Breast Cancer Research and Treatment

, Volume 105, Supplement 1, pp 75–89

Safety of aromatase inhibitors in the adjuvant setting

Open Access


The third-generation aromatase inhibitors (AIs) letrozole, anastrozole, and exemestane are replacing tamoxifen as adjuvant therapy in most postmenopausal women with early breast cancer. Although AIs have demonstrated superior efficacy and better overall safety compared with tamoxifen in randomized controlled trials, they may not provide the cardioprotective effects of tamoxifen, and bone loss may be a concern with their long-term adjuvant use. Patients require regular bone mineral density monitoring, and prophylactic bisphosphonates are being evaluated to determine whether they may protect long-term bone health. AIs decrease the risks of thromboembolic and cerebrovascular events compared with tamoxifen, and the overall rate of cardiovascular events in patients treated with AIs is within the range seen in age-matched, non-breast-cancer populations. AIs are also associated with a lower incidence of endometrial cancer and fewer vaginal bleeding/discharge events than tamoxifen. Compared with tamoxifen, the incidence of hot flashes is lower with anastrozole and letrozole but may be higher with exemestane. Generally, adverse events with AIs are predictable and manageable, whereas tamoxifen may be associated with life-threatening events in a minority of patients. Overall, the benefits of AIs over tamoxifen are achieved without compromising overall quality of life.


Adjuvant therapy Aromatase inhibitors Early breast cancer Letrozole Safety 


Tamoxifen became the standard adjuvant therapy for women with early breast cancer following the first demonstration of efficacy more than 20 years ago [1]. Administration of tamoxifen for 5 years has been shown to reduce breast cancer recurrence by 41% and mortality by 34% in women with hormone-responsive tumors [2]. Nevertheless, many limitations of tamoxifen have emerged with widespread use. In the landmark National Surgical Adjuvant Breast and Bowel Project B-14 trial, 66% of tamoxifen-treated patients experienced side effects compared with 58% of patients given placebo [3]. Severe, potentially life-threatening events such as thrombosis were more likely to occur in patients aged >60 years [3]. Long-term adverse effects associated with 5 years’ adjuvant tamoxifen include venous thromboembolic events, vaginal bleeding, vaginal discharge, ischemic cerebrovascular events, endometrial and uterine cancer, and hysterectomy [3, 4]. Experiencing side effects significantly increases the likelihood of patients discontinuing tamoxifen therapy (odds ratio 4.0; 95% confidence interval [CI] 1.1, 13.9 in women aged ≥ 55 years) [5]. Over time, resistance to tamoxifen may develop [6], and therapy beyond 5 years is not recommended because neither further disease-free survival nor survival benefit is gained [7].

The third-generation aromatase inhibitors (AIs) letrozole, anastrozole, and exemestane are rapidly replacing tamoxifen as initial adjuvant therapy [8, 9] or sequential adjuvant therapy after 2–5 years of tamoxifen [10, 11, 12, 13]. By potently inhibiting the aromatase enzyme, which converts androgens to estrogen [14, 15], AIs achieve almost total suppression of total body aromatization and dramatic reductions in estrogen concentrations in postmenopausal women [16, 17, 18]. AIs are now recommended in international guidelines for the management of breast cancer [19, 20, 21]. In addition, guidance is being developed for the management of common co-morbidities such as osteoporosis in postmenopausal women with hormone-sensitive breast cancer receiving AIs [20, 22]. This review examines the safety of AIs and assesses their advantages and disadvantages compared with tamoxifen. It also considers the impact of treatment on co-morbidities commonly encountered in this population.

Possible impact of treatment on common co-morbidities

Adjuvant therapy should be individualized on the basis of clinical and biologic risk factors [21], including the presence of co-morbidities [23, 24, 25, 26]. The most prevalent co-morbidities in the postmenopausal patient population are hypertension, arthritis, heart disease, diabetes, chronic obstructive pulmonary disease, eye problems, anemia, depression, fractures, hearing problems, osteoporosis, Parkinson’s disease, renal failure, and urinary tract problems [25]. Understanding the long-term effects of aromatase inhibition on bone and cardiovascular health are particularly important to consider because of the potential effects of altering estrogen concentrations.

Bone disease

Bone health typically may deteriorate as women age, particularly after reaching menopause [27, 28]. A decline in estrogen concentrations accelerates postmenopausal bone loss [29, 30, 31] while vitamin D deficiency also increases bone turnover and the risk of fracture [32, 33]. It is important to note that bone health is compromised in women with breast cancer compared with the general population [34]. In the Women’s Health Initiative Observational Study, breast cancer survivors had significantly lower total body bone mineral density (BMD) and total hip BMD [34] and a significantly higher risk of clinical fractures [35]. Of concern, osteoporosis was undiagnosed in more than three quarters of breast cancer survivors and the reference population [34]. Multiple factors contribute to the increased risk of osteoporosis and fractures in postmenopausal women with breast cancer [34]. Furthermore, tumor cells can have a direct effect on bone remodeling [36], and breast cancer therapy can lead to cancer treatment-induced bone loss (CTIBL) [37, 38, 39]. In a large cohort study, patients with early breast cancer who received anticancer therapy had a 30% higher risk for osteoporosis/osteopenia (odds ratio 1.29; 95% CI 1.13, 1.46) [38]. The study also showed that other factors such as poor health status, history of smoking, and alcohol abuse can contribute to CTIBL. The most serious consequence of CTIBL is an increased risk of fractures (Fig. 1) [35], which increase morbidity and healthcare costs [40]. The presence of bone metastases can contribute to CTIBL and lead to serious complications, including fractures, spinal compression, bone pain, and hypercalcemia of malignancy [41].
Fig. 1

