Prevention of Breast Cancer

Summary Type: Prevention
Summary Audience: Health professionals
Summary Language: English
Summary Description: Expert-reviewed information summary about factors that may increase the risk of developing breast cancer and about research aimed at the prevention of this disease.


Prevention of Breast Cancer

Summary of Evidence

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

Factors Associated with Increased Risk of Breast Cancer

Hormone replacement therapy/hormone therapy

Based on solid evidence, combination hormone replacement therapy (HRT; estrogen-progestin), also called hormone therapy (HT), is associated with an increased risk of developing breast cancer. The evidence concerning the association between estrogen-only therapy and breast cancer incidence is mixed.

    Description of the Evidence for Combination Therapy
  • Study Design : Evidence obtained from randomized controlled trials.
  • Internal Validity : Good.
  • Consistency : Good.
  • Magnitude of Effects on Health Outcomes : Approximately 24% increase in incidence of invasive breast cancer.
  • External Validity : Good.
    Description of the Evidence for Estrogen Only
  • Study Design : Evidence obtained from randomized controlled trials.
  • Internal Validity : Good.
  • Consistency : Poor.
  • Magnitude of Effects on Health Outcomes : Cannot determine because of mixed evidence.
  • External Validity : Not applicable.

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 dose and age at exposure, with the highest risk occurring during puberty.

    Description of the Evidence
  • Study Design : Evidence obtained from cohort or case-control studies.
  • Internal Validity : Good.
  • Consistency : Good.
  • Magnitude of Effects on Health Outcomes : Variable, but approximately a 6-fold increase in incidence overall.
  • External Validity : Good.

Obesity

Based on solid evidence, obesity is associated with increased breast cancer risk in postmenopausal women who have not used HRT/HT.

    Description of the Evidence
  • Study Design : Evidence obtained from an observational study.
  • Internal Validity : Good.
  • Consistency : Good.
  • Magnitude of Effects on Health Outcomes : The Women’s Health Initiative Study of 85,917 postmenopausal women found body weight to be associated with breast cancer. Comparing women weighing over 82.2 kg with those under 58.7 kg, the relative risk (RR) was 2.85 (95% confidence interval [CI], 1.81–4.49).
  • External Validity : Good.

Alcohol

Based on solid evidence, exposure to alcohol is associated with increased breast cancer risk in a dose-dependent fashion.

    Description of the Evidence
  • Study Design : Evidence obtained from case-control and cohort studies.
  • Internal Validity : Good.
  • Consistency : Good.
  • Magnitude of Effects of Health Outcomes : 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.
  • External Validity : Good.

Factors Associated with Decreased Risk of Breast Cancer

Selective estrogen receptor modulators (SERMs) - benefits

Based on solid evidence for tamoxifen and fair evidence for raloxifene, treatment reduces the incidence of breast cancer in postmenopausal women. Tamoxifen also reduced the risk of breast cancer in high-risk premenopausal women.

    Description of the Evidence
  • Study Design : Evidence obtained from randomized controlled trials.
  • Internal Validity : Good.
  • Consistency : Good.
  • Magnitude of Effects on Health Outcomes : Meta-analysis showed that tamoxifen reduced breast cancer by 49%, and one randomized trial of women at risk for osteoporosis showed that raloxifene reduced it by 66%.
  • External Validity : Good.

Selective estrogen receptor modulators (SERMs) - harms

Based on solid evidence, tamoxifen treatment increases the risk of endometrial cancer, thrombotic vascular events (pulmonary embolism, stroke, deep venous thrombosis), and cataracts. Based on fair evidence, raloxifene also increases venous pulmonary embolism and deep venous thrombosis but not endometrial cancer.

    Description of the Evidence
  • Study Design : Evidence obtained from randomized controlled trials.
  • Internal Validity : Good.
  • Consistency : Good.
  • Magnitude of Effects on Health Outcomes : Meta-analysis shows RR = 2.4 (95% CI, 1.5–4.0) for endometrial cancer and 1.9 (95% CI, 1.4–2.6) for venous thromboembolic events.
  • External Validity : Good.

Aromatase inhibitors or inactivators - benefits

Based on fair evidence, aromatase inhibitors or inactivators (AIs) reduce the incidence of new breast cancers in postmenopausal women who have a history of breast cancer.

    Description of the Evidence
  • Study Design : Evidence obtained from randomized controlled trials performed in postmenopausal women with a previous history of breast cancer.
  • Internal Validity : Good.
  • Consistency : Good.
  • Magnitude of Effects on Health Outcomes : Compared with tamoxifen, anastrazole reduces the incidence of new primary breast cancers by 50%. Similar results have been reported with letrozole and exemestane.
  • External Validity : Fair.

Aromatase inhibitors or inactivators - harms

Based on fair evidence, AIs are associated with decreased bone mineral density, increased falls, and decreased cognitive function.

