Breast Cancer Prevention (PDQ®)–Health Professional Version
Increased Breast Density
Widespread use of screening mammograms has revealed varying amounts of mammographically dense tissue and that women with a greater proportion of dense tissue have a higher incidence of breast cancer. Mammographic density also confounds the identification of cancers by that technology. The extent of increased risk was described in a report of three nested case-control studies in screened populations with 1,112 matched case-control pairs. Compared with women with density comprising less than 10% of breast tissue, women with density in 75% or more of their breast had an increased risk of breast cancer (odds ratio [OR], 4.7; 95% confidence interval [CI], 3.0–7.4), whether the cancer was detected by screening (OR, 3.5; 95% CI, 2.0–6.2) or detected less than 12 months after a negative screening examination (OR, 17.8; 95% CI, 4.8–65.9). Increased risk of breast cancer, whether detected by screening or other means, persisted for at least 8 years after study entry and was greater in younger women than in older women. For women younger than the median age of 56 years, 26% of all breast cancers and 50% of cancers detected less than 12 months after a negative screening test were identified in women with mammographic breast density of 50% or more.[34,35]
Women with dense breasts have increased risk, proportionate to the degree of density. This increased relative risk (RR) ranges from 1.79 for women with slightly increased breast density to 4.64 for women with very dense breasts, compared with women who have the lowest breast density.[36] There is no increased risk of breast cancer mortality among women with dense breast tissue.[37]
Factors With Adequate Evidence of Increased Risk of Breast Cancer
Hormone therapy
Based on a 1997 reanalysis of 51 epidemiological studies encompassing more than 150,000 women, hormone therapy (HT) after menopause was shown to be associated with increased breast cancer risk.[38]
The Heart and Estrogen/Progestin Replacement Study supported this finding in 2002.[39] In this study, 2,763 women with coronary heart disease at a mean age of 67 years were randomly assigned to receive either estrogen and progestin therapy or placebo. After a mean follow-up of 6.8 years, the RR for breast cancer was 1.27 (95% CI, 0.84–1.94). Although not statistically significant, the RR estimate is consistent with the much larger Women’s Health Initiative (WHI), also published in 2002.
The WHI investigated the effect of hormones and dietary interventions on heart disease and breast cancer risk.[40] Women aged 50 to 79 years with intact uteri were randomly assigned to receive combined conjugated estrogen with continuous progestin (n = 8,506) or placebo (n = 8,102). The trial was terminated early because combined HT did not decrease coronary heart disease risk but did increase the risk of stroke and breast cancer. An increased rate of invasive breast cancer risk (hazard ratio [HR], 1.24; 95% CI, 1.02–1.50), but not for in situ breast cancer, was observed in all subgroups of women. The combined HT-related cancers had similar grade, histology, and expression of estrogen receptor (ER), progesterone receptor, and HER2/neu, with a trend toward larger size and higher incidence of lymph node metastases in the combined HT group.[41] Extended follow-up of a mean of 11 years showed higher breast cancer–specific mortality for the HT group (25 vs. 12 deaths, 0.03% vs. 0.01% per year; HR, 1.95; 95% CI, 1.0–4.04; P = .049). Combined HT was also associated with a higher percentage of abnormal mammograms.[42]
