Breast Cancer:

For many years, "breast cancer prevention" for primary care clinicians meant ordering mammograms and ensuring that patients received appropriate follow-up. Certainly, screening for early disease is a crucial component of breast cancer prevention, because tumors found at the in situ or early stage are more amenable to treatment, and mammographic screening has been shown to reduce breast cancer mortality.¹

There are now, however, options that clinicians can offer patients to reduce their risk. Modifiable risk factors for breast cancer include alcohol use; a sedentary lifestyle; overweight and obesity; use of menopausal hormone therapy; and certain exposures, such as radiation. Avoidance of these factors, while not proved in clinical trials to reduce risk, is likely to be beneficial. A number of medications have either been approved for breast cancer risk reduction or are undergoing testing, including selective estrogen response modulators and aromatase inhibitors. Women at very high risk for breast cancer, such as those with a genetic predisposition, may wish to consider more definitive measures for prevention, including prophylactic mastectomy and bilateral oophorectomy.

In this article, I review several interventions that have been shown or are postulated to reduce breast cancer risk in women with no history of the disease; these include chemoprevention, physical activity, weight control, diet, alcohol use, and avoidance of specific carcinogens.

TAMOXIFEN

The American Society for Clinical Oncology (ASCO) published guidelines in 2002 for the use of medications to reduce the risk of breast cancer,² and more recent reviews have been published (Table 1).³

Benefits. For women with a 5-year projected breast cancer risk of 1.66%, tamoxifen (20 mg/d for 5 years) may be offered to reduce risk and is FDA-approved for this purpose. Benefit-versus-risk models suggest that the greatest clinical benefit with the fewest side effects is seen in younger (premenopausal) women (in whom the adverse events of thromboembolic disease and uterine cancer are less likely to develop), women without a uterus, and women at higher breast cancer risk. However, there is no evidence that tamoxifen provides an overall health benefit or increases survival.

Statisticians at the National Cancer Institute have estimated that of the more than 65 million American women aged 35 to 79 years in 2000, more than 10 million (15.5%) would be eligible for tamoxifen treatment for breast cancer risk reduction.⁴ A smaller percentage, 4.9%, would be expected to have a positive benefit-versus-risk ratio. The benefit-versus-risk ratio varied greatly by race and ethnicity, with the greatest benefit expected in white women.

A meta-analysis of the 4 randomized placebo-controlled trials that have tested the effect of tamoxifen on breast cancer incidence found that tamoxifen reduced risk of breast cancer in women at elevated risk by 38%.⁵ These numbers translate into an estimated absolute risk reduction of less than 2 per 100 women without breast cancer treated with tamoxifen for 5 years. None of the 4 tamoxifen trials were designed to assess the effect of tamoxifen on survival, but 3 of the trials have been redesigned to follow patients long-term to death.² The optimal duration of use of tamoxifen for breast cancer prevention is not clear. Two of the 4 trials involved 5 years of therapy.^6,7 Thus, there is no known benefit of use for longer than 5 years.²

Tamoxifen reduces risk of estrogen receptor-positive breast cancer only. Tamoxifen also reduces the risk of benign breast disease, which is a benefit in terms of cost and the psychological distress associated with breast biopsies. Tamoxifen is equally effective in reducing breast cancer risk in women with and without a history of benign breast disease and in women with and without a positive family history. Mixed results have been found regarding the effect of tamoxifen on risk of breast cancer among BRCA1 or BRCA2 gene mutation carriers.

Risks. If you have a patient for whom you are considering chemoprevention, the first step is to determine her level of risk. A patient 60 years or older (which automatically gives her a 5-year breast cancer risk of 1.66% or higher) without contraindications is eligible for tamoxifen treatment. If she is between the ages of 35 and 59 years, her risk can be estimated with the Gail model, available on several Web sites, such as the National Cancer Institute's PDQ breast cancer prevention site (http://www. cancer.gov/cancerinformation).

