Background
        Incidence and mortality
        Etiology and pathogenesis of breast cancer
        Endogenous estrogen
        Genetic mutations
Factors Associated with Increased Risk of Breast Cancer
        Hormone replacement therapy/hormone therapy
        Ionizing radiation exposure
        Obesity
        Alcohol
Factors Associated with Decreased Risk of Breast Cancer
        Exercise
Interventions Associated with Decreased Risk of Breast Cancer: Benefits and Harms
        Selective estrogen receptor modulators (SERMs)
        Aromatase inhibition or inactivation
        Prophylactic mastectomy
        Prophylactic oophorectomy
        Fenretinide
Factors of Unproven or Disproven Association
        Abortion
        Oral contraceptives
        Environmental factors
        Diet and vitamins
        Active and passive cigarette smoking
        Statins

Background

Incidence and mortality

In the United States, a cumulative risk by age 90 years of being diagnosed with breast cancer is one in eight.[1] With an estimated 184,450 cases expected, breast cancer will be the most frequently diagnosed nonskin malignancy in U.S. women in 2008.[2] In the same year, breast cancer will kill an estimated 40,930 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 1,990 new cases will be diagnosed in 2008.[2] 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 2.3% per year from 1990 to 2001.[3]

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.

The incidence of breast cancer is lower in patients using selective estrogen receptor modifiers, but it is too early to observe an impact on breast cancer mortality. Also, these agents have attendant side effects.

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.[4] 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.[5]

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.[6-8]

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.[9] Women who develop breast cancer tend to have higher endogenous estrogen and androgen levels.[10]

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.[11-14] The removal of one ovary also reduces the risk of breast cancer, but to a lesser degree than the removal of both ovaries.[15]

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.[14,16,17] In one study, women who experienced a first full-term pregnancy before age 20 years were one-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.[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.[10,23,24] 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.

The inherited genetic profile of an individual influences susceptibility to mutagens and growth factors that 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 mutations; BRCA2 mutations are also associated with male breast cancer, prostate cancer, pancreatic cancer, and lymphomas.[30]

Women who carry an abnormal ataxia telangiectasia (AT) gene may be at increased risk of breast cancer.[31]

Exogenous hormone therapy (HT) after menopause is associated with increased breast cancer risk.[32] The Women’s Health Initiative (WHI) investigated the effect of hormones and dietary interventions on breast cancer risk.[33] 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 HT, with a hazard ratio (HR) of 1.24 (95% confidence interval [CI], 1.02–1.50), resulting in early termination of the HT arm of the trial.[34] The excess risk was observed for invasive but not in situ breast cancer. The HT-related cancers were larger than those related to placebo, though grade and histology were similar. HT was also associated with a higher percentage of abnormal mammograms.

There is solid evidence of the impact of HT use on breast cancer incidence.[35-37] Almost immediately after the 2002 WHI publication of the negative cardiovascular effect of HT, HT use in the United States dropped dramatically. Coincident with this decrease in HT use, breast cancer incidence dropped by as much as 15% among postmenopausal women. The drop was observed exclusively in estrogen receptor–positive (ER+) disease. The slight decline in screening mammography rates over the same period was unlikely to account for the drop in breast cancer incidence.[36-38] Whether this decrease in incidence will translate into a mortality benefit is unclear.

The incidence of breast cancer increased dramatically in the United States and in many European countries between the 1980s and 1990s. Much of this increase was due to the widespread introduction of screening mammography. However, age-period-cohort modeling suggests that there would have been a substantial increase even without screening.[39,40]

The Heart and Estrogen/Progestin Replacement Study [41] included an open-label follow-up of a randomized controlled trial 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 breast cancer incidence increased (relative risk [RR] = 1.27; 95% CI, 0.84–1.94; absolute risk increase 4.7–5.9 cases per 1,000 person-years). Though not statistically significant, the RR estimate is consistent with the much larger WHI study.

There is little or no risk of breast cancer associated with estrogen-only HT as compared with the risk for combined HT.[42-45] In a case-control study of women aged 65 years and older, estrogen-only HT, even for more than 25 years' duration, was not associated with an increased risk of invasive breast cancer.[44] The estrogen-only WHI found a nearly statistically significant reduction in breast cancer incidence in the estrogen-only arm compared with placebo (HR = 0.77; 95% CI, 0.59–1.01; absolute risk from 33 to 26 breast cancers per 10,000 person-years). It is not clear whether such a reduction is a real effect of estrogen only or is a chance observation.

A well-established relationship exists between exposure to ionizing radiation and the risk of developing breast cancer.[46] 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.[47] An estimate of the risk of breast cancer associated with medical radiology puts the figure at less than 1% of the total.[48] However, it has been theorized that certain populations, such as AT heterozygotes, are at an increased risk of breast cancer from radiation exposure.[49] 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.[50]

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.[51,52] 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.[51] 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.[51,53,54] In these studies, most patients (85%–100%) who developed breast cancer did so either within the field of radiation or at the margin.[51-53] 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).[55] 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.[54] These studies suggest that ovarian hormones promote the proliferation of breast tissue with radiation-induced mutations.[54]

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.[56] Further evidence from three randomized controlled trials 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.[57] 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.[58] 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%.[59]

Obesity is associated with increased breast cancer risk, especially among postmenopausal women who do not use hormone replacement therapy (HRT)/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.[60] 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 HRT/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.[61] 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 to 44 g per day and 1.46 (95% CI, 1.33–1.61; P < .001) for those consuming at least 45 g 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.

