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[1]. In the same year, 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[1]. Despite a prior long-term trend of gradually increasing breast cancer incidence, 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[2].

Screening for breast cancer decreases mortality by identifying and treating cases at an earlier stage. Screening also identifies more cases than would become symptomatic in a woman’s lifetime, so breast cancer incidence is higher in screened populations.

Etiology and pathogenesis of breast cancer

Genetic, epidemiologic, and laboratory studies support a stochastic model of breast cancer development in which a series of genetic changes contribute to the dynamic process known as carcinogenesis[3]. An accumulation of genetic changes is thought to correspond to the phenotypic changes associated with the evolution of malignancy. The carcinogenesis sequence is viewed histologically as starting with tissue of normal appearance followed by changes that lead to hyperplasia and dysplasia, the most severe forms of which are difficult to distinguish from carcinoma in situ[4].

The concept that breast cancer may be preventable is supported by the wide international variation in breast cancer rates, which is an indicator that there are potentially modifiable environmental and lifestyle determinants of breast cancer. Migration studies reinforce this premise; for example, it has been observed that Japanese immigrants to the United States increase their breast cancer risk from Japanese to American levels within two generations[5][6][7].

Endogenous estrogen

Many of the risk factors for breast cancer, including age at menarche, first birth, and menopause, suggest hormonal influences for the development of the disease. Estrogen and progestin cause growth and proliferation of breast cells that may work through growth factors such as transforming growth factor (TGF)-alpha[8]. Women who develop breast cancer tend to have higher endogenous estrogen and androgen levels[9].

The role of ovarian hormones in the development of breast cancer is demonstrated by studies of artificial menopause. 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[10][11][12][13]. The removal of one ovary also reduces the risk of breast cancer but to a lesser degree than the removal of both ovaries[14].

Other hormonal changes also influence breast cancer risk. Childbirth is followed by a transient increase in risk and then a long-term reduction in risk, which is greater for younger women[13][15][16]. 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 who underwent a first full-term pregnancy at age 35 years or older[17][18]. Age at menarche also affects breast cancer risk. Women who experienced menarche at age 11 years or younger have about a 20% greater chance of developing breast cancer than women who experienced menarche at age 14 years or older[19]. Women who experience late menopause also have increased risk. Reproductive risk factors may interact with more predisposing genotypes. In the Nurses’ Health Study[20], 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. Breast-feeding is associated with a decreased risk of breast cancer[21][22].

A number of studies suggest that endogenous estrogen and androgen levels are higher in women who develop breast cancer than in women who do not[9][23][24]. Methods shown to decrease endogenous estrogen include maintenance of ideal body weight (refer to the Obesity section of this summary for more information), adoption of a low-fat diet in postmenopausal women[25], and moderate exercise in adolescent girls[26]. Whether such interventions will decrease breast cancer risk is worthy of study.

Genetic mutations

The inherited genetic profile of an individual influences susceptibility to mutagens and growth factors, which initiate or promote the carcinogenic process. Known genetic syndromes related to specific aberrant alleles account for approximately 5% of breast cancers. Identifying high-risk genes provides insight into breast cancer etiology and allows the development of preventive interventions for affected populations. (Refer to the PDQ summary on Genetics of Breast and Ovarian Cancer for more information.)

Women who inherit a deleterious mutation in BRCA1 [27][28] or BRCA2 [29] 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 [30] mutations; BRCA2 mutations are also associated with male breast cancer, prostate cancer, pancreatic cancer, and lymphomas[31].

Factors Associated With Increased Risk of Breast Cancer

Hormone therapy

Exogenous hormone therapy (HT) after menopause was shown to be associated with increased breast cancer risk in 1997[32].

The Heart and Estrogen/Progestin Replacement Study published in 2002 [33] included an open-label follow-up of a randomized, controlled trial (RCT) of estrogen and progestin therapy in 2,763 women (mean age, 67 years) who had coronary heart disease. 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) study.

The WHI-combined HT trial was terminated early (in July 2002) because the overall health risks exceeded benefits[34].

The randomized trial component of the WHI investigated the effect of hormones and dietary interventions on breast cancer risk[34]. Women aged 50 to 79 years who had intact uteri were randomly assigned to receive combined conjugated estrogen with continuous progestin (n = 8,506) or placebo (n = 8,102). Breast cancer risk was increased with combined HT, with a hazard ratio (HR) of 1.24 (95% CI, 1.02–1.50), consistent with prior reports from observational studies. The trial was terminated early because overall health risks, including cardiovascular disease and thrombotic events, exceeded benefit[34]. HT was also associated with a higher percentage of abnormal mammograms[35]. The excess risk 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 compared with those related to placebo, with a trend toward larger size and higher incidence of lymph node metastases[36]. Extended follow-up (mean follow-up of 11 years) of these women showed higher breast cancer-specific mortality for the HT group compared with those randomly assigned to receive placebo (25 vs. 12 deaths, 0.03% vs. 0.01% per year, HR = 1.95; 95% CI, 1.0–4.04; P = .049).