    Description of the Evidence
  • Study Design : Multiple randomized controlled trials demonstrate decreased bone mineral density with each AI. One randomized controlled trial shows an increase in fractures (anastrazole).
  • Internal Validity : Good.
  • Consistency : Good.
  • Magnitude of Effects on Health Outcomes : Fracture rate for women on anastrazole was 5.9% compared with 3.7% for those on tamoxifen.1,
  • External Validity : Good.

Prophylactic mastectomy - benefits

Based on solid evidence, bilateral prophylactic mastectomy reduces the risk of breast cancer in women with a strong family history.

    Description of the Evidence
  • Study Design : Evidence obtained from case-control and cohort studies.
  • Internal Validity : Good.
  • Consistency : Good.
  • Magnitude of Effects on Health Outcomes : Risk is reduced as much as 90%, but published study designs may have produced an overestimate.
  • External Validity: Good.

Prophylactic mastectomy - harms

Based on fair evidence, physical and psychological effects include anxiety, depression, and impaired body image.

    Description of the Evidence
  • Study Design : Convenience sample.
  • Internal Validity : Good.
  • Consistency : Good.
  • Magnitude of Effects on Health Outcomes : 6% of women were dissatisfied with their decision to have a prophylactic mastectomy, usually for cosmesis. Regrets about mastectomy were less in the 185 women who opted not to have reconstruction than in the 111 who chose it.2,
  • External Validity: Good.

Prophylactic oophorectomy or ovarian ablation - benefits

Based on good evidence, prophylactic oophorectomies in women with BRCA gene mutations document lower breast cancer incidence. Similarly, oophorectomy or ovarian ablation are associated with decreased breast cancer incidence in normal women or in those who received thoracic irradiation.

    Description of the Evidence
  • Study Design : Observational, case-control, and cohort studies
  • Internal Validity : Good.
  • Consistency : Good.
  • Magnitude of Effects on Health Outcomes : Breast cancer incidence is decreased by 50%, but published study designs may have produced an overestimate.
  • External Validity: Good.

Prophylactic oophorectomy or ovarian ablation - harms

Based on good 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.

    Description of the Evidence
  • Study Design : Case-control, cohort, and observational studies.
  • Internal Validity : Good.
  • Consistency : Good.
  • Magnitude of Effects on Health Outcomes : Nearly all women experience some sleep disturbances, mood changes, hot flashes, and bone demineralization, but the severity of these symptoms varies greatly. Nonhormonal medications are fairly effective in reducing or eliminating these symptoms of hormone deprivation.
  • External Validity : Good.

Exercise - benefits

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

    Description of the Evidence
  • Study Design : Prospective observational and case-control studies.
  • Internal Validity : Good.
  • Consistency : Good.
  • Magnitude of Effects on Health Outcomes : Average RR reduction is 30% to 40%. The effect may be greatest for premenopausal women of normal or low body weight.
  • External Validity : Good.

Exercise - harms

Musculoskeletal injury may occur.

    Description of the Evidence
  • Study Design : Many sources.
  • Internal Validity : Good.
  • Consistency : Good.
  • Magnitude of Effects on Health Outcomes : Injuries depend on the type of exercise.
  • External Validity : Good.


1 Smith IE, Dowsett M: Aromatase inhibitors in breast cancer. N Engl J Med 348 (24): 2431-42, 2003.

2 Montgomery LL, Tran KN, Heelan MC, et al.: Issues of regret in women with contralateral prophylactic mastectomies. Ann Surg Oncol 6 (6): 546-52, 1999.

Significance

Incidence and Mortality

In the United States, a woman who lives to the age of 90 years has a 1 in 8 risk of being diagnosed with breast cancer.1 With an estimated 178,480 cases expected, breast cancer will be the most frequently diagnosed nonskin malignancy in U.S. women in 2007.2 In the same year, breast cancer will kill an estimated 40,460 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 2,030 new cases will be diagnosed in 2007.2 Despite a prior long-term trend of gradually increasing breast cancer incidence, data from the Surveillance, Epidemiology, and End Results Program show that from 1990 to 2001 there was a decrease in breast cancer mortality of 2.3% per year.3,

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

Breast cancer prevention can be accomplished with selective estrogen receptor modifiers but has attendant side effects.

Etiology and Pathogenesis of Breast Cancer

Genetic, epidemiologic, and laboratory studies support a stochastic model of breast cancer development in which a series of genetic changes contribute to the dynamic process known as carcinogenesis.4 An accumulation of genetic changes is thought to correspond to the phenotypic changes associated with the evolution of malignancy. The carcinogenesis sequence is viewed histologically as starting with tissue of normal appearance, followed by changes that lead to hyperplasia and dysplasia, of which the most severe forms are difficult to distinguish from carcinoma in situ .5,

The concept that breast cancer may be preventable is supported by the wide international variation in breast cancer rates, which is an indicator that there are potentially modifiable environmental and lifestyle determinants of breast cancer. Migration studies reinforce this premise; for example, it has been observed that Japanese immigrants to the United States increase their breast cancer risk from Japanese to American levels within two generations.6,7,8,

