There is increasing evidence that lifestyle changes may alter an individual's breast cancer risk.
Exercise has been associated with a reduction in breast cancer risk. The benefit was greatest in younger, premenopausal women. The activity can be related to leisure or work-time activities.
Women who exercise 3.5 to 4 times per week may have a reduced incidence of breast cancer, when compared with women who do not exercise. The protective effect of exercise may be associated with a reduction in the frequency of ovulatory cycles and in circulating estrogen and progesterone(Drug information on progesterone) levels.
Numerous studies of the effects of alcohol(Drug information on alcohol) consumption on breast cancer risk and the results of a cohort study addressing this issue have been published. When compared with nondrinkers, women who consumed 2.3 to 4.5 bottles of beer per day, 2.5 to 5.6 glasses of wine per day, or 2 to 4 shots of liquor per day had a 41% higher risk of developing invasive breast cancer. Some reports indicate that the consumption of a moderate amount of alcohol (red wine) may decrease the risk of breast cancer, although these results are not conclusive. The biologic basis for the association between alcohol consumption and an increased risk of breast cancer is unclear. It has been proposed that there is a positive correlation between alcohol and estrogen levels.
Alterations in diet and tobacco use
A reduced incidence of breast cancer has been observed in countries where the diet is typically low in fat. However, no reduction in breast cancer risk has been observed in the United States when women followed low-fat diets.
Prentice et al randomly assigned postmenopausal women without prior breast cancer to an intervention designed to reduce total daily fat consumption to a minimum of 20% or to no dietary intervention. They found no statistically significant reduction in invasive breast cancer risk over a period of approximately 8 years of follow-up. However, women consuming a high-fat diet at baseline showed a significant reduction in breast cancer risk (P = .04). The authors also noted an effect that varied by hormone receptor status of the tumor.
There appears to be an association between cigarette smoking and breast cancer risk. It is not clear whether the risk for breast cancer decreases when someone stops smoking.
Although it has been suggested that lactation may protect against breast cancer, there are conflicting studies. A recent study failed to demonstrate any breast cancer risk reduction in women who breast-fed and showed no dose-response effect in women who breast-fed for longer periods. A retrospective study showed reduction breast cancer risk associated with breast feeding among BRCA carriers.
The NIH and NCI have publicized the results of the National Surgical Adjuvant Breast and Bowel Project (NSABP) Breast Cancer Prevention Trial (BCPT). Women who had a risk of developing breast cancer equivalent to that of women 60 years of age qualified as participants in this double-blind, randomized trial. (For representative eligibility profiles, see Table 5.) A total of 13,388 women were randomized to receive tamoxifen(Drug information on tamoxifen) or placebo.
Benefits of therapy
The summary results indicated that tamoxifen prevented about half of both invasive and noninvasive breast cancers in all age groups. A secondary benefit of tamoxifen appeared to be a reduction in the incidence of hip fracture (Table 6). At present, no survival advantage has been shown for participants in this trial.
Tamoxifen-treated women younger than age 50 had no apparent increase in side effects. However, women older than age 50 experienced serious side effects, including vascular events and endometrial cancer. Particularly worrisome was the increased incidence of endometrial cancer in the tamoxifen-treated patients (Table 6). In addition, a significant increase in pulmonary embolism and deep vein thrombosis was noted, especially in women older than age 50 (Table 6).
Based on results of the BCPT, the FDA has approved tamoxifen for use in women at high risk (> 1.66% chance of getting breast cancer in the next 5 years, based on the Gail model) of breast cancer.
The NCI and NSABP are in the process of developing risk profiles based on age, number of affected first-degree relatives with breast cancer, number of prior breast biopsies, presence or absence of atypical hyperplasia or LCIS, age at menarche, and age at first live birth. These risk profiles may help guide women in making the decision as to whether or not to take tamoxifen.
An ASCO working group published an assessment of tamoxifen use in the setting of breast cancer risk reduction. All women older than 35 years of age with a Gail model risk of > 1.66% (or the risk equivalent to that of women 60 years of age) should be considered candidates for this treatment strategy. Comorbid conditions, such as a history of deep vein thrombosis, must be a part of the consent process and treatment decision.
Although the BCPT results establish tamoxifen as the standard of care for the primary chemoprevention of breast cancer in high-risk women, concern over the side effects of tamoxifen prompted a search for an agent that displays a more desirable efficacy/toxicity profile. Raloxifene(Drug information on raloxifene) (Evista), approved for the prevention of osteoporosis in postmenopausal women, and for the reduction in risk of invasive breast cancer in postmenopausal women with osteoporosis, displays antiestrogenic properties in the breast and endometrium and estrogenic effects in the bone, making it an attractive candidate for comparison with tamoxifen.
The STAR (Study of Tamoxifen and Raloxifene) trial (or NSABP P-2) began in July 1999 at almost 400 centers in North America. A total of 19,747 postmenopausal women, or women > 35 years old at increased risk of breast cancer by Gail criteria, were randomized to receive either tamoxifen (20 mg/d) or raloxifene (60 mg/d) for 5 years. Study endpoints included invasive and noninvasive breast cancers, cardiovascular disease, endometrial cancer, bone fractures, and vascular events.
There were 163 cases of invasive breast cancer in women assigned to tamoxifen and 168 of those assigned to raloxifene (incidence, 4.30 per 1,000 vs 4.41 per 1,000; risk ratio, 1.02; 95%, 0.82-1.28). There were fewer cases of noninvasive breast cancer in the tamoxifen group (57 cases) than in the raloxifene group (80 cases); (incidence, 1.51 vs 2.11 per 1,000; risk ratio, 1.40; 95% CI, 0.98–2). There were 36 cases of uterine cancer with tamoxifen and 23 with raloxifene (risk ratio, 0.62; 95% CI, 0.35–1.08). The risk of other cancers, fractures, ischemic heart disease, and stroke is similar for both drugs. There was no difference in the total number of deaths (101 for tamoxifen vs 96 for raloxifene) or in causes of death. The authors concluded that raloxifene is as effective as tamoxifen in reducing the risk of invasive breast cancer and has a lower risk of thromboembolic events and cataracts but a nonstatistically significant higher risk of noninvasive breast cancer.