The WHI observational study was conducted in parallel with the WHI 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 than among nonusers (HR = 1.87; 95% CI, 1.37–2.54.) Overall, these findings were consistent with results from the RCT[37].

The WHI Estrogen-Alone Trial was a double-masked, placebo-controlled, randomized clinical trial conducted among women who have had a hysterectomy. Women aged 50 to 79 years (N = 10,739) were randomly assigned to receive either conjugated equine estrogen (CEE) or placebo. Estrogen-only preparations should only be considered among women who have had a hysterectomy because unopposed estrogen increases the risk of uterine cancer. Like the WHI combined-HT trial, this trial was stopped early because of an increased risk of stroke and no evidence of benefit as measured by a global index of risks and benefits[38][39]. After an average of 6.8 years of follow-up, the incidence of breast cancer was lower in the group receiving CEE compared with placebo, but the difference was not statistically significant (HR = 0.77; 95% CI, 0.59–1.01; 26 vs. 33 cases of invasive breast cancer per 10,000 person-years [annualized rate of 0.26% vs. 0.33%], respectively). For the global index of risks and benefits (based on outcomes of stroke, pulmonary embolus, breast cancer, colorectal cancer, hip fractures, and death), there was a nonstatistically significant excess of two events per 10,000 person-years[38]. An extended follow-up for a median of 11.8 years was conducted with 78% of the trial participants consenting to take part[39][40]. Characteristics among those in the extended follow-up who were randomly assigned to receive active intervention with CEE or placebo were similar, except for slight imbalances in history of prior breast biopsy (19.8% among the CEE group and 22.3% among the placebo group) and prior hormone use (48.9% among the CEE group and 50.4% among the placebo group). At the end of the follow-up period, 151 cases of breast cancer occurred among the CEE group (0.27% per year) compared with 199 cases of breast cancer among the placebo group (0.35% per year) (HR = 0.77; 95% CI, 0.62–0.95)[39][40]. Breast cancer mortality was statistically significantly lower in the CEE group (six deaths, 0.009% per year) than in the placebo group (16 deaths, 0.024% per year) (HR = 0.37; 95% CI, 0.13–0.91). All-cause mortality was also lower in the CEE group (0.046% per year) than in the placebo group (0.076% per year) (HR = 0.62; 95% CI 0.39–0.97). Following discontinuation of CEE, the risk of stroke decreased in the postintervention period. Over the entire follow-up period, there was no increased or decreased risk of coronary heart disease, deep vein thrombosis, stroke, hip fracture, or colorectal cancer[39]. Among the subset of women in the WHI trial who initiated estrogen-only therapy within the first 5 years of onset of menopause, neither an excess nor decreased risk of developing breast cancer was observed (HR = 1.06; 95% CI, 0.74–1.51).

A smaller trial from Denmark supports the results of the WHI Estrogen-Alone Trial. Between 1990 and 1993, 1,006 healthy, recently postmenopausal women aged 45 to 58 years were randomly assigned to receive either HT or no treatment. Follow-up continued for up to 16 years. In the treatment group, women with an intact uterus were treated with triphasic estradiol and norethisterone acetate; women who had undergone hysterectomy received 2 mg estradiol a day. The primary endpoints were cardiovascular, with incidence of breast cancer being secondary. The authors observed a nonsignificant reduction in the risk of breast cancer in the HT arm (HR = 0.58; 95% CI, 0.27–1.27) and a significant reduction in the risk of death or breast cancer (HR = 0.54; 95% CI, 0.32–0.91)[41].

The evidence from randomized trials should be put into context with the evidence from observational studies that suggests that there is an increased risk of developing breast cancer associated with estrogen-only postmenopausal HT. The Million Women Study [42] observed no increased risk of breast cancer among women whose first use of estrogen-only therapy was 5 or more years after menopause, but the risk was statistically significantly higher among women initiating therapy within 5 years of menopause (RR = 1.43; 95% CI, 1.36–1.49). Among that group, the risk increased with duration of hormone use. Overall, risks associated with estrogen-only HT were lower than those observed for combined estrogen-progestin HT[42]. Estrogen-only therapy, even for more than 25 years duration, was not associated with invasive breast cancer in a case-control study of women aged 65 years and older[43]. The Collaborative Group on Hormonal Factors in Breast Cancer, a reanalysis of data from 52 observational studies of HT and breast cancer, had information on specific hormonal preparations for 39% of eligible women and most of these women reported use of estrogen-alone preparations[32]. The combined analysis showed no marked variation between estrogen-only preparations and combined HT[32]. However, the collaborative analysis, overall, provided limited information on estrogen-only versus combination estrogen-progestin therapy. Factors that may explain the disparate findings of the association between estrogen-only use and the risk of developing breast cancer, which were observed in the clinical trial and observational studies, include an imbalance in the prevalence of routine screening between users and nonusers of hormones, and gap time between the onset of menopause and the first use of postmenopausal hormone therapy[44][45].