Endogenous Estrogen

Many of the risk factors for breast cancer, including the age at menarche, first birth, and menopause, suggest hormonal influences for the development of the disease. Estrogen and progestin cause growth and proliferation of breast cells that may work through growth factors such as transforming growth factor (TGF)-alpha.9 Women who develop breast cancer tend to have higher endogenous estrogen and androgen levels.10,

The role of ovarian hormones in the development of breast cancer is demonstrated by studies of artificial menopause. Following ovarian ablation, breast cancer risk may be reduced as much as 75%, depending on age, weight, and parity, with the greatest reduction for young, thin, nulliparous women.11,12,13,14 The removal of one ovary also reduces the risk of breast cancer, but to a lesser degree than the removal of both.15,

Other hormonal changes also influence breast cancer risk. Childbirth is followed by a transient increase in risk and then a long-term reduction in risk, which is greater for younger women.14,16,17 In one study, women who experienced a first full-term pregnancy before 20 years of age were one half as likely to develop breast cancer as nulliparous women or women who underwent a first full-term pregnancy at 35 years or older.18 Age at menarche also affects breast cancer risk. Women who experienced menarche at 11 years or younger have about a 20% greater chance of developing breast cancer than women who experienced menarche at 14 years or older.19 Women with late menopause also experience increased risk. Reproductive risk factors may interact with more predisposing genotypes. In the Nurses’ Health Study,20 the associations between age at first birth, menarche, and menopause and the development of breast cancer were observed only among women without a family history of breast cancer in a mother or sister. Breastfeeding is associated with a decreased risk of breast cancer.21,22,

A number of studies suggest that endogenous estrogen and androgen levels are higher in women who develop breast cancer than in women who do not.10,23,24 Methods shown to decrease endogenous estrogen include maintenance of ideal body weight (refer to the Obesity section), adoption of a low-fat diet in postmenopausal women,25 and moderate exercise in adolescent girls.26 Whether such interventions will decrease breast cancer risk is worthy of study.

Genetic Mutations

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

Women who inherit a deleterious mutation in BRCA1 27,28, or BRCA2 29 have an increased lifetime risk of breast cancer, which occurs at younger ages; ovarian cancer; and possibly colon cancer. Deleterious BRCA2 mutations are less common than those in BRCA1 and are also associated with male breast cancer, prostate cancer, pancreatic cancer, and lymphomas.30,

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



1 Feuer EJ, Wun LM, Boring CC, et al.: The lifetime risk of developing breast cancer. J Natl Cancer Inst 85 (11): 892-7, 1993.

2 American Cancer Society.: Cancer Facts and Figures 2007. Atlanta, Ga: American Cancer Society, 2007. Also available online. Last accessed March 5, 2007.

3 Ries LAG, Eisner MP, Kosary CL, et al.: SEER Cancer Statistics Review, 1975-2001. Bethesda, Md: National Cancer Institute, 2004. Also available online. Last accessed January 10, 2007.

4 Boone CW, Kelloff GJ, Freedman LS: Intraepithelial and postinvasive neoplasia as a stochastic continuum of clonal evolution, and its relationship to mechanisms of chemopreventive drug action. J Cell Biochem Suppl 17G: 14-25, 1993.

5 Kelloff GJ, Boone CW, Steele VE, et al.: Progress in cancer chemoprevention: perspectives on agent selection and short-term clinical intervention trials. Cancer Res 54 (7 Suppl): 2015s-2024s, 1994.

6 Parkin DM: Cancers of the breast, endometrium and ovary: geographic correlations. Eur J Cancer Clin Oncol 25 (12): 1917-25, 1989.

7 Dunn JE Jr: Breast cancer among American Japanese in the San Francisco Bay area. Natl Cancer Inst Monogr 47: 157-60, 1977.

8 Kliewer EV, Smith KR: Breast cancer mortality among immigrants in Australia and Canada. J Natl Cancer Inst 87 (15): 1154-61, 1995.

9 Knabbe C, Lippman ME, Wakefield LM, et al.: Evidence that transforming growth factor-beta is a hormonally regulated negative growth factor in human breast cancer cells. Cell 48 (3): 417-28, 1987.

10 Endogenous Hormones and Breast Cancer Collaborative Group.: Endogenous sex hormones and breast cancer in postmenopausal women: reanalysis of nine prospective studies. J Natl Cancer Inst 94 (8): 606-16, 2002.

11 Smith PG, Doll R: Late effects of x irradiation in patients treated for metropathia haemorrhagica. Br J Radiol 49 (579): 224-32, 1976.

12 Trichopoulos D, MacMahon B, Cole P: Menopause and breast cancer risk. J Natl Cancer Inst 48 (3): 605-13, 1972.

13 Feinleib M: Breast cancer and artificial menopause: a cohort study. J Natl Cancer Inst 41 (2): 315-29, 1968.

14 Kampert JB, Whittemore AS, Paffenbarger RS Jr: Combined effect of childbearing, menstrual events, and body size on age-specific breast cancer risk. Am J Epidemiol 128 (5): 962-79, 1988.

