Description of the Evidence
Incidence and mortality
With an estimated 232,670 cases expected, breast cancer will be the most frequently diagnosed nonskin malignancy in U.S. women in 2014. Also in 2014, breast cancer will kill an estimated 40,000 women, second only to lung cancer as a cause of cancer mortality in women. Breast cancer also occurs in men, and it is estimated that 2,360 new cases will be diagnosed in 2014. Despite a prior long-term trend of gradually increasing breast cancer incidence in women, data from the Surveillance, Epidemiology, and End Results Program show a decrease in breast cancer mortality of 1.9% per year from 1998 to 2007.
The major risk factor for breast cancer is advancing age. A 30-year-old woman has a 1 in 250 chance of being diagnosed with breast cancer in the next 10 years, whereas a 70-year-old woman has a 1 in 27 chance.
Breast cancer incidence and mortality risk also vary on the basis of geography, culture, race, ethnicity, and socioeconomic status. Compared with other races, white women have a higher incidence of breast cancer that may be attributable, in part, to screening behavior.
Screening by mammography decreases breast cancer mortality by identifying cases for treatment at an earlier stage. However, screening also identifies more cases than would become symptomatic in a woman’s lifetime, so screening increases breast cancer incidence. (Refer to the Overdiagnosis section in the PDQ summary on Breast Cancer Screening for more information.)
Etiology and pathogenesis of breast cancer
Breast cancer develops when a series of genetic mutations occurs. Initially, mutations do not change the histologic appearance of the tissue, but accumulated mutations will result in hyperplasia, dysplasia, carcinoma in situ, and eventually, invasive cancer. The longer a woman lives, the more somatic mutations occur and the more likely it is that these mutations will produce populations of cells that will evolve into malignancies. Estrogen and progestin cause growth and proliferation of breast cells that may work through growth factors such as transforming growth factor (TGF)-alpha. These hormones, whether endogenous or exogenous, may promote the development and proliferation of breast cancer cells.
International variation in breast cancer rates may be explained by differences in genetics, reproductive factors, diet, exercise and screening behavior. Some of these factors are modifiable, as evidenced by the observation that Japanese immigrants to the United States increase their breast cancer risk from lower Japanese levels to higher American levels within two generations.[6-8]
Many of the risk factors for breast cancer suggest that longer exposure to endogenous estrogen plays a role in the development of the disease. Women who experienced menarche at age 11 years or younger have about a 20% greater chance of developing breast cancer than do those who experienced menarche at age 14 years or older. Women who experience late menopause also have an increased risk. Women who develop breast cancer tend to have higher endogenous estrogen and androgen levels.
Conversely, women who experience premature menopause have a lower risk of breast cancer. Following ovarian ablation, breast cancer risk may be reduced as much as 75% depending on age, weight, and parity, with the greatest reduction for young, thin, nulliparous women.[11-14] The removal of one ovary also reduces the risk of breast cancer but to a lesser degree than does the removal of both ovaries.
Other hormonal changes also influence breast cancer risk. (Refer to the Early pregnancy and Breast-feeding sections in the Factors With Adequate Evidence of Decreased Risk of Breast Cancer section of this summary for more information.)
The interaction of endogenous estrogen levels, insulin levels, and obesity—all of which affect breast cancer risk—are poorly understood but suggest strategies for interventions to decrease that risk. It is likely that reproductive risk factors interact with predisposing genotypes. For example, in the Nurses’ Health Study, the associations between age at first birth, menarche, and menopause and the development of breast cancer were observed only among women without a family history of breast cancer in a mother or sister.
Major inheritable susceptibility
The inherited genetic profile of an individual influences susceptibility to mutagens and growth factors, which initiate or promote the carcinogenic process. (Refer to the Ionizing radiation exposure section in the Factors With Adequate Evidence of Increased Risk of Breast Cancer section of this summary for more information.) Known genetic syndromes related to specific aberrant alleles account for approximately 5% of breast cancers. (Refer to the PDQ summary on Genetics of Breast and Gynecologic Cancers for more information.)
Women who inherit a deleterious mutation in BRCA1 [17,18] or BRCA2  have an increased lifetime risk of breast cancer (which occurs at a younger age), ovarian cancer, and possibly colon cancer. Deleterious BRCA2 mutations are less common than BRCA1  mutations; BRCA2 mutations are also associated with male breast cancer, prostate cancer, pancreatic cancer, and lymphomas.
Factors With Adequate Evidence of Increased Risk of Breast Cancer
Based on a 1997 reanalysis of 51 epidemiological studies encompassing more than 150,000 women, hormone therapy (HT) after menopause was shown to be associated with increased breast cancer risk.
The Heart and Estrogen/Progestin Replacement Study supported this finding in 2002. In this study, 2,763 women with coronary heart disease who had a mean age of 67 years were randomly assigned to receive either estrogen and progestin therapy or placebo. After a mean follow-up of 6.8 years, the relative risk (RR) for breast cancer was 1.27 (95% confidence interval [CI], 0.84–1.94). Although not statistically significant, the RR estimate is consistent with the much larger Women’s Health Initiative (WHI), also published in 2002.