Following publication of the WHI results, HT use dropped dramatically in the United States and elsewhere. Follow-up of 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[46]. Analysis of changes in breast cancer rates in the United States observed a sharp decline in breast cancer incidence rates from 2002 to 2003, following the release of the WHI trial data among women aged 50 years and older[47][48]. The decreased incidence is primarily the result of changes in the incidence of ER–positive breast cancer [47], which provides additional support for the causal association between combined HT and the risk of breast cancer. Similarly, in multiple countries where the prevalence of HT use was high, breast cancer rates decreased in a similar time frame, coincident with changes in prescribing patterns and/or reported prevalence of use. [49] [50][51] 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[52]. Since the decline in breast cancer incidence noted from 2002 to 2003, rates in the United States have stabilized[52][53]. These observations support the causal effect of combined HT on breast cancer incidence and modification of breast cancer risk through either withdrawal of HT or never having used HT.

Ionizing radiation exposure

A well-established relationship exists between exposure to ionizing radiation and the risk of developing breast cancer[54]. Excess breast cancer risk is consistently observed in association with a variety of exposures such as fluoroscopy for tuberculosis and radiation treatments for acne, tinea, thymic enlargement, postpartum mastitis, or Hodgkin lymphoma. Although risk is inversely associated with age at radiation exposure, the manifestation of breast cancer risk occurs according to the usual age-related pattern[55]. An estimate of the risk of breast cancer associated with medical radiology puts the figure at less than 1% of the total[56]. However, it has been theorized that certain populations, such as AT heterozygotes, are at an increased risk of breast cancer from radiation exposure[57]. A large cohort study of women who carry mutations of BRCA1 or BRCA2 concluded that chest x-rays increase the risk of breast cancer still further (RR = 1.54; 95% CI, 1.1–2.1), especially for women who were x-rayed before age 20 years[58].

Women treated for Hodgkin lymphoma by age 16 years may have a subsequent risk, which is as high as 35%, of developing breast cancer by age 40 years[59][60]. One study suggests that higher doses of radiation (median dose, 40 Gy in breast cancer cases) and treatment received between the ages of 10 and 16 years corresponds with higher risk[59]. Unlike the risk for secondary leukemia, the risk of treatment-related breast cancer did not abate with duration of follow-up; that is, increased risk persisted more than 25 years after treatment[59][61][62]. In these studies, most patients (85%–100%) who developed breast cancer did so either within the field of radiation or at the margin[59][60][61]. 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 those treated with mantle radiation alone, possibly because of chemotherapy-induced ovarian suppression (RR = 0.06; 95% CI, 0.01–0.45)[63]. 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[62]. These studies suggest that ovarian hormones promote the proliferation of breast tissue with radiation-induced mutations[62].

The question arises whether breast cancer patients treated with lumpectomy and radiation therapy (L-RT) are at increased risk for second breast malignancies or other malignancies compared with those treated by mastectomy. Outcomes of 1,029 L-RT patients were compared with 1,387 patients who underwent mastectomies. After a median follow-up of 15 years, there was no difference in the risk of second malignancies[64]. 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[65]. 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[66]. 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 the treatment group, and the overall rate was 6%[67].


Obesity is associated with increased breast cancer risk, especially among postmenopausal women who do not use HT. The WHI observational study observed 85,917 women aged 50 to 79 years and collected information on weight history as well as known risk factors for breast cancer[68]. 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.


Many epidemiologic studies have shown an increased risk of breast cancer associated with alcohol consumption. Individual data from 53 case-control and cohort studies were included in a British meta-analysis[69]. Compared with 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. The same result was obtained, even after additional 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 Associated With Decreased Risk of Breast Cancer


Active exercise may reduce breast cancer risk, particularly in young parous women[70]. Numerous observational studies have examined the relationship between physical activity and breast cancer risk[71]. Most of these studies have shown an inverse relationship between level of physical activity and breast cancer incidence. The average RR reduction is reportedly 30% to 40%. However, it is not known to what degree, if at all, the observed association is to the result of confounding variables, such as diet or a genetic predisposition to breast cancer. A prospective study of more than 25,000 women in Norway suggests that doing heavy manual labor or exercising 4 or more hours per week is associated with a decrease in breast cancer risk. This decrease is more pronounced in premenopausal women and in women of normal or lower-than-normal body weight[72]. In a case-control study of African American women, strenuous recreational physical activity (>7 hours per week) was associated with decreased breast cancer incidence[73].

