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.)