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This information is produced and provided by the National Cancer Institute (NCI). The information in this topic may have changed since it was written. For the most current information, contact the National Cancer Institute via the Internet web site at http://cancer.gov or call 1-800-4-CANCER.
Note: Separate PDQ summaries on Breast Cancer Screening; Breast Cancer Treatment; Male Breast Cancer Treatment; Breast Cancer Treatment and Pregnancy; and Levels of Evidence for Cancer Screening and Prevention Studies are also available.
Factors Associated With Increased Risk of Breast Cancer
Hormone therapy
Based on solid evidence, combination hormone therapy (HT; estrogen-progestin) 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.
Magnitude of Effect for Combination Therapy: Approximately a 26% increase in incidence of invasive breast cancer; number needed to harm for every 237 patients participating in the Women's Health Initiative (WHI) trial and randomly assigned to the combination HT arm: 1 invasive breast cancer occurred beyond those that happened in the placebo arm of the trial.
Magnitude of Effect for Estrogen Only: Cannot determine because of mixed evidence.
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.
Magnitude of Effect: Variable, but approximately a sixfold increase in incidence overall.
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 reducing weight would decrease the risk of breast cancer.
Magnitude of Effect: The WHI 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 relative risk (RR) was 2.85 (95% confidence interval [CI], 1.81–4.49).
Based on solid evidence, exposure to alcohol is associated with an increased breast cancer risk in a dose-dependent fashion. It is uncertain whether decreasing alcohol exposure would decrease the risk of breast cancer.
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.
Major inheritance susceptibility
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.
Factors Associated With Decreased Risk of Breast Cancer
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.
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 those who give birth after age 35 years.
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.[1]
Interventions 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. The effects observed for tamoxifen show persistence several years after discontinuing active treatment.
Magnitude of Effect: Treatment with tamoxifen-reduced breast cancer by about 50%. Treatment with raloxifene has a similar effect on reduction of invasive breast cancer but appears to be less effective for prevention of noninvasive tumors.
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. Many of these risks, notably pulmonary embolism and deep venous thrombosis, are reduced after discontinuing active treatment with tamoxifen. Based on fair evidence, raloxifene also increases venous pulmonary embolism and deep venous thrombosis but not endometrial cancer.
Magnitude of Effect: 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.
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 of breast cancer.
Magnitude of Effect: After a median follow-up of 35 months, women aged 35 years and older who had at least one risk factor (e.g., women aged 60 years and older or those having a Gail 5-year risk >1.66% or ductal carcinoma in situ with mastectomy) and who took 25 mg of exemestane daily were less likely to be diagnosed with invasive breast cancer (hazard ratio [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 (number needed to treat [NNT], about 100).
Aromatase inhibitors or inactivators: Harms
Based on fair evidence because of a relatively short follow-up from a single RCT of 4,560 women over 35 months, exemestane is associated with slightly increased hot flashes (absolute increase, 8%) and fatigue (absolute increase, 2%), but not with fractures, osteoporosis, or cardiovascular (CV) events compared with placebo.
Magnitude of Effect: There was a small increase in adverse effects in the exemestane group compared with placebo, primarily in hot flashes (absolute increase, 8%) and fatigue (absolute increase, 2%). There was no difference in the occurrence of fractures or CV events.
Prophylactic mastectomy: Benefits
Based on solid evidence, bilateral prophylactic mastectomy reduces the risk of breast cancer in women with a strong family history.
Magnitude of Effect: Risk is reduced as much as 90%, but published study designs may have produced an overestimate.
Prophylactic mastectomy: Harms
Based on fair evidence, physical and psychological effects include anxiety, depression, and impaired body image.
Magnitude of Effect: Of the women who chose to have a prophylactic mastectomy, usually for cosmesis, 6% were dissatisfied with their decision. Regrets about mastectomy were fewer in 185 women who opted not to have reconstruction than in 111 women who chose to have it.[3]
Prophylactic oophorectomy or ovarian ablation: Benefits
Based on solid evidence, prophylactic oophorectomies in women with BRCA gene mutations document lower breast cancer incidence. Similarly, oophorectomy or ovarian ablation is associated with decreased breast cancer incidence in normal women or in those who received thoracic irradiation.
Magnitude of Effect: Breast cancer incidence is decreased by 50%, but published study designs may have produced an overestimate.
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.
Incidence and mortality
With an estimated 226,870 cases expected, breast cancer will be the most frequently diagnosed nonskin malignancy in U.S. women in 2012.[1] In the same year, breast cancer will kill an estimated 39,510 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 2,190 new cases will be diagnosed in 2012.[1] Despite a prior long-term trend of gradually increasing breast cancer incidence, data from the Surveillance, Epidemiology, and End Results Program show a decrease in breast cancer mortality of 1.9% per year from 1998 to 2007.[2]
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.
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.[3] An accumulation of genetic changes is thought to correspond to the phenotypic changes associated with the evolution of malignancy. The carcinogenesis sequence is viewed histologically as starting with tissue of normal appearance followed by changes that lead to hyperplasia and dysplasia, the most severe forms of which are difficult to distinguish from carcinoma in situ.[4]
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.[5,6,7]
Endogenous estrogen
Many of the risk factors for breast cancer, including age at menarche, first birth, and menopause, suggest hormonal influences for the development of the disease. Estrogen and progestin cause growth and proliferation of breast cells that may work through growth factors such as transforming growth factor (TGF)-alpha.[8] Women who develop breast cancer tend to have higher endogenous estrogen and androgen levels.[9]
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.[10,11,12,13] The removal of one ovary also reduces the risk of breast cancer, but to a lesser degree than the removal of both ovaries.[14]
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.[13,15,16] In one study, women who experienced a first full-term pregnancy before age 20 years were half as likely to develop breast cancer as nulliparous women or women who underwent a first full-term pregnancy at age 35 years or older.[17,18] Age at menarche also affects breast cancer risk. Women who experienced menarche at age 11 years or younger have about a 20% greater chance of developing breast cancer than women who experienced menarche at age 14 years or older.[19] Women who experience late menopause also have increased risk. Reproductive risk factors may interact with more predisposing genotypes. In the Nurses' Health Study,[20] the associations between age at first birth, menarche, and menopause and the development of breast cancer were observed only among women without a family history of breast cancer in a mother or sister. Breast-feeding is associated with a decreased risk of breast cancer.[21,22]
A number of studies suggest that endogenous estrogen and androgen levels are higher in women who develop breast cancer than in women who do not.[9,23,24] Methods shown to decrease endogenous estrogen include maintenance of ideal body weight (refer to the Obesity section of this summary for more information), adoption of a low-fat diet in postmenopausal women,[25] and moderate exercise in adolescent girls.[26] Whether such interventions will decrease breast cancer risk is worthy of study.
Genetic mutations
The inherited genetic profile of an individual influences susceptibility to mutagens and growth factors, which initiate or promote the carcinogenic process. Known genetic syndromes related to specific aberrant alleles account for approximately 5% of breast cancers. Identifying high-risk genes provides insight into breast cancer etiology and allows the development of preventive interventions for affected populations. (Refer to the PDQ summary on Genetics of Breast and Ovarian Cancer for more information.)
Women who inherit a deleterious mutation in BRCA1[27,28] or BRCA2[29] have an increased lifetime risk of breast cancer (which occurs at a younger age), ovarian cancer, and possibly colon cancer. Deleterious BRCA2 mutations are less common than BRCA1[30] mutations; BRCA2 mutations are also associated with male breast cancer, prostate cancer, pancreatic cancer, and lymphomas.[31]
Exogenous hormone therapy (HT) after menopause was shown to be associated with increased breast cancer risk in 1997.[32]
The Heart and Estrogen/Progestin Replacement Study published in 2002 [33] included an open-label follow-up of a randomized controlled trial (RCT) of estrogen and progestin therapy in 2,763 women (mean age, 67 years) who had coronary heart disease. After a mean follow-up of 6.8 years, the relative risk [RR] for breast cancer was 1.27 (95% confidence interval [CI], 0.84–1.94). Though not statistically significant, the RR estimate is consistent with the much larger Women's Health Initiative (WHI) study.