Interventions Associated With Decreased Risk of Breast Cancer: Benefits and Harms

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[74]. Tamoxifen also maintains bone density among postmenopausal women with breast cancer[75][76][77][78][79]. Adverse effects include hot flashes, venous thromboembolic events, and endometrial cancer[80][81][82].

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[83][84]. The independent Endpoint Review, Safety Monitoring, and Advisory Committee closed the study early because of a 49% reduction in the incidence of breast cancer for tamoxifen-treated versus placebo-treated participants. After about 4 years of follow-up, placebo-treated women had 154 cases of invasive breast cancer compared with 85 cases in women who received tamoxifen. Noninvasive breast cancers were also reduced, with 59 cases in the placebo group versus 31 in the tamoxifen-treated group. Another benefit of tamoxifen use was a reduction in fractures, with 47 occurring in the tamoxifen-treated women compared with 71 in the placebo group. These benefits were accompanied by an increased incidence of endometrial cancer and thrombotic events in women aged 50 years and older. There were 33 endometrial cancers and 99 vascular events (including 17 cases of pulmonary embolism and 30 cases of deep vein thrombosis) in women who received tamoxifen compared with 14 endometrial cancers and 70 vascular events (including 6 cases of pulmonary embolism and 19 cases of deep vein thrombosis) in women who received a placebo[84].

An update of the BCPT results after 7 years of follow-up demonstrates results similar to those in the initial report[85]. Follow-up was more complete for the tamoxifen group than for the placebo group because of a greater drop-out rate among women in the placebo group after early termination of the study. In addition, women who received a placebo were given the option of taking tamoxifen or participating in the Study of Tamoxifen and Raloxifene (STAR), and 32% did so. Breast cancer rates decreased among women in the placebo group from year 6 to year 7 of follow-up. A statistically significant RR of 43% for invasive breast cancer persisted at follow-up, despite the addition of women to the placebo arm. The rate of invasive breast cancer among women in the placebo group was 6.29 per 1,000 women versus 3.59 per 1,000 women for women in the tamoxifen group, for a risk reduction of 0.27%. Benefits and risks of tamoxifen were not significantly different from those in the original report, with persistent benefit of reductions in fracture and persistent risks 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).

Other trials of tamoxifen for primary prevention of breast cancer have been completed[86][87][88]. Initial analyses from two smaller trials, one in the United Kingdom (U.K.) [86] and one primarily in Italy[87], showed no protective effect, perhaps because of differences between target populations and study designs and those in the U.S. study. The U.K. study focused on 2,471 women at increased breast cancer risk because of their family history of breast and/or ovarian cancer; about 36% of participants were from families that had a greater than 80% chance of carrying a breast cancer susceptibility gene. After a median follow-up of nearly 6 years, no protective effect of tamoxifen was detected (RR = 1.06). Subsequent follow-up shows that at a median of 13 years, there was a statistically nonsignificant reduction in breast cancer risk in the tamoxifen arm compared with the placebo arm (HR = 0.78; 95% CI, 0.58–1.04). 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[89]. The Italian study focused on 5,408 women who had undergone hysterectomy and who were described as “low-to-normal risk” women. At the initial report, after a median follow-up of nearly 4 years, no protective effect of tamoxifen was observed. Longer follow-up and subgroup analysis in the Italian 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)[90][91].

The last trial of tamoxifen for primary prevention of breast cancer was the International Breast Cancer Intervention Study (IBIS-I). This trial randomly assigned 7,152 women aged 35 to 70 years who were at increased risk of breast cancer to receive tamoxifen (20 mg/day for 5 years) or placebo[88]. After a median follow-up of 50 months, 32% fewer women (95% CI, 8%–50%) in the tamoxifen group than in the placebo group had developed breast cancer (invasive plus carcinoma in situ with an absolute reduction from 6.75 to 4.6 breast cancers per 1,000 woman-years). The RR reduction in ER–positive invasive breast cancer was 31%; there was no reduction in ER–negative cancers. In this trial, but in none of the other tamoxifen trials, there was an excess of all-cause mortality in the tamoxifen group (25 vs. 11; P = .028), which the authors attributed to chance. The prophylactic effect of tamoxifen on breast cancer persisted after active treatment, with 27% fewer women in the tamoxifen arm developing breast cancer than did women in the placebo arm (142 vs. 195 cases, respectively; RR = 0.73, 95% CI, 0.58–0.91) over the full study period after a further 46 months of median follow-up[92]. In this report, most of the additional follow-up time accrued after the discontinuation of active treatment in the treatment arm.