Age-standardized fracture incident rates by survivor status. Standardized rates were calculated using the age distribution of the entire Women’s Health Initiative Observational Study cohort. Excess numbers of fractures per 10,000 person-years are above each set of bars [35]. ©2005 American Medical Association. Reproduced with permission

Aromatase inhibitors and bone disease

In a recent study, the bone health of 1,354 patients with breast cancer receiving an AI (anastrozole, exemestane, or letrozole) was compared with 11,014 controls [39]. Treatment with an AI increased the risk of bone loss (relative risk 1.3; 95% CI 1.1, 1.6; P = 0.01) and bone fracture (relative risk 1.4; 95% CI 1.2, 1.6; P = 0.001). The risks remained significantly higher for AI therapy after adjustment for age and co-morbidities [39]. An increase in the incidence of arthralgia is noted with all three AIs, when compared with tamoxifen.


Howell and colleagues reported fracture rates after a median follow-up of 68 months in the Arimidex, Tamoxifen, Alone or in Combination (ATAC) trial [42]. Fractures were reported in 577 (9.3%) of the 6,186 patients and were more common with anastrozole than with tamoxifen (11 vs. 8%, respectively; P < 0.0001). The incidence of hip fractures was 1% in both groups. The rate of fractures was low at approximately 2% per year and decreased to baseline levels after completion of 5 years of treatment. The effects of anastrozole and tamoxifen on BMD were assessed in a sub-analysis of 167 patients from the ATAC trial [43]. Anastrozole-treated patients had significant decreases in lumbar spine BMD (−8.1%; 95% CI −10.1, −6.1; P < 0.0001) and total hip BMD (−7.4%; 95% CI −9.6, −5.3; P < 0.0001) relative to tamoxifen-treated patients, in whom small increases were observed. Bone loss was greatest in the first 2 years of anastrozole treatment, as reported previously [44], but the rate of loss appeared to slow down from years 2 to 5. In the updated analysis after a median follow-up of 68 months, osteopenia or osteoporosis was reported in 11% of patients receiving anastrozole compared with 7% receiving tamoxifen (P < 0.0001) [42, 45]. Another sub-analysis of the ATAC trial showed that the majority of joint symptoms occur within 24 months of initiating treatment [46]. After 68 months’ median follow-up, joint symptoms were reported in 35.6 and 29.4% of patients in the anastrozole and tamoxifen arms, respectively. Most symptoms were mild in intensity, and 46% were reported as an exacerbation of a pre-existing condition. The incidence of serious joint symptoms was similar for anastrozole and tamoxifen (10.6 vs. 10.4%, respectively) and only 2.1 and 0.9%, respectively, discontinued treatment because of joint symptoms. After a median follow-up of 68 months, muscle cramps were less common with anastrozole than tamoxifen (4 vs. 8%, respectively; P < 0.0001), whereas carpal-tunnel syndrome was more common with anastrozole (3 vs. 1%, respectively; P < 0.0001) [42].

These updated results from the ATAC trial confirm that AIs are a well-tolerated initial treatment option in terms of bone health [43, 45, 46]. Although anastrozole is associated with BMD loss, no patient with normal bone at baseline became osteoporotic after 5 years of treatment, and the rate of bone loss in the lumbar spine region slowed down in years 2–5.

The ARNO/ABCSG8 trials investigated the efficacy and safety of switching to anastrozole after 2 years of tamoxifen [12]. Although there were significantly more fractures in patients switching to anastrozole (2.1%) than in those continuing on tamoxifen (1.0%) [12], the rate was lower than that seen at a similar point in the ATAC trial [12]. In the Italian Tamoxifen Anastrozole (ITA) trial, switching to anastrozole after 2–3 years of tamoxifen was not associated with an increase in fracture rate, although differences may emerge with longer follow-up [13].


In the Breast International Group (BIG) 1–98 trial of initial adjuvant therapy, there was a slight yet significant difference in the incidence of fractures (5.7% with letrozole vs. 4.0% with tamoxifen; P < 0.001) [8]. The MA.17 trial of extended adjuvant therapy showed that when compared with placebo, letrozole had no significant impact on fractures [10]. There was a small but significant difference in patient-reported diagnoses of new-onset osteoporosis (8% letrozole vs. 6% placebo, P = 0.003), and arthralgia and myalgia were significantly more common with letrozole than placebo [10]. A companion study to MA.17 demonstrated a significant decrease in lumbar spine BMD (−5.35 vs. −0.70%; P = 0.008) and total hip BMD (−3.6 vs. −0.71%; P = 0.044) over 2 years in patients treated with letrozole compared with placebo, although no patient went below the threshold for osteoporosis in total hip BMD [47]. Data from this companion study suggest that women with a BMD score of −1.0 or greater when starting letrozole after tamoxifen are less vulnerable to enhanced bone resorption and may not require prophylactic bisphosphonate therapy.