The WHI investigated the effect of hormones and dietary interventions on heart disease and breast cancer risk. Women aged 50 to 79 years with intact uteri were randomly assigned to receive combined conjugated estrogen with continuous progestin (n = 8,506) or placebo (n = 8,102). The trial was terminated early because combined HT did not decrease coronary heart disease risk but did increase the risk of stroke and breast cancer. The increased breast cancer risk (hazard ratio [HR], 1.24; 95% CI, 1.02–1.50) was observed in all subgroups of women for invasive breast cancer but not for in situ breast cancer. The combined HT-related cancers had similar grade, histology, and expression of estrogen receptor (ER), progesterone receptor, and HER2/neu, with a trend toward larger size and higher incidence of lymph node metastases in the combined HT group. Extended follow-up of a mean of 11 years showed higher breast cancer–specific mortality for the HT group (25 vs. 12 deaths, 0.03% vs. 0.01% per year; HR, 1.95; 95% CI, 1.0–4.04; P = .049). Combined HT was also associated with a higher percentage of abnormal mammograms.
The WHI observational study was conducted in parallel with the WHI randomized controlled trial (RCT), recruiting postmenopausal women aged 50 to 79 years. An analysis was conducted in the observational study of the WHI to further examine the prognosis of women taking combination HT who were diagnosed with breast cancer and the risks based on time between menopause and initiation of HT. After a mean follow-up of 11.3 years, the annualized incidence of breast cancer among women using estrogen plus progestin was 0.60%, compared with 0.42% among nonusers (HR, 1.55; 95% CI, 1.41–1.70). Survival after the diagnosis of breast cancer was similar for combined HT users and nonusers. Death from breast cancer was higher among combined HT users than among nonusers, but the difference was not statistically significant (HR, 1.3; 94% CI, 0.90–1.93). Risks were highest among women initiating HT at the time of menopause, and risks diminished but persisted with increasing time between menopause and starting combination HT. All-cause mortality after the diagnosis of breast cancer was statistically significantly higher among combined HT users than among nonusers (HR, 1.87; 95% CI, 1.37–2.54.) Overall, these findings were consistent with results from the RCT.
The WHI also studied women who had previously undergone a hysterectomy and thus were not at risk for endometrial cancer, which is associated with unopposed estrogen therapy. Women aged 50 to 79 years (N = 10,739) were randomly assigned to receive conjugated equine estrogen (CEE) or placebo. This trial was also stopped early because of an increased risk of stroke and no improvement in a global risk-benefit index.[28,29] After an average 6.8 years of follow-up, breast cancer incidence was lower in the group receiving CEE (0.26% per year vs. 0.33%; HR, 0.77; 95% CI, 0.59–1.01). The global risk-benefit index was slightly worse for CEE. An extended follow-up for a median of 11.8 years included 78% of the trial participants.[29,30] Results seen in the initial study persisted, with a similar risk reduction for breast cancer in CEE recipients (HR, 0.77; 95% CI, 0.62–0.95) [29,30] and a decrease in breast cancer mortality (6 vs. 16 deaths; HR, 0.37; 95% CI, 0.13–0.91). All-cause mortality was also lower in the CEE group (0.046% vs. 0.076% per year; HR, 0.62; 95% CI, 0.39–0.97). After CEE was discontinued, the risk of stroke decreased in the postintervention period. Over the entire follow-up period, there was no difference in the incidence of coronary heart disease, deep vein thrombosis, stroke, hip fracture, or colorectal cancer. Breast cancer incidence was similar for women who initiated CEE or placebo within the first 5 years after onset of menopause (HR, 1.06; 95% CI, 0.74–1.51).
A Danish trial of HT for 1,006 women entering menopause was designed to evaluate cardiovascular outcomes. Combined HT (triphasic estradiol and norethisterone) was given to 407 women with intact uteri, and estradiol was given to 95 women who had undergone hysterectomy. Controls (407 with intact uteri and 97 with hysterectomy) were not treated. At 10 years, there was considerable contamination. Only one-half of the women assigned to the HT group were still taking the prescribed HT, and 22% of the control women had begun HT. Cardiovascular outcomes favored HT-treated women, and there was no difference in breast cancer incidence.
Observational studies augment the information obtained in RCTs.
The Million Women Study  recruited 1,084,110 women aged 50 to 64 years in the United Kingdom between 1996 and 2001 and obtained information about HT use and other personal details. The women were followed for breast cancer incidence and death. One-half of the women had used HT. At 2.6 years of follow up, there were 9,364 incidences of invasive breast cancers; at 4.1 years, there were 637 breast cancer deaths. Current users of HT at recruitment were more likely than never-users to develop breast cancer (adjusted RR = 1.66; 95% CI, 1.58–1.75; P < .0001) and to die from the disease (adjusted RR, 1.22; 95% CI, 1.00–1.48; P = .05). Past users of HT were, however, not at an increased risk of incident or fatal breast cancer (1.01 [95% CI, 0.94–1.09] and 1.05 [95% CI, 0.82–1.34], respectively). Incidence was significantly increased for current users of estrogen only (RR, 1.30; 95% CI, 1.21–1.40; P < .0001), combined HT (RR, 2.00; 95% CI, 1.88–2.12; P < .0001), and tibolone (RR, 1.45; 95% CI, 1.25–1.68; P < .0001). The magnitude of the associated risk was substantially greater for combined HT than for other types of HT (P < .0001).
