Breast Cancer Prevention (PDQ®)—Health Professional Version - National Cancer Institute

Breast Cancer Prevention (PDQ®)–Health Professional Version

Who Is at Risk?

Besides female sex, advancing age is the biggest risk factor for breast cancer. Reproductive factors that increase exposure to endogenous estrogen, such as early menarche and late menopause, increase risk, as does the use of combination estrogen-progesterone hormones after menopause. Nulliparity and alcohol consumption also are associated with increased risk.

Women with a family history or personal history of invasive breast cancer, ductal carcinoma in situ or lobular carcinoma in situ, or a history of breast biopsies that show benign proliferative disease have an increased risk of breast cancer.[1-4]

Increased breast density is associated with increased risk. It is often a heritable trait but is also seen more frequently in nulliparous women, women whose first pregnancy occurs late in life, and women who use postmenopausal hormones and alcohol.

Exposure to ionizing radiation, especially during puberty or young adulthood, and the inheritance of detrimental genetic mutations increase breast cancer risk.

References

Kotsopoulos J, Chen WY, Gates MA, et al.: Risk factors for ductal and lobular breast cancer: results from the nurses' health study. Breast Cancer Res 12 (6): R106, 2010. [PUBMED Abstract]
Goldacre MJ, Abisgold JD, Yeates DG, et al.: Benign breast disease and subsequent breast cancer: English record linkage studies. J Public Health (Oxf) 32 (4): 565-71, 2010. [PUBMED Abstract]
Kabat GC, Jones JG, Olson N, et al.: A multi-center prospective cohort study of benign breast disease and risk of subsequent breast cancer. Cancer Causes Control 21 (6): 821-8, 2010. [PUBMED Abstract]
Worsham MJ, Raju U, Lu M, et al.: Risk factors for breast cancer from benign breast disease in a diverse population. Breast Cancer Res Treat 118 (1): 1-7, 2009. [PUBMED Abstract]

Overview

Note: Separate PDQ summaries on Breast Cancer Screening; Breast Cancer Treatment; Male Breast Cancer Treatment; Breast Cancer Treatment During Pregnancy; and Levels of Evidence for Cancer Screening and Prevention Studies are also available.

Factors With Adequate Evidence of Increased Risk of Breast Cancer

Sex and age

Based on solid evidence, female sex and increasing age are the major risk factors for the development of breast cancer.

Magnitude of Effect: Women have a lifetime risk of developing breast cancer that is approximately 100 times the risk for men. The short-term risk of breast cancer in a 70-year-old woman is about ten times that of a 30-year-old woman.

Study Design: Many epidemiologic trials.
Internal Validity: Good.
Consistency: Good.
External Validity: Good.

Inherited risk

Based on solid evidence, women who have a family history of breast cancer, especially in a first-degree relative, have an increased risk of breast cancer.

Magnitude of Effect: Risk is doubled if a single first-degree relative is affected; risk is increased fivefold if two first-degree relatives are diagnosed.

Study Design: Population studies, cohort studies, and case-control studies.
Internal Validity: Good.
Consistency: Good.
External Validity: Good.

Based on solid evidence, women who inherit gene mutations associated with breast cancer have an increased risk.

Magnitude of Effect: Variable, depending on gene mutation, family history, and other risk factors affecting gene expression.

Study Design: Cohort or case-control studies.
Internal Validity: Good.
Consistency: Good.
External Validity: Good.

Breast density

Based on solid evidence, women with dense breasts have an increased risk of breast cancer. This is most often an inherent characteristic, to some extent modifiable by reproductive behavior, medications, and alcohol.[1]

Magnitude of Effect: Women with dense breasts have increased risk, proportionate to the degree of density. This increased relative risk (RR) ranges from 1.79 for women with slightly increased density to 4.64 for women with very dense breasts, compared with women who have the lowest breast density.[2]

Study Design: Cohort, case-control studies.
Internal Validity: Good.
Consistency: Good.
External Validity: Good.

Modifiable Factors With Adequate Evidence of Increased Risk of Breast Cancer

Combination hormone therapy

Based on solid evidence, combination hormone therapy (HT) (estrogen-progestin) is associated with an increased risk of developing breast cancer.

Magnitude of Effect: Approximately a 26% increase in incidence of invasive breast cancer; the number needed to produce one excess breast cancer is 237.

Study Design: Randomized controlled trials (RCTs). Furthermore, cohort and ecological studies show that cessation of combination HT is associated with a decrease in rates of breast cancer.
Internal Validity: Good.
Consistency: Good.
External Validity: Good.

Ionizing radiation

Based on solid evidence, exposure of the breast to ionizing radiation is associated with an increased risk of developing breast cancer, starting 10 years after exposure and persisting lifelong. Risk depends on radiation dose and age at exposure, and is especially high if exposure occurs during puberty, when the breast develops.

Magnitude of Effect: Variable but approximately a sixfold increase overall.

Study Design: Cohort or case-control studies.
Internal Validity: Good.
Consistency: Good.
External Validity: Good.

Obesity

Based on solid evidence, obesity is associated with an increased breast cancer risk in postmenopausal women who have not used HT. It is uncertain whether weight reduction decreases the risk of breast cancer in obese women.

Magnitude of Effect: The Women's Health Initiative observational study of 85,917 postmenopausal women found body weight to be associated with breast cancer. Comparing women weighing more than 82.2 kg with those weighing less than 58.7 kg, the RR was 2.85 (95% confidence interval [CI], 1.81–4.49).

Study Design: Case-control and cohort studies.
Internal Validity: Good.
Consistency: Good.
External Validity: Good.

Alcohol

Based on solid evidence, alcohol consumption is associated with increased breast cancer risk in a dose-dependent fashion. It is uncertain whether decreasing alcohol intake by heavy drinkers reduces the risk.

Magnitude of Effect: The RR for women consuming approximately four alcoholic drinks per day compared with nondrinkers is 1.32 (95% CI, 1.19–1.45). The RR increases by 7% (95% CI, 5.5%–8.7%) for each drink per day.

Study Design: Case-control and cohort studies.
Internal Validity: Good.
Consistency: Good.
External Validity: Good.

Factors With Adequate Evidence of Decreased Risk of Breast Cancer

Early pregnancy

Based on solid evidence, women who have a full-term pregnancy before age 20 years have decreased breast cancer risk.

Magnitude of Effect: 50% decrease in breast cancer, compared with nulliparous women or women who give birth after age 35 years.

Study Design: Case-control and cohort studies.
Internal Validity: Good.
Consistency: Good.
External Validity: Good.

Breast-feeding

Based on solid evidence, women who breast-feed have a decreased risk of breast cancer.

Magnitude of Effect: The RR of breast cancer is decreased 4.3% for every 12 months of breast-feeding, in addition to 7% for each birth.[3]

Study Design: Case-control and cohort studies.
Internal Validity: Good.
Consistency: Good.
External Validity: Good.

Exercise

Based on solid evidence, exercising strenuously for more than 4 hours per week is associated with reduced breast cancer risk.

Magnitude of Effect: Average RR reduction is 30% to 40%. The effect may be greatest for premenopausal women of normal or low body weight.

Study Design: Prospective observational and case-control studies.
Internal Validity: Good.
Consistency: Good.
External Validity: Good.

Estrogen use by women with prior hysterectomy: benefits

Based on fair evidence, women who have undergone a prior hysterectomy and who are treated with conjugated equine estrogen have a lower incidence of breast cancer. However, epidemiological studies yield conflicting results.

Magnitude of Effect: After 6.8 years, incidence was 23% lower in women treated with estrogen in an RCT (0.27% per year, with a median of 5.9 years of use, compared with 0.35% per year among those taking a placebo), but was 30% higher in women treated with estrogen in an observational study. The difference in these results may be explained by different screening behavior by the women in both studies.