The WHI observational study was conducted in parallel with the WHI randomized controlled trial (RCT), recruiting postmenopausal women aged 50 to 79 years. An analysis was conducted in the observational study of the WHI to further examine the prognosis of women taking combination HT who were diagnosed with breast cancer and the risks based on time between menopause and initiation of HT. After a mean follow-up of 11.3 years, the annualized incidence of breast cancer among women using estrogen plus progestin was 0.60%, compared with 0.42% among nonusers (HR, 1.55; 95% CI, 1.41–1.70). Survival after the diagnosis of breast cancer was similar for combined HT users and nonusers. Death from breast cancer was higher among combined HT users than among nonusers, but the difference was not statistically significant (HR, 1.3; 94% CI, 0.90–1.93). Risks were highest among women initiating HT at the time of menopause, and risks diminished but persisted with increasing time between menopause and starting combination HT. All-cause mortality after the diagnosis of breast cancer was statistically significantly higher among combined HT users than among nonusers (HR, 1.87; 95% CI, 1.37–2.54.) Overall, these findings were consistent with results from the RCT.[43]
The WHI also studied women who had previously undergone a hysterectomy and thus were not at risk for endometrial cancer, which is associated with unopposed estrogen therapy. Women aged 50 to 79 years (N = 10,739) were randomly assigned to receive conjugated equine estrogen (CEE) or placebo. This trial was also stopped early because of an increased risk of stroke and no improvement in a global risk-benefit index.[44,45] After an average 6.8 years of follow-up, breast cancer incidence was lower in the group receiving CEE (0.26% per year vs. 0.33%; HR, 0.77; 95% CI, 0.59–1.01). The global risk-benefit index was slightly worse for CEE.[44] An extended follow-up for a median of 11.8 years included 78% of the trial participants.[45,46] Results seen in the initial study persisted, with a similar risk reduction for breast cancer in CEE recipients (HR, 0.77; 95% CI, 0.62–0.95) [45,46] and a decrease in breast cancer mortality (6 vs. 16 deaths; HR, 0.37; 95% CI, 0.13–0.91). All-cause mortality was also lower in the CEE group (0.046% vs. 0.076% per year; HR, 0.62; 95% CI, 0.39–0.97). After CEE was discontinued, the risk of stroke decreased in the postintervention period. Over the entire follow-up period, there was no difference in the incidence of coronary heart disease, deep vein thrombosis, stroke, hip fracture, or colorectal cancer.[45] Breast cancer incidence was similar for women who initiated CEE or placebo within the first 5 years after onset of menopause (HR, 1.06; 95% CI, 0.74–1.51).
A Danish trial of HT for 1,006 women entering menopause was designed to evaluate cardiovascular outcomes. Combined HT (triphasic estradiol and norethisterone) was given to 407 women with intact uteri, and estradiol was given to 95 women who had undergone hysterectomy. Controls (407 with intact uteri and 97 with hysterectomy) were not treated. At 10 years, there was considerable contamination. Only one-half of the women assigned to the HT group were still taking the prescribed HT, and 22% of the control women had begun HT. Cardiovascular outcomes favored HT-treated women, and there was no difference in breast cancer incidence.[47]
Observational studies augment the information obtained in RCTs.
The Million Women Study [48] recruited 1,084,110 women aged 50 to 64 years in the United Kingdom between 1996 and 2001 and obtained information about HT use and other personal details. The women were followed for breast cancer incidence and death. One-half of the women had used HT. At 2.6 years of follow up, there were 9,364 invasive breast cancers; at 4.1 years, there were 637 breast cancer deaths. Current users of HT at recruitment were more likely than never-users to develop breast cancer (adjusted RR = 1.66; 95% CI, 1.58–1.75; P < .0001) and to die from the disease (adjusted RR, 1.22; 95% CI, 1.00–1.48; P = .05). Past users of HT were, however, not at an increased risk of incident or fatal breast cancer (1.01 [95% CI, 0.94–1.09] and 1.05 [95% CI, 0.82–1.34], respectively). Incidence was significantly increased for current users of estrogen only (RR, 1.30; 95% CI, 1.21–1.40; P < .0001), combined HT (RR, 2.00; 95% CI, 1.88–2.12; P < .0001), and tibolone (RR, 1.45; 95% CI, 1.25–1.68; P < .0001). The magnitude of the associated risk was substantially greater for combined HT than for other types of HT (P < .0001).