A meta-analysis of the early report of these primary prevention trials was performed, and its findings showed a 38% reduction in the incidence of breast cancer without statistically significant heterogeneity[82]. 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.

Treatment decisions are complex and need to be individualized, weighing estimates of a woman’s chance of reducing breast cancer and fracture risks against the chance of developing detrimental side effects, some of which may be life threatening. The risks and benefits of taking tamoxifen have been estimated for women according to age, race, and risk group based on the results of the BCPT, additional risk/benefit analyses, and review of the literature[93]. Because adverse effects of tamoxifen increase with age, tamoxifen is most beneficial for women younger than 50 years who have an increased risk of developing breast cancer. Overall, the net benefit or risk depends on age, whether a woman has a uterus, and her baseline risk of breast cancer.

Women with a history of ductal carcinoma in situ (DCIS) are at increased risk (3.4%) for contralateral breast cancer but were not eligible for the BCPT because of competing treatment trials. In a trial of DCIS treatment, however, 13.4% of women treated with lumpectomy and radiation had breast cancer events within approximately 6 years, compared with 8.2% of those who also received tamoxifen[94]. The National Surgical Adjuvant Breast and Bowel Project (NSABP) B-24 RCT evaluated the added benefit of tamoxifen to lumpectomy and radiation therapy for women with DCIS[94]. The risk of all breast cancer events, invasive and noninvasive, was reduced with tamoxifen (rate ratio = 0.63; 95% CI, 0.47–0.83); the risk of contralateral breast cancer (invasive and noninvasive) associated with tamoxifen was 0.49 (95% CI, 0.26–0.87). Given the results of the NSABP B-24 trial and the BCPT, it is reasonable to consider the use of tamoxifen for breast cancer risk reduction among women with DCIS.

In addition to tamoxifen, other hormonal manipulations have been proposed to modulate the production of breast cell growth factors by suppressing ovarian function [95] or changing the endogenous hormonal environment[96]. The list of chemoprevention agents that may be used in breast cancer prevention is long.

Raloxifene hydrochloride is a SERM that has antiestrogenic effects on breast and endometrial tissue and estrogenic effects on bone, lipid metabolism, and blood clotting[97]. The Multiple Outcomes of Raloxifene Evaluation (MORE), a randomized, double-blind trial, evaluated 7,705 postmenopausal women with osteoporosis from 1994 to 1998 at 180 clinical centers in the United States. The effect on breast cancer incidence was a secondary endpoint and therefore should be judged with caution. After a median follow-up of 47 months, the risk of invasive breast cancer decreased by 72%[98]. Breast cancer was reported in 79 women and confirmed in 77 women. Invasive breast cancer occurred in 39 women treated with placebo and in 22 women who were randomly assigned to either of the two raloxifene arms (raloxifene 120 mg daily or raloxifene 60 mg; RR = 0.25; 95% CI, 0.17–0.45; 4.7–1.3 invasive breast cancers per 1,000 woman-years in the placebo and combined-treatment groups, respectively). DCIS occurred in five women treated with a placebo and in 11 women treated with raloxifene. After combining noninvasive and invasive cancer occurrences, the RR of breast cancer among women in the raloxifene group was 0.38 (95% CI, 0.24–0.58; 5.3–1.9 breast cancers per 1,000 woman-years in the placebo and combined-treatment groups, respectively). As with tamoxifen, raloxifene reduced the risk of ER–positive breast cancer but not ER–negative breast cancer. Similar to tamoxifen, raloxifene is associated with an excess risk of hot flashes and thromboembolic events. The risk of venous thromboembolic disease (deep venous thrombosis or pulmonary embolism) was 2.4 times higher in women assigned to the raloxifene groups compared with the placebo group. One woman (in the 60-mg raloxifene group) died from pulmonary embolism. There was little difference in the rate of venous thromboembolic disease between the 60-mg and 120-mg groups (3.32–3.63 events per 1,000 woman-years, respectively). No excess risk of endometrial cancer was observed after 47 months of follow-up; five cases occurred among women on placebo (0.77 cases per 1,000 woman-years), five cases among women treated with 60 mg of raloxifene (0.77 cases per 1,000 woman-years), and four cases among women treated with 120 mg of raloxifene (0.60 cases per 1,000 woman-years). Raloxifene did not increase the risk of endometrial hyperplasia[99]. Of 1,781 women who underwent transvaginal ultrasonography at baseline and had at least one follow-up test, endometrial thickness increased by an average of 0.01 mm in the raloxifene groups and decreased by 0.27 mm in the placebo group after 3 years of follow-up (P < .01 for the difference between the two groups). Sixty participants (10.1%) in the placebo group and 168 women (14.2%) in the raloxifene groups (P = .02) had endometrial thickness that was greater than 5 mm on at least one follow-up ultrasound. Among the 196 women who still had a uterus (48 in the placebo group and 148 in the raloxifene group), there were three cases of hyperplasia and two cases of endometrial cancer in the placebo group and three cases of hyperplasia and two cases of endometrial cancer in the combined raloxifene group. Subgroup analyses after 4 years of follow-up suggest that, among women who have osteoporosis, raloxifene reduces breast cancer incidence for both women at higher and lower risk of developing breast cancer.