15 Hirayama T, Wynder EL: A study of the epidemiology of cancer of the breast, II: the influence of hysterectomy. Cancer 15(1): 28-38, 1962.

16 Pike MC, Krailo MD, Henderson BE, et al.: 'Hormonal' risk factors, 'breast tissue age' and the age-incidence of breast cancer. Nature 303 (5920): 767-70, 1983.

17 Lambe M, Hsieh C, Trichopoulos D, et al.: Transient increase in the risk of breast cancer after giving birth. N Engl J Med 331 (1): 5-9, 1994.

18 Henderson BE, Pike MC, Ross RK, et al.: Epidemiology and risk factors. In: Bonadonna G, ed.: Breast Cancer: Diagnosis and Management. Chichester, NY: John Wiley & Sons, 1984, pp 15-33.

19 Brinton LA, Schairer C, Hoover RN, et al.: Menstrual factors and risk of breast cancer. Cancer Invest 6 (3): 245-54, 1988.

20 Colditz GA, Rosner BA, Speizer FE: Risk factors for breast cancer according to family history of breast cancer. For the Nurses' Health Study Research Group. J Natl Cancer Inst 88 (6): 365-71, 1996.

21 Furberg H, Newman B, Moorman P, et al.: Lactation and breast cancer risk. Int J Epidemiol 28 (3): 396-402, 1999.

22 Collaborative Group on Hormonal Factors in Breast Cancer.: 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.

23 Key TJ, Appleby PN, Reeves GK, et al.: Body mass index, serum sex hormones, and breast cancer risk in postmenopausal women. J Natl Cancer Inst 95 (16): 1218-26, 2003.

24 Onland-Moret NC, Kaaks R, van Noord PA, et al.: Urinary endogenous sex hormone levels and the risk of postmenopausal breast cancer. Br J Cancer 88 (9): 1394-9, 2003.

25 Prentice R, Thompson D, Clifford C, et al.: Dietary fat reduction and plasma estradiol concentration in healthy postmenopausal women. The Women's Health Trial Study Group. J Natl Cancer Inst 82 (2): 129-34, 1990.

26 Bernstein L, Ross RK, Lobo RA, et al.: The effects of moderate physical activity on menstrual cycle patterns in adolescence: implications for breast cancer prevention. Br J Cancer 55 (6): 681-5, 1987.

27 Miki Y, Swensen J, Shattuck-Eidens D, et al.: A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1. Science 266 (5182): 66-71, 1994.

28 Futreal PA, Liu Q, Shattuck-Eidens D, et al.: BRCA1 mutations in primary breast and ovarian carcinomas. Science 266 (5182): 120-2, 1994.

29 Wooster R, Neuhausen SL, Mangion J, et al.: Localization of a breast cancer susceptibility gene, BRCA2, to chromosome 13q12-13. Science 265 (5181): 2088-90, 1994.

30 Easton DF, Bishop DT, Ford D, et al.: Genetic linkage analysis in familial breast and ovarian cancer: results from 214 families. The Breast Cancer Linkage Consortium. Am J Hum Genet 52 (4): 678-701, 1993.

31 Athma P, Rappaport R, Swift M: Molecular genotyping shows that ataxia-telangiectasia heterozygotes are predisposed to breast cancer. Cancer Genet Cytogenet 92 (2): 130-4, 1996.

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.1 Tamoxifen also maintains bone density among postmenopausal women with breast cancer.2,3,4,5,6 Adverse effects include hot flashes, venous thromboembolic events, and endometrial cancer.7,8,9

These adjuvant trial results were the basis for the Breast Cancer Prevention Trial (BCPT) that randomly assigned 13,388 subjects at elevated risk of breast cancer to receive tamoxifen or placebo.10,11 The independent Monitoring Committee closed the study early because of a 49% reduction in the incidence of breast cancer for tamoxifen-treated versus placebo-treated participants. After about 4 years' follow-up, placebo-treated women had 154 cases of invasive breast cancer compared with 85 cases in women who received tamoxifen. Noninvasive breast cancers were also reduced, with 59 cases in the placebo group versus 31 in the tamoxifen-treated group. Another benefit of tamoxifen use was a reduction in fractures, with 47 occurring in the tamoxifen-treated women compared with 71 in the placebo group. These benefits were accompanied by an increased incidence in women aged 50 years and older of endometrial cancer and thrombotic events. There were 33 endometrial cancers and 99 vascular events (including 17 cases of pulmonary embolism and 30 cases of deep vein thrombosis) in women who received tamoxifen compared with 14 endometrial cancers and 70 vascular events (including 6 cases of pulmonary embolism and 19 cases of deep vein thrombosis) in women who received a placebo.11