A population-based survey of 965 women with breast cancer and 1,007 controls was conducted by the Cancer Surveillance System of Puget Sound. It showed that combined HT users had a 1.7-fold increased risk of invasive breast cancer, whereas estrogen-only users did not.[49]
The association between the use of combined HT and increased breast cancer risk is consistent throughout all the trials. In contrast, the association between estrogen-only HT and breast cancer incidence is confusing because some studies show increased risk and some show protection. It is possible that the timing of estrogen-only HT in relation to the onset of menopause is critical. Furthermore, observational studies may not account for different screening behavior between HT users and nonusers, whereas RCTs, by design, will control that variable.[50,51]
Following publication of the WHI results, HT use dropped dramatically in the United States and elsewhere. Follow-up of WHI participants on the combined HT arm demonstrated a rapid decrease in the elevated breast cancer risk of therapy within 2 years, despite similar rates of mammography screening.[52] Analysis of changes in breast cancer rates in the United States observed a sharp decline in breast cancer incidence rates from 2002 to 2003 among women aged 50 years and older, especially for ER–positive cancers.[53,54] Similarly, in multiple countries where HT use was high, breast cancer rates decreased in a similar time frame, coincident with decreases in prescribing patterns and/or reported prevalence of use.[55-57] A study among women receiving regular mammography screening supports that the observed sharp decline from 2002 to 2003 in breast cancer incidence was primarily caused by withdrawal of HT rather than declines in mammography rates.[58] After the decline in breast cancer incidence from 2002 to 2003, rates in the United States stabilized.[58,59]
Ionizing radiation exposure
A well-established relationship exists between exposure to ionizing radiation and subsequent breast cancer.[60] Excess breast cancer risk has been observed in association with atomic bomb exposure, frequent fluoroscopy for tuberculosis, and radiation therapy for acne, tinea, thymic enlargement, postpartum mastitis, and lymphoma. Risk is higher for the young, especially around puberty. An estimate of the risk of breast cancer associated with medical radiology puts the figure at less than 1% of the total.[61] However, it has been theorized that certain populations, such as AT heterozygotes, are at an increased risk of breast cancer from radiation exposure.[32] A large cohort study of women who carry mutations of BRCA1 or BRCA2 concluded that chest x-rays increase the risk of breast cancer even more (RR, 1.54; 95% CI, 1.1–2.1), especially for women who had x-rays before age 20 years.[62]
Women treated for Hodgkin lymphoma by age 16 years have a subsequent risk up to 35% of developing breast cancer by age 40 years.[63-65] Higher radiation doses (median dose, 40 Gy in breast cancer cases) and treatment between the ages of 10 and 16 years are associated with higher risk.[63] Unlike the risk for secondary leukemia, the risk of treatment-related breast cancer does not abate with duration of follow-up, persisting more than 25 years after treatment.[63,65,66] In these studies, most patients (85%–100%) who developed breast cancer did so either within the field of radiation or at the margin.[63,64,66] A Dutch study examined 48 women who developed breast cancer at least 5 years after treatment for Hodgkin disease and compared them with 175 matched female Hodgkin disease patients who did not develop breast cancer. Patients treated with chemotherapy and mantle radiation were less likely to develop breast cancer than were those treated with mantle radiation alone, possibly because of chemotherapy-induced ovarian suppression (RR, 0.06; 95% CI, 0.01–0.45).[67] Another study of 105 radiation-associated breast cancer patients and 266 age-matched and radiation-matched controls showed a similar protective effect for ovarian radiation.[65] These studies suggest that ovarian hormones promote the proliferation of breast tissue with radiation-induced mutations.[65]
The question arises whether breast cancer patients treated with lumpectomy and radiation therapy (L-RT) are at higher risk for second breast malignancies or other malignancies than are those treated by mastectomy. Outcomes of 1,029 L-RT patients were compared with outcomes of 1,387 patients who underwent mastectomies. After a median follow-up of 15 years, there was no difference in the risk of second malignancies.[68] Further evidence from three RCTs is also reassuring. One report of 1,851 women randomly assigned to undergo total mastectomy, lumpectomy alone, or L-RT showed rates of contralateral breast cancer to be 8.5%, 8.8%, and 9.4%, respectively.[69] Another study of 701 women randomly assigned to undergo radical mastectomy or breast-conserving surgery followed by radiation therapy demonstrated the rate of contralateral breast carcinomas per 100 woman-years to be 10.2 versus 8.7, respectively.[70] The third study compared 25-year outcomes of 1,665 women randomly assigned to undergo radical mastectomy, total mastectomy, or total mastectomy with radiation. There was no significant difference in the rate of contralateral breast cancer according to treatment group, and the overall rate was 6%.[71]
Obesity
Obesity is associated with increased breast cancer risk, especially among postmenopausal women who do not use HT. The WHI observed 85,917 women aged 50 to 79 years and collected information on weight history and known risk factors for breast cancer.[72,73] Height, weight, and waist and hip circumferences were measured. With a median follow-up of 34.8 months, 1,030 of the women developed invasive breast cancer. Among the women who never used HT, increased breast cancer risk was associated with weight at entry, body mass index (BMI) at entry, BMI at age 50 years, maximum BMI, adult and postmenopausal weight change, and waist and hip circumferences. Weight was the strongest predictor, with a RR of 2.85 (95% CI, 1.81–4.49) for women weighing more than 82.2 kg, compared with those weighing less than 58.7 kg.