An extension of the MORE study, the Continuing Outcomes Relevant to Evista (CORE) study, continued studying about 80% of MORE participants in their randomized groups for 4 years beyond the original 4 years of MORE. 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 breast cancer. As in MORE, this effect resulted from a reduction in ER–positive but not ER–negative invasive breast cancer. There was no reduction in noninvasive 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. Similar to the MORE and CORE studies, raloxifene reduced the risk of invasive breast cancer (HR = 0.56; 95% CI, 0.38–0.83). The annualized rate of invasive breast cancer in the raloxifene group was 0.20% compared with 0.29% in the placebo group. Raloxifene did not reduce the risk of ER–negative breast cancer or noninvasive breast cancer. The annualized rate of noninvasive breast cancer in the raloxifene group was 0.04% compared with 0.02% in the placebo group.

STAR (NSABP P-2) compared tamoxifen and raloxifene in 19,747 high-risk women during a mean of 3.9 years of follow-up. The primary outcome measure was breast cancer incidence, which was approximately the same for invasive cancer, but favored tamoxifen for noninvasive cancer. 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 favored tamoxifen, whereas vasomotor flushing, bladder control symptoms, gynecologic symptoms, and leg cramps favored raloxifene.

Incidence of Outcomes Per 1,000 Women
Incidence of Outcomes Per 1,000 Women
TamoxifenRaloxifeneRR, 95% CI
CI = confidence interval; RR = relative risk; VTE = venous thromboembolism.
Invasive breast cancer4.34.411.02, 0.82–1.28
Noninvasive breast cancer1.512.111.4, 0.98–2.00
Uterine cancer, 0.35–1.08
VTE3.82.60.7, 0.68–0.99
Cataracts12.39.720.79, 0.68–0.92
Incidence of Symptoms (0–4 scale)
Favor Tamoxifen
Dyspareunia0.680.78P < .001
Musculoskeletal problems1.101.15P = .002
Weight gain0.760.82P < .001
Favor Raloxifene
Vasomotor symptoms0.960.85P < .001
Bladder control symptoms0.880.73P < .001
Leg cramps1.100.91P < .001
Gynecologic problems0.290.19P < .001

Aromatase inhibition or inactivation

Another class of agents, commercially available for the treatment of hormone-sensitive breast cancer, may also prevent breast cancer. These three drugs interfere with the adrenal enzyme aromatase, which is responsible for estrogen production in postmenopausal women. Anastrozole (Arimidex) and letrozole (Femara) inhibit aromatase activity, whereas exemestane (Aromasin) inactivates the enzyme. All three drugs have similar side effects, infrequently causing fatigue, arthralgia, and myalgia. Bone mineral density may be decreased, and fracture rate is increased, possibly because of the decreased bone density.

All three drugs decrease the incidence of new breast cancers in women with a history of breast cancer. The Arimidex, Tamoxifen, Alone or in Combination (ATAC) trial compared anastrozole, tamoxifen, and the combination when used as an adjuvant HT after treatment of the primary breast cancer. Anastrozole-treated patients had a 7.1% rate of locoregional and distant recurrence versus 8.5% for those treated with tamoxifen and 9.1% for the combination. A more impressive result was the decreased rate of primary contralateral breast cancers (0.4% vs. 1.1% vs. 0.9%). Another trial analyzed the use of letrozole versus placebo in 5,187 women with breast cancer, following 5 years of treatment with adjuvant tamoxifen. 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 rate of contralateral breast cancer (14 vs. 26). A third trial randomly assigned 4,742 women who had already received 2 years of adjuvant tamoxifen. Women either continued the tamoxifen or switched to exemestane. After 2.4 years’ median follow-up, the women assigned to receive exemestane had a decreased risk of local or metastatic recurrence and a decreased risk of new primary contralateral breast cancer (9 vs. 20 women).