Study Design: One RCT, observational studies.
Internal Validity: Fair.
Consistency: Poor.
External Validity: Poor.

Estrogen use by women with prior hysterectomy: harms

Based on solid evidence, women who have undergone hysterectomy and who are taking postmenopausal estrogen have an increased risk of stroke and total cardiovascular disease.

Magnitude of Effect: There is a 39% increase in the incidence of stroke (RR, 1.39; 95% CI, 1.1–1.77) and a 12% increase in cardiovascular disease (RR, 1.12; 95% CI, 1.01–1.24).

Study Design: RCTs, observational studies.
Internal Validity: Good.
Consistency: Good.
External Validity: Poor.

Interventions With Adequate Evidence of Decreased Risk of Breast Cancer

Selective estrogen receptor modulators (SERMs): benefits

Based on solid evidence, tamoxifen and raloxifene reduce the incidence of breast cancer in postmenopausal women, and tamoxifen reduces the risk of breast cancer in high-risk premenopausal women. The effects observed for tamoxifen and raloxifene show persistence several years after active treatment is discontinued, with longer duration of effect noted for tamoxifen than for raloxifene.[4]

All fractures were reduced by SERMs, primarily noted with raloxifene but not with tamoxifen. Reductions in vertebral fractures (34% reduction) and small reductions in nonvertebral fractures (7%) were noted.[4]

Magnitude of Effect: Tamoxifen reduced breast cancer incidence in high-risk women from about 30% to about 50% over 5 years of treatment but only for estrogen receptor–positive (ER-positive) cancer and ductal carcinoma in situ (DCIS). The reduction in ER-positive invasive breast cancer was maintained at about this level for at least 16 years after starting treatment, 11 years after cessation of tamoxifen. There was no loss of effect between years 10 and 16 after starting tamoxifen (for 5 years) compared with years 0 to 10. There was no effect on breast cancer mortality.[5]

Study Design: RCTs.
Internal Validity: Good.
Consistency: Good.
External Validity: Good.

Selective estrogen receptor modulators: harms

Based on solid evidence, tamoxifen treatment increases the risk of endometrial cancer, which was apparent in the first 5 years of follow-up but not beyond; thrombotic vascular events (i.e., pulmonary embolism, stroke, and deep venous thrombosis); and cataracts. Many of these risks are reduced after active treatment with tamoxifen is discontinued. Based on solid evidence, raloxifene also increases venous pulmonary embolism and deep venous thrombosis but not endometrial cancer.

Magnitude of Effect: Meta-analysis showed RR of 2.4 (95% CI, 1.5–4.0) for endometrial cancer and 1.9 (95% CI, 1.4–2.6) for venous thromboembolic events. Meta-analysis showed the hazard ratio (HR) for endometrial cancer was 2.18 (95% CI, 1.39–3.42) for tamoxifen and 1.09 (95% CI, 0.74–1.62) for raloxifene. Overall, HR for venous thromboembolic events was 1.73 (95% CI, 1.47–2.05). Harms were significantly higher in women over 50 years than in younger women.

Study Design: RCTs.
Internal Validity: Good.
Consistency: Good.
External Validity: Good.

Aromatase inhibitors or inactivators: benefits

Based on solid evidence, aromatase inhibitors or inactivators (AIs) reduce the incidence of new breast cancers in postmenopausal women who have an increased risk.

Magnitude of Effect: After a median follow-up of 35 months, women aged 35 years and older who had at least one risk factor (age >60 years, a Gail 5-year risk >1.66%, or DCIS with mastectomy) and who took 25 mg of exemestane daily had a decreased risk of invasive breast cancer (HR, 0.35; 95% CI, 0.18–0.70). The absolute risk reduction was 21 cancers avoided out of 2,280 participants over 35 months. The number needed to treat was about 100.[6]

Study Design: One RCT.
Internal Validity: Good.
Consistency: One study in women with no history of breast cancer but consistent with RCTs in women with history of breast cancer.
External Validity: Good for women who meet inclusion criteria.

Aromatase inhibitors or inactivators: harms

Based on fair evidence from a single RCT of 4,560 women over 35 months, exemestane is associated with hot flashes and fatigue but not with fractures, osteoporosis, or cardiovascular events, compared with placebo.[6,7]

Magnitude of Effect: The absolute increase in hot flashes was 8% and the absolute increase in fatigue was 2%.

Study Design: One RCT.
Internal Validity: Good.
Consistency: Good.
External Validity: Good for women who meet inclusion criteria.

Prophylactic mastectomy: benefits

Based on solid evidence, bilateral prophylactic mastectomy reduces the risk of breast cancer in women with a strong family history, and most women experience relief from anxiety about breast cancer risk. There are no studies examining breast cancer outcomes in women who undergo contralateral prophylactic mastectomy after surgery for ipsilateral breast cancer.

Magnitude of Effect: Breast cancer risk after bilateral prophylactic mastectomy in women at high risk is reduced as much as 90%, but published study designs may have produced an overestimate.

Study Design: Evidence obtained from case-control and cohort studies.
Internal Validity: Good.
Consistency: Good.
External Validity: Good.

Prophylactic oophorectomy or ovarian ablation: benefits

Based on solid evidence, premenopausal women with BRCA gene mutations who undergo prophylactic oophorectomy have lower breast cancer incidence. Similarly, oophorectomy or ovarian ablation is associated with decreased breast cancer incidence in normal premenopausal women and in women with increased breast cancer risk resulting from thoracic irradiation.

Magnitude of Effect: Breast cancer incidence is decreased by 50%, but published study designs may have produced an overestimate.

Study Design: Observational, case-control, and cohort studies.
Internal Validity: Good.
Consistency: Good.
External Validity: Good.

Prophylactic oophorectomy or ovarian ablation: harms

Based on solid evidence, castration may cause the abrupt onset of menopausal symptoms such as hot flashes, insomnia, anxiety, and depression. Long-term effects include decreased libido, vaginal dryness, and decreased bone mineral density.

Magnitude of Effect: Nearly all women experience some sleep disturbances, mood changes, hot flashes, and bone demineralization, but the severity of these symptoms varies greatly.

Study Design: Observational, case-control, and cohort studies.
Internal Validity: Good.
Consistency: Good.
External Validity: Good.

References

Boyd NF, Martin LJ, Rommens JM, et al.: Mammographic density: a heritable risk factor for breast cancer. Methods Mol Biol 472: 343-60, 2009. [PUBMED Abstract]
McCormack VA, dos Santos Silva I: Breast density and parenchymal patterns as markers of breast cancer risk: a meta-analysis. Cancer Epidemiol Biomarkers Prev 15 (6): 1159-69, 2006. [PUBMED Abstract]
Col: Breast cancer and breastfeeding: collaborative reanalysis of individual data from 47 epidemiological studies in 30 countries, including 50302 women with breast cancer and 96973 women without the disease. Lancet 360 (9328): 187-95, 2002. [PUBMED Abstract]
Cuzick J, Sestak I, Bonanni B, et al.: Selective oestrogen receptor modulators in prevention of breast cancer: an updated meta-analysis of individual participant data. Lancet 381 (9880): 1827-34, 2013. [PUBMED Abstract]
Cuzick J, Sestak I, Cawthorn S, et al.: Tamoxifen for prevention of breast cancer: extended long-term follow-up of the IBIS-I breast cancer prevention trial. Lancet Oncol 16 (1): 67-75, 2015. [PUBMED Abstract]
Goss PE, Ingle JN, Alés-Martínez JE, et al.: Exemestane for breast-cancer prevention in postmenopausal women. N Engl J Med 364 (25): 2381-91, 2011. [PUBMED Abstract]
Maunsell E, Goss PE, Chlebowski RT, et al.: Quality of life in MAP.3 (Mammary Prevention 3): a randomized, placebo-controlled trial evaluating exemestane for prevention of breast cancer. J Clin Oncol 32 (14): 1427-36, 2014. [PUBMED Abstract]