In a model of ovariectomized rats, the steroidal AI exemestane was shown to prevent bone loss, presumably via its androgenic properties (both exemestane and its metabolite 17-hydro-exemestane demonstrate affinity for the androgen receptor) [48]. However, a randomized study to compare the effects of progestins and AIs on bone remodeling markers in patients with metastatic breast cancer found that exemestane increased osteoclast activity [49]. In the adjuvant treatment setting, a randomized trial involving 147 patients with early breast cancer demonstrated a non-significant effect of exemestane compared with placebo on the annual rate of BMD loss in the lumbar spine (2.17 vs. 1.84%; P = 0.568) and a small but significant effect in the femoral neck (2.72 vs. 1.48%; P = 0.024) [50]. Of note was the finding that BMD may rapidly improve following AI discontinuation: this trial showed that bone resorption markers returned to or below baseline values, and bone formation markers remained moderately increased within 6 months of stopping exemestane [51].

In the Intergroup Exemestane Study (IES) of exemestane following 2–3 years of tamoxifen, fractures were reported more frequently with exemestane than with tamoxifen after a median follow-up of 30.6 months, although this difference was not statistically significant (3.1 vs. 2.3%; P = 0.08) [52]. However, the difference in incidence of fractures was statistically significant (7.0% with exemestane vs. 4.9% with tamoxifen; P = 0.003) after a median follow-up of 55.7 months [11]. The incidence of osteoporosis was also significantly higher with exemestane than with tamoxifen (9.2 vs. 7.2%, respectively; P = 0.01). Recent results from a 1-year sub-study revealed that patients on exemestane experienced a significant decrease in hip BMD, while patients on tamoxifen did not [53]. These results were confirmed by another recent study, which evaluated the effects of exemestane on bone turnover markers and BMD in 70 postmenopausal women (62.0 ± 8.9 years) with early breast cancer who were switched to exemestane after 2–3 years on tamoxifen [54]. Patients in the exemestane group had a significant decrease in BMD and early parathyroid hormone (at month 6) and an increase in bone alkaline phosphatase (B-ALP) and the carboxy-terminal telopeptide of type I collagen after 24 months. These studies suggest that switching postmenopausal women from tamoxifen to exemestane causes a marked increase in bone turnover markers with a consequent reduction in BMD.

Arthralgia was also significantly more common with exemestane than with tamoxifen (5.4 vs. 3.6%, P = 0.01) in the IES [52]. A study by Lønning et al. discovered a high prevalence of vitamin D deficiency in postmenopausal women treated with exemestane (52 of 59 patients) or placebo (56 of 62 patients), and this could be the most important factor causing bone loss in both groups [55]. Vitamin D substitution is therefore recommended for postmenopausal women, particularly those with breast cancer receiving an AI. The incidence of carpal-tunnel syndrome in the IES was higher in the exemestane arm (2.8%) than in the tamoxifen arm (0.4%; P < 0.001) [11].

Comparative studies of aromatase inhibitors

A randomized trial (Letrozole, Exemestane, and Anastrozole Pharmacodynamics [LEAP]) of healthy volunteers demonstrated that letrozole, exemestane, and anastrozole have similar effects on bone biochemical measurements and all result in increases in bone turnover [56]. There were no statistically significant differences between the AIs in changes from baseline to 24 weeks for B-ALP, serum C-telopeptide crosslinks, and propeptide of type I procollagen. The only difference in the bone remodeling markers was a greater decrease in parathyroid hormone with exemestane than with anastrozole (P = 0.04).

Thus, all AIs seem to have similar effects on bone health. The ATAC bone sub-study results are reassuring for the entire AI class, and women with breast cancer who have normal BMD measurements at the onset of AI treatment may be able to undergo 5 years of therapy without the risk of developing osteoporosis. Patients at risk of clinically relevant BMD loss during treatment should be identified and managed according to evolving clinical guidelines [20, 57].


In the American Society of Clinical Oncology (ASCO) guidelines postmenopausal patients with breast cancer who receive AIs are identified as being at high risk for osteoporosis, and it is recommended that they have baseline BMD evaluation and regular monitoring to guide subsequent therapeutic interventions such as bisphosphonates [20, 58]. Preliminary results have been reported from a small number of clinical trials of bisphosphonates in women receiving adjuvant AI therapy. In one trial, premenopausal breast cancer patients receiving goserelin plus anastrozole or goserelin plus tamoxifen were randomly assigned to the bisphosphonate zoledronic acid (ZA) (4 mg IV every 6 months) or placebo. After 36 months, it was shown that ZA given every 6 months helped prevent bone loss in these premenopausal patients in both the lumbar spine and hip regardless of endocrine therapy [59]. Two randomized trials have shown that bisphosphonates may be beneficial in postmenopausal patients at a higher risk of osteoporosis [60, 61]. In the Zometa-Femara Adjuvant Synergy Trial (Z-FAST) (North American) trial, 602 postmenopausal women with hormone-responsive breast cancer starting adjuvant therapy with letrozole were randomized to receive upfront ZA (4 mg IV infusion every 6 months) or delayed ZA when indicated (either post-baseline T-score decreases < −2 SD or occurrence of fracture) [60, 62]. Preliminary results after 12 months’ follow-up indicate that initial treatment with ZA may be used to prevent CTIBL, and results at 24 months confirm these initial findings [62, 63] although the rate of clinical fractures was not changed. In addition, the small proportion of patients (8%) requiring ZA in the first year highlights the short-term bone tolerability of letrozole [62]. Results from the similarly designed ZO-FAST (European; N = 1,065) trial also support the use of ZA to potentially manage CTIBL in postmenopausal women with early breast cancer receiving adjuvant letrozole [61].