An update of the BCPT results after 7 years of follow-up demonstrates similar results to the initial report.12 Follow-up was more complete for the tamoxifen group compared with the placebo group due to a greater drop-out rate among women in the placebo group after early termination of the study. In addition, women who received a placebo were given the option of taking tamoxifen or participating in the Study of Tamoxifen and Raloxifene (STAR) trial, and 32% did so. Breast cancer rates decreased among women in the placebo group from year 6 to year 7 of follow-up. A statistically significant relative risk (RR) of 43% for invasive breast cancer persisted at follow-up despite the addition of women to the placebo arm. The rate of invasive breast cancer among women in the placebo group was 6.29 per 1,000 women versus 3.59 per 1,000 women for women in the tamoxifen group, for a risk reduction of 0.27%. Benefits and risks of tamoxifen were not significantly different from those in the original report, with persistent benefit of reductions in fracture and persistent risks of endometrial cancer, thrombosis, and cataract surgery. No overall mortality benefit was observed after 7 years of follow-up (RR = 1.10; 95% CI, 0.85–1.43).

Other trials of tamoxifen for primary prevention of breast cancer have been completed.13,14,15 Initial analyses from two smaller trials, one in the United Kingdom (U.K.) 13 and one primarily in Italy,14, showed no protective effect, perhaps because of differences between their target populations and study designs and those in the U.S. study. The U.K. study focused on 2,471 women at increased breast cancer risk because of their family history of breast and/or ovarian cancer; about 36% of participants were from families that had a greater than 80% chance of carrying a breast cancer susceptibility gene. After a median follow-up of nearly 6 years, no protective effect of tamoxifen was detected (RR = 1.06). The Italian study focused on 5,408 women who had undergone hysterectomy, who were described as “low-to-normal risk” women; about 18% of the women had a family history of breast cancer among first-degree relatives or aunts. After a median follow-up of nearly 4 years, no protective effect of tamoxifen was observed.

Further follow-up of both of these trials provides results consistent with the BCPT.16 Longer follow-up and subgroup analysis in the Italian trial found a protective effect of tamoxifen among women who were taking HRT/HT during the trial.

The last trial of tamoxifen for primary prevention of breast cancer was the International Breast Cancer Intervention Study (IBIS-I). This trial randomly assigned 7,152 women aged 35 to 70 years at increased risk of breast cancer to receive tamoxifen (20 mg/day for 5 years) or placebo.15 After a median follow-up of 50 months, 32% fewer women (95% CI, 8%–50%) in the tamoxifen group than in the placebo group had developed breast cancer (invasive plus carcinoma in situ with an absolute reduction from 6.75 to 4.6 breast cancers per 1,000 woman-years). The RR reduction in estrogen-receptor positive (ER+) invasive breast cancer was 31%; there was no reduction in ER negative (ER-) cancers. In this trial but in none of the other tamoxifen trials, there was an excess of all-cause mortality in the tamoxifen group (25 vs. 11, P = .028), which the authors attributed to chance.

A meta-analysis of these primary prevention trials was performed, finding a 38% reduction in the incidence of breast cancer without statistically significant heterogeneity.9 ER+ tumors were reduced by 48%. Rates of endometrial cancer were increased (consensus RR = 2.4; 95% CI, 1.5–4.0), as were venous thromboembolic events (RR = 1.9; 95% CI, 1.4–2.6). None of these primary prevention trials was designed to detect differences in breast cancer mortality.

Decisions are complex and need to be individualized, weighing estimates of a woman’s chance of reducing breast cancer and fracture risks against the chance of developing detrimental side effects, some of which may be life threatening. The risks and benefits of taking tamoxifen have been estimated for women according to age, race, and risk group based on the results of the BCPT, additional risk/benefit analyses, and review of the literature.17 Because adverse effects of tamoxifen increase with age, tamoxifen is most beneficial for women younger than 50 years with an increased risk of developing breast cancer. Overall, the net benefit or risk depends on age, whether or not a woman has a uterus, and her baseline risk of breast cancer.

Women with a history of ductal carcinoma in situ (DCIS) are at increased risk (3.4%) for contralateral breast cancer but were not eligible for the BCPT because of competing treatment trials. In a trial of DCIS treatment, however, 13.4% of women treated with lumpectomy and radiation had breast cancer events within approximately 6 years, compared with 8.2% of those who also received tamoxifen.18 The National Surgical Adjuvant Breast and Bowel Project (NSABP) B-24 randomized controlled trial evaluated the added benefit of tamoxifen to lumpectomy and radiation therapy for women with DCIS.18 The risk of all breast cancer events, invasive and noninvasive, was reduced with tamoxifen (rate ratio 0.63; 95% CI, 0.47–0.83); the risk of contralateral breast cancer (invasive and noninvasive) associated with tamoxifen was 0.49 (95% CI, 0.26–0.87). Given the results of the NSABP B-24 trial and the BCPT, it is reasonable to consider the use of tamoxifen for breast cancer risk reduction among women with DCIS.