A population-based survey of 965 women with breast cancer and 1,007 controls was conducted by the Cancer Surveillance System of Puget Sound. It showed that combined HT users had a 1.7-fold increased risk of invasive breast cancer, whereas estrogen-only users did not.
The association between the use of combined HT and increased breast cancer risk is consistent throughout all the trials. In contrast, the association between estrogen-only HT and breast cancer incidence is confusing because some studies show increased risk and some show protection. It is possible that the timing of estrogen-only HT in relation to the onset of menopause is critical. Furthermore, observational studies may not account for different screening behavior between HT users and nonusers, whereas RCTs, by design, will control that variable.[34,35]
Following publication of the WHI results, HT use dropped dramatically in the United States and elsewhere. Follow-up of WHI participants on the combined HT arm demonstrated a rapid decrease in the elevated breast cancer risk of therapy within 2 years, despite similar rates of mammography screening. Analysis of changes in breast cancer rates in the United States observed a sharp decline in breast cancer incidence rates from 2002 to 2003 among women aged 50 years and older, especially for estrogen receptor (ER)–positive cancers.[37,38] Similarly, in multiple countries where HT use was high, breast cancer rates decreased in a similar time frame, coincident with decreases in prescribing patterns and/or reported prevalence of use.[39-41] A study among women receiving regular mammography screening supports that the observed sharp decline from 2002 to 2003 in breast cancer incidence was primarily caused by withdrawal of HT rather than declines in mammography rates. After the decline in breast cancer incidence from 2002 to 2003, rates in the United States stabilized.[42,43]
Ionizing radiation exposure
A well-established relationship exists between exposure to ionizing radiation and subsequent breast cancer. Excess breast cancer risk has been observed in association with atomic bomb exposure, frequent fluoroscopy for tuberculosis, and radiation therapy for acne, tinea, thymic enlargement, postpartum mastitis, and lymphoma. Risk is higher for the young, especially around puberty. An estimate of the risk of breast cancer associated with medical radiology puts the figure at less than 1% of the total. However, it has been theorized that certain populations, such as AT heterozygotes, are at an increased risk of breast cancer from radiation exposure. A large cohort study of women who carry mutations of BRCA1 or BRCA2 concluded that chest x-rays increase the risk of breast cancer even more (RR, 1.54; 95% CI, 1.1–2.1), especially for women who were x-rayed before age 20 years.
Women treated for Hodgkin lymphoma by age 16 years may have a subsequent risk, up to 35%, of developing breast cancer by age 40 years.[48,49] Higher radiation doses (median dose, 40 Gy in breast cancer cases) and treatment between the ages of 10 and 16 years are associated with higher risk. Unlike the risk for secondary leukemia, the risk of treatment-related breast cancer does not abate with duration of follow-up, persisting more than 25 years after treatment.[48,50,51] In these studies, most patients (85%–100%) who developed breast cancer did so either within the field of radiation or at the margin.[48-50] A Dutch study examined 48 women who developed breast cancer at least 5 years after treatment for Hodgkin disease and compared them with 175 matched female Hodgkin disease patients who did not develop breast cancer. Patients treated with chemotherapy and mantle radiation were less likely to develop breast cancer than were those treated with mantle radiation alone, possibly because of chemotherapy-induced ovarian suppression (RR, 0.06; 95% CI, 0.01–0.45). Another study of 105 radiation-associated breast cancer patients and 266 age-matched and radiation-matched controls showed a similar protective effect for ovarian radiation. These studies suggest that ovarian hormones promote the proliferation of breast tissue with radiation-induced mutations.
The question arises whether breast cancer patients treated with lumpectomy and radiation therapy (L-RT) are at higher risk for second breast malignancies or other malignancies than are those treated by mastectomy. Outcomes of 1,029 L-RT patients were compared with outcomes of 1,387 patients who underwent mastectomies. After a median follow-up of 15 years, there was no difference in the risk of second malignancies. Further evidence from three RCTs is also reassuring. One report of 1,851 women randomly assigned to undergo total mastectomy, lumpectomy alone, or L-RT showed rates of contralateral breast cancer to be 8.5%, 8.8%, and 9.4%, respectively. Another study of 701 women randomly assigned to undergo radical mastectomy or breast-conserving surgery followed by radiation therapy demonstrated the rate of contralateral breast carcinomas per 100 woman-years to be 10.2 versus 8.7, respectively. The third study compared 25-year outcomes of 1,665 women randomly assigned to undergo radical mastectomy, total mastectomy, or total mastectomy with radiation. There was no significant difference in the rate of contralateral breast cancer according to treatment group, and the overall rate was 6%.