Lipid metabolism: A cohort study demonstrated that total and low-density lipoprotein (LDL) cholesterol concentrations are positively correlated with years since diagnosis of breast cancer [64]. In addition, during menopause, women experience adverse changes in cardiovascular risk factors, including declines in concentrations of high-density lipoprotein (HDL) cholesterol and increases in concentrations of total cholesterol, LDL cholesterol, HDL3 cholesterol, and triglycerides [65, 66]. These changes are independent of age and body mass index.

Assessing the impact of AIs on lipid profiles is difficult in trials where tamoxifen is the comparator. The selective estrogen-receptor modulators (SERMs) such as tamoxifen are known to have lipid-lowering properties [67, 68]. What is clear is that the studies comparing AIs with tamoxifen indicate only that the AIs lack the lipid-lowering effects of tamoxifen.

Aromatase inhibitors and lipid metabolism


In the ATAC trial, the incidence of hypercholesterolemia was higher in patients receiving anastrozole than tamoxifen (9 vs. 3%, respectively; P < 0.0001) [42]. In the ITA trial, lipid metabolism disorders were reported in 9.3% of patients treated with anastrozole and 4.0% receiving tamoxifen (P = 0.04) [13].

A recent multicenter study in patients with estrogen-receptor positive breast cancer investigated the effects of adjuvant anastrozole and toremifene, a SERM, on serum lipids [68]. Results showed that only toremifene had a beneficial effect on lipid profile, indicated by a decrease in total cholesterol, LDL cholesterol, triglycerides, and apolipoprotein B, and an increase in HDL cholesterol and apolipoprotein A1. Changes in total cholesterol, HDL, LDL, and apolipoproteins were significantly different between toremifene and anastrozole at 6 and 12 months (P < 0.05).


In the BIG 1–98 trial, according to the protocol, cholesterol concentrations (fasting or non-fasting) were collected systematically in the case-report forms every 6 months and even patients with only a single measurement above the upper limit of normal were defined as hypercholesterolemic [8]. Hypercholesterolemia was reported in 5.4% of the letrozole arm compared with 1.2% of the tamoxifen arm in patients with baseline values within normal limits, who then had an increase of 1.5 times the upper limit of normal [69]. Hypercholesterolemia was typically a single event and in the majority of these patients (80%) occurred at only grade 1 intensity (meaning a slight numerical increase above normal, not requiring medications). Moreover, the majority of cases were single measurements collected in non-fasting patients. Furthermore, when looking at total serum cholesterol levels, there was a 12% median decrease from baseline in total cholesterol in the tamoxifen arm after 6 months, consistent with previous reports demonstrating the lipid-lowering effect of tamoxifen [67], while in the letrozole group total cholesterol values remained stable [8]. Hypercholesterolemia was not predefined as an adverse event in the ATAC trial, and lipid concentrations were not routinely assessed [42].


Hypercholesterolemia was not reported in the IES trial of sequential exemestane after tamoxifen [11, 52].

Another study examined the longitudinal changes in body composition and lipid profiles in 55 postmenopausal women with early breast cancer switched to exemestane after at least 2 years of tamoxifen treatment [70]. Fat mass significantly decreased (P < 0.01) while the fat-free mass to fat mass ratio significantly increased (P < 0.05) by month 12 in the exemestane but not in the tamoxifen group. In addition, triglycerides and HDL cholesterol significantly decreased (P < 0.01 and P < 0.05, respectively) in the exemestane group, while LDL cholesterol significantly increased (P < 0.01) at the end of the 1-year study period.

Aromatase inhibitors versus placebo

When compared with placebo (the most accurate way to assess the true impact of AIs on serum lipids), the final analysis of the MA.17 trial demonstrated the incidence of hypercholesterolemia was 16% in the letrozole and the placebo arms [10]. Results from an MA.17 lipid sub-study showed that in 347 postmenopausal women with primary breast cancer treated for up to 36 months, letrozole (n = 183) does not significantly alter lipid profile (samples drawn under fasting conditions) compared with placebo (n = 164) [71]. In a placebo-controlled study involving 147 postmenopausal women with early breast cancer, exemestane had no major effect on lipid profile except for a modest but significant decrease from baseline in HDL cholesterol (P < 0.001) and apolipoprotein A1 (P = 0.004) [50]. On the basis of these results, it is clear that when compared with placebo, AIs do not have a detrimental effect on lipid profile. However, it should be noted that there have been no placebo-controlled trials of adjuvant anastrozole in women with breast cancer.