In addition to tamoxifen, other hormonal manipulations have been proposed to modulate the production of breast cell growth factors by suppressing ovarian function 19 or changing the endogenous hormonal environment.20 The list of chemoprevention agents that may be used in breast cancer prevention is long.

Raloxifene hydrochloride is a SERM that has antiestrogenic effects on breast and endometrial tissue and estrogenic effects on bone, lipid metabolism, and blood clotting.21 The Multiple Outcomes of Raloxifene Evaluation (MORE), a randomized, double-blind trial evaluated 7,705 postmenopausal women with osteoporosis from 1994 to1998 at 180 clinical centers in the United States. The effect on breast cancer incidence was a secondary endpoint, and therefore should be judged with caution. Raloxifene is still investigational for this use. After a median follow-up of 47 months, the risk of invasive breast cancer decreased by 72%.22 Breast cancer was reported in 79 women and confirmed in 77 women. Invasive breast cancer occurred in 39 women treated with placebo and 22 women randomly assigned to either of the two raloxifene arms (raloxifene 120 mg daily; or raloxifene 60 mg; RR = .248; 95% CI, 0.17–0.446; 4.7 and 1.3 invasive breast cancers/1,000 woman-years in the placebo and combined-treatment groups, respectively). DCIS occurred in 5 women treated with a placebo and 11 women treated with raloxifene. After combining noninvasive and invasive cancer occurrences, the RR of breast cancer among women in the raloxifene group was 0.38 (95% CI, 0.24–0.58; 5.3 and 1.9 breast cancers/1,000 woman-years in the placebo and combined-treatment groups, respectively). As with tamoxifen, raloxifene appeared to reduce the risk of ER+ breast cancer but not ER- breast cancer. Similar to tamoxifen, raloxifene is associated with an excess risk of hot flashes and thromboembolic events. The risk of venous thromboembolic disease (deep venous thrombosis or pulmonary embolism) was 2.4 times higher in women assigned to the raloxifene groups than to the placebo group. One woman (in the 60 mg raloxifene group) died due to pulmonary embolism. There was little difference in the rate of venous thromboembolic disease between the 60 mg and 120 mg groups (3.32 and 3.63 events/1,000 woman-years, respectively). No excess risk of endometrial cancer was observed after 47 months of follow-up; five cases occurred among women on placebo (0.77 cases/1,000 woman-years), five cases among women treated with 60 mg of raloxifene (0.77 cases/1,000 woman-years), and four cases among women treated with 120 mg of raloxifene (0.60 cases/1,000 woman years). Raloxifene did not increase the risk of endometrial hyperplasia.23 Of 1,781 women who underwent transvaginal ultrasonography at baseline and had at least one follow-up test, endometrial thickness increased by an average of 0.01 mm in the raloxifene groups and decreased by 0.27 mm in the placebo group after 3 years of follow-up (P <.01 for the difference between the two groups). Sixty participants (10.1%) in the placebo group and 168 women (14.2%) in the raloxifene groups (P = .02) had endometrial thickness that was greater than 5 mm on at least one follow-up ultrasound. Among the 196 women who still had a uterus (48 in the placebo group and 148 in the raloxifene group), there were three cases of hyperplasia and two cases of endometrial cancer in the placebo group and three cases of hyperplasia and two cases of endometrial cancer in the combined raloxifene group. Subgroup analyses after 4 years of follow-up suggest that, among women who have osteoporosis, raloxifene reduces breast cancer incidence for both women at higher and lower risk of developing breast cancer.

An extension of the MORE study, the Continuing Outcomes Relevant to Evista (CORE) study, continued studying about 80% of MORE participants in their randomized groups for 4 years beyond the original 4 years of the MORE study. Although there was a median 10-month gap between the two studies, and only about 55% of women were adherent to their assigned medications, the raloxifene group continued to experience a lower incidence of invasive breast cancer. As in the MORE study, this was due to a reduction in ER+ but not ER- invasive breast cancer. There was no reduction in noninvasive breast cancer. The overall reduction in invasive breast cancer over the 8 years of MORE and CORE was 66% (HR = 0.34; 95% CI, 0.22–0.50); the reduction for ER+ invasive breast cancer was 76% (HR = 0.24; 95% CI, 0.15–0.40).24,

The STAR trial (NSABP P-2) compared tamoxifen and raloxifene in 19,747 high-risk women with a mean follow-up of 3.9 years. There was no difference in the incidence of breast cancer, but the use of tamoxifen reduced the risk of noninvasive breast cancer when compared with the use of raloxifene (RR = 1.40; 95% CI, 0.98–2.00). The raloxifene group had fewer incidences of uterine cancer, thromboembolic events, and cataracts. Between the groups, there was no difference in ischemic heart disease events, strokes, or fractures.25 Patient-reported symptom scores found small differences between the groups, with some symptoms favoring tamoxifen (e.g., musculoskeletal problems, dyspareunia, and weight gain) and some symptoms favoring raloxifene (e.g., gynecological problems, vasomotor symptoms, leg cramps, and bladder control).26,

