Initiative study (10) to increase the risk of breast cancer by 26%. The effect of oral contraceptive use on breast cancer risk has been more controversial. However, the most recent data from prospective analyses and meta-analyses provide solid evidence that oral contraceptive use is not associated with increased risk of breast cancer (18,19).

Previous breast disease
Benign breast disease is a term that encompasses a heterogeneous group of histologic entities, including chronic cystic mastitis, fibroadenoma, fibrocystic disease, and hyperplastic, or proliferative, lesions. Women with hyperplasia or a previous breast biopsy showing a proliferative lesion have up to twice the risk of breast cancer compared with women with nonproliferative lesions (11). If atypical cells are seen, there is a greater increase in risk.

Atypical hyperplasias can be divided into two histologic subtypes: lobular and ductal. Lobular neoplasia refers to a spectrum of histologic changes, from atypical lobular hyperplasia to lobular carcinoma in situ, that carry a fourfold to 10-fold increased risk of breast cancer (11). Atypical ductal hyperplasia is thought to increase the risk by fourfold to fivefold (11). Although not considered malignant, these conditions are seen as markers for increased risk of breast cancer. In contrast, ductal carcinoma in situ, though noninvasive, is considered breast cancer and therefore requires definitive treatment. Women with a history of breast cancer, either invasive or noninvasive, are at increased risk of a contralateral breast cancer.

Mammographic density
Breast tissue density, as determined by mammography, is an independent risk factor for breast cancer. Numerous studies have shown an association between the finding of dense breast tissue on mammography and breast cancer risk (12). Most studies using quantitative methods for defining breast density show a fourfold to sixfold increase in risk in women with the most dense breasts compared with those with little or no tissue density. The determinants of breast tissue density are not fully defined but include age, estrogen exposure, and family history.

Lifestyle and environmental factors
Because they are potentially modifiable, lifestyle factors represent an important class of risk factors for breast cancer. Obesity has been extensively studied and in general has been found to increase the risk of breast cancer by up to two and a half times in postmenopausal women (13). Conversely, obesity appears to be protective in premenopausal women. This is likely due to an increase in anovulatory cycles, resulting in lower levels of circulating estrogens in young obese women. Epidemiologic data about physical activity suggest a 20% to 30% reduction in the risk of breast cancer in women who are physically active compared with those who are inactive (14). Finally, moderate to heavy alcohol intake (more than 45 g of alcohol, or three drinks, per day) has been shown to confer a modest but statistically significant increase in risk of breast cancer, in an apparent dose-response relationship (15).

Radiation exposure, such as thoracic irradiation used in the treatment of Hodgkin's lymphoma, significantly increases the risk of breast cancer. The magnitude of this risk is variable, and studies show a range of relative risk from 4.5 to 25 (20). Risk is related to radiation dose received and age at treatment, and the highest risk is seen in women treated before age 21 years.

Risk assessment

A complete breast cancer risk assessment includes evaluating for known risk factors, using appropriate risk-assessment tools, and obtaining a thorough family history. Family history should include information on three generations (both maternal and paternal) and ethnic background. In women with a family history suggestive of an inherited syndrome, referral to a cancer genetics specialist for further assessment and counseling may also be appropriate.

Assessment models
There are two types of models used in breast cancer risk assessment--those that estimate the risk of breast cancer over time and those that estimate the risk of a mutation in one of the BRCA genes. The Gail (21) and Claus (22,23) models are the most commonly used models for estimating breast cancer risk over time.

The Gail model was developed in 1989 by Mitchell Gail and colleagues, who used data from the Breast Cancer Detection Demonstration Project. The original model produced risk estimates for both invasive and noninvasive breast cancer in women undergoing annual screening mammography. It has subsequently been modified with data from the Surveillance, Epidemiology, and End Results (SEER) database and has been adapted to project risks for African American women, although it has not been validated in this setting (24).

The version of the Gail model currently in use incorporates a number of risk factors to estimate a woman's 5-year and lifetime risks of invasive breast cancer (see table 1). A 5-year Gail model risk of 1.67% or greater is considered elevated and is used as a criterion for entry into many breast cancer prevention trials.

The Gail model has several limitations. It may underestimate risk in women with a family history of breast cancer because it only considers first-degree relatives (mothers, sisters, and daughters) and does not include their age at diagnosis. It also does not consider paternal family history. Furthermore, the Gail model does not take into account a family history of ovarian cancer, which may be of crucial importance in women with hereditary breast and ovarian cancer syndrome.