Description of the Evidence

Incidence and Mortality

With an estimated 268,600 cases expected, breast cancer will be the most frequently diagnosed nonskin malignancy in U.S. women in 2019.[1] Also in 2019, breast cancer will kill an estimated 41,760 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 2,670 new cases will be diagnosed in 2019.[1] Despite a prior long-term trend of gradually increasing breast cancer incidence in women, data from the Surveillance, Epidemiology, and End Results Program show a decrease in breast cancer mortality of 1.8% per year from 2007 to 2016.[1,2]

The major risk factor for breast cancer is advancing age. A 30-year-old woman has a 1 in 250 chance of being diagnosed with breast cancer in the next 10 years, whereas a 70-year-old woman has a 1 in 27 chance.[3]

Breast cancer incidence and mortality risk also vary on the basis of geography, culture, race, ethnicity, and socioeconomic status. Compared with other races, white women have a higher incidence of breast cancer that may be attributable, in part, to screening behavior. However, breast cancer incidence rates increased slightly in black women by 0.3% per year between 2005 and 2014, resulting in the convergence of rates in blacks with those in whites.[4,5]

Screening by mammography decreases breast cancer mortality by identifying cases for treatment at an earlier stage. However, screening also identifies more cases than would become symptomatic in a woman’s lifetime, so screening increases breast cancer incidence. (Refer to the Overdiagnosis section in the PDQ summary on Breast Cancer Screening for more information.)

Etiology and Pathogenesis of Breast Cancer

Breast cancer develops when a series of genetic mutations occurs.[6] Initially, mutations do not change the histologic appearance of the tissue, but accumulated mutations will result in hyperplasia, dysplasia, carcinoma in situ, and eventually, invasive cancer.[7] The longer a woman lives, the more somatic mutations occur, and the more likely it is that these mutations will produce populations of cells that will evolve into malignancies. Estrogen and progestin cause growth and proliferation of breast cells that may work through growth factors such as transforming growth factor (TGF)-alpha.[8] These hormones, whether endogenous or exogenous, may promote the development and proliferation of breast cancer cells.

International variation in breast cancer rates may be explained by differences in genetics, reproductive factors, diet, exercise and screening behavior. Some of these factors are modifiable, as evidenced by the observation that Japanese immigrants to the United States increase their breast cancer risk from lower Japanese levels to higher American levels within two generations.[9-11]

Endogenous Estrogen

Many of the risk factors for breast cancer suggest that longer exposure to endogenous estrogen plays a role in the development of the disease. Women who experienced menarche at age 11 years or younger have about a 20% greater chance of developing breast cancer than do those who experienced menarche at age 14 years or older.[12-14] Women who experience late menopause also have an increased risk. Women who develop breast cancer tend to have higher endogenous estrogen and androgen levels.[14-18]

Conversely, women who experience premature menopause have a lower risk of breast cancer. Following ovarian ablation, breast cancer risk may be reduced as much as 75% depending on age, weight, and parity, with the greatest reduction for young, thin, nulliparous women.[19-22] The removal of one ovary also reduces the risk of breast cancer but to a lesser degree than does the removal of both ovaries.[23]

Other hormonal changes also influence breast cancer risk. (Refer to the Early pregnancyand Breast-feeding sections in the Factors With Adequate Evidence of Decreased Risk of Breast Cancer section of this summary for more information.)

The interaction of endogenous estrogen levels, insulin levels, and obesity—all of which affect breast cancer risk—are poorly understood but suggest strategies for interventions to decrease that risk. It is likely that reproductive risk factors interact with predisposing genotypes. For example, in the Nurses’ Health Study,[24] 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.

Inherited Risk

Breast cancer risk increases in women with a positive family history, particularly if first-degree relatives are affected.[24] The following risk assessment models, derived from databases, cohort, and case-control studies, quantitate this risk:

Specific abnormal alleles are associated with approximately 5% of breast cancers. (Refer to the PDQ summary on Genetics of Breast and Gynecologic Cancers for more information.) Mutations in BRCA genes are inherited in an autosomal dominant fashion and are highly penetrant in causing cancer, often at a younger age.[25-27] Family history and mutation location within the BRCA1 or BRCA2 gene may contribute to the risk of cancer development among those with an inherited predisposition to breast cancer.[28] The lifetime risk of breast cancer is 55% to 65% for BRCA1 mutation carriers and 45% to 47% for BRCA2mutation carriers.[29,30] In comparison, the lifetime risk of breast cancer is 12.4% in the general population.[31]

Some women inherit a susceptibility to mutagens or growth factors, which increase breast cancer risk.[32,33] (Refer to the Ionizing radiation exposure section in the Factors With Adequate Evidence of Increased Risk of Breast Cancer section of this summary for more information.)

Increased Breast Density

Widespread use of screening mammograms has revealed varying amounts of mammographically dense tissue and that women with a greater proportion of dense tissue have a higher incidence of breast cancer. Mammographic density also confounds the identification of cancers by that technology. The extent of increased risk was described in a report of three nested case-control studies in screened populations with 1,112 matched case-control pairs. Compared with women with density comprising less than 10% of breast tissue, women with density in 75% or more of their breast had an increased risk of breast cancer (odds ratio [OR], 4.7; 95% confidence interval [CI], 3.0–7.4), whether the cancer was detected by screening (OR, 3.5; 95% CI, 2.0–6.2) or detected less than 12 months after a negative screening examination (OR, 17.8; 95% CI, 4.8–65.9). Increased risk of breast cancer, whether detected by screening or other means, persisted for at least 8 years after study entry and was greater in younger women than in older women. For women younger than the median age of 56 years, 26% of all breast cancers and 50% of cancers detected less than 12 months after a negative screening test were identified in women with mammographic breast density of 50% or more.[34,35]

Women with dense breasts have increased risk, proportionate to the degree of density. This increased relative risk (RR) ranges from 1.79 for women with slightly increased breast density to 4.64 for women with very dense breasts, compared with women who have the lowest breast density.[36] There is no increased risk of breast cancer mortality among women with dense breast tissue.[37]

Factors With Adequate Evidence of Increased Risk of Breast Cancer

Hormone therapy

Based on a 1997 reanalysis of 51 epidemiological studies encompassing more than 150,000 women, hormone therapy (HT) after menopause was shown to be associated with increased breast cancer risk.[38]

The Heart and Estrogen/Progestin Replacement Study supported this finding in 2002.[39] In this study, 2,763 women with coronary heart disease at a mean age of 67 years were randomly assigned to receive either estrogen and progestin therapy or placebo. After a mean follow-up of 6.8 years, the RR for breast cancer was 1.27 (95% CI, 0.84–1.94). Although not statistically significant, the RR estimate is consistent with the much larger Women’s Health Initiative (WHI), also published in 2002.