The MAP3 trial investigated the role of an aromatase inhibitor, exemestane(Drug information on exemestane), in the prevention of breast cancer. In this randomized, double-blind trial, 4,560 postmenopausal women who were at moderately increased risk for breast cancer were randomly assigned to either exemestane or placebo. At a median follow-up of 35 months, 11 invasive breast cancers were detected in those given exemestane and in 32 of those given placebo, with a 65% relative reduction in the annual incidence of invasive breast cancer (0.19% vs 0.55%; HR, 0.35; 95% CI, 0.18–0.70; P = .002). The annual incidence of invasive plus noninvasive (ductal carcinoma in situ) breast cancers was 0.35% on exemestane and 0.77% on placebo (HR, 0.47; 95% CI, 0.27–0.79; P = .004). Adverse events occurred in 88% of the exemestane group and 85% of the placebo group (P = .003), with no significant differences between the two groups in terms of skeletal fractures, cardiovascular events, other cancers, or treatment-related deaths. During a median follow-up period of 3 years, exemestane was associated with no serious toxic effects and only minimal changes in health-related quality of life.
Vitamin D is a regulator of cellular growth and differentiation. In a prospective Canadian study, vitamin D levels in women newly diagnosed with breast cancer (T1-3, N0-1, M0) more than 10 years before the study began were assessed in archived blood samples taken after surgery and prior to systemic therapy (n = 512). Vitamin D deficiency was associated with an increased risk of distant recurrence (independent of age, BMI, insulin level, and T and N stage, and not significantly modified by ER status, or use of adjuvant chemotherapy or tamoxifen) and death, while patients with insufficient vs sufficient vitamin D levels had similar outcomes. These early findings raise the question of whether vitamin D supplementation might improve breast cancer-specific survival.
The most widely used system to stage breast cancer is the American Joint Committee on Cancer (AJCC) classification, which is based on tumor size, the status of regional lymph nodes, and the presence of distant metastasis (Table 7).
Assessment of clinical stage is performed initially and is determined after the physical examination and appropriate radiologic studies have been performed.
Pathologic stage is determined following surgery for operable breast cancer. Pathologic tumor size may differ from clinical tumor size. In addition, axillary nodal metastases that were not clinically evident may be detected after pathologic examination. With the advent of powerful molecular techniques, isolated tumor cells (ITCs) can be identified in histologically negative nodes. In the current AJCC staging, pathologic staging of nodes for detection of ITCs was included to obtain more information and, it is hoped, gain insight into the biologic significance of these ITCs.
Numerous prognostic factors for breast cancer have been identified.
Lymph node status
Axillary nodal metastasis is the most important prognostic factor in patients with breast cancer. Survival was examined relative to the number of nodes involved and the location of nodes that contained metastatic deposits. For any given number of positive nodes, survival was independent of the level of involvement but was directly related to the number of involved nodes.
Overall, patients who have node-negative disease have a 10-year survival rate of 70% and a 5-year recurrence rate of 19%. As the number of positive nodes increases, so does the likelihood of relapse. Patients with > 10 positive lymph nodes have a recurrence rate of 72% to 82%. The majority of patients who develop recurrence after initial curative treatment of early-stage breast cancer will have distant metastases.
In general, hormone receptor–positive tumors have a more indolent course than do hormone receptor–negative tumors.
Other considerations used to predict outcome are tumor size, histologic grade, lymphovascular permeation, S-phase fraction, and ploidy. Well differentiated breast cancers have a better prognosis than moderately or poorly differentiated cancers. Likewise smaller tumors are more favorable than larger ones and the absence of lymphovascular invasion is better than its presence.
More recently, molecular prognostic factors have been evaluated to determine their utility in predicting outcome. They include the growth factor receptors (epidermal growth factor receptor and HER2), tumor suppressor genes (TP53), proteolytic enzymes that may be associated with invasion of disease and metastasis (cathepsin D), and metastasis suppressor genes (NME1). Of these molecular markers, HER2 is probably the most widely studied in breast cancer to date.
All breast cancers should be evaluated by immunohistochemistry (IHC) staining for estrogen and progesterone receptor status and HER2 overexpression. The presence of the estrogen receptor (ER) and/or the progesterone receptor (PR) imparts a more favorable prognosis. In addition, these receptors are predictive of response to hormonal therapy. HER2, also referred to as HER2/neu or ErbB2, is a 185-kd transmembrane tyrosine kinase that regulates cell growth, survival, migration, differentiation, and adhesion. Overexpression of HER2 leads to dimerization of the receptors, which causes activation of the tyrosine kinase. HER2 overexpression is seen in approximately 20% to 30% of all breast cancers and was traditionally considered a more aggressive and a less favorable disease with reduced disease-free and overall survival. However, the development of biologic agents such as trastuzumab(Drug information on trastuzumab) has revolutionized the treatment of this type of breast cancer. A HER2 IHC score of 0-1+ is considered negative, 2+ is equivocal, and 3+ is positive. Equivocal HER2-positive tumors undergo fluorescence in situ hybridization (FISH) analysis for evaluation of HER2 gene amplification. Despite ASCO-CAP guidelines classifying tumors with amplification 1.8 to 2.2 as equivocal, HER2 amplification of 2 or greater is sufficient for a patient to be considered eligible for anti-HER2 therapy (ie, trastuzumab).