The Claus model is useful for assessing breast cancer risk in women with a family history of the disease. This model is based on two papers by Elizabeth Claus and colleagues that present a series of tables with risk estimates determined on the basis of family history of breast (22) and ovarian (23) cancer. It considers both maternal and paternal family history, takes into account second-degree relatives (maternal and paternal aunts), and also uses age at diagnosis of family members.

These two models are useful in different settings. Because the Gail model integrates a number of well-established breast cancer risk factors, it is best used for assessing risk in the general population of women who are undergoing screening mammography but do not have a strong family history. However, in women with a family history of breast cancer, the Claus model is likely to provide a more accurate estimate.

Strong family history
If a patient's family history is strongly suggestive of an inherited susceptibility to breast cancer, referral to a cancer genetics specialist is recommended. In this situation, several models can be used to estimate the risk of having a BRCA1 or BRCA2 mutation. These include the Couch, Shattuck-Eidens, and Frank models and the BRCAPRO computer model (25). Referral to a genetics specialist ensures a complete evaluation for the likelihood of an inherited cancer susceptibility syndrome and allows for gene testing, if appropriate. In patients with a strong family history of breast cancer, a thorough cancer risk management plan, including screening, chemoprevention, and consideration of other risk-reducing options, is crucial.

Risk reduction

Screening mammography remains the mainstay of breast cancer risk management. According to American Cancer Society guidelines, all women, regardless of their risk of breast cancer, should undergo yearly clinical breast examinations beginning at age 20 and annual mammography beginning at age 40. In women with a history of thoracic irradiation, it is recommended that screening mammography be instituted 8 to 10 years after radiation therapy or at age 40, whichever comes first. In women with known BRCA1 or BRCA2 mutations, screening mammography should begin at age 25 (26). In addition, women at risk for breast cancer should be counseled to either avoid hormone replacement therapy or restrict its use to the short term if needed for control of menopausal symptoms.

A number of lifestyle modifications may also affect breast cancer risk. These include weight loss or maintenance of ideal body weight (body mass index, 19 to 25 kg/m²), physical activity according to American College of Sports Medicine guidelines (moderate physical activity for at least 30 minutes most days of the week), and little or no alcohol consumption.

In women who have a greater-than-average risk of breast cancer, additional risk-reduction strategies should be considered. These include earlier and more intensive screening, chemoprevention, participation in breast cancer prevention clinical trials, prophylactic surgery, and use of additional imaging techniques. Figure 2 provides an algorithm for management based on breast cancer risk factors.

Chemoprevention
The term chemoprevention refers to the use of medications to reduce cancer risk. Currently, tamoxifen citrate (Nolvadex), a selective estrogen receptor modulator (SERM), is the only agent approved by the US Food and Drug Administration (FDA) for breast cancer risk reduction. In 1998, results of a large randomized trial (27) showed that tamoxifen reduced the incidence of breast cancer by 49% in women at high risk for the disease. The most marked risk reduction was seen in women with a history of atypical hyperplasia, who had an 86% decrease in risk. Tamoxifen use is also associated with a decreased risk of osteoporotic bone fracture in postmenopausal women.

However, tamoxifen does have significant side effects, most of which are seen in women older than 50 years. In this population, there was a fourfold increase in the risk of endometrial cancer, although most tumors were early stage and were cured by hysterectomy (27). There was also a threefold increase seen in the rate of pulmonary embolism, which is on the order of that seen with hormone replacement therapy. In addition, cataract formation was also increased in older study participants. The most bothersome side effect seen with tamoxifen is hot flashes.

Individual characteristics and side effect profile must be reviewed when a patient is being evaluated for tamoxifen therapy. A variety of factors should be considered in this assessment for treatment (table 5).

Table 5. Factors to consider before tamoxifen therapy

Greatest clinical benefit seen in women aged <50 yr who are at high risk for breast cancer Most side effects seen in women aged >50 yr Highest risk reduction seen in women with history of atypical hyperplasia Risk-benefit ratio more favorable in women who have had a hysterectomy Net risk-benefit ratio varies by race Risk of thromboembolic events must be considered Uncertain role in women with BRCA1 or BRCA2 mutations and women with history of thoracic irradiation Information from Gail MH, Costantino JP, Bryant J, et al. Weighing the risks and benefits of tamoxifen treatment for preventing breast cancer. J Natl Cancer Inst 1999;91(21):1829-46 [Erratum, J Natl Cancer Inst 2000;92(3):275].