Obesity is associated with increased breast cancer risk, especially among postmenopausal women who do not use HT. The WHI observed 85,917 women aged 50 to 79 years and collected information on weight history and known risk factors for breast cancer. Height, weight, and waist and hip circumferences were measured. With a median follow-up of 34.8 months, 1,030 of the women developed invasive breast cancer. Among the women who never used HT, increased breast cancer risk was associated with weight at entry, body mass index (BMI) at entry, BMI at age 50 years, maximum BMI, adult and postmenopausal weight change, and waist and hip circumferences. Weight was the strongest predictor, with a RR of 2.85 (95% CI, 1.81–4.49) for women weighing more than 82.2 kg, compared with those weighing less than 58.7 kg.
The association between obesity, diabetes, and insulin levels with breast cancer risk have been studied but not clearly defined. The British Women’s Heart and Health Study of women aged 60 to 79 years compared 151 women who had a diagnosis of breast cancer with 3,690 women who did not. The age adjusted odds ratio (OR) was 1.34 (95% CI, 1.02–1.77) for each unit increase in log(e) insulin level among nondiabetic women. The association was observed, after adjustment for confounders and for potential mediating factors, and was seen for both pre- and postmenopausal breast cancers. In addition, fasting glucose level, homeostatic model assessment score (the product of fasting glucose and insulin levels divided by 22.5), diabetes, and a history of gestational glycosuria or diabetes were also associated with breast cancer.
Alcohol consumption increases the risk of breast cancer. A British meta-analysis included individual data from 53 case-control and cohort studies. Compared with the RR of breast cancer for women who reported no alcohol consumption, the RR of breast cancer was 1.32 (95% CI, 1.19–1.45; P < .001) for women consuming 35 g to 44 g of alcohol per day and 1.46 (95% CI, 1.33–1.61; P < .001) for those consuming at least 45 g of alcohol per day. The RR of breast cancer increases by about 7% (95% CI, 5.5%–8.7%; P < .001) for each 10 g of alcohol (i.e., one drink) consumed per day. These findings persist after stratification for race, education, family history, age at menarche, height, weight, BMI, breast-feeding, oral contraceptive use, menopausal hormone use and type, and age at menopause.
Factors With Adequate Evidence of Decreased Risk of Breast Cancer
Childbirth is followed by an increase in risk of breast cancer for several years, and then a long-term reduction in risk, which is greater for younger women.[14,60,61] In one study, women who experienced a first full-term pregnancy before age 20 years were half as likely to develop breast cancer as nulliparous women or women whose first full-term pregnancy occurred at age 35 years or older.[62,63]
Breast-feeding is associated with a decreased risk of breast cancer. A reanalysis of individual data from 47 epidemiological studies in 30 countries of 50,302 women with breast cancer and 96,973 controls revealed that breast cancer incidence was lower in parous women who had ever breast-fed than in parous women who had not. It was also proportionate to duration of breast-feeding. The RR of breast cancer decreased by 4.3% (95%, CI, 2.9–5.8; P < .0001) for every 12 months of breast-feeding in addition to a decrease of 7.0% (95% CI, 5.0–9.0; P < .0001) for each birth.
Active exercise may reduce breast cancer risk, particularly in young parous women. Numerous observational studies on the relationship between the level of physical activity and breast cancer risk have shown an inverse relationship. The average RR reduction is 30% to 40%, but confounding variables—such as diet or a genetic predisposition to breast cancer— have not been addressed. A prospective study of more than 25,000 Norwegian women found that heavy manual labor or at least 4 hours of exercise per week is associated with decreased breast cancer risk, especially in premenopausal women and those of normal or lower-than-normal body weight. In a case-control study of African American women, strenuous recreational physical activity more than 7 hours per week was associated with decreased breast cancer incidence.
Interventions With Adequate Evidence of Benefit
Selective estrogen receptor modulators (SERMs)
Data from adjuvant breast cancer trials using tamoxifen have shown that tamoxifen not only suppresses the recurrence of breast cancer but also prevents new primary contralateral breast cancers. Tamoxifen also maintains bone density among postmenopausal women with breast cancer.[71-75] Adverse effects include hot flashes, venous thromboembolic events, and endometrial cancer.[76-78]
These adjuvant trial results were the basis for the Breast Cancer Prevention Trial (BCPT) that randomly assigned 13,388 patients at elevated risk of breast cancer to receive tamoxifen or placebo.[79,80] The study was closed early because of a 49% reduction in the incidence of breast cancer for the tamoxifen group (85 vs. 154 invasive breast cancer cases and 31 vs. 59 in situ cases at 4 years). Tamoxifen-treated women also had fewer fractures (47 vs. 71) but more endometrial cancer (33 vs. 14 cases) and thrombotic events (99 vs. 70), including pulmonary emboli (17 vs. 6).
