Factors Associated with Increased Risk of Breast Cancer
        Exogenous Hormones (OC and HRT)
        Ionizing Radiation Exposure
        Obesity
        Alcohol
Factors Associated with Decreased Risk of Breast Cancer
        Selective Estrogen Receptor Modulators (SERMs)
        Aromatase Inhibition or Inactivation
        Prophylactic Mastectomy
        Prophylactic Oophorectomy
        Exercise

Factors Associated with Increased Risk of Breast Cancer



Exogenous Hormones (OC and HRT)

Many of the risk factors for breast cancer, such as 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.[1] Women who go on to develop breast cancer tend to have higher endogenous circulating levels of estrogen and androgens.[2]

Oral contraceptives have been associated with a small increased risk of breast cancer associated with current use that diminishes over time.[3] A recent well-conducted case-control study did not observe an association between breast cancer risk and oral contraceptive use for ever use, duration of use, or recency of use.[4]

Evidence supporting an association between use of exogenous hormones after menopause and breast cancer is more consistent than that for oral contraceptive use.[5] The Women’s Health Initiative, a randomized controlled trial of the impact of hormone therapy and dietary interventions on women’s health, terminated the arm of the study investigating the effect of combination estrogen and progestin therapy on health risks.[6] Eligible women aged 50 to 79 years who had a uterus were randomized to receive conjugated estrogens in combination with continuous progestin therapy (N=8,506) or placebo (N=8,102). The trial showed an excess risk of breast cancer (hazard ratio (HR) 1.24, 95% confidence interval (CI) 1.02-1.50) associated with combination therapy compared with placebo.[7] The statistically significant excess risk was observed for invasive but not in situ breast cancer.[7] Women taking combination hormone therapy who developed breast cancer developed tumors that were similar in grade and histology but were larger than in women taking placebo.[7] Within 1 year on the trial, women taking hormones had a higher percentage of abnormal mammograms that persisted throughout the trial.

An extension of the Heart and Estrogen/Progestin Replacement Trial,[8] an open-label follow-up of a randomized controlled trial of estrogen and progestin therapy in 2,763 women (mean age 67 years) with coronary heart disease, found a nonstatistically significant increase in breast cancer incidence after a mean of 6.8 years of follow-up (relative risk [RR] 1.27, 95% CI 0.84-1.94; absolute-risk increase 4.7-5.9 cases per 1000 person-years). This finding is consistent with the results of the Women's Health Initiative Study (WHI) noted above.

The risk of breast cancer associated with hormone therapy may differ for combination therapy and estrogen-only therapy. In those studies that were able to examine women who were exclusive users of estrogen-only therapy, risks of breast cancer associated with estrogen were lower than those for combination therapy.[9-12] In a case-control study limited to women 65 and older, exclusive use of estrogen only, even for greater than 25 years duration, was not associated with risk of invasive breast cancer; risk did not differ for invasive ductal or lobular cancer or by estrogen receptor status.[11] The estrogen-only WHI found a nearly-statistically significant reduction in breast cancer incidence in the estrogen-only arm compared with placebo (HR 0.77, 95% CI 0.59-1.01; absolute-risk reduction from 33-26 breast cancers per 10,000 person-years). It is not clear whether this finding is a real effect of estrogen only or due to chance.

There is a well-established relationship between exposure to ionizing radiation and the risk of developing breast cancer.[13] Excess breast cancer risk is consistently observed in association with a variety of exposures such as fluoroscopy for tuberculosis and radiation treatments for acne, tinea, thymic enlargement, postpartum mastitis, or Hodgkin’s lymphoma. Although risk is inversely associated with age at radiation exposure, the manifestation of breast cancer risk occurs according to the usual age-related pattern.[14] An estimate of the risk of breast cancer associated with medical radiology puts the figure at less than 1% of the total;[15] however, it has been theorized that certain populations, such as AT (ataxia telangiectasia) heterozygotes, are at increased risk from the usual sources of radiation exposure.[16]

Women treated for Hodgkin’s lymphoma by age 16 may have a subsequent risk of developing breast cancer as high as 35% by age 40.[17] One study suggests that higher doses of radiation (median dose, 40 Gy in breast cancer cases) and treatment between 10 and 16 years of age correspond with higher risk.[17] An earlier study suggests a high level of breast cancer risk in women treated for Hodgkin’s lymphoma, especially those treated before age 15 with radiation to the thorax and/or neck.[18] When radiation therapy was administered after age 14, but before age 30, risk of developing breast cancer was also elevated, but to a lesser degree.[18] Unlike the risk for secondary leukemia, the risk of treatment-related breast cancer did not abate with duration of follow-up, i.e., increased risk persisted more than 25 years after treatment.[17,19,20] In these studies, the great majority (85%-100%) of patients who developed breast cancer did so either within the field of radiation or at the margin.[17-19] A Dutch study examined 48 women who developed breast cancer at least 5 years after treatment for Hodgkin’s disease, compared with 175 matched female Hodgkin’s disease patients who did not. Patients treated with chemotherapy and mantle radiation were less likely to develop breast cancer than those treated with mantle radiation alone, probably because of chemotherapy-induced ovarian suppression (RR = 0.06, 95% CI 0.01-0.45).[21] A collaborative study was performed in 6 centers, including the aforementioned Dutch group. One hundred five women with radiation-associated breast cancer were compared to 266 age-matched and radiation-matched controls. Ovarian radiation was found to exert a similar protective effect as was seen with alkylator chemotherapy. This finding suggests a promotional effect of hormones on breast cells that have sustained radiation-induced mutations.[20]