The WHI-combined HT trial was terminated early (in July 2002) because the overall health risks exceeded benefits.[34]
The randomized trial component of the WHI investigated the effect of hormones and dietary interventions on breast cancer risk.[34] Women aged 50 to 79 years who had intact uteri were randomly assigned to receive combined conjugated estrogen with continuous progestin (n = 8,506) or placebo (n = 8,102). Breast cancer risk was increased with combined HT, with a hazard ratio (HR) of 1.24 (95% CI, 1.02–1.50), consistent with prior reports from observational studies. The trial was terminated early because overall health risks, including cardiovascular disease and thrombotic events, exceeded benefit.[34] HT was also associated with a higher percentage of abnormal mammograms.[35] The excess risk was observed in all subgroups of women for invasive breast cancer but not for in situ breast cancer. The combined HT-related cancers had similar grade, histology, and expression of estrogen receptor (ER), progesterone receptor, and HER2/neu compared with those related to placebo, with a trend toward larger size and higher incidence of lymph node metastases.[36] Extended follow-up (mean follow-up of 11 years) of these women showed higher breast cancer-specific mortality for the HT group compared with those randomly assigned to receive placebo (25 vs. 12 deaths, 0.03% vs. 0.01% per year, HR = 1.95; 95% CI, 1.0–4.04; P = .049).
The WHI Estrogen-Alone Trial was a double-masked, placebo-controlled randomized clinical trial conducted among women who have had a hysterectomy. Women aged 50 to 79 years (N = 10,739) were randomly assigned to receive either conjugated equine estrogen (CEE) or placebo. Estrogen-only preparations should only be considered among women who have had a hysterectomy since unopposed estrogen increases the risk of uterine cancer. Like the WHI combined-HT trial, this trial was stopped early because of an increased risk of stroke and no evidence of benefit as measured by a global index of risks and benefits.[37,38] After an average of 6.8 years of follow-up, the incidence of breast cancer was lower in the group receiving CEE compared with placebo but the difference was not statistically significant (HR = 0.77; 95% CI, 0.59–1.01; 26 vs. 33 cases of invasive breast cancer per 10,000 person-years [annualized rate of 0.26% vs. 0.33%], respectively). For the global index of risks and benefits (based on outcomes of stroke, pulmonary embolus, breast cancer, colorectal cancer, hip fractures, and death), there was a nonstatistically significant excess of two events per 10,000 person-years.[37] An extended follow-up for a median of 11.8 years was conducted with 78% of the trial participants consenting to take part.[38,39] Characteristics among those in the extended follow-up who were randomly assigned to receive active intervention with CEE or placebo were similar, except for slight imbalances in history of prior breast biopsy (19.8% among the CEE group and 22.3% among the placebo group) and prior hormone use (48.9% among the CEE group and 50.4% among the placebo group). At the end of the follow-up period, 151 cases of breast cancer occurred among the CEE group (0.27% per year) compared with 199 cases of breast cancer among the placebo group (0.35% per year) (HR = 0.77; 95% CI, 0.62–0.95).[38,39] Breast cancer mortality was statistically significantly lower in the CEE group (6 deaths, 0.009% per year) than in the placebo group (16 deaths, 0.024% per year) (HR = 0.37; 95% CI, 0.13–0.91). All-cause mortality was also lower in the CEE group (0.046% per year) than in the placebo group (0.076% per year) (HR = 0.62; 95% CI 0.39–0.97). Following discontinuation of CEE, the risk of stroke decreased in the postintervention period. Over the entire follow-up period, there was no increased or decreased risk of coronary heart disease, deep vein thrombosis, stroke, hip fracture, or colorectal cancer.[38] Among the subset of women in the WHI trial who initiated estrogen-only therapy within the first 5 years of onset of menopause, neither an excess nor decreased risk of developing breast cancer was observed (HR = 1.06; 95% CI, 0.74–1.51).
The evidence from randomized trials should be put into context with the evidence from observational studies that suggests that there is an increased risk of developing breast cancer associated with estrogen-only postmenopausal HT. The Million Women Study [40] observed no increased risk of breast cancer among women whose first use of estrogen-only therapy was 5 or more years after menopause, but the risk was statistically significantly higher among women initiating therapy within 5 years of menopause (RR = 1.43; 95% CI, 1.36–1.49). Among that group, the risk increased with duration of hormone use. Overall, risks associated with estrogen-only HT were lower than those observed for combined estrogen-progestin HT.[40] Estrogen-only therapy, even for more than 25 years duration, was not associated with invasive breast cancer in a case-control study of women aged 65 years and older.[41] The Collaborative Group on Hormonal Factors in Breast Cancer, a reanalysis of data from 52 observational studies of HT and breast cancer, had information on specific hormonal preparations for 39% of eligible women and most of these women reported use of estrogen-alone preparations.[32] The combined analysis showed no marked variation between estrogen-only preparations and combined HT.[32] However, the collaborative analysis, overall, provided limited information on estrogen-only versus combination estrogen-progestin therapy. Factors that may explain the disparate findings of the association between estrogen-only use and the risk of developing breast cancer, which were observed in the clinical trial and observational studies, include an imbalance in the prevalence of routine screening between users and nonusers of hormones, and gap time between the onset of menopause and the first use of postmenopausal hormone therapy.[42,43]
Following publication of the WHI results, HT use dropped dramatically in the United States and elsewhere. Follow-up of participants on the combined HT arm demonstrated a rapid decrease in the elevated breast cancer risk of therapy within 2 years, despite similar rates of mammography screening.[44] Analysis of changes in breast cancer rates in the United States observed a sharp decline in breast cancer incidence rates from 2002 to 2003, following the release of the WHI trial data among women aged 50 years and older.[45,46] The decreased incidence is primarily the result of changes in the incidence of ER–positive breast cancer [45], which provides additional support for the causal association between combined HT and the risk of breast cancer. Similarly, in multiple countries where the prevalence of HT use was high, breast cancer rates decreased in a similar time frame, coincident with changes in prescribing patterns and/or reported prevalence of use. [47,48,49] A study among women receiving regular mammography screening supports that the observed sharp decline from 2002 to 2003 in breast cancer incidence was primarily caused by withdrawal of HT rather than declines in mammography rates.[50] Since the decline in breast cancer incidence noted from 2002 to 2003, rates in the United States have stabilized.[50,51] These observations support the causal effect of combined HT on breast cancer incidence and modification of breast cancer risk through either withdrawal of HT or never having used HT.
Ionizing radiation exposure
A well-established relationship exists between exposure to ionizing radiation and the risk of developing breast cancer.[52] Excess breast cancer risk is consistently observed in association with a variety of exposures such as fluoroscopy for tuberculosis and radiation treatments for acne, tinea, thymic enlargement, postpartum mastitis, or Hodgkin lymphoma. Although risk is inversely associated with age at radiation exposure, the manifestation of breast cancer risk occurs according to the usual age-related pattern.[53] An estimate of the risk of breast cancer associated with medical radiology puts the figure at less than 1% of the total.[54] However, it has been theorized that certain populations, such as AT heterozygotes, are at an increased risk of breast cancer from radiation exposure.[55] A large cohort study of women who carry mutations of BRCA1 or BRCA2 concluded that chest x-rays increase the risk of breast cancer still further (RR = 1.54; 95% CI, 1.1–2.1), especially for women who were x-rayed before age 20 years.[56]
Women treated for Hodgkin lymphoma by age 16 years may have a subsequent risk, which is as high as 35%, of developing breast cancer by age 40 years.[57,58] One study suggests that higher doses of radiation (median dose, 40 Gy in breast cancer cases) and treatment received between the ages of 10 and 16 years corresponds with higher risk.[57] Unlike the risk for secondary leukemia, the risk of treatment-related breast cancer did not abate with duration of follow-up; that is, increased risk persisted more than 25 years after treatment.[57,59,60] In these studies, most patients (85%–100%) who developed breast cancer did so either within the field of radiation or at the margin.[57,58,59] A Dutch study examined 48 women who developed breast cancer at least 5 years after treatment for Hodgkin disease and compared them with 175 matched female Hodgkin disease patients who did not develop breast cancer. Patients treated with chemotherapy and mantle radiation were less likely to develop breast cancer than those treated with mantle radiation alone, possibly because of chemotherapy-induced ovarian suppression (RR = 0.06; 95% CI, 0.01–0.45).[61] Another study of 105 radiation-associated breast cancer patients and 266 age-matched and radiation-matched controls showed a similar protective effect for ovarian radiation.[60] These studies suggest that ovarian hormones promote the proliferation of breast tissue with radiation-induced mutations.[60]
The question arises whether breast cancer patients treated with lumpectomy and radiation therapy (L-RT) are at increased risk for second breast malignancies or other malignancies compared with those treated by mastectomy. Outcomes of 1,029 L-RT patients were compared with 1,387 patients who underwent mastectomies. After a median follow-up of 15 years, there was no difference in the risk of second malignancies.[62] Further evidence from three RCTs is also reassuring. One report of 1,851 women randomly assigned to undergo total mastectomy, lumpectomy alone, or L-RT showed rates of contralateral breast cancer to be 8.5%, 8.8%, and 9.4%, respectively.[63] Another study of 701 women randomly assigned to undergo radical mastectomy or breast-conserving surgery followed by radiation therapy demonstrated the rate of contralateral breast carcinomas per 100 woman-years to be 10.2 versus 8.7, respectively.[64] The third study compared 25-year outcomes of 1,665 women randomly assigned to undergo radical mastectomy, total mastectomy, or total mastectomy with radiation. There was no significant difference in the rate of contralateral breast cancer according to the treatment group, and the overall rate was 6%.[65]
Obesity is associated with increased breast cancer risk, especially among postmenopausal women who do not use HT. The WHI observational study observed 85,917 women aged 50 to 79 years and collected information on weight history as well as known risk factors for breast cancer.[66] Height, weight, and waist and hip circumferences were measured. With a median follow-up of 34.8 months, 1,030 of the women developed invasive breast cancer. Among the women who never used HT, increased breast cancer risk was associated with weight at entry, body mass index (BMI) at entry, BMI at age 50 years, maximum BMI, adult and postmenopausal weight change, and waist and hip circumferences. Weight was the strongest predictor, with a RR of 2.85 (95% CI, 1.81–4.49) for women weighing more than 82.2 kg, compared with those weighing less than 58.7 kg.