An update of the BCPT results after 7 years of follow-up demonstrated results similar to those in the initial report. There were some dropouts among women in the placebo arm; some of them enrolled in a subsequent trial, so new women were added to the placebo group. Benefits and risks of tamoxifen were not significantly different from those in the original report, with persistent benefit of fewer fractures and persistent increased risk of endometrial cancer, thrombosis, and cataract surgery. No overall mortality benefit was observed after 7 years of follow-up (RR, 1.10; 95% CI, 0.85–1.43).
- A study in the United Kingdom  focused on 2,471 women at increased breast cancer risk because of their family history of breast and/or ovarian cancer. After a median follow-up of nearly 6 years, no protective effect of tamoxifen was detected (RR, 1.06), but there was a slight reduction in breast cancer risk in the tamoxifen arm (HR, 0.78; 95% CI, 0.58–1.04) at a median of 13 years. However, risk of ER-positive breast cancer was significantly reduced in the treatment arm (HR, 0.61; 95% CI, 0.43–0.86), an effect noted predominantly in the posttreatment period.
- An Italian study  focused on 5,408 women who had undergone hysterectomy and who were described as low to normal risk. After a median follow-up of nearly 4 years, no protective effect of tamoxifen was observed. Longer follow-up and subgroup analysis in this trial found a protective effect of tamoxifen among women at high risk for hormone receptor–positive breast cancer (RR, 0.24; 95% CI, 0.10–0.59) and among women who were taking HT during the trial (RR, 0.43; 95% CI, 0.20–0.95).[86,87]
- The International Breast Cancer Intervention Study (IBIS-I) randomly assigned 7,152 women aged 35 to 70 years who were at increased risk of breast cancer to receive tamoxifen (20 mg/day ) or placebo for 5 years. After a median follow-up of 50 months, fewer tamoxifen-treated women had developed invasive or in situ breast cancer (absolute rate, 4.6 vs. 6.75 per 1,000 woman-years; risk reduction, 32%; 95% CI, 8%–50%). The RR reduction in ER-positive invasive breast cancer was 31%; there was no reduction in ER-negative cancers. There was an excess of all-cause mortality in the tamoxifen group (25 vs. 11; P = .028), which the authors attributed to chance. The beneficial effect of tamoxifen on breast cancer persisted after active treatment, with a median posttherapy follow-up of 46 months; 27% fewer women in the tamoxifen arm developed breast cancer (142 vs. 195 cases, respectively; RR, 0.73, 95% CI, 0.58–0.91).
A meta-analysis of these primary prevention tamoxifen trials showed a 38% reduction in the incidence of breast cancer without statistically significant heterogeneity. ER-positive tumors were reduced by 48%. Rates of endometrial cancer were increased (consensus RR, 2.4; 95% CI, 1.5–4.0), as were venous thromboembolic events (RR, 1.9; 95% CI, 1.4–2.6). None of these primary prevention trials was designed to detect differences in breast cancer mortality.
Women with a history of ductal carcinoma in situ (DCIS) are at increased risk for contralateral breast cancer. The National Surgical Adjuvant Breast and Bowel Project (NSABP) trial B-24 addressed their management. Women were randomly assigned to receive lumpectomy and radiation therapy (L-RT) either with or without adjuvant tamoxifen. At 6 years, the tamoxifen-treated women had fewer invasive and in situ breast cancers (8.2% vs. 13.4%; RR, 0.63; 95% CI, 0.47–0.83). The risk of contralateral breast cancer was also lower in women treated with tamoxifen (RR, 0.49; 95% CI, 0.26 – 0.87).
Raloxifene hydrochloride (Evista) is a SERM that has antiestrogenic effects on breast and estrogenic effects on bone, lipid metabolism, and blood clotting. Unlike tamoxifen, it has antiestrogenic effects on the endometrium. The Multiple Outcomes of Raloxifene Evaluation (MORE) trial was a randomized, double-blind trial that evaluated 7,705 postmenopausal women with osteoporosis from 1994 to 1998 at 180 clinical centers in the United States. Vertebral fractures were reduced. The effect on breast cancer incidence was a secondary endpoint. After a median follow-up of 47 months, the risk of invasive breast cancer decreased in the raloxifene-treated women (RR, 0.25; 95% CI, 0.17–0.45). As with tamoxifen, raloxifene reduced the risk of ER-positive breast cancer but not ER-negative breast cancer and was associated with an excess risk of hot flashes and thromboembolic events. No excess risk of endometrial cancer or hyperplasia was observed after 47 months of follow-up.
An extension of the MORE trial was the Continuing Outcomes Relevant to Evista (CORE) trial, which studied about 80% of MORE participants in their randomized groups for an additional 4 years. Although there was a median 10-month gap between the two studies, and only about 55% of women were adherent to their assigned medications, the raloxifene group continued to experience a lower incidence of invasive ER-positive breast cancer. The overall reduction in invasive breast cancer during the 8 years of MORE and CORE was 66% (HR, 0.34; 95% CI, 0.22–0.50); the reduction for ER-positive invasive breast cancer was 76% (HR, 0.24; 95% CI, 0.15–0.40).