The association between obesity, diabetes, and insulin levels with breast cancer risk have been studied but not clearly defined. The British Women’s Heart and Health Study of women aged 60 to 79 years compared 151 women who had a diagnosis of breast cancer with 3,690 women who did not. The age-adjusted OR was 1.34 (95% CI, 1.02–1.77) for each unit increase in log(e) insulin level among nondiabetic women. The association was observed, after adjustment for confounders and for potential mediating factors, for both pre- and postmenopausal breast cancers. In addition, fasting glucose level, homeostatic model assessment score (the product of fasting glucose and insulin levels divided by 22.5), diabetes, and a history of gestational glycosuria or diabetes were also associated with breast cancer.[74]
Alcohol
Alcohol consumption increases the risk of breast cancer. A British meta-analysis included individual data from 53 case-control and cohort studies.[75] Compared with the RR of breast cancer for women who reported no alcohol consumption, the RR of breast cancer was 1.32 (95% CI, 1.19–1.45; P < .001) for women consuming 35 g to 44 g of alcohol per day and 1.46 (95% CI, 1.33–1.61; P < .001) for those consuming at least 45 g of alcohol per day. The RR of breast cancer increases by about 7% (95% CI, 5.5%–8.7%; P < .001) for each 10 g of alcohol (i.e., one drink) consumed per day. These findings persist after stratification for race, education, family history, age at menarche, height, weight, BMI, breast-feeding, oral contraceptive use, menopausal hormone use and type, and age at menopause.
Factors With Adequate Evidence of Decreased Risk of Breast Cancer
Early pregnancy
Childbirth is followed by an increase in risk of breast cancer for several years, and then a long-term reduction in risk, which is greater for younger women.[22,76,77] In one study, women who experienced a first full-term pregnancy before age 20 years were half as likely to develop breast cancer as nulliparous women or women whose first full-term pregnancy occurred at age 35 years or older.[78,79]
The association of childbirth with breast cancer risk was demonstrated by the International Premenopausal Breast Cancer Collaborative Group, which undertook a pooled analysis of individual-level data from about 890,000 women from 15 prospective cohort studies. When compared with nulliparous women, parous women had an increased risk of developing both ER–positive and ER–negative breast cancer for up to 20 years after childbirth. However, after about 24 years, the risk of developing ER–positive breast cancer decreased, but the risk of developing ER–negative breast cancer remained elevated. Thus, the association between parity and breast cancer risk is complex and appears to be influenced by the time period after childbirth and tumor phenotype.[80]
Breast-feeding
Breast-feeding is associated with a decreased risk of breast cancer.[81] A reanalysis of individual data from 47 epidemiological studies in 30 countries of 50,302 women with breast cancer and 96,973 controls revealed that breast cancer incidence was lower in parous women who had ever breast-fed than in parous women who had not. It was also proportionate to duration of breast-feeding.[82] The RR of breast cancer decreased by 4.3% (95%, CI, 2.9%–5.8%; P < .0001) for every 12 months of breast-feeding in addition to a decrease of 7.0% (95% CI, 5.0%–9.0%; P < .0001) for each birth.