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.[67] Compared with women who reported no alcohol consumption, the RR of breast cancer was 1.32 (95% CI, 1.19–1.45; P < .001) for women consuming 35 g to 44 g of alcohol per day and 1.46 (95% CI, 1.33–1.61; P < .001) for those consuming at least 45 g of alcohol per day. The RR of breast cancer increases by about 7% (95% CI, 5.5%–8.7%; P < .001) for each 10 g of alcohol (i.e., one drink) consumed per day. The same result was obtained, even after additional stratification for race, education, family history, age at menarche, height, weight, BMI, breast-feeding, oral contraceptive use, menopausal hormone use and type, and age at menopause.
Active exercise may reduce breast cancer risk, particularly in young parous women.[68]Numerous observational studies have examined the relationship between physical activity and breast cancer risk.[69] Most of these studies have shown an inverse relationship between level of physical activity and breast cancer incidence. The average RR reduction is reportedly 30% to 40%. However, it is not known to what degree, if at all, the observed association is to the result of 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.[70] In a case-control study of African American women, strenuous recreational physical activity (>7 hours per week) was associated with decreased breast cancer incidence.[71]
Interventions Associated With Decreased Risk of Breast Cancer: Benefits and Harms
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.[72] Tamoxifen also maintains bone density among postmenopausal women with breast cancer.[73,74,75,76,77] Adverse effects include hot flashes, venous thromboembolic events, and endometrial cancer.[78,79,80]
These adjuvant trial results were the basis for the Breast Cancer Prevention Trial (BCPT) that randomly assigned 13,388 patients at elevated risk of breast cancer to receive tamoxifen or placebo.[81,82] The independent Endpoint Review, Safety Monitoring, and Advisory Committee closed the study early because of a 49% reduction in the incidence of breast cancer for tamoxifen-treated versus placebo-treated participants. After about 4 years of follow-up, placebo-treated women had 154 cases of invasive breast cancer compared with 85 cases in women who received tamoxifen. Noninvasive breast cancers were also reduced, with 59 cases in the placebo group versus 31 in the tamoxifen-treated group. Another benefit of tamoxifen use was a reduction in fractures, with 47 occurring in the tamoxifen-treated women compared with 71 in the placebo group. These benefits were accompanied by an increased incidence of endometrial cancer and thrombotic events in women aged 50 years and older. There were 33 endometrial cancers and 99 vascular events (including 17 cases of pulmonary embolism and 30 cases of deep vein thrombosis) in women who received tamoxifen compared with 14 endometrial cancers and 70 vascular events (including 6 cases of pulmonary embolism and 19 cases of deep vein thrombosis) in women who received a placebo.[82]
An update of the BCPT results after 7 years of follow-up demonstrates results similar to those in the initial report.[83] Follow-up was more complete for the tamoxifen group than for the placebo group because of a greater drop-out rate among women in the placebo group after early termination of the study. In addition, women who received a placebo were given the option of taking tamoxifen or participating in the Study of Tamoxifen and Raloxifene (STAR), and 32% did so. Breast cancer rates decreased among women in the placebo group from year 6 to year 7 of follow-up. A statistically significant RR of 43% for invasive breast cancer persisted at follow-up despite the addition of women to the placebo arm. The rate of invasive breast cancer among women in the placebo group was 6.29 per 1,000 women versus 3.59 per 1,000 women for women in the tamoxifen group, for a risk reduction of 0.27%. Benefits and risks of tamoxifen were not significantly different from those in the original report, with persistent benefit of reductions in fracture and persistent risks of endometrial cancer, thrombosis, and cataract surgery. No overall mortality benefit was observed after 7 years of follow-up (RR = 1.10; 95% CI, 0.85–1.43).
Other trials of tamoxifen for primary prevention of breast cancer have been completed.[84,85,86] Initial analyses from two smaller trials, one in the United Kingdom (U.K.) [84] and one primarily in Italy,[85] showed no protective effect, perhaps because of differences between target populations and study designs and those in the U.S. study. The U.K. study focused on 2,471 women at increased breast cancer risk because of their family history of breast and/or ovarian cancer; about 36% of participants were from families that had a greater than 80% chance of carrying a breast cancer susceptibility gene. After a median follow-up of nearly 6 years, no protective effect of tamoxifen was detected (RR = 1.06). Subsequent follow-up shows that at a median of 13 years, there was a statistically nonsignificant reduction in breast cancer risk in the tamoxifen arm compared with the placebo arm (HR = 0.78; 95% CI, 0.58–1.04). However, risk of ER–positive breast cancer was significantly reduced in the treatment arm (HR = 0.61; 95% CI, 0.43–0.86), an effect noted predominantly in the posttreatment period.[87] The Italian study focused on 5,408 women who had undergone hysterectomy and who were described as "low-to-normal risk" women. At the initial report, after a median follow-up of nearly 4 years, no protective effect of tamoxifen was observed. Longer follow-up and subgroup analysis in the Italian trial found a protective effect of tamoxifen among women at high risk for hormone receptor–positive breast cancer (RR = 0.24; 95% CI, 0.10–0.59) and among women who were taking HT during the trial (RR = 0.43; 95% CI, 0.20–0.95).[88,89]
The last trial of tamoxifen for primary prevention of breast cancer was the International Breast Cancer Intervention Study (IBIS-I). This trial randomly assigned 7,152 women aged 35 to 70 years who were at increased risk of breast cancer to receive tamoxifen (20 mg/day for 5 years) or placebo.[86] After a median follow-up of 50 months, 32% fewer women (95% CI, 8%–50%) in the tamoxifen group than in the placebo group had developed breast cancer (invasive plus carcinoma in situ with an absolute reduction from 6.75 to 4.6 breast cancers per 1,000 woman-years). The RR reduction in ER–positive 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), which the authors attributed to chance. The prophylactic effect of tamoxifen on breast cancer persisted after active treatment, with 27% fewer women in the tamoxifen arm developing breast cancer than did women in the placebo arm (142 vs. 195 cases, respectively; RR = 0.73, 95% CI, 0.58–0.91) over the full study period after a further 46 months of median follow-up.[90] In this report, most of the additional follow-up time accrued after the discontinuation of active treatment in the treatment arm.
A meta-analysis of the early report of these primary prevention trials was performed, and its findings showed a 38% reduction in the incidence of breast cancer without statistically significant heterogeneity.[80] ER–positive tumors were reduced by 48%. Rates of endometrial cancer were increased (consensus RR = 2.4; 95% CI, 1.5–4.0), as were venous thromboembolic events (RR = 1.9; 95% CI, 1.4–2.6). None of these primary prevention trials was designed to detect differences in breast cancer mortality.