If the patient is eligible, the next step is to determine her risk of adverse effects from tamoxifen. If she has a uterus, she is at risk for endometrial cancer, particularly if she has used menopausal hormone therapy or is obese. If she has a history of thromboembolic disease, including deep venous thrombosis, pulmonary embolus, stroke, or transient ischemic attack, her risk from these adverse events of tamoxifen therapy may outweigh potential benefits.

Discuss the benefits and risks of tamoxifen with the patient, and warn her about potential side effects, such as hot flashes and vaginal discharge. If she opts to take tamoxifen, she should return for follow-up visits every 6 months (Table 2).⁸ No routine blood work is indicated. If she has a uterus, she should have yearly pelvic examinations. The ASCO review did not recommend particular endometrial cancer screening, such as aspirations or transvaginal ultrasonography.² Advise the patient to contact you if vaginal bleeding develops; this could be an early sign of endometrial cancer. Note that thickening of the endometrial stripe on transvaginal ultrasonography is common in patients taking tamoxifen,⁸ so evaluation of vaginal bleeding should be aggressive. At each semiannual visit, ask patients about thromboembolic symptoms (eg, leg pain or swelling, pleuritic chest pain, or shortness of breath) and instruct them to report these symptoms immediately.

Patients taking tamoxifen should have regular ophthalmologic screening because of the increased risk of cataracts. Because tamoxifen increases the risk of stroke, evaluate stroke risk factors (hypertension, cholesterol, transient ischemic attack symptoms). Counsel obese patients to lose weight. Instruct premenopausal patients to avoid pregnancy and to use barrier methods of contraception. Advise patients that tamoxifen therapy does not obviate the need for regular mammograms and clinical breast examinations, both of which should be continued yearly.

Many women report significant hot flashes with tamoxifen therapy. These sometimes diminish over time. Several agents have been found to reduce hot flashes in breast cancer patients taking tamoxifen; these include vitamin E (800 U/d), vitamin C, clonidine patch (0.1 mg/wk), ergotamine tartrate, belladonna alkaloids, phenobarbital, and paroxetine (10 to 20 mg at bedtime).⁸ Note that selective serotonin reuptake inhibitors, such as paroxetine, may interfere with the metabolism of tamoxifen and thus reduce its effectiveness.⁹

Some women respond to a change in tamoxifen dosing (eg, 10 mg bid), or to discontinuing the drug for 2 to 4 weeks and then restarting it. Many women report an increase in vaginal discharge or in vaginal dryness. The latter condition can be treated with nonhormonal vaginal lubricants. Some physicians treat vaginal dryness with vaginal estrogens, but the lowest possible dose should be used because many women absorb significant amounts of estrogen through the vagina.

OTHER MEDICATIONS

The ASCO guidelines do not recommend raloxifene or aromatase inhibitors for breast cancer risk reduction, largely because clinical trial data are still pending regarding the effect of these medications on breast cancer incidence. The Multiple Outcomes for Raloxifene (MORE) trial, which was designed to test the effect of raloxifene compared with placebo on the risk of fractures in postmenopausal women with osteoporosis, found a 72% reduction in breast cancer risk.¹⁰ The Study of Tamoxifen And Raloxifene (STAR) is comparing the effect of raloxifene with that of tamoxifen on breast cancer incidence in 22,000 women who are at elevated risk for breast cancer.¹¹ The Raloxifene Use for The Heart (RUTH) trial is comparing raloxifene with placebo in women at increased risk for cardiac disease and has included breast cancer incidence as a secondary endpoint.¹²

Two randomized controlled trials are currently recruiting patients at elevated risk for breast cancer and will test the effect of aromatase inhibitors on incident breast cancer. The second International Breast Cancer Intervention Study (IBIS-II) will compare anastrozole, 1 mg/d for 5 years, with placebo in 10,000 women.¹³ The ExCel trial is testing the effect of exemestane, 25 mg/d for 5 years, in 5100 women.¹⁴