The Raloxifene Use for the Heart trial was a randomized, placebo-controlled trial to evaluate the effects of raloxifene on incidence of coronary events and invasive breast cancer. As in the MORE and CORE studies, raloxifene reduced the risk of invasive breast cancer (HR, 0.56; 95% CI, 0.38–0.83).
The Study of Tamoxifen and Raloxifene (STAR) (NSABP P-2) compared tamoxifen and raloxifene in 19,747 high-risk women who were monitored for a mean of 3.9 years. Invasive breast cancer incidence was approximately the same for both drugs, but there were fewer noninvasive cancers in the tamoxifen group. Adverse events of uterine cancer, venous thrombolic events, and cataracts were more common in tamoxifen-treated women, and there was no difference in ischemic heart disease events, strokes, or fractures. Treatment-associated symptoms of dyspareunia, musculoskeletal problems, and weight gain occurred less frequently in tamoxifen-treated women, whereas vasomotor flushing, bladder control symptoms, gynecologic symptoms, and leg cramps occurred less frequently in those receiving raloxifene.
|Tamoxifen||Raloxifene||RR, 95% CI|
|CI = confidence interval; RR = relative risk; VTE = venous thromboembolism.|
|Invasive breast cancer||4.3||4.41||1.02, 0.82–1.28|
|Noninvasive breast cancer||1.51||2.11||1.4, 0.98–2.00|
|Uterine cancer||2.0||1.25||0.62, 0.35–1.08|
|Incidence of Symptoms (0–4 scale)|
|Dyspareunia||0.68||0.78||P < .001|
|Musculoskeletal problems||1.10||1.15||P = .002|
|Weight gain||0.76||0.82||P < .001|
|Vasomotor symptoms||0.96||0.85||P < .001|
|Bladder control symptoms||0.88||0.73||P < .001|
|Leg cramps||1.10||0.91||P < .001|
|Gynecologic problems||0.29||0.19||P < .001|
Aromatase inhibition or inactivation
Another class of agents that is commercially available for the treatment of women with hormone-sensitive breast cancer may also prevent breast cancer. These drugs interfere with aromatase, the adrenal enzyme that allows estrogen production in postmenopausal women. Anastrozole and letrozole inhibit aromatase activity, whereas exemestane inactivates the enzyme. Side effects for all three drugs include fatigue, arthralgia, myalgia, decreased bone mineral density, and increased fracture rate.
All three drugs decrease the incidence of new breast cancers in women with a prior breast cancer diagnosis. In the Arimidex, Tamoxifen, Alone or in Combination trial, comparing anastrozole to tamoxifen as adjuvant therapy for primary breast cancer, the rate of locoregional and distant recurrence was lower for anastrozole (7.1% vs. 8.5%) but higher for the combination (9.1%). Anastrozole was also more effective in preventing new contralateral breast cancer (0.4% vs. 1.1% vs. 0.9%).
Another trial of 5,187 women who had received 5 years of adjuvant tamoxifen randomly assigned women to receive either letrozole or placebo. After only 2.5 years of median follow-up, the study was terminated because previously defined efficacy endpoints had been reached. Not only did letrozole-treated patients have a lower incidence of locoregional and distant cancer recurrence, they also had a lower incidence of new contralateral breast cancer (14 vs. 26).
A third trial randomly assigned 4,742 women who had received 2 years of adjuvant tamoxifen to either continue the tamoxifen or switch to exemestane. After 2.4 years of median follow-up, the exemestane group had a decreased risk of local or metastatic recurrence and a decreased incidence of new contralateral breast cancer (9 vs. 20).
A single RCT of primary prevention of breast cancer compared exemestane to placebo in 4,560 women with at least one risk factor (age >60 years, a Gail 5-year risk >1.66%, or a history of DCIS with mastectomy). After 35 months of median follow-up, invasive breast cancer was diagnosed less frequently in the exemestane group (11 vs. 32; HR, 0.35; 95% CI, 0.18–0.70; number needed to treat, about 100 for 35 months). Compared with the placebo group, the exemestane-treated women had more hot flashes (increase, 8%) and fatigue (increase, 2%) but no difference in fractures or cardiovascular events.