The WHI investigated the effect of hormones and dietary interventions on heart disease and breast cancer risk.[40] Women aged 50 to 79 years with intact uteri were randomly assigned to receive combined conjugated estrogen with continuous progestin (n = 8,506) or placebo (n = 8,102). The trial was terminated early because combined HT did not decrease coronary heart disease risk but did increase the risk of stroke and breast cancer. An increased rate of invasive breast cancer risk (hazard ratio [HR], 1.24; 95% CI, 1.02–1.50), but not for in situ breast cancer, was observed in all subgroups of women. The combined HT-related cancers had similar grade, histology, and expression of estrogen receptor (ER), progesterone receptor, and HER2/neu, with a trend toward larger size and higher incidence of lymph node metastases in the combined HT group.[41] Extended follow-up of a mean of 11 years showed higher breast cancer–specific mortality for the HT group (25 vs. 12 deaths, 0.03% vs. 0.01% per year; HR, 1.95; 95% CI, 1.0–4.04; P = .049). Combined HT was also associated with a higher percentage of abnormal mammograms.[42]

The WHI observational study was conducted in parallel with the WHI randomized controlled trial (RCT), recruiting postmenopausal women aged 50 to 79 years. An analysis was conducted in the observational study of the WHI to further examine the prognosis of women taking combination HT who were diagnosed with breast cancer and the risks based on time between menopause and initiation of HT. After a mean follow-up of 11.3 years, the annualized incidence of breast cancer among women using estrogen plus progestin was 0.60%, compared with 0.42% among nonusers (HR, 1.55; 95% CI, 1.41–1.70). Survival after the diagnosis of breast cancer was similar for combined HT users and nonusers. Death from breast cancer was higher among combined HT users than among nonusers, but the difference was not statistically significant (HR, 1.3; 94% CI, 0.90–1.93). Risks were highest among women initiating HT at the time of menopause, and risks diminished but persisted with increasing time between menopause and starting combination HT. All-cause mortality after the diagnosis of breast cancer was statistically significantly higher among combined HT users than among nonusers (HR, 1.87; 95% CI, 1.37–2.54.) Overall, these findings were consistent with results from the RCT.[43]

The WHI also studied women who had previously undergone a hysterectomy and thus were not at risk for endometrial cancer, which is associated with unopposed estrogen therapy. Women aged 50 to 79 years (N = 10,739) were randomly assigned to receive conjugated equine estrogen (CEE) or placebo. This trial was also stopped early because of an increased risk of stroke and no improvement in a global risk-benefit index.[44,45] After an average 6.8 years of follow-up, breast cancer incidence was lower in the group receiving CEE (0.26% per year vs. 0.33%; HR, 0.77; 95% CI, 0.59–1.01). The global risk-benefit index was slightly worse for CEE.[44] An extended follow-up for a median of 11.8 years included 78% of the trial participants.[45,46] Results seen in the initial study persisted, with a similar risk reduction for breast cancer in CEE recipients (HR, 0.77; 95% CI, 0.62–0.95) [45,46] and a decrease in breast cancer mortality (6 vs. 16 deaths; HR, 0.37; 95% CI, 0.13–0.91). All-cause mortality was also lower in the CEE group (0.046% vs. 0.076% per year; HR, 0.62; 95% CI, 0.39–0.97). After CEE was discontinued, the risk of stroke decreased in the postintervention period. Over the entire follow-up period, there was no difference in the incidence of coronary heart disease, deep vein thrombosis, stroke, hip fracture, or colorectal cancer.[45] Breast cancer incidence was similar for women who initiated CEE or placebo within the first 5 years after onset of menopause (HR, 1.06; 95% CI, 0.74–1.51).

A Danish trial of HT for 1,006 women entering menopause was designed to evaluate cardiovascular outcomes. Combined HT (triphasic estradiol and norethisterone) was given to 407 women with intact uteri, and estradiol was given to 95 women who had undergone hysterectomy. Controls (407 with intact uteri and 97 with hysterectomy) were not treated. At 10 years, there was considerable contamination. Only one-half of the women assigned to the HT group were still taking the prescribed HT, and 22% of the control women had begun HT. Cardiovascular outcomes favored HT-treated women, and there was no difference in breast cancer incidence.[47]

Observational studies augment the information obtained in RCTs.

The Million Women Study [48] recruited 1,084,110 women aged 50 to 64 years in the United Kingdom between 1996 and 2001 and obtained information about HT use and other personal details. The women were followed for breast cancer incidence and death. One-half of the women had used HT. At 2.6 years of follow up, there were 9,364 invasive breast cancers; at 4.1 years, there were 637 breast cancer deaths. Current users of HT at recruitment were more likely than never-users to develop breast cancer (adjusted RR = 1.66; 95% CI, 1.58–1.75; P < .0001) and to die from the disease (adjusted RR, 1.22; 95% CI, 1.00–1.48; P = .05). Past users of HT were, however, not at an increased risk of incident or fatal breast cancer (1.01 [95% CI, 0.94–1.09] and 1.05 [95% CI, 0.82–1.34], respectively). Incidence was significantly increased for current users of estrogen only (RR, 1.30; 95% CI, 1.21–1.40; P < .0001), combined HT (RR, 2.00; 95% CI, 1.88–2.12; P < .0001), and tibolone (RR, 1.45; 95% CI, 1.25–1.68; P < .0001). The magnitude of the associated risk was substantially greater for combined HT than for other types of HT (P < .0001).

A population-based survey of 965 women with breast cancer and 1,007 controls was conducted by the Cancer Surveillance System of Puget Sound. It showed that combined HT users had a 1.7-fold increased risk of invasive breast cancer, whereas estrogen-only users did not.[49]

The association between the use of combined HT and increased breast cancer risk is consistent throughout all the trials. In contrast, the association between estrogen-only HT and breast cancer incidence is confusing because some studies show increased risk and some show protection. It is possible that the timing of estrogen-only HT in relation to the onset of menopause is critical. Furthermore, observational studies may not account for different screening behavior between HT users and nonusers, whereas RCTs, by design, will control that variable.[50,51]

Following publication of the WHI results, HT use dropped dramatically in the United States and elsewhere. Follow-up of WHI participants on the combined HT arm demonstrated a rapid decrease in the elevated breast cancer risk of therapy within 2 years, despite similar rates of mammography screening.[52] Analysis of changes in breast cancer rates in the United States observed a sharp decline in breast cancer incidence rates from 2002 to 2003 among women aged 50 years and older, especially for ER–positive cancers.[53,54] Similarly, in multiple countries where HT use was high, breast cancer rates decreased in a similar time frame, coincident with decreases in prescribing patterns and/or reported prevalence of use.[55-57] 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.[58] After the decline in breast cancer incidence from 2002 to 2003, rates in the United States stabilized.[58,59]

Ionizing radiation exposure

A well-established relationship exists between exposure to ionizing radiation and subsequent breast cancer.[60] Excess breast cancer risk has been observed in association with atomic bomb exposure, frequent fluoroscopy for tuberculosis, and radiation therapy for acne, tinea, thymic enlargement, postpartum mastitis, and lymphoma. Risk is higher for the young, especially around puberty. An estimate of the risk of breast cancer associated with medical radiology puts the figure at less than 1% of the total.[61] However, it has been theorized that certain populations, such as AT heterozygotes, are at an increased risk of breast cancer from radiation exposure.[32] A large cohort study of women who carry mutations of BRCA1 or BRCA2 concluded that chest x-rays increase the risk of breast cancer even more (RR, 1.54; 95% CI, 1.1–2.1), especially for women who had x-rays before age 20 years.[62]

Women treated for Hodgkin lymphoma by age 16 years have a subsequent risk up to 35% of developing breast cancer by age 40 years.[63-65] Higher radiation doses (median dose, 40 Gy in breast cancer cases) and treatment between the ages of 10 and 16 years are associated with higher risk.[63] Unlike the risk for secondary leukemia, the risk of treatment-related breast cancer does not abate with duration of follow-up, persisting more than 25 years after treatment.[63,65,66] In these studies, most patients (85%–100%) who developed breast cancer did so either within the field of radiation or at the margin.[63,64,66] A Dutch study examined 48 women who developed breast cancer at least 5 years after treatment for Hodgkin disease and compared them with 175 matched female Hodgkin disease patients who did not develop breast cancer. Patients treated with chemotherapy and mantle radiation were less likely to develop breast cancer than were those treated with mantle radiation alone, possibly because of chemotherapy-induced ovarian suppression (RR, 0.06; 95% CI, 0.01–0.45).[67] 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.[65] These studies suggest that ovarian hormones promote the proliferation of breast tissue with radiation-induced mutations.[65]