Exercise
Active exercise may reduce breast cancer risk, particularly in young parous women.[83] Numerous observational studies on the relationship between the level of physical activity and breast cancer risk have shown an inverse relationship.[84] The average RR reduction is 30% to 40%, but confounding variables—such as diet or a genetic predisposition to breast cancer—have not been addressed. A prospective study of more than 25,000 Norwegian women found that heavy manual labor or at least 4 hours of exercise per week is associated with decreased breast cancer risk, especially in premenopausal women and those of normal or lower-than-normal body weight.[85] In a case-control study of African American women, strenuous recreational physical activity more than 7 hours per week was associated with decreased breast cancer incidence.[86]
Interventions With Adequate Evidence of Benefit
Selective estrogen receptor modulators (SERMs)
Data from adjuvant breast cancer trials using tamoxifen have shown that tamoxifen not only suppresses the recurrence of breast cancer but also prevents new primary contralateral breast cancers.[87] Tamoxifen also maintains bone density among postmenopausal women with breast cancer.[88-92] Adverse effects include hot flashes, venous thromboembolic events, and endometrial cancer.[93-95]
These adjuvant trial results were the basis for the Breast Cancer Prevention Trial (BCPT) that randomly assigned 13,388 patients at elevated risk of breast cancer to receive tamoxifen or placebo.[96,97] The study was closed early because of a 49% reduction in the incidence of breast cancer for the tamoxifen group (85 vs. 154 invasive breast cancer cases and 31 vs. 59 in situ cases at 4 years). Tamoxifen-treated women also had fewer fractures (47 vs. 71) but more endometrial cancer (33 vs. 14 cases) and thrombotic events (99 vs. 70), including pulmonary emboli (17 vs. 6).[97]
An update of the BCPT results after 7 years of follow-up demonstrated results similar to those in the initial report.[98] There were some dropouts among women in the placebo arm; some of them enrolled in a subsequent trial, so new women were added to the placebo group. Benefits and risks of tamoxifen were not significantly different from those in the original report, with persistent benefit of fewer fractures and persistent increased risk of endometrial cancer, thrombosis, and cataract surgery. No overall mortality benefit was observed after 7 years of follow-up (RR, 1.10; 95% CI, 0.85–1.43).
Three other trials of tamoxifen for primary prevention of breast cancer have been completed.[99-101]
- A study in the United Kingdom [99] focused on 2,471 women at increased breast cancer risk because of their family history of breast and/or ovarian cancer. After a median follow-up of nearly 6 years, no protective effect of tamoxifen was detected (RR, 1.06), but there was a slight reduction in breast cancer risk in the tamoxifen arm (HR, 0.78; 95% CI, 0.58–1.04) at a median of 13 years. However, risk of ER-positive breast cancer was significantly reduced in the treatment arm (HR, 0.61; 95% CI, 0.43–0.86), an effect noted predominantly in the posttreatment period.[102]
- An Italian study [100] focused on 5,408 women who had undergone hysterectomy and who were described as low to normal risk. After a median follow-up of nearly 4 years, no protective effect of tamoxifen was observed. Longer follow-up and subgroup analysis in this trial found a protective effect of tamoxifen among women at high risk for hormone receptor–positive breast cancer (RR, 0.24; 95% CI, 0.10–0.59) and among women who were taking HT during the trial (RR, 0.43; 95% CI, 0.20–0.95).[103,104]
- The International Breast Cancer Intervention Study (IBIS-I) randomly assigned 7,152 women aged 35 to 70 years who were at an increased risk of breast cancer to receive tamoxifen (20 mg/day ) or placebo for 5 years.[101] After a median follow-up of 50 months, fewer tamoxifen-treated women had developed invasive or in situ breast cancer (absolute rate, 4.6 vs. 6.75 per 1,000 woman-years; risk reduction, 32%; 95% CI, 8%–50%). The RR reduction in ER-positive invasive breast cancer was 31%; there was no reduction in ER-negative cancers. There was an excess of all-cause mortality in the tamoxifen group (25 vs. 11; P = .028), which the authors attributed to chance. The beneficial effect of tamoxifen on breast cancer persisted after active treatment, with a median posttherapy follow-up of 46 months; 27% fewer women in the tamoxifen arm developed breast cancer (142 vs. 195 cases, respectively; RR, 0.73, 95% CI, 0.58–0.91).[105]
A meta-analysis of these primary prevention tamoxifen trials showed a 38% reduction in the incidence of breast cancer without statistically significant heterogeneity.[95] ER-positive tumors were reduced by 48%. Rates of endometrial cancer were increased (consensus RR, 2.4; 95% CI, 1.5–4.0), as were venous thromboembolic events (RR, 1.9; 95% CI, 1.4–2.6). None of these primary prevention trials was designed to detect differences in breast cancer mortality.