The International Breast Cancer Intervention Study II (IBIS-II) randomly assigned 3,864 postmenopausal women who were at increased risk of developing breast cancer to receive either daily anastrazole (1 mg) or placebo for 5 years. The definition of high risk varied by age and was defined by the RR compared with the general population: women aged 40 to 44 years had to have an RR of at least 4; women aged 45 to 60 years had to have an RR of 2.0; and women aged 60 to 70 years had to have an RR of at least 1.5. Alternatively, women with an estimated 10-year risk rate of developing breast cancer of at least 5% (per the Tyer-Cuzick model) were eligible for inclusion. Women with DCIS diagnosed within 6 months and treated with unilateral mastectomy were eligible for the trial, and 326 were assigned randomly. After a median follow-up of 5 years, fewer breast cancers (invasive and DCIS) occurred in the anastrazole-treated group than in the placebo group (HR, 0.47; 95% CI, 0.32–0.68). The risk of hormone receptor–positive, but not hormone receptor–negative, forms of breast cancer was reduced. Based on predicted cumulative incidence over 7 years, the number of high-risk women (per the IBIS-II eligibility criteria) needed to treat for 5 years to prevent one breast cancer in 7 years of follow-up was estimated to be 36 (95% CI, 33–44). Women treated with anastrazole were more likely than those taking placebo to have musculoskeletal symptoms, including arthralgias (51% vs. 46%), joint stiffness (7% vs. 5%), pain in hand or foot (9% vs. 8%) , and carpal tunnel syndrome (3% vs. 2%); hypertension (5% vs. 3%); vasomotor symptoms (57% vs. 49%); and dry eyes (4% vs. 2%). The association between hand or foot pain with anastrazole treatment was of borderline statistical significance; all other side effects noted above were statistically significantly associated with anastrazole treatment.
A retrospective cohort study evaluated the impact of bilateral prophylactic mastectomy on breast cancer incidence among women at high and moderate risk on the basis of family history. BRCA mutation status was not known. Subcutaneous, rather than total, mastectomy was performed in 90% of these women. After a median follow-up of 14 years postsurgery, the risk reduction for the 425 moderate-risk women was 89%; for the 214 high-risk women, it was 90% to 94%, depending on the method used to calculate expected rates of breast cancer. The risk reduction for breast cancer mortality was 100% for moderate-risk women and 81% for high-risk women. This study probably overestimated breast cancer risk on the basis of family history rather than genetic studies.
No studies have been done on the benefits of prophylactic mastectomy to prevent contralateral breast cancer in women with an ipsilateral breast cancer.
Ovarian ablation and oophorectomy are associated with decreased breast cancer risk in normal women and in women with increased risk resulting from thoracic irradiation. (Refer to the Endogenous estrogen section in the Description of the Evidence section of this summary for more information.) Observational studies of women with high breast cancer risk due to BRCA1 or BRCA2 gene mutations showed that prophylactic oophorectomy to prevent ovarian cancer was also associated with a 50% decrease in breast cancer incidence.[103-105] These studies are confounded by selection bias, family relationships between patients and controls, indications for oophorectomy, and inadequate information about hormone use. A prospective cohort study had similar findings, with a greater breast cancer risk reduction in BRCA2 mutation carriers than in BRCA1 carriers.
Factors and Interventions With Inadequate Evidence of an Association
Oral contraceptives have been associated with a small increased risk of breast cancer in current users that diminishes over time. A well-conducted case-control study did not observe an association between breast cancer risk and oral contraceptive use for every use, duration of use, or recency of use.
Another case-control study found no increased risk of breast cancer associated with the use of injectable or implantable progestin-only contraceptives in women aged 35 to 64 years.
Occupational, environmental, or chemical exposures have been proposed as causes of breast cancer. Although some findings suggest that organochlorine exposures, such as those associated with insecticides, might be associated with an increase in breast cancer risk,[110,111] other case-control and nested case-control studies do not.[112-117] Studies reporting positive associations have been inconsistent in the identification of responsible organochlorines. Some of these substances have weak estrogenic effects, but their effect on breast cancer risk remains unproven. The use of dichloro-diphenyl-trichloroethane was banned in the United States in 1972, and the production of polychlorinated biphenyls was stopped in 1977.
Factors and Interventions With Adequate Evidence of No Association
Abortion has been proposed as a cause of breast cancer, and the possible association has been used as an argument against abortion. However, the studies that were cited to demonstrate an association had used recalled information in populations where induced abortion had a social or religious stigma. Subsequently, a meta-analysis demonstrated that women with breast cancer were more likely to report prior abortions than were control women, whereas both groups reported prior miscarriages equally. It also showed no association between either abortion or miscarriage and breast cancer if the data was collected prospectively. Importantly, an association with breast cancer was not shown in seven trials conducted in social environments where abortion is accepted [119-125] or in four trials that collected abortion data prospectively.[126-129]
Diet and vitamins
Despite enthusiasm for dietary manipulations and vitamin ingestion to prevent breast cancer, there is no evidence that these interventions are effective.
A summary of ecologic studies published before 1975 showed a positive correlation between international age-adjusted breast cancer mortality rates and the estimated per capita consumption of dietary fat. Results of case-control studies have been mixed. Twenty years later, a pooled analysis of results from seven cohort studies found no association between total dietary fat intake and breast cancer risk.
A randomized controlled dietary modification study was undertaken among 48,835 postmenopausal women aged 50 to 79 years who were also enrolled in the WHI. The intervention promoted a goal of reducing total fat intake by 20%, by increasing vegetable, fruit, and grain consumption. The intervention group reduced fat intake by approximately 10% for more than 8.1 years of follow-up, resulting in lower estradiol and gamma-tocopherol levels, but no persistent weight loss. The incidence of invasive breast cancer was slightly lower in the intervention group, with an HR of 0.91 (95% CI, 0.83–1.01), but no difference in all-cause mortality, overall mortality, or cardiovascular disease.