Treatment decisions are complex and need to be individualized, weighing estimates of a woman's chance of reducing breast cancer and fracture risks against the chance of developing detrimental side effects, some of which may be life threatening. The risks and benefits of taking tamoxifen have been estimated for women according to age, race, and risk group based on the results of the BCPT, additional risk/benefit analyses, and review of the literature.[91] Because adverse effects of tamoxifen increase with age, tamoxifen is most beneficial for women younger than 50 years who have an increased risk of developing breast cancer. Overall, the net benefit or risk depends on age, whether a woman has a uterus, and her baseline risk of breast cancer.
Women with a history of ductal carcinoma in situ (DCIS) are at increased risk (3.4%) for contralateral breast cancer but were not eligible for the BCPT because of competing treatment trials. In a trial of DCIS treatment, however, 13.4% of women treated with lumpectomy and radiation had breast cancer events within approximately 6 years, compared with 8.2% of those who also received tamoxifen.[92] The National Surgical Adjuvant Breast and Bowel Project (NSABP) B-24 RCT evaluated the added benefit of tamoxifen to lumpectomy and radiation therapy for women with DCIS.[92] 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 [93] or changing the endogenous hormonal environment.[94] 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.[95] The Multiple Outcomes of Raloxifene Evaluation (MORE), a randomized, double-blind trial, evaluated 7,705 postmenopausal women with osteoporosis from 1994 to 1998 at 180 clinical centers in the United States. The effect on breast cancer incidence was a secondary endpoint and therefore should be judged with caution. After a median follow-up of 47 months, the risk of invasive breast cancer decreased by 72%.[96] Breast cancer was reported in 79 women and confirmed in 77 women. Invasive breast cancer occurred in 39 women treated with placebo and in 22 women who were randomly assigned to either of the two raloxifene arms (raloxifene 120 mg daily or raloxifene 60 mg; RR = 0.25; 95% CI, 0.17–0.45; 4.7–1.3 invasive breast cancers per 1,000 woman-years in the placebo and combined-treatment groups, respectively). DCIS occurred in five women treated with a placebo and in 11 women treated with raloxifene. After combining noninvasive and invasive cancer occurrences, the RR of breast cancer among women in the raloxifene group was 0.38 (95% CI, 0.24–0.58; 5.3–1.9 breast cancers per 1,000 woman-years in the placebo and combined-treatment groups, respectively). As with tamoxifen, raloxifene reduced the risk of ER–positive breast cancer but not ER–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 compared with the placebo group. One woman (in the 60-mg raloxifene group) died from pulmonary embolism. There was little difference in the rate of venous thromboembolic disease between the 60-mg and 120-mg groups (3.32–3.63 events per 1,000 woman-years, respectively). No excess risk of endometrial cancer was observed after 47 months of follow-up; five cases occurred among women on placebo (0.77 cases per 1,000 woman-years), five cases among women treated with 60 mg of raloxifene (0.77 cases per 1,000 woman-years), and four cases among women treated with 120 mg of raloxifene (0.60 cases per 1,000 woman-years). Raloxifene did not increase the risk of endometrial hyperplasia.[97] Of 1,781 women who underwent transvaginal ultrasonography at baseline and had at least one follow-up test, endometrial thickness increased by an average of 0.01 mm in the raloxifene groups and decreased by 0.27 mm in the placebo group after 3 years of follow-up (P < .01 for the difference between the two groups). Sixty participants (10.1%) in the placebo group and 168 women (14.2%) in the raloxifene groups (P = .02) had endometrial thickness that was greater than 5 mm on at least one follow-up ultrasound. Among the 196 women who still had a uterus (48 in the placebo group and 148 in the raloxifene group), there were three cases of hyperplasia and two cases of endometrial cancer in the placebo group and three cases of hyperplasia and two cases of endometrial cancer in the combined raloxifene group. Subgroup analyses after 4 years of follow-up suggest that, among women who have osteoporosis, raloxifene reduces breast cancer incidence for both women at higher and lower risk of developing breast cancer.
An extension of the MORE study, the Continuing Outcomes Relevant to Evista (CORE) study, continued studying about 80% of MORE participants in their randomized groups for 4 years beyond the original 4 years of MORE. Although there was a median 10-month gap between the two studies and only about 55% of women were adherent to their assigned medications, the raloxifene group continued to experience a lower incidence of invasive breast cancer. As in MORE, this effect resulted from a reduction in ER–positive but not ER–negative invasive breast cancer. There was no reduction in noninvasive breast cancer. The overall reduction in invasive breast cancer during the 8 years of MORE and CORE was 66% (HR = 0.34; 95% CI, 0.22–0.50); the reduction for ER–positive invasive breast cancer was 76% (HR = 0.24; 95% CI, 0.15–0.40).[98]
The Raloxifene Use for the Heart trial was a randomized, placebo-controlled trial to evaluate the effects of raloxifene on incidence of coronary events and invasive breast cancer. Similar to the MORE and CORE studies, raloxifene reduced the risk of invasive breast cancer (HR = 0.56; 95% CI, 0.38–0.83). The annualized rate of invasive breast cancer in the raloxifene group was 0.20% compared with 0.29% in the placebo group. Raloxifene did not reduce the risk of ER–negative breast cancer or noninvasive breast cancer. The annualized rate of noninvasive breast cancer in the raloxifene group was 0.04% compared with 0.02% in the placebo group.[99]
STAR (NSABP P-2) compared tamoxifen and raloxifene in 19,747 high-risk women during a mean of 3.9 years of follow-up. The primary outcome measure was breast cancer incidence, which was approximately the same for invasive cancer, but favored tamoxifen for noninvasive cancer. Adverse events of uterine cancer, venous thrombolic events, and cataracts were more common in tamoxifen-treated women, and there was no difference in ischemic heart disease events, strokes, or fractures.[100] Treatment-associated symptoms of dyspareunia, musculoskeletal problems, and weight gain favored tamoxifen, whereas vasomotor flushing, bladder control symptoms, gynecologic symptoms, and leg cramps favored raloxifene.[101]
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. Anastrozole (Arimidex) and letrozole (Femara) inhibit aromatase activity, whereas exemestane (Aromasin) inactivates the enzyme. All three drugs have similar side effects, infrequently causing fatigue, arthralgia, and myalgia. Bone mineral density may be decreased, and fracture rate is increased, possibly because of the decreased bone density.
All three drugs decrease the incidence of new breast cancers in women with a history of breast cancer. The Arimidex, Tamoxifen, Alone or in Combination (ATAC) trial compared anastrozole, tamoxifen, and the combination when used as an adjuvant HT after treatment of the primary breast cancer.[102] Anastrozole-treated patients had a 7.1% rate of locoregional and distant recurrence versus 8.5% for those treated with tamoxifen and 9.1% for the combination. A more impressive result was the decreased rate of primary contralateral breast cancers (0.4% vs. 1.1% vs. 0.9%). Another trial analyzed the use of letrozole versus placebo in 5,187 women with breast cancer, following 5 years of treatment with adjuvant tamoxifen.[103] 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.[104] After 2.4 years' median follow-up, the women assigned to receive exemestane had a decreased risk of local or metastatic recurrence and a decreased risk of new primary contralateral breast cancer (9 vs. 20).
An RCT has reported the effect of aromatase inhibitors in preventing invasive breast cancer among women who have no history of breast cancer. In this study, 4,560 women aged 35 years and older who had at least one risk factor (e.g., women aged 60 years and older or those having a Gail 5-year risk >1.66% or a history of DCIS with mastectomy) were randomly assigned to receive exemestane 25 mg daily or a placebo. After 35 months median follow-up, 32 women of the 2,275 in the placebo group had been diagnosed with invasive breast cancer, compared with 11 women in the exemestane group (HR, 0.35; 95% CI, 0.18–0.70; NNT, about 100 for 35 months). There was a small increase in adverse effects in the exemestane group compared with the placebo group, primarily in hot flashes (increase, 8%) and fatigue (increase, 2%). There was no difference in the occurrence of fractures or cardiovascular events.[105] A second trial (IBIS-2) is under way.