The question arises whether breast cancer patients treated with lumpectomy and radiation therapy (L-RT) are at higher risk for second breast malignancies or other malignancies than are those treated by mastectomy. Outcomes of 1,029 L-RT patients were compared with outcomes of 1,387 patients who underwent mastectomies. After a median follow-up of 15 years, there was no difference in the risk of second malignancies.[68] 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.[69] 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.[70] 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%.[71]

Obesity

Obesity is associated with increased breast cancer risk, especially among postmenopausal women who do not use HT. The WHI observed 85,917 women aged 50 to 79 years and collected information on weight history and known risk factors for breast cancer.[72,73] Height, weight, and waist and hip circumferences were measured. With a median follow-up of 34.8 months, 1,030 of the women developed invasive breast cancer. Among the women who never used HT, increased breast cancer risk was associated with weight at entry, body mass index (BMI) at entry, BMI at age 50 years, maximum BMI, adult and postmenopausal weight change, and waist and hip circumferences. Weight was the strongest predictor, with a RR of 2.85 (95% CI, 1.81–4.49) for women weighing more than 82.2 kg, compared with those weighing less than 58.7 kg.

The association between obesity, diabetes, and insulin levels with breast cancer risk have been studied but not clearly defined. The British Women’s Heart and Health Study of women aged 60 to 79 years compared 151 women who had a diagnosis of breast cancer with 3,690 women who did not. The age-adjusted OR was 1.34 (95% CI, 1.02–1.77) for each unit increase in log(e) insulin level among nondiabetic women. The association was observed, after adjustment for confounders and for potential mediating factors, for both pre- and postmenopausal breast cancers. In addition, fasting glucose level, homeostatic model assessment score (the product of fasting glucose and insulin levels divided by 22.5), diabetes, and a history of gestational glycosuria or diabetes were also associated with breast cancer.[74]

Alcohol

Alcohol consumption increases the risk of breast cancer. A British meta-analysis included individual data from 53 case-control and cohort studies.[75] Compared with the RR of breast cancer for women who reported no alcohol consumption, the RR of breast cancer was 1.32 (95% CI, 1.19–1.45; P < .001) for women consuming 35 g to 44 g of alcohol per day and 1.46 (95% CI, 1.33–1.61; P < .001) for those consuming at least 45 g of alcohol per day. The RR of breast cancer increases by about 7% (95% CI, 5.5%–8.7%; P < .001) for each 10 g of alcohol (i.e., one drink) consumed per day. These findings persist after stratification for race, education, family history, age at menarche, height, weight, BMI, breast-feeding, oral contraceptive use, menopausal hormone use and type, and age at menopause.

Factors With Adequate Evidence of Decreased Risk of Breast Cancer

Early pregnancy

Childbirth is followed by an increase in risk of breast cancer for several years, and then a long-term reduction in risk, which is greater for younger women.[22,76,77] In one study, women who experienced a first full-term pregnancy before age 20 years were half as likely to develop breast cancer as nulliparous women or women whose first full-term pregnancy occurred at age 35 years or older.[78,79]

The association of childbirth with breast cancer risk was demonstrated by the International Premenopausal Breast Cancer Collaborative Group, which undertook a pooled analysis of individual-level data from about 890,000 women from 15 prospective cohort studies. When compared with nulliparous women, parous women had an increased risk of developing both ER–positive and ER–negative breast cancer for up to 20 years after childbirth. However, after about 24 years, the risk of developing ER–positive breast cancer decreased, but the risk of developing ER–negative breast cancer remained elevated. Thus, the association between parity and breast cancer risk is complex and appears to be influenced by the time period after childbirth and tumor phenotype.[80]

Breast-feeding

Breast-feeding is associated with a decreased risk of breast cancer.[81] A reanalysis of individual data from 47 epidemiological studies in 30 countries of 50,302 women with breast cancer and 96,973 controls revealed that breast cancer incidence was lower in parous women who had ever breast-fed than in parous women who had not. It was also proportionate to duration of breast-feeding.[82] The RR of breast cancer decreased by 4.3% (95%, CI, 2.9%–5.8%; P < .0001) for every 12 months of breast-feeding in addition to a decrease of 7.0% (95% CI, 5.0%–9.0%; P < .0001) for each birth.

Exercise

Active exercise may reduce breast cancer risk, particularly in young parous women.[83] Numerous observational studies on the relationship between the level of physical activity and breast cancer risk have shown an inverse relationship.[84] The average RR reduction is 30% to 40%, but confounding variables—such as diet or a genetic predisposition to breast cancer—have not been addressed. A prospective study of more than 25,000 Norwegian women found that heavy manual labor or at least 4 hours of exercise per week is associated with decreased breast cancer risk, especially in premenopausal women and those of normal or lower-than-normal body weight.[85] In a case-control study of African American women, strenuous recreational physical activity more than 7 hours per week was associated with decreased breast cancer incidence.[86]

Interventions With Adequate Evidence of Benefit

Selective estrogen receptor modulators (SERMs)

Data from adjuvant breast cancer trials using tamoxifen have shown that tamoxifen not only suppresses the recurrence of breast cancer but also prevents new primary contralateral breast cancers.[87] Tamoxifen also maintains bone density among postmenopausal women with breast cancer.[88-92] Adverse effects include hot flashes, venous thromboembolic events, and endometrial cancer.[93-95]

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.[96,97] The study was closed early because of a 49% reduction in the incidence of breast cancer for the tamoxifen group (85 vs. 154 invasive breast cancer cases and 31 vs. 59 in situ cases at 4 years). Tamoxifen-treated women also had fewer fractures (47 vs. 71) but more endometrial cancer (33 vs. 14 cases) and thrombotic events (99 vs. 70), including pulmonary emboli (17 vs. 6).[97]

An update of the BCPT results after 7 years of follow-up demonstrated results similar to those in the initial report.[98] There were some dropouts among women in the placebo arm; some of them enrolled in a subsequent trial, so new women were added to the placebo group. Benefits and risks of tamoxifen were not significantly different from those in the original report, with persistent benefit of fewer fractures and persistent increased risk of endometrial cancer, thrombosis, and cataract surgery. No overall mortality benefit was observed after 7 years of follow-up (RR, 1.10; 95% CI, 0.85–1.43).

Three other trials of tamoxifen for primary prevention of breast cancer have been completed.[99-101]

A study in the United Kingdom [99] focused on 2,471 women at increased breast cancer risk because of their family history of breast and/or ovarian cancer. After a median follow-up of nearly 6 years, no protective effect of tamoxifen was detected (RR, 1.06), but there was a slight reduction in breast cancer risk in the tamoxifen arm (HR, 0.78; 95% CI, 0.58–1.04) at a median of 13 years. However, risk of ER-positive breast cancer was significantly reduced in the treatment arm (HR, 0.61; 95% CI, 0.43–0.86), an effect noted predominantly in the posttreatment period.[102]
An Italian study [100] focused on 5,408 women who had undergone hysterectomy and who were described as low to normal risk. After a median follow-up of nearly 4 years, no protective effect of tamoxifen was observed. Longer follow-up and subgroup analysis in this trial found a protective effect of tamoxifen among women at high risk for hormone receptor–positive breast cancer (RR, 0.24; 95% CI, 0.10–0.59) and among women who were taking HT during the trial (RR, 0.43; 95% CI, 0.20–0.95).[103,104]
The International Breast Cancer Intervention Study (IBIS-I) randomly assigned 7,152 women aged 35 to 70 years who were at an increased risk of breast cancer to receive tamoxifen (20 mg/day ) or placebo for 5 years.[101] After a median follow-up of 50 months, fewer tamoxifen-treated women had developed invasive or in situ breast cancer (absolute rate, 4.6 vs. 6.75 per 1,000 woman-years; risk reduction, 32%; 95% CI, 8%–50%). The RR reduction in ER-positive invasive breast cancer was 31%; there was no reduction in ER-negative cancers. There was an excess of all-cause mortality in the tamoxifen group (25 vs. 11; P = .028), which the authors attributed to chance. The beneficial effect of tamoxifen on breast cancer persisted after active treatment, with a median posttherapy follow-up of 46 months; 27% fewer women in the tamoxifen arm developed breast cancer (142 vs. 195 cases, respectively; RR, 0.73, 95% CI, 0.58–0.91).[105]