Active exercise may reduce breast cancer risk, particularly in young parous women.[62]Numerous observational studies have examined the relationship between physical activity and breast cancer risk.[63] Most of these studies have shown an inverse relationship between level of physical activity and breast cancer incidence. The average relative risk reduction is reportedly 30% to 40%. However, it is not known whether or to what degree the observed association is due to 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.[64] In a case-control study of African American women, strenuous recreational physical activity (>7 hours per week) was associated with decreased breast cancer incidence.[65]

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.[66] Tamoxifen also maintains bone density among postmenopausal women with breast cancer.[67-71] Adverse effects include hot flashes, venous thromboembolic events, and endometrial cancer.[72-74]

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.[75,76] 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.[76]

An update of the BCPT results after 7 years of follow-up demonstrates results similar to those in the initial report.[77] 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.[78-80] Initial analyses from two smaller trials, one in the United Kingdom (U.K.) [78] and one primarily in Italy,[79] 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+ 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.[81] 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 HRT/HT during the trial (RR = 0.43; 95% CI, 0.20–0.95).[82,83]

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.[80] 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+ invasive breast cancer was 31%; there was no reduction in estrogen receptor–negative (ER-) 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 (95% CI, 0.58–0.91) in the tamoxifen arm developing breast cancer over the full study period (absolute RR from 6.82 to 4.97 per 1,000 women-years) after a further 46 months of median follow-up.[84] 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, finding a 38% reduction in the incidence of breast cancer without statistically significant heterogeneity.[74] ER+ 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.[85] 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.[86] The National Surgical Adjuvant Breast and Bowel Project (NSABP) B-24 randomized controlled trial evaluated the added benefit of tamoxifen to lumpectomy and radiation therapy for women with DCIS.[86] 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 [87] or changing the endogenous hormonal environment.[88] 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.[89] 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%.[90] 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 that 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+ breast cancer but not ER- 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 and 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.[91] 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+ but not ER- invasive breast cancer. There was no reduction in noninvasive breast cancer. The overall reduction in invasive breast cancer over the 8 years of MORE and CORE was 66% (HR = 0.34; 95% CI, 0.22–0.50); the reduction for ER+ invasive breast cancer was 76% (HR = 0.24; 95% CI, 0.15–0.40).[92]

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- 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 over 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.[93] 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.[94]

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.[95] 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.[96] 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.[97] After 2.4 years’ median follow-up, the women assigned to receive exemestane had a decreased risk of local or metastatic recurrence as well as a decreased risk of new primary contralateral breast cancer (9 vs. 20).

The use of these drugs as primary breast cancer prophylaxis should not be adopted until results are available from trials performed in populations of women without prior breast cancer. One such trial (IBIS-2) is under way to define the efficacy and toxicities of aromatase inhibitors and inactivators in breast cancer prevention.

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.[98] 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.[99] For example, 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. It is important to note that most of the women 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.[76]

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.[100] A higher dissatisfaction rate occurred among women who chose reconstruction over those who did not.[101]

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.[102-104] 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.

These findings are similar to those for women who undergo castration for nononcologic diagnoses and for women treated with thoracic radiation who undergo radiation therapy or chemotherapy that results in ovarian ablation.

A multicenter phase III randomized controlled trial of fenretinide versus no treatment was performed in 2,867 women who received local therapy for stage 0 DCIS or stage 1 (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.[105] 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.[106] Although the daily fenretinide 200 mg was withheld for 3 days each month, there was a cumulative incidence of low-grade dark adaptation (night blindness) and dermatologic disorders. As with any vitamin A analog, women taking this drug should avoid pregnancy because of potential teratogenic effects.

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.[107-112]

A meta-analysis of women from 53 studies in 16 countries with liberal abortion laws was performed.[113] Analyses were performed separately on 44,000 women with breast cancer who had information on abortion collected prospectively (13 studies) versus 39,000 women with breast cancer from whom information was collected retrospectively (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.[113]

Oral contraceptives have been associated with a small increased risk of breast cancer in current users that diminishes over time.[114] 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.[115]

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.[116]

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,[117,118] other case-control and nested case-control studies do not.[119-124] 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.

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.[125] 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.[126] 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 accomplished a reduction of fat intake of approximately 10% for more than 8.1 years of follow-up and were found to have lower estradiol and lower gamma-tocopherol levels, but no 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).[127] 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.[128] Likewise, there was no benefit derived from the low-fat diet for all cancer mortality, overall mortality, or cardiovascular disease.[129]

Fruit and vegetable consumption has been examined for any protective effect against breast cancer.[130] 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.[131] 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.[132] 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.

Micronutrient intake may also play a role. Case-control studies show an inverse association between dietary beta carotene intake and breast cancer risk.[133,134] In the Women’s Health Study, however, 39,876 women were assigned to take beta carotene or placebo, with no difference in cancer incidence at 2 years.[135] In this same study, no overall effect on cancer was seen in women taking 600 IU of vitamin E every other day.[136] High intake of foods containing folate,[137] beta carotene, and vitamins A and C [133] may also reverse the increased risk associated with alcohol use.

Fenretinide [138] 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.[105]

The potential role of active cigarette smoking in the etiology of breast cancer has been studied for more than 3 decades with no clear-cut evidence of an association.[139] 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.[139,140]

Two well-conducted meta-analyses of randomized controlled trials [141] and randomized controlled trials plus observational studies [142] found no evidence that statin use either increases or decreases the risk of breast cancer.

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