Aromatase Inhibition or Inactivation

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

All three drugs decrease the incidence of new breast cancers in women with a prior history of breast cancer. The ATAC trial compared anastrazole, tamoxifen, and the combination, when used as an adjuvant hormone therapy after treatment of the primary breast cancer.27 Anastrazole-treated patients had a 7.1% rate of locoregional and distant recurrence versus 8.5% for those treated with tamoxifen and 9.1% for the combination. A more impressive result was the decreased rate of contralateral breast primaries (0.4% vs. 1.1% vs. 0.9%). Another trial analyzed the use of letrozole versus placebo in 5,187 women with breast cancer, following 5 years treatment with adjuvant tamoxifen.28 After only 2.5 years of median follow-up, the study was terminated, because previously defined efficacy endpoints had been reached. Not only did letrozole-treated patients have a lower incidence of locoregional and distant cancer recurrence, they also had a lower rate of contralateral breast cancer (14 vs. 26). A third trial randomly assigned 4,742 women who had already received 2 years of adjuvant tamoxifen. Women either continued the tamoxifen or switched to exemestane.29 After 2.4 years median follow-up, the women assigned to receive exemestane had a decreased risk of local or metastatic recurrence, as well as a decreased risk of new primary contralateral breast cancer (9 vs. 20).

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

Prophylactic Mastectomy

A retrospective cohort study was conducted to evaluate the impact of bilateral prophylactic mastectomy on the subsequent occurrence of breast cancer among women at high and moderate risk of breast cancer on the basis of family history.30 Most women in this retrospective series (90%) had undergone subcutaneous rather than total mastectomy, which is the procedure of choice for maximum breast tissue removal. Median follow-up after surgery was 14 years. All women included in the report had some family history of cancer and were classified as high risk or moderate risk for breast cancer based on the pattern of breast cancer in the family. Expected cases of breast cancer were estimated for moderate- and high-risk women using the Gail model and the observed rates of breast cancer among sisters of the probands. The reduction in risk for moderate-risk women was 89% and for high-risk women the reduction ranged from 90% to 94% depending on the method used to calculate expected rates of breast cancer. The reduction in risk of death from breast cancer ranged from 100% among moderate-risk women to 81% among high-risk women. Information of BRCA1 or BRCA2 mutation status was not known. Although this study provides the best evidence available to date that prophylactic surgery offers benefits despite the fact that some breast tissue remains following surgery, some factors may bias the estimate of benefit.31 For example, criteria used to classify women at high risk would include women from families misclassified as an autosomal-dominant inherited pattern and women from inherited syndrome families who are not at high risk because they did not inherit the susceptibility genotype. These factors may tend to overestimate the benefits of prophylactic surgery. It is important to note that most of the women who underwent prophylactic surgery would never have gone on to develop breast cancer. Thus, many were treated for the few who truly benefitted by having their breast cancer prevented. Among the 425 moderate-risk women who had prophylactic mastectomy, the estimated number of breast cancer cases expected to occur was 37.4; among the 214 high-risk women, the estimates ranged from 30.0 to 52.9, depending on the model used to estimate breast cancer occurrence. Thus, consideration of bilateral prophylactic mastectomy as an option for women should be done in association with cancer risk assessment and counseling regarding all the available preventive options, which now include tamoxifen as a preventive agent.11,

Studies of the harms of prophylactic mastectomy have been retrospective. Most women reported relief of anxiety about breast cancer, and few were dissatisfied with their choice to undergo the procedure.32 A higher dissatisfaction rate occurred among women who chose reconstruction over those who did not.33,

Prophylactic Oophorectomy

Women at high risk due to BRCA1 or BRCA2 gene mutations who had prophylactic oophorectomies to prevent ovarian cancer were found to have a lower incidence of breast cancer than age-matched controls.34,35,36 The reported reductions in relative risk were approximately 50%. These observational studies, however, are confounded by selection bias, family relationships between patients and controls, indications for oophorectomy, and inadequate information about hormone use.

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

Exercise

Active exercise may reduce breast cancer risk particularly in young parous women.37 There are numerous observational studies that have examined the relationship between physical activity and breast cancer risk.38 Most of these studies have shown an inverse relationship between level of physical activity and breast cancer incidence. The average relative risk reduction is reportedly 30% to 40%. However, it is not known if or to what degree the observed association is due to confounding variables, such as diet or a genetic predisposition to breast cancer. A prospective study of more than 25,000 women in Norway suggests that doing heavy manual labor or exercising 4 or more hours per week is associated with a decrease in breast cancer risk. This decrease is more pronounced in premenopausal women and in women of normal or lower-than-normal body weight.39 In a case-control study of African American women, strenuous recreational physical activity (>7 hours/week) was associated with decreased breast cancer incidence.40