A meta-analysis of these primary prevention tamoxifen trials showed a 38% reduction in the incidence of breast cancer without statistically significant heterogeneity.[95] ER-positive tumors were reduced by 48%. Rates of endometrial cancer were increased (consensus RR, 2.4; 95% CI, 1.5–4.0), as were venous thromboembolic events (RR, 1.9; 95% CI, 1.4–2.6). None of these primary prevention trials was designed to detect differences in breast cancer mortality.

Women with a history of ductal carcinoma in situ (DCIS) are at increased risk for contralateral breast cancer. The National Surgical Adjuvant Breast and Bowel Project (NSABP) trial B-24 addressed their management. Women were randomly assigned to receive L-RT either with or without adjuvant tamoxifen. At 6 years, the tamoxifen-treated women had fewer invasive and in situ breast cancers (8.2% vs. 13.4%; RR, 0.63; 95% CI, 0.47–0.83). The risk of contralateral breast cancer was also lower in women treated with tamoxifen (RR, 0.49; 95% CI, 0.26–0.87).[106]

Raloxifene hydrochloride (Evista) is a SERM that has antiestrogenic effects on breast and estrogenic effects on bone, lipid metabolism, and blood clotting. Unlike tamoxifen, it has antiestrogenic effects on the endometrium.[107] The Multiple Outcomes of Raloxifene Evaluation (MORE) trial was a randomized, double-blind trial that evaluated 7,705 postmenopausal women with osteoporosis from 1994 to 1998 at 180 clinical centers in the United States. Vertebral fractures were reduced. The effect on breast cancer incidence was a secondary endpoint. After a median follow-up of 47 months, the risk of invasive breast cancer decreased in the raloxifene-treated women (RR, 0.25; 95% CI, 0.17–0.45).[108] As with tamoxifen, raloxifene reduced the risk of ER-positive breast cancer but not ER-negative breast cancer and was associated with an excess risk of hot flashes and thromboembolic events. No excess risk of endometrial cancer or hyperplasia was observed after 47 months of follow-up.[109]

An extension of the MORE trial was the Continuing Outcomes Relevant to Evista (CORE) trial, which studied about 80% of MORE participants in their randomly assigned groups for an additional 4 years. Although there was a median 10-month gap between the two studies, and only about 55% of women were adherent to their assigned medications, the raloxifene group continued to experience a lower incidence of invasive ER-positive breast cancer. The overall reduction in invasive breast cancer during the 8 years of MORE and CORE was 66% (HR, 0.34; 95% CI, 0.22–0.50); the reduction for ER-positive invasive breast cancer was 76% (HR, 0.24; 95% CI, 0.15–0.40).[110]

The Raloxifene Use for the Heart trial was a randomized, placebo-controlled trial to evaluate the effects of raloxifene on incidence of coronary events and invasive breast cancer. As in the MORE and CORE studies, raloxifene reduced the risk of invasive breast cancer (HR, 0.56; 95% CI, 0.38–0.83).[111]

The Study of Tamoxifen and Raloxifene (STAR) (NSABP P-2) compared tamoxifen and raloxifene in 19,747 high-risk women who were monitored for a mean of 3.9 years. Invasive breast cancer incidence was approximately the same for both drugs, but there were fewer noninvasive cancers in the tamoxifen group. Adverse events of uterine cancer, venous thrombolic events, and cataracts were more common in tamoxifen-treated women, and there was no difference in ischemic heart disease events, strokes, or fractures.[112] Treatment-associated symptoms of dyspareunia, musculoskeletal problems, and weight gain occurred less frequently in tamoxifen-treated women, whereas vasomotor flushing, bladder control symptoms, gynecologic symptoms, and leg cramps occurred less frequently in those receiving raloxifene.[113]

Incidence of Outcomes Per 1,000 Women

	Tamoxifen	Raloxifene	RR, 95% CI
CI = confidence interval; RR = relative risk; VTE = venous thromboembolism.
Invasive breast cancer	4.3	4.41	1.02, 0.82–1.28
Noninvasive breast cancer	1.51	2.11	1.4, 0.98–2.00
Uterine cancer	2.0	1.25	0.62, 0.35–1.08
VTE	3.8	2.6	0.7, 0.68–0.99
Cataracts	12.3	9.72	0.79, 0.68–0.92
Incidence of Symptoms (0–4 scale)
Favor Tamoxifen
Dyspareunia	0.68	0.78	P < .001
Musculoskeletal problems	1.10	1.15	P = .002
Weight gain	0.76	0.82	P < .001
Favor Raloxifene
Vasomotor symptoms	0.96	0.85	P < .001
Bladder control symptoms	0.88	0.73	P < .001
Leg cramps	1.10	0.91	P < .001
Gynecologic problems	0.29	0.19	P < .001

Aromatase inhibitors or inactivators (Als)

Another class of agents that is commercially available for the treatment of women with hormone-sensitive breast cancer may also prevent breast cancer. These drugs interfere with aromatase, the adrenal enzyme that allows estrogen production in postmenopausal women. Anastrozole and letrozole inhibit aromatase activity, whereas exemestane inactivates the enzyme. Side effects for all three drugs include fatigue, arthralgia, myalgia, decreased bone mineral density, and increased fracture rate.

Women with a previous diagnosis of breast cancer have a lower risk of recurrence and of new breast cancers when treated with AIs, as shown in the following studies:

In the Arimidex, Tamoxifen, Alone or in Combination trial, which compared anastrozole with tamoxifen as adjuvant therapy for primary breast cancer, the rate of locoregional and distant recurrence was lower for anastrozole (7.1% vs. 8.5%) but higher for the combination (9.1%).[114] Anastrozole was also more effective in reducing the incidence of new contralateral breast cancer (0.4% vs. 1.1% vs. 0.9%).
In another trial, 5,187 women who received 5 years of adjuvant tamoxifen were randomly assigned to receive either letrozole or placebo.[115] After only 2.5 years of median follow-up, the study was terminated because previously defined efficacy endpoints had been reached. Not only did patients treated with letrozole have a lower incidence of locoregional and distant cancer recurrence, they also had a lower incidence of new contralateral breast cancer (14 vs. 26).
Another placebo-controlled trial of 1,918 women with breast cancer examined the effect of extending letrozole treatment for an additional 5 years in women who had received adjuvant tamoxifen followed by 5 years of letrozole.[116] At a median of 6.3 years from study entry, the extended letrozole group had an improved 5-year disease-free survival of 95% (95% CI, 93%–96%) compared with 91% (95% CI, 89%–93%) for the control group (HR, 0.66) but no difference in overall survival. The difference in new contralateral breast cancer diagnoses was statistically significant: 21% (95% CI, 10%–32%) for the extended letrozole group compared with 49% (32%–67%) for the control group (HR, 0.42). Women treated with letrozole had an increased risk of bone pain (18% vs. 14%), bone fracture (14% vs. 9%), and new-onset osteoporosis (11% vs. 6%).
A trial randomly assigned 4,742 women who had received 2 years of adjuvant tamoxifen to either continue the tamoxifen or switch to exemestane.[117] After 2.4 years of median follow-up, the exemestane group had a decreased risk of local or metastatic recurrence and a decreased incidence of new contralateral breast cancer (9 vs. 20).