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.[106] Most women in this retrospective series (90%) had undergone subcutaneous rather than total mastectomy, which is the procedure of choice for maximum breast tissue removal. Median follow-up after surgery was 14 years. All women included in the report had some family history of cancer and were classified as high risk or moderate risk for breast cancer based on the pattern of breast cancer in the family. Expected cases of breast cancer were estimated for moderate- and high-risk women using the Gail model and the observed rates of breast cancer among sisters of the probands. The reduction in risk for moderate-risk women was 89%; for high-risk women, the reduction ranged from 90% to 94% depending on the method used to calculate expected rates of breast cancer. The reduction in risk of death from breast cancer ranged from 100% among moderate-risk women to 81% among high-risk women. Information on BRCA1 or BRCA2 mutation status was not known. Although this study provides the best evidence available to date that prophylactic surgery offers benefits despite the fact that some breast tissue remains postsurgery, some factors may bias the estimate of benefit.[107] Criteria used to classify women at high risk would include women from families misclassified as having an autosomal-dominant inherited pattern and women from inherited-syndrome families who are not at high risk because they did not inherit the susceptibility genotype. These factors may tend to overestimate the benefits of prophylactic surgery. Most of the women, however, who underwent prophylactic surgery would never have gone on to develop breast cancer. Thus, many were treated for the few who truly benefited by having their breast cancer prevented. Among the 425 moderate-risk women who had prophylactic mastectomy, the estimated number of breast cancer cases expected to occur was 37.4; among the 214 high-risk women, the estimates ranged from 30.0 to 52.9, depending on the model used to estimate breast cancer occurrence. Thus, bilateral prophylactic mastectomy as an option for women should be considered in association with cancer risk assessment and counseling regarding all the available preventive options, which now include tamoxifen as a preventive agent.[82]
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.[108] A higher dissatisfaction rate occurred among women who chose reconstruction over those who did not.[109]
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 mutation carriers who did not undergo prophylactic oophorectomy.[110,111,112] The reported reductions in RR were approximately 50%. These observational studies, however, are confounded by selection bias, family relationships between patients and controls, indications for oophorectomy, and inadequate information about hormone use. A prospective cohort study has confirmed a reduction in breast cancer risk by about 50% with prophylactic oophorectomy, and a greater reduction in BRCA2 mutation carriers than in BRCA1 carriers.[113]
These findings are similar to those for women who undergo castration for nononcologic diagnoses. Women treated with thoracic radiation who undergo radiation therapy or chemotherapy, which often results in ovarian ablation, also have similar findings.
A multicenter phase III RCT of fenretinide versus no treatment was performed in 2,867 women who received local therapy for stage 0 (DCIS) or stage I (T1–T2, N0, M0; T = tumor, N = node, M = metastasis) breast cancer. An analysis at 8 years showed no difference in contralateral or ipsilateral breast cancer, but a post hoc analysis revealed differential effects for premenopausal and postmenopausal women.[114] A subsequent analysis at 15 years of the 1,739 women enrolled at the organizing center confirmed the beneficial effect in premenopausal women, reducing both contralateral and ipsilateral cancers, HR = 0.62 (95% CI, 0.46–0.83). This beneficial effect was age dependent, with the youngest women achieving the most benefit.[115] Although the daily fenretinide 200 mg was withheld for 3 days each month, there was a cumulative incidence of low-grade dark adaptation (i.e., night blindness) and dermatologic disorders. As with any vitamin A analog, women taking this drug should avoid pregnancy because of potential teratogenic effects.
Factors of Unproven or Disproven Association
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.[116,117,118,119,120,121]
A meta-analysis of women from 53 studies in 16 countries with liberal abortion laws was performed.[122] Analyses were performed separately on 44,000 women with breast cancer who had information on abortion collected prospectively (i.e., 13 studies) versus 39,000 women with breast cancer from whom information was collected retrospectively (i.e., 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.[122]
Oral contraceptives
Oral contraceptives have been associated with a small increased risk of breast cancer in current users that diminishes over time.[123] A well-conducted case-control study did not observe an association between breast cancer risk and oral contraceptive use for every use, duration of use, or recency of use.[124]
Another case-control study found no increased risk of breast cancer associated with the use of injectable or implantable progestin-only contraceptives in women aged 35 to 64 years.[125]
Environmental factors
Whether occupational, environmental, or chemical exposures have an effect on breast cancer risk is controversial. Although some findings suggest that organochlorine exposures, such as those associated with insecticides, might be associated with an increase in breast cancer risk,[126,127] other case-control and nested case-control studies do not.[128,129,130,131,132,133] Studies reporting positive associations have been inconsistent in the identification of responsible organochlorines. Some of these substances have weak estrogenic effects, but their effect on breast cancer risk remains unproven. The use of dichloro-diphenyl-trichloroethane was banned in the United States in 1972, and the production of polychlorinated biphenyls was stopped in 1977.
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.[134] 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.[135] A randomized controlled dietary modification study was undertaken among 48,835 postmenopausal women aged 50 to 79 years who were also enrolled in the WHI. The intervention promoted a goal of reducing total fat intake by 20%, using five servings per day of vegetables and fruit and six servings per day of grains. The intervention group was successful in reducing fat intake by approximately 10% for more than 8.1 years of follow-up, and the group was found to have lower estradiol and lower gamma-tocopherol levels, but no weight loss was shown. The incidence of invasive breast cancer was slightly lower in the intervention group, with an HR of 0.91 (95% CI, 0.83–1.01).[136] 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.[137] Likewise, there was no benefit derived from the low-fat diet for all cancer mortality, overall mortality, or cardiovascular disease.[138]
Fruit and vegetable consumption has been examined for any protective effect against breast cancer.[139] A pooled analysis of adult dietary data from eight cohort studies, which included 351,823 women in whom 7,377 incident cases of breast cancer occurred, provides little support for an association.[140] When examining the dietary data treated as a continuous variable (based on grams of intake per day), there was no association with breast cancer. Comparing highest to lowest quartiles of intake, the pooled multivariate RRs of breast cancer were 0.93 (95% CI, 0.86–1.00) for total fruits, 0.96 (95% CI, 0.89–1.04) for total vegetables, and 0.93 (95% CI, 0.86–1.00) for total fruits and vegetables combined. Additionally, no statistically significant association was observed between any of the specific fruits and vegetables examined and breast cancer risk.
No randomized prevention trials examining the effect of fruit and vegetable consumption on breast cancer incidence have been conducted; however, evidence for the lack of an association between fruit and vegetable consumption and prevention of breast cancer is supported by results of the Women's Healthy Eating and Living Randomized Trial.[141] Although the trial was a secondary prevention study, the outcomes included new primary breast cancers. More than 3,000 women were enrolled and randomly assigned to an intense regimen of fruit and vegetable intake, high fiber and low fat, or a comparison group receiving printed materials on the "5-A-Day" dietary guidelines. Both groups were consuming more than seven servings of vegetables and fruits at baseline. Increased fruit and vegetable consumption was monitored through dietary assessment and measures of serum carotenoid concentrations. After a mean of 7.3 years follow-up, there was no reduction in new primary cancers (43 new primary breast cancers among the 1,537 randomly assigned to the intervention; compared with 35 new primary breast cancers in 1,551 randomly assigned to the comparison group). There was no difference in disease-free survival between the two groups and no difference in overall survival.