In theory, breast cancer patients treated with lumpectomy and radiation therapy (L-RT) may be at increased risk for second breast or other malignancies, compared with those treated by mastectomy. Outcomes of 1,029 L-RT patients treated at Yale, however, were compared with 1,387 patients who had mastectomy. After a median follow-up of 15 years, there was no difference in the risk of second malignancies.[22] Further evidence from 3 randomized controlled trials is also reassuring. One report of 1,851 women randomized to total mastectomy, lumpectomy alone, or L-RT showed rates of contralateral breast cancer to be 8.5%, 8.8%, and 9.4%, respectively.[23] Another study of 701 women randomized to radical mastectomy or breast-conserving surgery followed by radiation therapy demonstrated the rate of contralateral breast carcinomas/100 woman-years to be 10.2 vs. 8.7, respectively.[24] The third study compared 25-year outcomes of 1,665 women randomized to 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, with an overall rate of 6%.[25]

Obesity is associated with increased breast cancer risk, especially among postmenopausal women who do not use hormone replacement therapy/hormone therapy. The Women’s Health Initiative Observational Study studied 85,917 women aged 50 to 79 and collected information on weight history as well as known risk factors for breast cancer.[26] Height, weight, and waist and hip circumferences were measured. With a median follow-up of 34.8 months, 1,030 developed invasive breast cancer. Among women who never used hormone replacement therapy/hormone therapy, increased breast cancer risk was associated with weight at entry, body mass index (BMI) at entry, BMI at age 50, maximum BMI, adult and postmenopausal weight change, and waist and hip circumference. Weight was the strongest predictor, with a RR of 2.85 (95% CI 1.81-4.49) for women weighing more than 82.2 kg, compared with those weighing less than 58.7 kg.

Many epidemiologic studies have shown an increased risk of breast cancer associated with alcohol consumption. Individual data from 53 case-control and cohort studies were included in a British meta-analysis.[27] Compared with women who reported no alcohol consumption, the relative risk of breast cancer was 1.32 (95% CI 1.19-1.45, P<.00001) for women consuming 35 to 44 g/day, and it was 1.46 (95% CI 1.33-1.61, P<.00001) for those consuming 45+ g/d. The relative risk of breast cancer increases by about 7% (95% CI 5.5-8.7%, P<.00001) for each 10 g (1 drink) per day. The same result was obtained, even after additional stratification for race, education, family history, age of menarche, height, weight, BMI, breastfeeding, oral contraceptive use, menopausal hormone use, and type and age of menopause. In this same study, smoking had no independent effect on breast cancer risk.

Data from adjuvant breast cancer trials using tamoxifen have shown that tamoxifen not only suppresses the recurrence of breast cancer but also prevents the occurrence of second primary breast cancers in the contralateral breast.[28] Tamoxifen may also have additional favorable effects by maintaining bone density among postmenopausal women with breast cancer.[29-33] Adverse effects include an increased risk of endometrial cancer and an increase in venous thromboembolic events.[34-36]

Observations from adjuvant breast cancer trials were the basis for a large chemoprevention trial (13,388 subjects at elevated risk of breast cancer) for the evaluation of the usefulness of tamoxifen for breast cancer prevention.[37,38] The independent Monitoring Committee for the Breast Cancer Prevention Trial (BCPT) concluded that the strength of the results justified an early conclusion to the trial with announcement of the results. The main finding was a 49% reduction in the incidence of breast cancer among the participants who were randomly assigned to receive tamoxifen. Among the 13,388 participants, after a mean follow-up of about 4 years, 154 cases of invasive breast cancer had developed in the women taking placebo compared with 85 cases of invasive breast cancer in the women taking tamoxifen. A similar reduction in noninvasive breast cancers was observed with 59 cases in the placebo group compared with 31 cases in women taking tamoxifen. 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 and above 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 taking 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 taking placebo.[38]

Three other trials of tamoxifen for primary prevention of breast cancer have been completed.[39-41] Initial analyses from 2 smaller trials, 1 in the United Kingdom [39] and 1 primarily in Italy,[40] showed no protective effect, perhaps because of differences in their target populations and study designs compared with the US 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.[42] Longer follow-up and subgroup analysis in the Italian Trial found a protective effect among women who were taking HRT/HT during the trial, the expected outcome given the mechanism of action of tamoxifen.