One RCT has reported the effect of aromatase inhibitors in preventing invasive breast cancer among women who have no history of breast cancer. In this study, 4,560 women aged 35 years and older who had at least one risk factor (e.g., women aged 60 years and older or those having a Gail 5-year risk >1.66% or a history of DCIS with mastectomy) were randomly assigned to receive exemestane 25 mg daily or a placebo. After 35 months median follow-up, 32 women of the 2,275 in the placebo group had been diagnosed with invasive breast cancer, compared with 11 women in the exemestane group (HR, 0.35; 95% CI, 0.18–0.70; NNT, about 100 for 35 months). There was a small increase in adverse effects in the exemestane group compared with the placebo group, primarily in hot flashes (increase, 8%) and fatigue (increase, 2%). There was no difference in the occurrence of fractures or cardiovascular events. A second trial (IBIS-2) is under way.

Prophylactic mastectomy

A retrospective cohort study was conducted to evaluate the impact of bilateral prophylactic mastectomy on the subsequent occurrence of breast cancer among women at high and moderate risk of breast cancer on the basis of family history. Most women in this retrospective series (90%) had undergone subcutaneous rather than total mastectomy, which is the procedure of choice for maximum breast tissue removal. Median follow-up after surgery was 14 years. All women included in the report had some family history of cancer and were classified as high risk or moderate risk for breast cancer based on the pattern of breast cancer in the family. Expected cases of breast cancer were estimated for moderate- and high-risk women using the Gail model and the observed rates of breast cancer among sisters of the probands. The reduction in risk for moderate-risk women was 89%; for high-risk women, the reduction ranged from 90% to 94% depending on the method used to calculate expected rates of breast cancer. The reduction in risk of death from breast cancer ranged from 100% among moderate-risk women to 81% among high-risk women. Information on BRCA1 or BRCA2 mutation status was not known. Although this study provides the best evidence available to date that prophylactic surgery offers benefits despite the fact that some breast tissue remains postsurgery, some factors may bias the estimate of benefit. Criteria used to classify women at high risk would include women from families misclassified as having an autosomal-dominant inherited pattern and women from inherited-syndrome families who are not at high risk because they did not inherit the susceptibility genotype. These factors may tend to overestimate the benefits of prophylactic surgery. Most of the women, however, who underwent prophylactic surgery would never have gone on to develop breast cancer. Thus, many were treated for the few who truly benefited by having their breast cancer prevented. Among the 425 moderate-risk women who had prophylactic mastectomy, the estimated number of breast cancer cases expected to occur was 37.4; among the 214 high-risk women, the estimates ranged from 30.0 to 52.9, depending on the model used to estimate breast cancer occurrence. Thus, bilateral prophylactic mastectomy as an option for women should be considered in association with cancer risk assessment and counseling regarding all the available preventive options, which now include tamoxifen as a preventive agent[84].

Studies of the harms of prophylactic mastectomy have been retrospective. Most women reported relief of anxiety about breast cancer, and few were dissatisfied with their choice to undergo the procedure. A higher dissatisfaction rate occurred among women who chose reconstruction over those who did not.

Prophylactic oophorectomy

Women at high risk due to BRCA1 or BRCA2 gene mutations who had prophylactic oophorectomies to prevent ovarian cancer were found to have a lower incidence of breast cancer than age-matched mutation carriers who did not undergo prophylactic oophorectomy. The reported reductions in RR were approximately 50%. These observational studies, however, are confounded by selection bias, family relationships between patients and controls, indications for oophorectomy, and inadequate information about hormone use. A prospective cohort study has confirmed a reduction in breast cancer risk by about 50% with prophylactic oophorectomy, and a greater reduction in BRCA2 mutation carriers than in BRCA1 carriers.

These findings are similar to those for women who undergo castration for nononcologic diagnoses. Women treated with thoracic radiation who undergo radiation therapy or chemotherapy, which often results in ovarian ablation, also have similar findings.


A multicenter phase III RCT of fenretinide versus no treatment was performed in 2,867 women who received local therapy for stage 0 (DCIS) or stage I (T1–T2, N0, M0; T = tumor, N = node, M = metastasis) breast cancer. An analysis at 8 years showed no difference in contralateral or ipsilateral breast cancer, but a post hoc analysis revealed differential effects for premenopausal and postmenopausal women. A subsequent analysis at 15 years of the 1,739 women enrolled at the organizing center confirmed the beneficial effect in premenopausal women, reducing both contralateral and ipsilateral cancers, HR = 0.62 (95% CI, 0.46–0.83). This beneficial effect was age dependent, with the youngest women achieving the most benefit. Although the daily fenretinide 200 mg was withheld for 3 days each month, there was a cumulative incidence of low-grade dark adaptation (i.e., night blindness) and dermatologic disorders. As with any vitamin A analog, women taking this drug should avoid pregnancy because of potential teratogenic effects.