Other medications, including retinoids and NSAIDs, have been considered for breast cancer prevention; some of these agents are either in preclinical or early-phase testing, or have not been found to have a high enough benefit-versus-risk ratio to warrant administration for cancer prevention.^2,15

PHYSICAL ACTIVITY

More than 20 large epidemiologic cohort studies have investigated the association between physical activity and the risk of breast cancer; most showed clear evidence of a reduced risk in women who were classified at the highest levels of physical activity.^16,17 On average, the risk was 30% to 40% lower for women who exercised for 3 to 4 hours per week at moderate to vigorous levels, and was evident for women with and without a family history of breast cancer and for women at every level of risk for breast cancer.

For general health, weight control, and breast cancer risk reduction, all women should be encouraged to perform aerobic activity for 30 to 60 minutes on most days of the week. For younger women, vigorous activity, such as jogging, is most beneficial. For postmenopausal women, moderate activity, such as brisk walking, is sufficient.

WEIGHT CONTROL

More than 100 studies have examined the association of weight or body mass index (BMI), central fat distribution, adult weight gain, and the risk of breast cancer.^18,19 Taken together, the studies found that women who are overweight or obese have a 30% to 50% higher risk of postmenopausal breast cancer than leaner women. Women who are overweight or obese (BMI of 25 kg/m² or more) should be strongly encouraged to lose weight. Years of clinical research suggest that a combination of behavioral counseling, calorie reduction, and increased physical activity are the keys to successful weight loss and maintenance. For the physician, appropriate management includes following weight and BMI on the medical chart, regular follow-up visits, and appropriate referral to a nutritionist or weight-loss program. For the patient, diet and activity logs, as well as regular weighings (at least weekly), are helpful tools for weight loss.

Adult weight gain has been consistently associated with an increased risk of postmenopausal breast cancer.^20,21 Findings from 2 of the largest cohort studies suggest that the doubling of risk associated with a gain in BMI greater than 9.7 kg/m² after age 18 years or a weight gain of more than 20 kg was limited to women who had never used postmenopausal hormonal therapy.^20,21 In these studies, a 20% increase in risk was observed for BMI gains between 3.5 and 6.2 kg/m² and weight gains between 2 and 20 kg, although the confidence intervals around these gains were not statistically significant.

Monitor the weight of all patients. Evidence of yearly gains of more than 1 lb should trigger a discussion about methods of lifetime weight maintenance (eg, increased physical activity; eating a diet high in non-starchy vegetables and fresh fruit and low in fat and refined carbohydrates; and avoidance of high-calorie drinks, such as non-diet sodas).

DIETARY FACTORS

Vegetables and fruits. Early epidemiologic studies suggested that increased consumption of vegetables and fruits was associated with a decreased risk of breast cancer.²² A combined analysis of 8 cohort studies representing 351,825 women (including 7377 breast cancer patients), however, found no association.²³ Nevertheless, a diet high in non-starchy vegetables is crucial for weight loss and maintenance and should be encouraged for all patients.

Soy isoflavones and lignins. Epidemiologic data suggest that consumption of soy products is associated with a reduced risk of breast cancer.²⁴ However, recent animal model evidence indicates that genistein, a component of soy, may promote the growth of some estrogen-sensitive tumors and reduce the efficacy of tamoxifen.²⁵ Additional studies are needed to determine whether soy is safe for women who have or who are at increased risk for breast cancer. Phytoestrogens can act as weak estrogens or as estrogen antagonists, depending on the hormonal milieu. Thus, increased dietary phytoestrogens can compete with endogenous estrogens in premenopausal women and reduce overall estrogen exposure to target tissue. Conversely, phytoestrogens can increase estrogen activities in women with low endogenous levels of estrogens, such as postmenopausal women. These findings have been confirmed in animal experiments and in a small number of experimental studies in humans.²²

Dietary intake of soy and soy products is probably safe for most women, but regular use of concentrated forms of soy (powders, pills, or capsules) may not be advisable for women who have or who are at high risk for breast cancer.