Women with a history of ductal carcinoma in situ (DCIS) are at increased risk for contralateral breast cancer. The National Surgical Adjuvant Breast and Bowel Project (NSABP) trial B-24 addressed their management. Women were randomly assigned to receive L-RT either with or without adjuvant tamoxifen. At 6 years, the tamoxifen-treated women had fewer invasive and in situ breast cancers (8.2% vs. 13.4%; RR, 0.63; 95% CI, 0.47–0.83). The risk of contralateral breast cancer was also lower in women treated with tamoxifen (RR, 0.49; 95% CI, 0.26 – 0.87).[106]
Raloxifene hydrochloride (Evista) is a SERM that has antiestrogenic effects on breast and estrogenic effects on bone, lipid metabolism, and blood clotting. Unlike tamoxifen, it has antiestrogenic effects on the endometrium.[107] The Multiple Outcomes of Raloxifene Evaluation (MORE) trial was a randomized, double-blind trial that evaluated 7,705 postmenopausal women with osteoporosis from 1994 to 1998 at 180 clinical centers in the United States. Vertebral fractures were reduced. The effect on breast cancer incidence was a secondary endpoint. After a median follow-up of 47 months, the risk of invasive breast cancer decreased in the raloxifene-treated women (RR, 0.25; 95% CI, 0.17–0.45).[108] As with tamoxifen, raloxifene reduced the risk of ER-positive breast cancer but not ER-negative breast cancer and was associated with an excess risk of hot flashes and thromboembolic events. No excess risk of endometrial cancer or hyperplasia was observed after 47 months of follow-up.[109]
An extension of the MORE trial was the Continuing Outcomes Relevant to Evista (CORE) trial, which studied about 80% of MORE participants in their randomly assigned groups for an additional 4 years. Although there was a median 10-month gap between the two studies, and only about 55% of women were adherent to their assigned medications, the raloxifene group continued to experience a lower incidence of invasive ER-positive breast cancer. The overall reduction in invasive breast cancer during the 8 years of MORE and CORE was 66% (HR, 0.34; 95% CI, 0.22–0.50); the reduction for ER-positive invasive breast cancer was 76% (HR, 0.24; 95% CI, 0.15–0.40).[110]
The Raloxifene Use for the Heart trial was a randomized, placebo-controlled trial to evaluate the effects of raloxifene on incidence of coronary events and invasive breast cancer. As in the MORE and CORE studies, raloxifene reduced the risk of invasive breast cancer (HR, 0.56; 95% CI, 0.38–0.83).[111]
The Study of Tamoxifen and Raloxifene (STAR) (NSABP P-2) compared tamoxifen and raloxifene in 19,747 high-risk women who were monitored for a mean of 3.9 years. Invasive breast cancer incidence was approximately the same for both drugs, but there were fewer noninvasive cancers in the tamoxifen group. Adverse events of uterine cancer, venous thrombolic events, and cataracts were more common in tamoxifen-treated women, and there was no difference in ischemic heart disease events, strokes, or fractures.[112] Treatment-associated symptoms of dyspareunia, musculoskeletal problems, and weight gain occurred less frequently in tamoxifen-treated women, whereas vasomotor flushing, bladder control symptoms, gynecologic symptoms, and leg cramps occurred less frequently in those receiving raloxifene.[113]
Aromatase inhibitors or inactivators (Als)
Another class of agents that is commercially available for the treatment of women with hormone-sensitive breast cancer may also prevent breast cancer. These drugs interfere with aromatase, the adrenal enzyme that allows estrogen production in postmenopausal women. Anastrozole and letrozole inhibit aromatase activity, whereas exemestane inactivates the enzyme. Side effects for all three drugs include fatigue, arthralgia, myalgia, decreased bone mineral density, and increased fracture rate.
Women with a previous diagnosis of breast cancer have a lower risk of recurrence and of new breast cancers when treated with AIs, as shown in the following studies:
- In the Arimidex, Tamoxifen, Alone or in Combination trial, which compared anastrozole with tamoxifen as adjuvant therapy for primary breast cancer, the rate of locoregional and distant recurrence was lower for anastrozole (7.1% vs. 8.5%) but higher for the combination (9.1%).[114] Anastrozole was also more effective in reducing the incidence of new contralateral breast cancer (0.4% vs. 1.1% vs. 0.9%).