A pooled analysis of adult dietary data from eight cohort studies, which included 351,823 women with 7,377 incident breast cancers, showed minimal or no association. If the dietary data were treated as a continuous variable (based on grams of intake per day), there was no association with breast cancer. Comparing highest to lowest quartiles of intake, the pooled multivariate RRs of breast cancer were 0.93 (95% CI, 0.86–1.00) for total fruits, 0.96 (95% CI, 0.89–1.04) for total vegetables, and 0.93 (95% CI, 0.86–1.00) for total fruits and vegetables combined.
The Women's Healthy Eating and Living Randomized Trial  examined the effect of diet on the incidence of new primary breast cancers. More than 3,000 women were enrolled and randomly assigned to an intense regimen of increased fruit and vegetable intake, increased fiber intake, and decreased fat intake, or a comparison group receiving printed materials on the “5-A-Day” dietary guidelines. After a mean of 7.3 years of follow-up, there was no reduction in new primary cancers, no difference in disease-free survival, and no difference in overall survival.
The potential role of specific micronutrients for breast cancer risk reduction has been examined in clinical trials, with cardiovascular disease and cancer as outcomes. The Women’s Health Study, a randomized trial with 39,876 women, found no difference in breast cancer incidence at 2 years between women assigned to take either beta carotene or placebo. In this same study, no overall effect on cancer was seen in women taking 600 IU of vitamin E every other day. The Women’s Antioxidant Cardiovascular Study examined 8,171 women for incidence of total cancer and invasive breast cancer and found no effect for vitamin C, vitamin E, or beta carotene. Two years later, a subset of 5,442 women were randomly assigned to take 1.5 mg of folic acid, 50 mg of vitamin B6, and 1 mg of B12, or placebo. After 7.3 years, there was no difference in the incidence of total invasive cancer or invasive breast cancer.
Fenretinide  is a vitamin A analog that has been shown to reduce breast carcinogenesis in preclinical studies. A phase III Italian trial compared the efficacy of a 5-year intervention with fenretinide versus no treatment in 2,972 women, aged 30 to 70 years, with surgically removed stage I breast cancer or DCIS. At a median observation time of 97 months, there were no statistically significant differences in the occurrence of contralateral breast cancer (P = .642), ipsilateral breast cancer (P = .177), incidence of distant metastases, nonbreast malignancies, and all-cause mortality.
Active and passive cigarette smoking
The potential role of active cigarette smoking in the etiology of breast cancer has been studied for more than three decades, with no clear-cut evidence of an association. Since the mid-1990s, studies of cigarette smoking and breast cancer have more carefully accounted for secondhand smoke exposure.[142,143] A recent meta-analysis suggests that there is no overall association between passive smoking and breast cancer and that study methodology (ascertainment of exposure after breast cancer diagnosis) may be responsible for the apparent risk associations seen in some studies.
Despite warnings to women in lay publications that underarm deodorants and antiperspirants cause breast cancer, there is no evidence to support these concerns. A study based on interviews with 813 women who had breast cancer and 793 controls found no association between the risk of breast cancer and the use of antiperspirants, the use of deodorants, or the use of blade razors before these products were applied. In contrast, a study of 437 breast cancer survivors found that women who used antiperspirants/deodorants and shaved their underarms more frequently had cancer diagnosed at a significantly younger age. A possible explanation for this finding is that these women had an earlier menarche or higher levels of endogenous hormones, both known to be risk factors for breast cancer and to increase body hair. Finally, an Iraqi study of 54 women with breast cancer and 50 controls showed no association between antiperspirant use and risk of breast cancer.
Oral and intravenous bisphosphonates for the treatment of hypercalcemia and osteoporosis have been studied for a possible beneficial effect on breast cancer prevention. Initial observational studies suggested that women who used these drugs for durations of approximately 1 to 4 years had a lower incidence of breast cancer.[150-153] These findings are confounded by the fact that women with osteoporosis have lower breast cancer risk than those with normal bone density. Additional evidence came from studies of women with a breast cancer diagnosis; the use of these drugs was associated with fewer new contralateral cancers. With this background, two large randomized placebo-controlled trials were done. The Fracture Intervention Trial (FIT) treated 6,194 postmenopausal osteopenic women with either alendronate or placebo and found no difference at 3.8 years in breast cancer incidence, with incidence of 1.8% and 1.5%, respectively (HR, 1.24; CI, 0.84–1.83). The Health Outcomes and Reduced Incidence With Zoledronic Acid Once Yearly-Pivotal Fracture Trial (HORIZON-PRT) examined 7,580 postmenopausal osteoporotic women with either intravenous zoledronate or placebo and found no difference at 2.8 years in breast cancer incidence, with incidence of 0.8% and 0.9%, respectively (HR, 1.15; CI, 0.7–1.89).
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