Meat and dairy products. Some studies have pointed to increased intake of meats as a risk factor for breast cancer, but other data have not supported this finding.²² Part of the discrepancy may arise from the fact that different levels of carcinogens and mutagens are found in meats in different areas around the world. There is no evidence that meat intake is associated with increased breast cancer risk, although judicious portion control will help reduce calorie intake and control weight.

Consumption of dairy foods has not been associated with an increased risk of breast cancer. Although theoretically the relatively high fat content of dairy products could increase the risk by increasing energy intake, the high calcium and vitamin D content of many dairy products may be protective.²²

Vitamins and minerals. Several epidemiologic studies have investigated the association between dietary and supplemental intake of various vitamins and minerals and the risk of breast cancer. Micronutrients that have been associated with decreased risk include carotenoids, folate, calcium, vitamins C and D, and lycopene.²² The studies have had mixed results, however, and, because they have all been observational, are not conclusive. At this time, there is no evidence that taking any one supplement will reduce breast cancer risk.

Other dietary patterns. The Women's Health Initiative Dietary Modification Trial recently released results that showed a nonstatistically significant 9% reduction in risk of incident breast cancer in women randomized to a low-fat dietary pattern (goal: less than 20% of calories from fat; 5 vegetables/fruits and 6 servings of grains per day) for 8.1 years, compared with those assigned to usual diet.²⁶ There was some suggestion of increased risk reduction among women whose baseline dietary fat intake was greater than the median (more than 32% of calories from fat) and among women who were more adherent to the dietary program. In addition, there was a suggestion of increased risk reduction with time.

Presently, there is insufficient clinical evidence to recommend a low-fat dietary pattern for breast cancer risk reduction. However, reduced dietary fat intake in conjunction with calorie reduction is an important step in weight loss and should be recommended for overweight and obese patients.

AVOIDING CARCINOGENS

Alcohol. Several meta-analyses and major reviews of epidemiologic data confirm a moderate but statistically significant association between moderate to heavy alcohol intake and a subsequent risk of breast cancer.^22,27 There is evidence of a dose-response relationship--that is, as little as 1 to 2 drinks per day may increase risk. One combined analysis of data from 53 studies around the world estimated that the relative risk of breast cancer increased 7% for each 10-g increase in daily alcohol consumption.²⁸ The association between alcohol intake and increased breast cancer risk has been observed regardless of the type of alcohol consumed, and increased consumption has been shown to raise the risk of both premenopausal and postmenopausal breast cancer. Alcohol consumption may particularly increase the risk of breast cancer in women with suboptimal intake of certain nutrients, such as folate, β-carotene, lutein/zeaxanthin, and vitamin C.²⁹

Menopausal hormone therapy. The Women's Health Initiative, which involved more than 27,000 postmenopausal women, found that the combination of estrogen and progesterone (conjugated equine estrogens, 0.625 mg/d, plus medroxyprogesterone, 2.5 mg/d) increased the risk of breast cancer by more than 30% in less than 5 years,³⁰ and that unopposed conjugated equine estrogens, 0.625 mg/d, did not increase breast cancer risk.³¹ Multiple observational studies support these trial results, with the caveat that long-term use of unopposed estrogen may also increase risk slightly.³² In addition, menopausal hormone therapy increases mammographic density, which may reduce screening efficacy.³³ Therefore, the long-term use of this therapy is discouraged in any woman concerned about her risk of breast cancer. Menopausal symptoms such as hot flashes can be treated in the same way as those associated with tamoxifen.

RADIATION

Radiation exposure from radiographs or from environmental contamination increases the risk of breast cancer.³⁴ Unnecessary exposure to radiographs should be avoided. Women who are exposed to radiation treatments to the chest, such as for Hodgkin disease, are at increased risk for breast cancer and must be carefully monitored throughout life.³⁵

References:

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