- In another trial, 5,187 women who received 5 years of adjuvant tamoxifen were randomly assigned to receive either letrozole or placebo.[115] After only 2.5 years of median follow-up, the study was terminated because previously defined efficacy endpoints had been reached. Not only did patients treated with letrozole have a lower incidence of locoregional and distant cancer recurrence, they also had a lower incidence of new contralateral breast cancer (14 vs. 26).
- Another placebo-controlled trial of 1,918 women with breast cancer examined the effect of extending letrozole treatment for an additional 5 years in women who had received adjuvant tamoxifen followed by 5 years of letrozole.[116] At a median of 6.3 years from study entry, the extended letrozole group had an improved 5-year disease-free survival of 95% (95% CI, 93%–96%) compared with 91% (95% CI, 89%–93%) for the control group (HR, 0.66) but no difference in overall survival. The difference in new contralateral breast cancer diagnoses was statistically significant: 21% (95% CI, 10%–32%) for the extended letrozole group compared with 49% (32%–67%) for the control group (HR, 0.42). Women treated with letrozole had an increased risk of bone pain (18% vs. 14%), bone fracture (14% vs. 9%), and new-onset osteoporosis (11% vs. 6%).
- A trial randomly assigned 4,742 women who had received 2 years of adjuvant tamoxifen to either continue the tamoxifen or switch to exemestane.[117] After 2.4 years of median follow-up, the exemestane group had a decreased risk of local or metastatic recurrence and a decreased incidence of new contralateral breast cancer (9 vs. 20).
Aromatase inhibitors or inactivators also have been shown to prevent breast cancer in women at increased risk, as shown in the following studies:
- An RCT of primary prevention of breast cancer compared exemestane with placebo in 4,560 women with at least one risk factor (age >60 years, a Gail 5-year risk >1.66%, or a history of DCIS with mastectomy). After 35 months of median follow-up, invasive breast cancer was diagnosed less frequently in the exemestane group (11 vs. 32; HR, 0.35; 95% CI, 0.18–0.70; number needed-to-treat, about 100 for 35 months). Compared with the placebo group, the exemestane-treated women had more hot flashes (increase, 8%) and fatigue (increase, 2%) but no difference in fractures or cardiovascular events.[118]
- The International Breast Cancer Intervention Study II (IBIS-II) randomly assigned 3,864 postmenopausal women who were at increased risk of developing breast cancer to receive either daily anastrazole (1 mg) or placebo for 5 years.[119] The definition of high risk varied by age and was defined by the RR compared with the general population: women aged 40 to 44 years had to have an RR of at least 4; women aged 45 to 60 years had to have an RR of at least 2; and women aged 60 to 70 years had to have an RR of at least 1.5. Alternatively, women with an estimated 10-year risk of developing breast cancer of at least 5% (per the Tyer-Cuzick model) were eligible for inclusion. Women with DCIS diagnosed within 6 months and treated with unilateral mastectomy were eligible for the trial, and 326 were assigned randomly. After a median follow-up of 5 years, fewer breast cancers (invasive and DCIS) occurred in the anastrazole-treated group than in the placebo group (HR, 0.47; 95% CI, 0.32–0.68). The risk of hormone receptor–positive, but not hormone receptor–negative, breast cancer was reduced. Based on predicted cumulative incidence over 7 years, the number of high-risk women (per the IBIS-II eligibility criteria) needed-to-treat for 5 years to prevent one breast cancer in 7 years of follow-up was estimated to be 36 (95% CI, 33–44). Women treated with anastrazole were more likely than those taking placebo to have musculoskeletal symptoms, including arthralgias (51% vs. 46%), joint stiffness (7% vs. 5%), pain in hand or foot (9% vs. 8%) , and carpal tunnel syndrome (3% vs. 2%); hypertension (5% vs. 3%); vasomotor symptoms (57% vs. 49%); and dry eyes (4% vs. 2%). The association between hand or foot pain with anastrazole treatment was of borderline statistical significance; all other side effects noted above were statistically significantly associated with anastrazole treatment.
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