Factors of Unproven or Disproven Association

Abortion

Abortion has been suggested as a cause of subsequent breast cancer. Studies showing an association used recalled information in populations in which induced abortion had a social or religious stigma, differential reporting of prior abortion by breast cancer patients, and controls. Trials conducted in social environments where abortion is accepted, however, have not shown an association with breast cancer.41,42,43,44,45,46,

A meta-analysis of women from 53 studies in 16 countries with liberal abortion laws was performed.47 Analyses were performed separately on 44,000 women with breast cancer who had prospective information on abortion (13 studies) versus 39,000 women with breast cancer in whom information was recorded retrospectively (40 studies). The RR of breast cancer for women with spontaneous abortion was 0.98 (95% CI, 0.92–1.04 for those with prospective data collection and 0.94–1.02 for retrospective data). The RR after induced abortion was 0.93 (95% CI, 0.89–0.96; P = .0002) if the information was collected prospectively, but was 1.11 (95% CI, 1.06–1.16) if it was collected retrospectively. Additional analyses of the number and timing of aborted pregnancies were performed, but none showed a significant association with breast cancer.47,

Environmental factors

The effect of occupational, environmental, or chemical exposures on breast cancer risk is controversial. Although some findings suggest that organochlorine exposures, such as those associated with insecticides, might be associated with an increase in breast cancer risk,48,49 other case-control and nested case-control studies do not.50,51,52,53,54,55 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 DDT (dichloro-diphenyl-trichloroethane) was banned in the United States in 1972, and the production of PCBs (polychlorinated biphenyls) was stopped in 1977.

Diet and vitamins

A low-fat diet might influence breast cancer risk through hormonal mechanisms. Ecologic studies show a positive correlation between international age-adjusted breast cancer mortality rates and the estimated per capita consumption of dietary fat.56 Results of case-control studies have been mixed. A pooled analysis of results from seven cohort studies found no evidence for an association between total dietary fat intake and breast cancer risk.57 A randomized controlled dietary modification study was undertaken among 48,835 postmenopausal women aged 50 to 79 years who were also enrolled in the Women's Health Initiative. The intervention promoted a goal of reducing total fat intake by 20%, using five servings per day of vegetables and fruit and six servings per day of grains. The intervention group accomplished a reduction of fat intake of approximately 10% over the 8.1 years' follow-up, and were found to have lower estradiol and lower γ -tocopherol levels, but no weight loss. The incidence of invasive breast cancer was slightly lower in the intervention group, with HR 0.91 (95% CI, 0.83–1.01).58 Because the intervention group also initially lost weight relative to the control group, it is not clear whether any potential effect in reducing breast cancer results from lower dietary fat or lower weight.59 Likewise, there was no benefit of the low-fat diet on all cancer mortality, overall mortality, or cardiovascular disease.60,

Fruit and vegetable consumption (or specific fruits or vegetables) may be associated with reduced breast cancer risk.61 A pooled analysis of adult dietary data from eight cohort studies, which included 351,823 women in whom 7,377 incident cases of breast cancer occurred, however, provides little support for an association.62 When examining the dietary data treated as continuous variables (based on grams of intake/day), there was no association. Comparing highest to lowest quartiles of intake, the pooled multivariate RRs of breast cancer were 0.93 (95% CI, 0.86–1.00) for total fruits, 0.96 (95% CI, 0.89–1.04) for total vegetables, and 0.93 (95% CI, 0.86–1.00) for total fruit and vegetables combined. Likewise, no statistically significant association was made between any of the specific fruits and vegetables examined and breast cancer risk. This analysis was limited by the common problem of reconciling information obtained from different food frequency questionnaires. One may conclude that any association between decreased breast cancer risk and fruit and vegetable consumption is weak or nonexistent.

Micronutrient intake may also play a role. Case-control studies show an inverse association between dietary beta-carotene intake and breast cancer risk.63,64 In the Women’s Health Study, however, 39,876 women were assigned to take beta-carotene or placebo, with no difference in cancer incidence at 2 years.65 In this same study, no overall effect on cancer was seen in women taking 600 IU of vitamin E every other day.66 High intake of foods containing folate,67 beta-carotene, and vitamins A and C 63 may also reverse the increased risk associated with alcohol use.

Fenretinide 68 is a vitamin A analogue 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.69,

Active and passive cigarette smoking

The potential role of active cigarette smoking in the etiology of breast cancer has been studied for more than 3 decades with no clear-cut evidence of an association.70 Since the mid-1990s, studies of cigarette smoking and breast cancer have more carefully accounted for secondhand smoke exposure. Some of these studies have observed both active and passive smoking to be associated with breast cancer risk, but the consensus of most review groups continues to be that the body of evidence does not clearly demonstrate that either active or passive cigarette smoking contributes to breast cancer risk.70,71

Statins

Two well-conducted meta-analyses of randomized controlled trials 72 and randomized controlled trials plus observational studies 73 found no evidence that statin use either increases or decreases the risk of breast cancer.



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