The potential role of specific micronutrients for breast cancer risk reduction has been examined in clinical trials, with cardiovascular disease and cancer as outcomes. The Women's Health Study, a randomized trial with 39,876 women found no difference in breast cancer incidence at 2 years between women assigned to take beta carotene versus placebo.[142] In this same study, no overall effect on cancer was seen in women taking 600 IU of vitamin E every other day.[143] The Women's Antioxidant Cardiovascular Study (WACS) examined total cancer and invasive breast cancer as secondary outcomes following supplementation with either vitamin C, vitamin E, or beta carotene, which were assigned randomly according to a 2 x 2 x 2 factorial design.[144] Women were recruited from the parent Women's Health Study and were eligible for the trial if they had cardiovascular disease or at least three cardiac risk factors. A total of 8,171 women were enrolled. For the analysis of cancer outcome, women were excluded if they had a prior history of cancer (n = 544). Neither total cancer nor breast cancer incidence was statistically significantly different between supplementation groups and the placebo arm. Two years after enrollment for WACS, a subset of participating women who were willing not to use folic acid and vitamin B6 or B12 supplements (n = 5,442) were randomly assigned to supplementation with a combination of 1.5 mg of folic acid, 50 mg of vitamin B6, and 1 mg of B12, or placebo. After 7.3 years of treatment, there was no statistically significant difference in the incidence of total invasive cancer or invasive breast cancer between the supplemented group and the placebo arm.[145]
Fenretinide [146] is a vitamin A analog that has been shown to reduce breast carcinogenesis in preclinical studies. A phase III Italian trial compared the efficacy of a 5-year intervention with fenretinide versus no treatment in 2,972 women, aged 30 to 70 years, with surgically removed stage I breast cancer or DCIS. At a median observation time of 97 months, there were no statistically significant differences in the occurrence of contralateral breast cancer (P = .642), ipsilateral breast cancer (P = .177), incidence of distant metastases, nonbreast malignancies, and all-cause mortality.[114]
Active and passive cigarette smoking
The potential role of active cigarette smoking in the etiology of breast cancer has been studied for more than three decades with no clear-cut evidence of an association.[147] 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.[147,148]
A recent meta-analysis suggests that there is no overall association between passive smoking and breast cancer and that study methodology (ascertainment of exposure after breast cancer diagnosis) may be responsible for the apparent risk associations seen in some studies.[149]
Two well-conducted meta-analyses of RCTs [150] and RCTs plus observational studies [151] found no evidence that statin use either increases or decreases the risk of breast cancer.
The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.
Description of Evidence
Revised text to state that exogenous hormone therapy after menopause was shown to be associated with increased breast cancer risk in 1997.
Revised text to state that the Heart and Estrogen/Progestin Replacement Study published in 2002 included an open-label follow-up of a randomized controlled trial of estrogen and progestin therapy in 2,763 women (mean age, 67 years) who had coronary heart disease.
Revised text to state that women aged 50 to 79 years (N = 10,739) were randomly assigned to receive either conjugated equine estrogens or placebo.
Revised text to state that the evidence from randomized trials should be put into context with the evidence from observational studies that suggests that there is an increased risk of developing breast cancer associated with estrogen-only postmenopausal hormone therapy.
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This summary is reviewed regularly and updated as necessary by the PDQ Screening and Prevention Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).
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Current Rockway Institute Research Projects
LGBT Scientific Accuracy in Media Project:
Funded in part by a grant from the Gill Foundation, the Rockway Institute is assembling a national cadre of 75-100 scientists studying LGBT issues to convey the results of their research to the media. The Gay and Lesbian Alliance Against Defamation (GLAAD) will provide media training to these experts, and we will deploy them for television, radio, and print media interviews, especially when spokespeople are needed on talk shows to debate antigay ideologues or as commentators on current LGBT events. In addition, Rockway Institute will write (and GLAAD will help distribute to news media) a steady stream of press releases, a public policy newsletter, and public policy reports describing the latest LGBT research findings with policy implications. In this way, the Institute will serve as a scientific counterpoint to antigay groups distributing misinformation and propaganda to the media.
Emotional Intelligence in Children of Lesbian, Gay, or Heterosexual Parents:
This study being conducted by researcher Shawn Giammattei examines parenting styles that may be associated with the emotional intelligence of children raised by lesbian, gay male, or heterosexual parents. Of special importance, the emotional intelligence of the children is being measured not only through self-report questionnaires but also by teachers' ratings of the children in the three types of families. This study is likely to have significant implications for legal and social policy pertaining to lesbians and gay men's parenting rights (child custody, adoption).
Gay Male Couples Longitudinal Follow-up Study:
This study being conducted by researcher Jason Jones will follow-up on a sample of 126 gay male couples whose interactional patterns were carefully assessed 8 years ago by CSPP researcher Kevin Campbell. The follow-up study seeks to determine which couples stayed together versus separated, and what are the predictors and reasons for breaking-up over an 8-year period. Variables examined at the initial assessment included the partners' closeness, openness of communication, and intrusiveness with each other. Variables examined at the second assessment include whether the couple is still together and, if so, their current levels of satisfaction with the relationship. For couples who are separated, reasons for breaking-up also are assessed. The long-range goal is to design intervention programs that will help gay couples maintain satisfying, committed, long-term relationships.
Comparing Lesbian, Gay, and Heterosexual Couples from the Mid-1970s to 2000:
This study being coordinated by researcher Gabrielle Gotta compares responses to the same questionnaire from a national sample of lesbian, gay male, and heterosexual couples in the mid-1970s to a different national sample of such couples in the year 2000. The mid-1970s data originally were collected by researchers Phillip Blumstein and Pepper Schwartz at the University of Washington and are archived at Radcliffe College. The more recent data were collected by Esther Rothblum, Sondra Solomon, and Kimberly Balsam at the University of Vermont and have been given to the Rockway Institute for the present study. Comparing these two cohorts will shed light on what changes, if any, have occurred in these three types of couple relationships over the last 30 years in the United States.
Gay Men's Coming-Out Follow-up Study
This study being conducted by researcher Robert McMillan will follow-up on 155 gay men studied 10 years ago by researcher Kevin Pedretti.Of these men, 127 had come out to their parents whereas 28 had not come out to their parents between the ages of 18 and 36. Although there have been several studies of the initial coming-out process, there have been few studies of what happens to family relationships afterwards. This 10-year follow-up study will examine changes in parent/son relationships as a function of length of time being out and as a function of the kinds of conversations about being gay that parents and sons have after coming out. The ultimate goals are to understand what factors predict parents' levels of closeness, openness of communication, and intrusiveness after the initial disclosure, and to design intervention programs to improve family relationships of gay men.


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Pennsylvania's abundant natural gas resources continue to benefit our region. In fact, the Pennsylvania Public Utility Commission recently announced disbursements of shale impact fee tax revenues - which totaled nearly $225 million for 2013 - to local counties and municipalities across the commonwealth, bringing the three-year total to over $630 million.
Montgomery County and its municipalities, for example, received $775,000 this year alone, bringing the county's total impact fee revenues to more than $2.1 million. From making important infrastructure investments, to purchasing new safety equipment and helping improve strained local budgets, these revenues are helping our communities and improving our quality of life.
Without question, shale development is breathing new economic life into our region while protecting and enhancing our environment through lower-cost, clean burning natural gas. We're creating more jobs and providing the energy we need to keep our economy strong. And a new poll shows that Pennsylvanians overwhelmingly support more jobs over new energy taxes. Unfortunately, some elected officials and those seeking office want to pass new energy taxes that could hurt job creation, stifle manufacturing and increase energy costs.
Let's continue to see through election-year politics and work together to get this generational opportunity right - now and for years to come.
SHARI WILLIAMS Community Outreach Manager
Marcellus Shale Coalition


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Rod Stewart Live in Las Vegas Contest Winners Announced
Congratulations to Douglas Zilisch and Ann Loughran — they have each won a trip for two to Las Vegas to see Rod Stewart at Caesars Palace.
Douglas and Ann will each get roundtrip airfare for two to Las Vegas. Plus, we are putting both winners up in a hotel for two nights with their guests.
They are also both getting $500 in spending cash to use on the trip. While they are in Sin City, Douglas and Ann will each get two tickets to see Rod Stewart's show on July 27th at Caesars Palace.
Who will win next? Our VIP program has tons of great contests happening right now—including the hottest gadgets, shopping sprees, cash, trips and more. You can also play games, access exclusive content, and share your feedback.


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Magnum Plus tire balancing compound offers an exciting new way of balancing all your medium and light truck tires. Consisting of ultra-smooth microbeads that are placed inside the tire, Magnum Plus is a dynamic balance that keeps the tire continuously balanced throughout its life.
Magnum Plus uses the rotational forces of the tire and wheel assembly, to adjust to the varying conditions of the road and offset any imbalance in the tire - see the introductory video below.
Magnum Plus is particularly suitable for keeping transport and trailer tires balanced at an economical cost, for providing the best way to keep those off-road tires balanced from asphalt to mud and back, and for offering an 'invisible' balance for custom wheels.