Comparative studies of aromatase inhibitors

The LEAP trial directly compared safety parameters between the steroidal AI exemestane and the non-steroidal AIs anastrozole and letrozole in 90 healthy postmenopausal women (Table 1) [72]. Initial results from the trial showed that there were no significant differences between anastrozole and letrozole in effects on LDL:HDL ratios, triglyceride concentrations, and non-HDL concentrations. Exemestane was associated with an increase in LDL:HDL ratio (+17) (P = 0.047) compared with anastrozole. There was no median change from baseline in total serum cholesterol for letrozole, a slight increase for anastrozole (+0.4), and a non-significant decrease for exemestane (−3.9) (P = 0.164 vs. anastrozole) [72].
Table 1

Comparative effects of third-generation aromatase inhibitors on lipids [72]

Percentage change from baseline

Anastrozole (n = 29)

Letrozole (n = 29)

P value vs. anastrozole

Exemestane (n = 32)

P value vs. anastrozole

Total cholesterol

 Week 12






 Week 24








 Week 12






 Week 24






Ratio of LDL-C:HDL-C

 Week 12






 Week 24








 Week 12






 Week 24






Ratio of apo B:apo A1

 Week 12






 Week 24






LDL-C low-density lipoprotein cholesterol, HDL-C high-density lipoprotein, apo B apolipoprotein B, apo A1 apolipoprotein A1

Cardiovascular disease

Cardiovascular risk increases substantially and progressively in women aged ≥65 years [73, 74, 75, 76, 77]. Isolated systolic hypertension, associated with arterial stiffening, is predominant in middle- and older-aged hypertensives [75] and predisposes individuals to coronary heart disease, heart failure, stroke, vascular dementia, and chronic kidney disease [73]. The risk of cardiac disease is also influenced by ethnicity, smoking, obesity, physical inactivity, alcohol abuse, and the presence of co-morbid diseases such as diabetes.

In patients with breast cancer the presence of co-morbidities, including cardiovascular disease and diabetes, is associated with a poorer prognosis than when co-morbid disease is absent [78] and may explain disparities in outcome between different ethnic groups [79]. There is also evidence that breast cancer is associated with a higher prevalence of hypertension compared with other tumor types [80] and a significantly increased risk of stroke compared with the general population (relative risk 1.12; 95% CI 1.07, 1.17) [81]. Many breast cancer therapies increase the risk of cardiovascular events [82, 83, 84, 85, 86, 87, 88]; tamoxifen, however, may have some cardio-protective effects [89, 90].

Tamoxifen and cardiovascular disease

Several studies have demonstrated the potential cardioprotective properties of tamoxifen, including a reduction in hospital admissions due to cardiac disease [89, 90, 91] and decreased mortality from cardiac disease [92]. In a meta-analysis, tamoxifen was associated with a significantly decreased incidence of myocardial infarction (relative risk 0.90) and death from myocardial infarction (relative risk 0.62) [93]. This finding is consistent with results from an earlier cohort study [94] and the Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) meta-analysis, which demonstrated decreases in the risk of cardiac death and overall mortality from vascular disease in patients receiving tamoxifen compared with those receiving placebo [2].

Aromatase inhibitors and cardiovascular disease

Assessing the impact of different AIs on cardiovascular disease in postmenopausal women with breast cancer is difficult and inter-trial comparisons are confounded by differences in data collection and end points; for example, in the BIG 1–98 trial all potential adverse events were predefined in the case-report forms whereas the ATAC trial used non-specific case-report forms to report adverse events [8, 95]. Furthermore, comparisons with tamoxifen are complicated by its cardioprotective properties. Placebo-controlled trials thus provide the best source of data to delineate the effects of AIs in a patient population with an inherently elevated risk of cardiac events.


The ATAC trial provided data on the cardiovascular effects of anastrozole as initial adjuvant therapy compared with tamoxifen. The incidence of ischemic cardiovascular disease was higher (but not significantly) with anastrozole than placebo (127/3092, 4.1% vs. 104/3094, 3.4%; P = 0.1). The incidence of angina was also higher with anastrozole (71/3092, 2.3% vs. 51/3094, 1.6%; P = 0.07), while myocardial infarction occurred with similar frequency (37/3092, 1.2% vs. 34/3094, 1.1%; P = 0.7 [42]. Hypertension was statistically significantly more common with anastrozole than with tamoxifen (13 vs. 11%, respectively; P = 0.04) [42]. In the ARNO95 trial vascular events, including hot flashes, ischemic cardiovascular events, deep vein thrombosis, and ischemic cerebrovascular events, occurred in 9.2% of the anastrozole arm compared with 8.8% of the tamoxifen arm [96].


The BIG 1–98 trial demonstrated a similar incidence of cardiac events in the letrozole and tamoxifen groups (4.1 vs. 3.8%, respectively; not significant). However, more women in the letrozole group had grade 3, 4, or 5 cardiac events (2.1 vs. 1.1%, respectively; P < 0.001), but these events remain rare [8]. Of note, a recent update of the monotherapy arms of BIG 1–98 after a longer median follow-up of 51 months showed that the overall incidence of cardiac events was comparable in the two groups (134 events [5.5%] in the letrozole group vs. 122 [5.0%] in the tamoxifen arm), thus confirming the safe cardiac profile of letrozole reported at 26 months [97].


In the IES, there was no significant difference between exemestane and tamoxifen in the incidence of combined cardiovascular disease/thromboembolic events (22.1 vs. 20.9%, respectively; P = 0.34) after a median follow-up of 55.7 months [11]. The incidence of myocardial infarction was higher with exemestane than with tamoxifen, although the difference between treatment groups was not significant (1.3 vs. 0.8%, respectively; P = 0.08) [11].

Overall, the rate of cardiovascular events in patients treated with AIs is well within the range seen in age-matched, non-breast-cancer populations; for example, for women 57–65 years of age, the rates of fatal myocardial infarction and other fatal coronary artery disease are 1.1 and 0.81 per 1,000 patient-years, respectively [98]. Similar rates were recorded in the UK General Practice Research Database and Swedish MI register [99]. Currently, there is insufficient information to fully determine the effect of AIs on cardiovascular disease, especially coronary heart disease.