Aromatase inhibitors or inactivators also have been shown to prevent breast cancer in women at increased risk, as shown in the following studies:

An RCT of primary prevention of breast cancer compared exemestane with placebo in 4,560 women with at least one risk factor (age >60 years, a Gail 5-year risk >1.66%, or a history of DCIS with mastectomy). After 35 months of median follow-up, invasive breast cancer was diagnosed less frequently in the exemestane group (11 vs. 32; HR, 0.35; 95% CI, 0.18–0.70; number needed-to-treat, about 100 for 35 months). Compared with the placebo group, the exemestane-treated women had more hot flashes (increase, 8%) and fatigue (increase, 2%) but no difference in fractures or cardiovascular events.[118]
The International Breast Cancer Intervention Study II (IBIS-II) randomly assigned 3,864 postmenopausal women who were at increased risk of developing breast cancer to receive either daily anastrazole (1 mg) or placebo for 5 years.[119] The definition of high risk varied by age and was defined by the RR compared with the general population: women aged 40 to 44 years had to have an RR of at least 4; women aged 45 to 60 years had to have an RR of at least 2; and women aged 60 to 70 years had to have an RR of at least 1.5. Alternatively, women with an estimated 10-year risk of developing breast cancer of at least 5% (per the Tyer-Cuzick model) were eligible for inclusion. Women with DCIS diagnosed within 6 months and treated with unilateral mastectomy were eligible for the trial, and 326 were assigned randomly. After a median follow-up of 5 years, fewer breast cancers (invasive and DCIS) occurred in the anastrazole-treated group than in the placebo group (HR, 0.47; 95% CI, 0.32–0.68). The risk of hormone receptor–positive, but not hormone receptor–negative, breast cancer was reduced. Based on predicted cumulative incidence over 7 years, the number of high-risk women (per the IBIS-II eligibility criteria) needed-to-treat for 5 years to prevent one breast cancer in 7 years of follow-up was estimated to be 36 (95% CI, 33–44). Women treated with anastrazole were more likely than those taking placebo to have musculoskeletal symptoms, including arthralgias (51% vs. 46%), joint stiffness (7% vs. 5%), pain in hand or foot (9% vs. 8%) , and carpal tunnel syndrome (3% vs. 2%); hypertension (5% vs. 3%); vasomotor symptoms (57% vs. 49%); and dry eyes (4% vs. 2%). The association between hand or foot pain with anastrazole treatment was of borderline statistical significance; all other side effects noted above were statistically significantly associated with anastrazole treatment.

Prophylactic mastectomy

A retrospective cohort study evaluated the impact of bilateral prophylactic mastectomy on breast cancer incidence among women at high and moderate risk on the basis of family history.[120] BRCA mutation status was not known. Subcutaneous, rather than total, mastectomy was performed in 90% of these women. After a median follow-up of 14 years postsurgery, the risk reduction for the 425 moderate-risk women was 89%; for the 214 high-risk women, it was 90% to 94%, depending on the method used to calculate expected rates of breast cancer. The risk reduction for breast cancer mortality was 100% for moderate-risk women and 81% for high-risk women. Because the study used family history as a risk indicator rather than genetic testing, breast cancer risk may be overestimated.

The rate of bilateral mastectomy among women with unilateral disease (DCIS and early-stage invasive breast cancer) was reported to have increased from 1.9% in 1998 to 11.2% in 2011 based on data from the U.S. National Cancer Data Base.[121]

No studies have been done on the benefits of prophylactic mastectomy in the average-risk population to prevent contralateral breast cancer in women with an ipsilateral breast cancer.

Prophylactic oophorectomy

Ovarian ablation and oophorectomy are associated with decreased breast cancer risk in normal women and in women with increased risk resulting from thoracic irradiation. (Refer to the Endogenous estrogen section in the Description of the Evidence section of this summary for more information.) Observational studies of women with high breast cancer risk resulting from BRCA1 or BRCA2 gene mutations showed that prophylactic oophorectomy to prevent ovarian cancer was also associated with a 50% decrease in breast cancer incidence.[122-124] These studies are confounded by selection bias, family relationships between patients and controls, indications for oophorectomy, and inadequate information about hormone use. A prospective cohort study had similar findings, with a greater breast cancer risk reduction in BRCA2 mutation carriers than in BRCA1 carriers.[125]

Factors and Interventions With Inadequate Evidence of an Association

Hormonal contraceptives

Oral contraceptives have been associated with a small increased risk of breast cancer in current users that diminishes over time.[126] 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.[127]

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.[128]

A nationwide prospective cohort study in Denmark found that women who currently or recently used contemporary hormonal contraceptives had a higher risk of breast cancer than did women who had never used hormonal contraceptives. Moreover, the risk of breast cancer increased with longer duration of hormonal contraceptive use. However, in absolute terms, the effect of oral contraceptives on breast cancer risk was very small. Thus, approximately one extra case of breast cancer would be expected for every 7,690 women using hormonal contraception for 1 year.[129]

Environmental factors

Occupational, environmental, or chemical exposures have all been proposed as causes of breast cancer. Meta-analyses, describing up to 134 environmental chemicals, their sources, and biomarkers of their exposures, suggest that they may be associated with cancer.[130,131] Some studies suggest that organochlorine exposures, such as those associated with insecticides, might be associated with an increase in breast cancer risk,[132,133] but other case-control and nested case-control studies do not.[134-139] 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. Overall, the epidemiological and animal study evidence that support an association between breast cancer and specific environmental exposures is generally weak. Because so many factors must be considered, any associations with breast cancer or other cancers could be confounded by the analytical problems of multiplicities, measurement challenges, and recall and publication bias.[140,141]

Factors and Interventions With Adequate Evidence of Little or No Association

Abortion

Abortion has been proposed as a risk factor for breast cancer. Findings from observational studies have varied; some studies showed an association, while other studies did not. Observational studies that support this association were less rigorous and potentially biased because of differential recall by women on a socially sensitive issue.[142-145] For example, the impact of recall or reporting bias was demonstrated in a study that compared regions with different social attitudes on abortion.[146] The Committee on Gynecologic Practice of the American College of Obstetricians and Gynecologists has concluded that “more rigorous recent studies demonstrate no causal relationship between induced abortion and a subsequent increase in breast cancer risk.”[147] Studies that used prospectively recorded data regarding abortion, thereby avoiding recall bias, largely showed no association with the subsequent development of breast cancer.[148-153]

Diet

Any effect of dietary modifications on breast cancer would likely depend on the type of modification. However, there is little evidence that dietary modifications of any kind have an impact on the incidence of breast cancer.

There are very few randomized trials in humans comparing cancer incidence for different diets. Most studies are observational—including post hoc analyses of randomized trials—and are subject to biases that may be so large as to render the observation difficult to interpret. In particular, p-values and CIs do not have the same interpretation as when calculated for the primary endpoint in a randomized trial.