Another SERM that has shown promise as a chemopreventive agent is raloxifene (Evista), which has FDA approval for the treatment and prevention of osteoporosis (28). The Multiple Outcomes of Raloxifene Evaluation (MORE) trial (29), which was designed to evaluate the effect of raloxifene on osteoporosis risk, showed a significant reduction in the risk of breast cancer in participants (30), although this was a secondary end point of the trial. The risk of thromboembolic events with raloxifene use is similar to that with tamoxifen, but raloxifene does not increase the risk of endometrial cancer. Hot flashes are also seen with raloxifene. The Study of Tamoxifen and Raloxifene (STAR) trial, which includes postmenopausal women at high risk for breast cancer, is a head-to-head comparison of these two agents. Data from this important study are expected in 2006 (31).

A number of other agents, including aromatase inhibitors, retinoids such as fenretinide, and nonsteroidal anti-inflammatory drugs, such as celecoxib (Celebrex), are currently being evaluated for breast cancer prevention in clinical trials (28). (A listing of breast cancer prevention trials open for accrual can be found at http://www.cancer.gov.) Referral for prevention clinical trials should be strongly considered for motivated patients with increased breast cancer risk.

Prophylactic surgery
In women with known or suspected hereditary breast and ovarian cancer syndrome, prophylactic surgery can significantly reduce the risk of cancer. In patients with known genetic mutations, prophylactic mastectomy has been shown to reduce the risk of breast cancer by at least 90% (32). Prophylactic oophorectomy reduced the risk of ovarian cancer in these patients by greater than 90% (33,34). When performed before menopause, this procedure also reduced the risk of breast cancer by 50% (33,34). As a result, it is recommended that patients with known genetic mutations consider the option of prophylactic oophorectomy once childbearing is completed.

Imaging techniques
There is some concern that mammography does not have sufficient sensitivity in young women with a very high risk of breast cancer and that the cancer may be more difficult to detect by mammography in premenopausal women because of denser breast tissue. Breast magnetic resonance imaging is not limited by dense tissue and has recently been found to be a useful adjunct to mammography in this population (35). While this technique is thought to be highly sensitive for the detection of mammographically occult cancers, it has low specificity, and its use may lead to additional imaging and biopsy procedures (36). It should therefore be reserved for women at very high risk of breast cancer or in a clinical trial setting.

Conclusion

Breast cancer is an important public health issue, tallying over 200,000 new cases each year. While the vast majority of these cancers occur in women with no family history of breast cancer, a small but significant percentage are associated with a hereditary breast and ovarian cancer syndrome, which greatly increases the risk of breast and ovarian cancer. It is important for primary care physicians to be well versed in breast cancer risk assessment and to be able to use quantitative risk-assessment tools such as the Gail and Claus models. It is also essential for physicians to be aware of factors associated with a high probability of a genetic mutation for breast cancer so that they can identify patients who should be referred for genetic counseling and testing. Finally, physicians should be aware of potential risk-reduction strategies that can be offered to patients at increased risk for breast cancer.

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Dr Korde is a fellow in cancer prevention and medical oncology, division of cancer prevention and Center for Cancer Research, National Cancer Institute, Bethesda, Maryland. Ms Calzone is senior nurse specialist, genetics branch, Center for Cancer Research, National Cancer Institute. Dr Zujewski is medical director, clinical research operations, Center for Cancer Research, and head, breast cancer section, medical oncology clinical research unit, National Cancer Institute. Correspondence: Larissa A. Korde, MD, MPH, National Cancer Institute, 10 Center Dr, Bldg 10, Room 12N226, Bethesda, MD 20892. E-mail: kordel@mail.nih.gov.

Symposium Index

• ASSESSING BREAST CANCER RISK: Genetic factors are not the whole story. By Larissa A. Korde, MD, MPH, Kathleen A. Calzone, RN, MSN, APNG, JoAnne Zujewski, MD
• MANAGING EARLY BREAST CANCER: Prognostic features guide choice of therapy. By Hamid R. Mirshahidi, MD, Jame Abraham, MD
• Clinical Commentary. CARE OF THE BREAST CANCER SURVIVOR: Increased survival rates present a new set of challenges. By Nicole J. McCarthy, MBBS, MHSc, FRACP

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