Aromatase inhibitors versus placebo

Cardiovascular events occurred with similar frequency in the letrozole and placebo arms in the MA.17 trial (5.8 vs. 5.6%, respectively; P = 0.76) [10]. Similar incidences were reported in the letrozole and placebo arms for stroke/transient ischemic attack (0.7 vs. 0.6%, respectively), myocardial infarction (0.3 vs. 0.4%, respectively), new or worsening angina (1.2 vs. 0.9%), angina requiring coronary artery bypass graft (0.2 vs. 0.5%), and thromboembolic events (0.4 vs. 0.2%, respectively) [10]. These results clearly indicate that when compared with placebo, AIs do not have a detrimental effect on cardiovascular safety.

Gynecologic health

The onset of menopause is characterized by numerous adverse events associated with a decline in estrogen concentrations [100, 101, 102]. Early symptoms include abnormal vaginal bleeding, hot flashes, and mood changes, while vaginal dryness and irritation, osteoporosis, and heart disease are late symptoms [29, 103, 104]. Vasomotor symptoms, particularly hot flashes, are common during transition to menopause [105, 106, 107, 108, 109] and may lead to disturbed sleep, depressive symptoms, and significant reductions in quality of life [110, 111, 112, 113, 114, 115]. Cigarette smoking may be associated with increased risk of hot flashes in menopausal women [116]. Sexual dysfunction is also prevalent in menopausal women and is associated with vaginal atrophy, vaginal/genital dryness, dyspareunia (pain during sexual intercourse), vaginitis, cystitis, and urinary tract infections [117].

Aromatase inhibitors and gynecologic health


In the ATAC trial, the incidence of hot flashes was significantly lower with anastrozole than with tamoxifen (36 vs. 41%; P < 0.0001) [9]. In the latest analysis, anastrozole was associated with a significantly lower incidence of gynecologic events (endometrial hyperplasia, endometrial neoplasia, cervical neoplasm, and enlarged uterine fibroids: 3 vs. 10% with tamoxifen; P < 0.0001) [42]. A quality-of-life (QOL) analysis confirmed that vaginal discharge, vaginal itching/irritation, and vaginal bleeding were less common with anastrozole but found that vaginal dryness, pain during intercourse, and loss of interest in sex were more common [118]. After 2 years of treatment there was a non-significant trend towards a lower incidence of endometrial abnormalities with anastrozole than tamoxifen (odds ratio 0.44; 95% CI 0.146, 1.314; P = 0.14) [119]. The latest update of the ATAC trial revealed reduced libido in significantly more patients receiving anastrozole (1%) than tamoxifen (<1%; P = 0.0001) [42]. Patients receiving anastrozole also experienced a significantly higher incidence of dyspareunia than those receiving tamoxifen (1 vs. < 1%, respectively; P = 0.002), whereas urinary incontinence and urinary tract infection were significantly less common among patients receiving anastrozole (urinary incontinence: 2 vs. 4%, respectively, P < 0.0001; urinary tract infection: 8 vs. 10%, respectively, P = 0.002).

In a randomized study of postmenopausal women in whom abnormal vaginal bleeding and/or asymptomatic endometrial thickening occurred during treatment with tamoxifen, switching to anastrozole was associated with a significant reduction in mean endometrial thickness compared with continuation of tamoxifen (P < 0.0001) [120]. Significantly fewer anastrozole patients required a repeat hysteroscopy and dilation and curettage compared with those taking tamoxifen (4.8 vs. 33.0%, respectively; P < 0.0001).


In the BIG 1–98 trial [8], endometrial biopsies were significantly less common in patients receiving letrozole than tamoxifen (2.3 vs. 9.1%, respectively; P < 0.001), and there was a trend towards fewer invasive endometrial cancers (0.1 vs. 0.3%, respectively; not significant). There was a significantly lower incidence of vaginal bleeding with letrozole than with tamoxifen (3.3 vs. 6.6%, respectively; P < 0.001), and the incidence of hot flashes was also significantly lower (33.5 vs. 38.0%, respectively; P < 0.001). In another study in patients intolerant of tamoxifen, switching to letrozole for 6 weeks was associated with a 53.7% decrease in hot flashes (hot-flash score 97.0–52.1; P = 0.001) [121]. In the MA.17 trial, letrozole was associated with less vaginal bleeding than placebo (6 vs. 8%, respectively; P = 0.005) but a greater incidence of hot flashes (58 vs. 54%, respectively; P = 0.003) [10]. There was no significant difference in the incidence of vaginal dryness between letrozole and placebo.


In the IES, there were no significant differences between the exemestane and tamoxifen treatment arms in the incidence of endometrial cancer (0.4 vs. 0.7%, respectively; P = 0.17) [11], or the incidence of hot flashes (42 vs. 40%, respectively; P = 0.28) [52]. Overall, gynecologic symptoms were lower with exemestane than with tamoxifen (6 vs. 9%; P < 0.001) [52]; however, vaginal dryness was significantly more common among women taking exemestane than those taking tamoxifen, while vaginal discharge was significantly more common with tamoxifen [122]. Vaginal bleeding was significantly more common in the tamoxifen arm (7.1%) than in the exemestane group (4.8%; P = 0.001) [11].