A summary of ecological studies published before 1975 showed a positive correlation between international age-adjusted breast cancer mortality rates and the estimated per capita consumption of dietary fat.[154] Results of case-control studies have been mixed. Twenty years later, a pooled analysis of results from seven cohort studies found no association between total dietary fat intake and breast cancer risk.[155]

A randomized, controlled, dietary modification study was undertaken among 48,835 postmenopausal women aged 50 to 79 years who were also enrolled in the WHI. The intervention promoted a goal of reducing total fat intake by 20% by increasing vegetable, fruit, and grain consumption. The intervention group reduced fat intake by approximately 10% for more than 8.1 years of follow-up, resulting in lower estradiol and gamma-tocopherol levels, but no persistent weight loss. The incidence of invasive breast cancer was numerically, but not statistically lower in the intervention group, with an HR of 0.91 (95% CI, 0.83–1.01).[156] There was no difference in all-cause mortality, overall mortality, or the incidence of cardiovascular events.[157]

With regard to fruit and vegetable intake, a pooled analysis of eight cohort studies including more than 350,000 women with 7,377 incident breast cancers showed little or no association for various assumed statistical models.[158]

The Women's Healthy Eating and Living Randomized Trial [159] examined the effect of diet on the incidence of new primary breast cancers in women previously diagnosed with breast cancer. More than 3,000 women were enrolled and randomly assigned to an intense regimen of increased fruit and vegetable intake, increased fiber intake, and decreased fat intake, or a comparison group receiving printed materials on the “5-A-Day” dietary guidelines. After a mean of 7.3 years of follow-up, there was no reduction in new primary cancers, no difference in disease-free survival, and no difference in overall survival.

A randomized trial in Spain [160] assigned participants who were at high cardiovascular risk to one of three diets: a Mediterranean diet supplemented with extra-virgin olive oil, a Mediterranean diet supplemented with mixed nuts, or a control Mediterranean diet (counseling to reduce dietary fat). The investigators reported a statistically significant reduction in major cardiovascular events, which was the trial’s primary endpoint.[161] The investigators also addressed other endpoints, including the incidence of breast cancer, although it is not specified how many were examined. Based on only 35 cases of invasive breast cancer (as compared with 288 major cardiovascular events), the respective rates of breast cancer were 8 of 1,476 (0.54%); 10 of 1,285 (0.78%); and 17 of 1,391 (1.22%) with respective average follow-up durations of 4.8, 4.3, and 4.2 years. The circumstances of the study make it difficult to determine the statistical significance of these differences.

Vitamins

The potential role of specific micronutrients for breast cancer risk reduction has been examined in clinical trials, with cardiovascular disease and cancer as outcomes. The Women’s Health Study, a randomized trial with 39,876 women, found no difference in breast cancer incidence at 2 years between women assigned to take either beta carotene or placebo.[162] In this same study, no overall effect on cancer was seen in women taking 600 IU of vitamin E every other day.[163] The Women’s Antioxidant Cardiovascular Study examined 8,171 women for incidence of total cancer and invasive breast cancer and found no effect for vitamin C, vitamin E, or beta carotene.[164] Two years later, a subset of 5,442 women were randomly assigned to take 1.5 mg of folic acid, 50 mg of vitamin B6, and 1 mg of vitamin B12, or placebo. After 7.3 years, there was no difference in the incidence of total invasive cancer or invasive breast cancer.[165]

Fenretinide [166] 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.[167]

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.[168] Since the mid-1990s, studies of cigarette smoking and breast cancer have more carefully accounted for secondhand smoke exposure.[168,169] 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.[170]

Underarm deodorants/antiperspirants

Despite warnings to women in lay publications that underarm deodorants and antiperspirants cause breast cancer, there is no evidence to support these concerns. A study based on interviews with 813 women who had breast cancer and 793 controls found no association between the risk of breast cancer and the use of antiperspirants, the use of deodorants, or the use of blade razors before these products were applied.[171] In contrast, a study of 437 breast cancer survivors found that women who used antiperspirants/deodorants and shaved their underarms more frequently had cancer diagnosed at a significantly younger age. A possible explanation for this finding is that these women had an earlier menarche or higher levels of endogenous hormones, both known to be risk factors for breast cancer and to increase body hair.[172]

Statins

Two well-conducted meta-analyses of RCTs [173] and RCTs plus observational studies [174] found no evidence that statin use either increases or decreases the risk of breast cancer.

Bisphosphonates

Oral and intravenous bisphosphonates for the treatment of hypercalcemia and osteoporosis have been studied for a possible beneficial effect on breast cancer prevention. Initial observational studies suggested that women who used these drugs for durations of approximately 1 to 4 years had a lower incidence of breast cancer.[175-178] These findings are confounded by the fact that women with osteoporosis have lower breast cancer risk than those with normal bone density. Additional evidence came from studies of women with a breast cancer diagnosis; the use of these drugs was associated with fewer new contralateral cancers.[179] With this background, two large randomized placebo-controlled trials were done. The Fracture Intervention Trial (FIT) treated 6,194 postmenopausal osteopenic women with either alendronate or placebo and found no difference at 3.8 years in breast cancer incidence, with incidence of 1.8% and 1.5%, respectively (HR, 1.24; CI, 0.84–1.83). The Health Outcomes and Reduced Incidence With Zoledronic Acid Once Yearly-Pivotal Fracture Trial (HORIZON-PRT) examined 7,580 postmenopausal osteoporotic women with either intravenous zoledronate or placebo and found no difference at 2.8 years in breast cancer incidence, with incidence of 0.8% and 0.9%, respectively (HR, 1.15; CI, 0.7–1.89).[180]

Working night shifts

In 2007, the World Health Organization’s International Agency for Research on Cancer (IARC) classified shift work that involves circadian disruption as a probable breast carcinogen. The principal evidence was from animal studies. There was limited evidence from human studies at the time.[181] In 2013, a meta-analysis of 15 epidemiologic studies concluded that there was weak evidence of an increased incidence of breast cancer among women who had ever worked night shifts.[182] In 2016, the results from three recent prospective studies from the United Kingdom, involving nearly 800,000 women, were combined with results from seven other prospective studies and showed no evidence of any association between breast cancer incidence and night shift work. In particular, the confidence intervals for the incidence rate ratios were narrow, even for 20 years or more of night shift work (rate ratio, 1.01; 95% CI, 0.93–1.10). These results exclude a moderate association of breast cancer incidence with long duration of night shift work.[183]

The U.K. Generations Study was established in 2003 to address risk factors and causes of breast cancer. In a prospective cohort of 105,000 women, information was obtained by questionnaire on bedroom light levels at night at the time of study recruitment and at age 20 years. They followed women for an average of 6.1 years and observed 1,775 breast cancers. Adjusting for potentially confounding factors, including night shift work, they found no evidence that the amount of bedroom light at night was associated with breast cancer risk. For the highest-to-lowest levels of light at night, the HR of breast cancer incidence was 1.01 (95% CI, 0.88–1.15).[184]

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Changes to This Summary (06/18/2019)

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.

Description of the Evidence

Added text to state that meta-analyses, describing up to 134 environmental chemicals, their sources, and biomarkers of their exposures, suggest that they may be associated with cancer (cited Brody et al. as reference 130 and Rodgers et al. as reference 131). Also added text to state that overall, the epidemiological and animal study evidence that support an association between breast cancer and specific environmental exposures is generally weak; because so many factors must be considered, any associations with breast cancer or other cancers could be confounded by the analytical problems of multiplicities, measurement challenges, and recall and publication bias (cited Berry as reference 140 and Dickersin as reference 141).

Added text to state that the U.K. Generations Study was established in 2003 to address risk factors and causes of breast cancer; in a prospective cohort of 105,000 women, information was obtained by questionnaire on bedroom light levels at night at the time of study recruitment and at age 20 years. Also added that adjusting for potentially confounding factors, including night shift work, they found no evidence that the amount of bedroom light at night was associated with breast cancer risk (cited Johns et al. as reference 184).

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About This PDQ Summary

Purpose of This Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about breast cancer prevention. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.

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PDQ® Screening and Prevention Editorial Board. PDQ Breast Cancer Prevention. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: https://www.cancer.gov/types/breast/hp/breast-prevention-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389323]

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