Dansk, Deutsch, Español, Francais, Magyar, Nederlands, Norsk, Polski, Português, русский язык, Slovenčina, Suomen


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You can copy data directly from the old phone to the new phone. If you no longer have the old phone, but you have backed it up to a compatible PC at some stage, you may still be able to transfer the backup data to your new phone. Note that only the data that was saved in the old phone when you last backed it up with the PC can be transferred. For more information, refer to the PC Suite documentation.
The security code helps to protect your phone against unauthorised use. The preset code is 12345. When you have changed the code, keep the new code secret and in a safe place separate from your phone. To change the code, and to set the phone to request it.
Your phone is especially designed for easy and comfortable text writing. A good way is to write with your thumbs using the messaging keyboard. You can, for example start writing a message using the keyboard, close the flip and continue writing with either traditional or predictive text input. Note that predictive text input is not available, when the flip is open.
The phone offers you an extensive range of functions, which are grouped into menus. Most of the menu functions are provided with a brief help text. To view the help text, scroll to the menu function you want and wait for 15 seconds.
You can send and receive e-mails, and access the Internet when your phone is connected to a compatible PC via an IR or Bluetooth connection, or a data cable. You can use your phone with a variety of PC connectivity and data communications applications, provided that you have subscribed to the necessary services.
Nokia 6810 User Guide


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AMERICUS - A converted header off a corner kick by Georgia College with 14 seconds remaining in the first half would prove to be enough as the Bobcats defeated Georgia Southwestern, 3-0, on Wednesday afternoon in Peach Belt Conference action at Hurricane Field.
Kacey McInerney led Georgia College (8-6-2, 5-3-2 PBC) with a goal and an assist.
GC finished with a 13-0 shots on goal advantage and 8-0 margin in corner kicks.
GSW keeper Vanne Lucke saved 10 shots. Jessica Catapano and Taylor Cornelius took a half apiece between the pipes for GC and neither had to make a stop in the contest.
The Lady Hurricanes have been shutout in 13 consecutive matches.
Southwestern (0-16-1, 0-10-1 PBC) hosts Palm Beach Atlantic on Sunday at 2:30 p.m. to wrap up the 2013 season.


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To all subscribers to my blog: My blog has moved to a new home bit.ly/js8GV. Please join me there, I'll be able to share a lot more videos with you and the new blog has more flexibility and features and it is an integrated part of our whole website.
The other day, I was thinking about when I went to my first motivational conference. It was a Super Bowl size "Rah, Rah! You Can Do it!" conference held at a sports arena. I dragged my ever-such-a-good-sport husband along with me. It was hosted by motivational speaker extraordinaire Anthony Robbins (the guy with the big white teeth). I admit much of it was coated in thick cheddar cheese, a bit over the top for my tastes, but reflecting on it I realize how that was money well spent. Let me tell you why.
The other day, I was thinking about when I went to my first motivational conference. It was a Super Bowl size "Rah, Rah! You Can Do it!" conference held at a sports arena. I dragged my ever-such-a-good-sport husband along with me. It was hosted by motivational speaker extraordinaire Anthony Robbins (the guy with the big white teeth). I admit much of it was coated in thick cheddar cheese, a bit over the top for my tastes, but reflecting on it I realize how that was money well spent. Let me tell you why.
We heard from a "who's who" list of business leaders and motivational speakers. We paid a couple hundred dollars for the day. Afterwards, while reflecting on it, we laughed thinking that of the hours and hours of speakers we heard from, we could really only remember about three things. I recall feeling a tangible click in my brain when I heard these three things. There were only three that hit me hard; but I reinforced those ideas by immediately putting them into practice. Come to think of it, these three things were invaluable. When I sit next to a stranger on a plane, or read a new book, or record Oprah, I'm always hoping to take away one new perspective. Three is actually a lot. Sometimes just a single word can improve your life....more on that in a future blog. Allow me to give you the cliff note version of what I took away from that day.
1. FAILURE IS NOT AN OPTION: Donald Trump was there. He was not the pop culture icon he is today, but certainly well known. He told a story about the power to accomplish anything if you believe you can. It was 1991 and he was at the lowest point of his career and facing certain bankruptcy. He recalled walking down 5th Avenue in NYC with former wife Marla Maples. They were in front of Tiffany's when they both noticed a homeless man holding a cup for donations. Marla remarked something to the effect that the man "had nothing." Trump recalled saying to her, "He has $900 million dollars more than me."
2. DO THE YUCKIEST THING ON YOUR TO DO LIST FIRST. It's called "Eating the frog", a term explained to us by one of my favorite authors, Brian Tracy. For those who make a to-do list everyday, if you had a list of 10 things to do and one of them was to "eat a frog", that item would likely remain undone for months. We all have a frog on our list. It's that one thing on your "to-do" list that reaches the top. For whatever reason, we are either intimidated, uncomfortable, nervous, embarrassed or too lazy to tackle it. There it lives and grows. The longer it stays on your list the bigger it grows in your imagination. Everyday we expend energy avoiding it. If it's the 10th thing on your list, you'll make up a 9A, a 9B, and a 9C just to avoid "eating the frog". We hardly enjoy crossing off the 9 other things, knowing number 10 is still out there. We waste time to avoid it. Number 10 on the list festers in the back of your mind like an energy eating tumor. Just when you've blocked it out... boom...headache, stomach drops, your mood takes a dive south, and your self-esteem plummets. Brian Tracy's advice....Wake up each day and make the "frog" the first thing you do. It never takes as long as you think and it really never tastes as bad as you think. I'm getting better at this. My favorite book of his on this subject is aptly titled, "Eat that Frog". If you don't yet write a list everyday, you will after you read this book. Get it.
3. APPLY THE 80/20 RULE TO YOUR WHOLE LIFE: It's simple...20% of what you do accounts for 80% of your positive results. It's true of everything. Think about it. Of all of your friends only 20% of them really want to see you do well and support you, the other 80% are fun to be around, but not all that concerned with your well being, so give 20% of your friends 80% of your "friend time". 20% of what you do in your home directly improves the well being of your family. 20% of what you do at work that no one else could do as well as you, 80% could probably be done by someone who is paid less, allowing you to focus your time on the 20% that get results. Often 80% of the way you spend your day bring you no closer to living the life you want to live, 20% of your activities do. You never wear 80% of the clothes bursting from your closet. What is it you want for your family, your health, your marriage, your career, your life? Figure out which area you want to tackle first. Next make a list of everything you're doing. Finally select the 20% of that list that truly brings you closer to your goal. Focus. Focus on the 20%. Focus on a way of freeing yourself from the other 80% and feel 100% better. Every couple of months step back and re-focus on your 20%.
That's the beauty of life improvement workshops, books, articles, posts, television. It's kind of like cleaning out your closet. You can't just G.I the place once and hope that your sweaters and shoes stay all nice and neat. Pick up a book, do an on-line search for a topic you're looking to improve. If you're spiritual, attend a motivational service. Call a friend who is blessed with words of wisdom and listen this time. Watch Oprah. Listen to Dr. Phil. Tune in for Dr. Laura. Read a blog. Even if you only remember three sentences, the results of implementing positive change will be life improving.
In order to purchase my lecture DVDs please click here: http://www.turbokick.com/store/home.php?cat=81
It is Halloween and Powder Blue Productions has a monster of a sale, all CD/DVDs are 50% off and you can get additional 20% off by either joining FAN club or becoming a VIP. Please click here http://bit.ly/h5Uj1


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Energy IT sees smart-grid boon for data storage
The economic stimulus package set aside billions of dollars for smart grids and smart meters, and storage admins at early-adopter energy companies are already managing hundreds of terabytes and even petabytes of data.
IT pros and consultants working at energy utilities say smart-meter and smart-grid projects to modernize U.S. energy delivery will be a boon for the data storage industry, as the digitized grid is projected to generate massive amounts of data.
Smart grid is in the news after the passage of the American Recovery and Reinvestment Act of 2009, also known as the economic stimulus bill. The bill set aside close to $5 billion to get digitized energy grid projects under way.
Major consultancies and integrators like Accenture, IBM Business Services and Capgemini have already established energy grid practices and are deep into city-wide projects both abroad and in the United States. But efforts to transform these systems nationwide will go on for the next decade or more. Even the larger integrators acknowledge there will be room for their smaller counterparts.
"I think this is an area that will develop an entire ecosystem with large and small players," said Jeffrey Taft, global architect for smart grid at Accenture. "Some companies are going to be best suited to work with really big players. But in North America, we have 3,000 small utilities, and a lot of those will turn to smaller players to get what they need."