Factors of Unproven or Disproven Association


Abortion has been suggested as a cause of subsequent breast cancer. Studies showing an association used recalled information in populations in which induced abortion had a social or religious stigma, differential reporting of prior abortion by breast cancer patients, and controls. Trials conducted in social environments where abortion is accepted, however, have not shown an association with breast cancer.

A meta-analysis of women from 53 studies in 16 countries with liberal abortion laws was performed. Analyses were performed separately on 44,000 women with breast cancer who had information on abortion collected prospectively (i.e., 13 studies) versus 39,000 women with breast cancer from whom information was collected retrospectively (i.e., 40 studies). The RR of breast cancer for women with spontaneous abortion was 0.98 (95% CI, 0.92–1.04 for those with prospective data collection and 0.94–1.02 for retrospective data). The RR after induced abortion was 0.93 (95% CI, 0.89–0.96; P = .0002) if the information was collected prospectively but was 1.11 (95% CI, 1.06–1.16) if it was collected retrospectively. Additional analyses of the number and timing of aborted pregnancies were performed, but none showed a significant association with breast cancer.

Oral contraceptives

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.

Environmental factors

Whether occupational, environmental, or chemical exposures have an effect on breast cancer risk is controversial. Although some findings suggest that organochlorine exposures, such as those associated with insecticides, might be associated with an increase in breast cancer risk, other case-control and nested case-control studies do not. 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.

Diet and vitamins

A low-fat diet might influence breast cancer risk through hormonal mechanisms. Ecologic studies show 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. A pooled analysis of results from seven cohort studies found no evidence for an 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%, using five servings per day of vegetables and fruit and six servings per day of grains. The intervention group was successful in reducing fat intake by approximately 10% for more than 8.1 years of follow-up, and the group was found to have lower estradiol and lower gamma-tocopherol levels, but no weight loss was shown. 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). Because the intervention group also initially lost weight relative to the control group, it is not clear whether any potential effect in reducing breast cancer results from lower dietary fat or lower weight. Likewise, there was no benefit derived from the low-fat diet for all cancer mortality, overall mortality, or cardiovascular disease.

Fruit and vegetable consumption has been examined for any protective effect against breast cancer. A pooled analysis of adult dietary data from eight cohort studies, which included 351,823 women in whom 7,377 incident cases of breast cancer occurred, provides little support for an association. When examining the dietary data 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. Additionally, no statistically significant association was observed between any of the specific fruits and vegetables examined and breast cancer risk.

No randomized prevention trials examining the effect of fruit and vegetable consumption on breast cancer incidence have been conducted; however, evidence for the lack of an association between fruit and vegetable consumption and prevention of breast cancer is supported by results of the Women's Healthy Eating and Living Randomized Trial. Although the trial was a secondary prevention study, the outcomes included new primary breast cancers. More than 3,000 women were enrolled and randomly assigned to an intense regimen of fruit and vegetable intake, high fiber and low fat, or a comparison group receiving printed materials on the “5-A-Day” dietary guidelines. Both groups were consuming more than seven servings of vegetables and fruits at baseline. Increased fruit and vegetable consumption was monitored through dietary assessment and measures of serum carotenoid concentrations. After a mean of 7.3 years follow-up, there was no reduction in new primary cancers (43 new primary breast cancers among the 1,537 randomly assigned to the intervention; compared with 35 new primary breast cancers in 1,551 randomly assigned to the comparison group). There was no difference in disease-free survival between the two groups 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 beta carotene versus 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 (WACS) examined total cancer and invasive breast cancer as secondary outcomes following supplementation with either vitamin C, vitamin E, or beta carotene, which were assigned randomly according to a 2 x 2 x 2 factorial design. Women were recruited from the parent Women’s Health Study and were eligible for the trial if they had cardiovascular disease or at least three cardiac risk factors. A total of 8,171 women were enrolled. For the analysis of cancer outcome, women were excluded if they had a prior history of cancer (n = 544). Neither total cancer nor breast cancer incidence was statistically significantly different between supplementation groups and the placebo arm. Two years after enrollment for WACS, a subset of participating women who were willing not to use folic acid and vitamin B6 or B12 supplements (n = 5,442) were randomly assigned to supplementation with a combination of 1.5 mg of folic acid, 50 mg of vitamin B6, and 1 mg of B12, or placebo. After 7.3 years of treatment, there was no statistically significant difference in the incidence of total invasive cancer or invasive breast cancer between the supplemented group and the placebo arm.

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. Some of these studies have observed both active and passive smoking to be associated with breast cancer risk, but the consensus of most review groups continues to be that the body of evidence does not clearly demonstrate that either active or passive cigarette smoking contributes to breast cancer risk.

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.


Two well-conducted meta-analyses of RCTs and RCTs plus observational studies found no evidence that statin use either increases or decreases the risk of breast cancer.


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