The fourth trial of tamoxifen for primary prevention of breast cancer was the International Breast Cancer Intervention Study (IBIS-I). This trial randomized 7,152 women aged 35 to 70 at increased risk of breast cancer to tamoxifen (20 mg/day for 5 years) or placebo groups.[41] 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; absolute reduction from 6.75-4.6 breast cancers per 1000 woman-years). The RR reduction in estrogen-receptor positive (ER+) invasive breast cancer was 31%; there was no reduction in ER-negative cancers. In this trial, but in none of the other tamoxifen trials, there was an excess of all-cause mortality in the tamoxifen group (25 vs. 11, P=.028). The authors believe that this increase was due to chance.

A meta-analysis of the 4 primary prevention trials was performed, finding a 38% reduction in the incidence of breast cancer (no statistically significant heterogeneity).[36] 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 were designed to detect differences in breast cancer mortality, and no differences were found.

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.[43] 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 a subsequent contralateral breast cancer similar to or greater than the risk for women with atypical hyperplasia or lobular carcinoma in situ (LCIS).[44] Five-year rates of all breast cancer (ipsilateral and contralateral) for women with DCIS treated with lumpectomy and radiation are 13.4%, a rate markedly higher than for women with LCIS or atypical hyperplasia.[44] While women with atypical hyperplasia or LCIS were eligible for the BCPT, women with DCIS were not because of competing treatment trials. Thus, a question may arise as to whether or not women with DCIS should consider tamoxifen in order to lower their risk of subsequent breast cancer. 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.[44] 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 that may modulate the production of breast cell growth factors by suppressing ovarian function [45] or changing the endogenous hormonal environment.[46] 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.[47] The Multiple Outcomes of Raloxifene Evaluation (MORE), a randomized, double-blind trial evaluated 7,705 postmenopausal women with osteoporosis from 1994-1998 at 180 clinical centers in the United States. The effect on breast cancer incidence was a secondary endpoint, and therefore should be judged with caution. Raloxifene is still investigational for this use. After a median follow-up of 47 months, the risk of invasive breast cancer decreased by 72%.[48] Breast cancer was reported in 79 women and confirmed in 77. Invasive breast cancer occurred in 39 women on placebo and 22 women randomized to either of the 2 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 on placebo and 11 women on raloxifene. After combining noninvasive and invasive cancer occurrences, the relative risk of breast cancer among women on raloxifene 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 estrogen receptor-positive breast cancer but not estrogen receptor-negative breast cancer. Similar to tamoxifen, raloxifene is associated with an excess risk of hot flashes and thromboembolic events. The risk of venous thromboembolic disease (deep venous thrombosis or pulmonary embolism) was 2.4 times higher in women assigned to the raloxifene groups 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; 5 cases occurred among women on placebo (0.77 cases/1,000 woman-years), 5 among women treated with 60 mg raloxifene (0.77 cases/1,000 woman-years), and 4 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.[49] Of 1,781 women who underwent transvaginal ultrasonography at baseline and had at least 1 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 2 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 more than 5 mm on at least 1 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 3 cases of hyperplasia and 2 cases of endometrial cancer in the placebo group and 3 cases of hyperplasia and 2 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. It is not known if women without osteoporosis would benefit in the same way.[50] Raloxifene is being compared directly to tamoxifen in a randomized trial, called the Study of Tamoxifen and Raloxifene (STAR) to be conducted in 22,000 women by the NSABP.[51]

Another class of agents, commercially available for the treatment of hormone-sensitive breast cancer, may also prevent breast cancer. These 3 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 3 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 3 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.[52] Anastrazole-treated patients had a 7.1% rate of locoregional and distant recurrence versus 8.5% for those receiving 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.[53] 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 randomized 4,742 women who had already received 2 years of adjuvant tamoxifen. Women either continued the tamoxifen or switched to exemestane.[54] 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.

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.[55] 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 using the Gail model for moderate-risk women and for high-risk women, 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.[56] 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.[38]

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.[57-59] 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.

Active exercise may reduce breast cancer risk particularly in young parous women.[60] There are numerous observational studies that have examined the relationship between physical activity and breast cancer risk.[61] 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 over 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 less than normal body weight.[62] In a case-control study of African American women, strenuous recreational physical activity (greater than 7 hours per week), was associated with decreased breast cancer incidence.[63] Until further study results are available, there will be uncertainty about the existence of modifiable breast cancer risks related to alcohol, exercise, and low-fat diet.

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