Smart-grid rollouts have two phases. First comes the deployment of Advanced Metering Infrastructures (AMI), or smart meters, followed by the rollout of true smart grids that can absorb and redeploy distributed sources of alternative energy. True smart grids would also balance energy delivery loads through IP networking and data analysis.
The earliest adopters in the energy space so far have gotten to the smart-metering stage. Austin Energy of Austin, Texas, is one of the furthest along in its deployment, with the Pecan Street Project announced last December. Austin Energy CIO Andres Carvallo says Phase 1 of the smart-grid project is expected to be complete in July, when a half-million smart-meter devices will have been rolled out across the company's entire service territory.
Even in this first phase, the data storage requirements are huge.
"Our total information online was 20 TB before we began this project. With the smart grid, we're projecting 100 TB of data a year," Carvallo said. The data won't be kept long -- probably only 20 TB will be retained for compliance purposes for longer than a year -- but the requirements probably won't slow down.
"Right now we're capturing data from the smart meters every 15 minutes," Carvallo said. That requires 200 TB of storage space when disaster recovery redundancy is factored in. "If we move to five minutes, that 200 TB would become 800," he said. "If we moved to one minute, it would be 1.5 PB."
This doesn't factor in Phase 2 of the smart-grid project, in which Austin hopes its customers will be able to plug in local sources of alternative energy to the grid, like solar panels or fuel cells. "We are entering the petabyte age," Carvallo said. "Other hydroelectric utilities will eventually be where I am today."
Meanwhile, California's Pacific Gas and Electric Co. (PG&E) has also been working to roll out smart meters since 2006, and has some 700,000 smart-meter devices deployed so far. When all is said and done, said David Ping, PG&E data center storage team lead, there will probably be about a million devices in the field.
The company began in 2006 with between 600 and 800 TB of storage to support open systems within the company. As it's rolled out smart meters, it's brought in new storage subsystems, adding six IBM DS8300 storage arrays to support the initial rollout -- approximately 1.2 PB of storage. Today, that number has grown to 12 DS8300s, and the company is managing a total of 3.2 PB of storage between open systems and the smart-meter project, and there's talk of boosting that to 4 PB, Ping said.
"The bottom line is that once utilities go to the smart-meter concept, constantly reading and sending information, the storage requirements within the company grow quite a bit," he said. As with Austin Energy, the frequency of meter readings at PG&E could also increase. Right now PG&E's meters are being read twice a day, once every 12 hours, but there's talk of moving to hourly readings to improve the company's forecasts about how much energy it needs to purchase for distribution.
A challenge for the industry
The sheer size of the data set combined with performance requirements to do data warehousing and analytics on it in real time present a challenge to today's storage technology, Ping said. "We have terabyte drives now, but do they allow the performance to support polling meters every five minutes? If so, what does that system look like?" he asked. As an IBM user, Ping says he's learned about the SATA-based parallel-processing XIV system, but discussions about long-term data center design at the company are still at a very early stage.
Not every company will be able to reduce its long-term retention of smart-meter and billing data, according to Capgemini Vice President of North American Utilities Andy Roehr. Capgemini has been consulting with San Diego Gas and Electric on its smart-meter project. "Depending on where they are in the country, some users will have to keep 36 months of reads," Roehr said. "People are using the word 'exabyte' in casual conversation now."
Just storing the data is also only the first step in gleaning benefits from smart meters and smart grids, he added. "The industry as a whole has a challenge in front of it as we learn how to use the data. Right now, we're trying to figure out what the right technologies are and appropriate data collection intervals. People are going to learn as they go."
Given that power and cooling are already concerns in the data center, at what point does the massive data storage and processing required to run a smart grid outweigh the energy savings of the grid project itself? "That's a fascinating question, but I don't know that anyone's actually done the ROI analysis," Roehr said. "The potential savings in conservation [on the energy grid] are fairly huge -- I don't really think the power consumed by data storage will be a significant factor in offsetting the gains, but it's something users will have to think about."
"Existing storage systems at utilities will be stressed and taxed -- they will certainly need to be evaluated and probably upgraded," said Paul Williams, an IBM Business Services Group energy and utilities software solutions architect who has worked with Austin Energy on the Pecan Street Project. "But it's great news for the storage industry -- there will be tons of data that needs to be stored, analyzed and turned into operational information."
SearchNetworkingChannel.com Site Editor Rivka Gewirtz Little contributed to this story.


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Mocha Milk Chocolate Pot de Creme
A pot de crème is an egg custard that is very often flavored with chocolate. It's sort of a French version of chocolate pudding.
Preparing it is very easy. You basically follow the recipe for crème brûlée, but you bake the custard a little longer to get a thicker result.
Yields: 6 pots de creme2 egg yolks
4 teaspoon sugar
1/8 teaspoon salt
1/2 teaspoon vanilla extract
1 teaspoon mocha extract
1/4 cup whole milk
1 cup heavy cream
4 ounces milk chocolate , (3/4 cup)
Preheat the oven to 325°F.
Break the chocolate bar and cut into small morsels using a chef's knife.
On the stove, pour the milk and cream into a sauce pan, bring to a boil. Remove from the heat right away and add to the milk chocolate. Keep stirring until the chocolate is melted. Add the pinch of salt. Set aside.
Separately, whisk the egg yolks with the sugar in a mixing bowl until it becomes a pale yellow. Add the vanilla extract and combine the chocolate liquid with the egg mixture by slowly adding a ladle of the chocolate/milk mixture at a time to prevent the yolks from curdling.
Strain through a fine mesh to make sure there are no chunks of chocolate left. Fill 6 10-oz mini ramekins with the mixture. Place them in a warm water bath in a deep baking pan. The water should go half way up the side of the ramekins. Cover the dish with a sheet of aluminum foil and bake for 40-50 minutes. The texture of the cream should be jiggly but not too liquid.
Let the pots de crèmes cool first, then plastic-wrap each individual ramekin and place in the refrigerator for at least an hour. The fat from the cream may pick up some other odors from the refrigerator if the ramekins are not sealed properly.
When serving, add a dollop of whipped cream and decorate with a small berry and a teeny mint leaf (I get them from my garden). Finish the decoration by sprinkling a little powdered sugar on each ramekin.
Bon appétit!
I like to serve my pot de cremes in tiny size ramekins so that my guests always ask for more. I serve them in 6 mini-ramekins or you can serve them in 4 regular ramekins for very hungry (greedy) dessert eaters.
Set aside the egg whites in the refrigerator and save for tuiles (literally roof tiles in French).
While waiting for the milk and cream to boil, you have to be very careful. Don't go anywhere else. If the phone rings or someone's at the door, let it be. You gotta focus on your milk and cream otherwise you'll be cleaning your stove and scraping the burnt milk all night long. As soon as some bubbles come up, remove from the stove and immediately add to your chocolate chips.
I used Valrhona French Milk Chocolate. I got them directly from my local market but you can order through Amazon if you can't find them.
When you take the pot de cremes out of the oven, they should be a little jiggly. Refrigerating them for at least 3 hours helps create a firmer consistency.
Salt brings out all the flavors. Don't believe me? Hear Cory Barret, Pastry Chef at Lola who just compete against Iron Chef Michael Simon.
Published By: on March 11, 2009.


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EN 100% • Korea
A follow up of the drama "Scent of a Woman". "Live in Style" tells the story of the love and conflicts of each member of a large family, all of whom have unusual experiences. The family is in a difficult situation now, but they try hard to overcome their obstacles and live in style.
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Seo HeadlineYour Tools
Menstrual Health Centre
Periods helped to kick-start mathematics! Scholars think that most early calendars were based on the length of women's menstrual cycles.
http://facts.randomhistory.com/random-facts-about-menstruation.htmlGo to the Menstrual health centre
Knowing when your
period is due each
month can be really useful
- you can make a note of the dates in your diary to remind you to pop a couple of tampons or sanitary towels in your bag
and have some painkillers to hand so the cramps don't catch you off guard.


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I understand that someone's work phone might have an extension. What do you call the main number of that office, which would normally be answered by an operator or a computer voice system?
Would it be the "Main Line", the "Main Station", the "Root of Extension"? I would like to know the technical name as well as some more informal or slang terms, if there are any.