Other adverse events

Secondary cancer

The association between tamoxifen and endometrial and uterine cancers is well-established [4] and is not observed with AIs. However, a safety analysis of the ATAC trial [42] showed a surprisingly higher incidence of head and neck cancer with anastrozole compared with tamoxifen (10/3092 vs. 3/3094, respectively). Similarly, there was an excess of lung cancer (25/3092 vs. 16/3094) and lung cancer deaths with anastrozole; however, further analyses are required to confirm these findings. Of note, a higher incidence of secondary cancer was not noted in the IES (72 events exemestane vs. 107 tamoxifen) or in the BIG 1–98 trial (69 letrozole vs. 82 tamoxifen) [8, 11].

A meta-analysis showed that tamoxifen is associated with a modest but statistically significant increase in the risk of developing gastrointestinal cancer (relative risk 1.31; 95% CI 1.01, 1.69), particularly for postmenopausal women (relative risk 1.77) [93].

Gastrointestinal health

Diarrhea was significantly more common among patients receiving the steroidal AI exemestane than in those taking tamoxifen (4.2 vs. 2.2%, respectively) [123] but is not a typical side effect of the non-steroidal AIs letrozole and anastrozole. However, an updated safety analysis of the ATAC trial showed that anastrozole was associated with an increased incidence of diarrhea compared with tamoxifen (9 vs. 7%; P = 0.02) [42].

Neurologic effects and visual disturbance

It has been suggested that endocrine therapy may affect cognitive function in patients with breast cancer [124]. In a study comparing patients from the ATAC trial with healthy controls, anastrozole was associated with significant impairments in a processing speed task and on a measure of immediate verbal memory [125]. Another study conducted in healthy, estrogen-treated postmenopausal women treated with testosterone did not reveal any effects of aromatase inhibition on cognition [126].

The impact of adjuvant AI therapy on cognition and other neurologic processes is clearly an important issue that will require further studies in the future. Neurologic effects reported with exemestane, including dizziness and vertigo [127] and significantly more visual disturbances compared with tamoxifen [52], are not characteristic of non-steroidal AIs.

Dry mouth

The latest analysis of the ATAC trial demonstrated a significantly greater incidence of dry mouth in patients receiving anastrozole (4%) compared with tamoxifen (2%; P = 0.003) [42].

Cosmetic effects

Weight gain is common after breast cancer therapy and increases the risk of recurrence, cardiovascular disease, and diabetes [64]. A study of Japanese patients showed that more women reported weight gain in the anastrozole group than in the tamoxifen group (35.8 vs. 12.5%, respectively; P ≤ 0.0036) [128], but no difference was seen among patients from the ATAC trial included in a QOL sub-analysis [118].

The androgen structure of exemestane may lead to androgenic side effects. Hypertrichosis, hair loss, hoarseness, and acne were reported in about 10% of patients treated with daily exemestane doses of 200 mg or more in dose-finding studies [129, 130], but have not emerged as a significant issue in phase II or phase III trials with this agent.

Anastrozole treatment was associated with a lower incidence of nail disorders (2 vs. 3%; P = 0.002) and fungal infection (1 vs. 1%; p = 0.01) compared with tamoxifen [42].

Quality of life and patient preference


The QOL of patients treated in the ATAC trial was studied during a 5-year follow-up period [118, 131]. Anastrozole and tamoxifen had similar overall effects on QOL (Functional Assessment of Cancer Therapy-Breast [FACT-B] trial outcome index plus endocrine sub-scale) in the first 2 years of treatment [118], and an initial worsening of endocrine symptoms gradually improved over time [131]. The authors concluded that the benefits of anastrozole are achieved without detrimental effects on QOL. However, another study conducted in Japanese patients demonstrated that FACT-G, FACT-B, and FACT-ES scores were significantly better with tamoxifen than with anastrozole (P = 0.012, P = 0.010, and P = 0.015, respectively) [132].


The MA.17 and BIG 1–98 trials have demonstrated that adjuvant letrozole is well-tolerated compared with placebo [10] and better tolerated than tamoxifen [8]. In another study of postmenopausal women who were experiencing distressing side effects while taking adjuvant tamoxifen and were switched to letrozole, after 6 weeks 66% of patients preferred to remain on letrozole, 24% preferred to go back to tamoxifen, and 10% stopped all therapy [121].

In the placebo-controlled MA.17 trial, letrozole significantly improved outcomes and did not impair overall QOL [133] (Fig. 2). Minor differences seen in some domains (physical functioning, bodily pain, vitality, vasomotor, and sexual) were consistent with a minority of patients experiencing changes in QOL compatible with a reduction in estrogen synthesis. A sub-analysis of US subjects in MA.17 demonstrated no significant differences between letrozole and placebo in overall QOL summary scores (mental and physical) and five of eight sub-domains of SF-36 [134]. There were no differences in SF-36 mental and physical QOL scores and MENQOL (menopause symptom scale) psychosocial and physical domains [134].
Fig. 2

Mean change score in Short Form 36-item Health Survey. A positive score indicates a favorable change in quality of life. (A) Physical component summary; P = not significant for all time points. (B) Mental component summary; P = not significant for all time points. [133]. ©2005 American Society of Clinical Oncology. Reproduced with permission


Results from the IES QOL sub-protocol indicate that switching to exemestane from tamoxifen improves outcome without a significant detrimental impact upon QOL [135]. At entry, there was a high prevalence of severe endocrine symptoms (vasomotor complaints and sexual problems), and these persisted with exemestane and tamoxifen during the study. No significant differences between groups were seen for any endocrine symptoms apart from vaginal discharge, which was more pronounced with tamoxifen (P < 0.001).


Clinical trials show that the third-generation AIs lack the serious risks of thromboembolism and endometrial cancers associated with tamoxifen and are generally well tolerated, with the majority of adverse events occurring at mild to moderate intensity [8, 9, 10, 11].

AIs are associated with a mild to modest increased risk of osteoporosis compared with tamoxifen, and it is therefore essential that patients have regular BMD assessments and be monitored proactively to minimize the risk of clinical fractures [20, 57]. The increased risk of fractures with an AI compared with tamoxifen needs to be balanced against the increased risk of endometrial and cerebrovascular/thromboembolic morbidity with tamoxifen [136]. Of note, the updated ATAC analysis shows that the majority of excess adverse events associated with tamoxifen occurred during the first 2.5 years of treatment; there were 142 (8%) fewer predefined adverse events in the anastrozole arm [137]. Thus, it appears that many excess gynecologic, thromboembolic, and cerebrovascular adverse effects occurring in tamoxifen-treated patients could be avoided if patients were treated initially with an AI [136].

Although AIs do not have the cholesterol-lowering and potential cardioprotective properties of tamoxifen, they do not significantly worsen total cholesterol concentrations and do not appear to increase cardiovascular risk when compared with placebo. Nevertheless, it is prudent to recommend that all patients at risk of cardiovascular effects are properly monitored and managed, and all breast cancer patients should be routinely monitored for cardiovascular disease. It is difficult to draw meaningful conclusions from comparisons of randomized trials of tamoxifen versus anastrozole, letrozole, or exemestane because of differences in assessing and reporting risk of cardiovascular disease [8, 52, 95, 138].

Current information is insufficient to determine the effects of AIs on cardiovascular disease and coronary heart disease risk [20]. Similarly, further follow-up is required to determine the late consequences of AI therapy [20]. Despite these provisos, ASCO now recommends that optimal adjuvant hormonal therapy for a postmenopausal woman with receptor-positive breast cancer includes an AI as initial therapy or after treatment with tamoxifen. Results from several ongoing trials, including the Femara versus Anastrozole Clinical Evaluation, MA.27, the National Surgical Adjuvant Breast and Bowel Project, LATER, and MILER, should provide more information on the long-term tolerance and the optimal duration of adjuvant AI therapy and help determine which strategy has the best ratio of efficacy to tolerance.

In conclusion, the efficacy benefits of AIs outweigh the risks when AIs are used as adjuvant therapy in postmenopausal women with early breast cancer. Safety, QOL, and patient preference must all be considered in the determination of the optimal strategy for long-term endocrine therapy, bearing in mind that patients may require treatment for 10 years or more. Every patient is unique, and endocrine therapy must be individualized according to clinical, biologic, and patient factors such as lifestyle, the presence of significant co-morbidities, and use of concomitant medications. Tolerability should no longer be an obstacle to effective, long-term endocrine therapy.


  1. 1.
    Nolvadex Adjuvant Trial Organization (1983) Controlled trial of tamoxifen as adjuvant agent in management of early breast cancer. Interim analysis at four years by Nolvadex Adjuvant Trial Organisation. Lancet 1:257–261Google Scholar
  2. 2.
    Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) (2005) Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. Lancet 365:1687–1717Google Scholar
  3. 3.
    Fisher B, Dignam J, Bryant J, DeCillis A, Wickerham DL, Wolmark N, Costantino J, Redmond C, Fisher ER, Bowman DM, Deschenes L, Dimitrov NV, Margolese RG, Robidoux A, Shibata H, Terz J, Paterson AH, Feldman MI, Farrar W, Evans J, Lickley HL (1996) Five versus more than five years of tamoxifen therapy for breast cancer patients with negative lymph nodes and estrogen receptor-positive tumors. J Natl Cancer Inst 88:1529–1542PubMedGoogle Scholar
  4. 4.
    Fisher B, Costantino JP, Redmond CK, Fisher ER, Wickerham DL, Cronin WM (1994) Endometrial cancer in tamoxifen-treated breast cancer patients: findings from the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-14. J Natl Cancer Inst 86:527–537PubMedGoogle Scholar
  5. 5.
    Demissie S, Silliman RA, Lash TL (2001) Adjuvant tamoxifen: predictors of use, side effects, and discontinuation in older women. J Clin Oncol 19:322–328PubMedGoogle Scholar
  6. 6.
    Meijer D, van Agthoven T, Bosma PT, Nooter K, Dorssers LC (2006) Functional screen for genes responsible for tamoxifen resistance in human breast cancer cells. Mol Cancer Res 4:379–386PubMedGoogle Scholar
  7. 7.
    Fisher B, Dignam J, Bryant J, Wolmark N (2001) Five versus more than five years of tamoxifen for lymph node-negative breast cancer: updated findings from the National Surgical Adjuvant Breast and Bowel Project B-14 randomized trial. J Natl Cancer Inst 93:684–690PubMedGoogle Scholar
  8. 8.
    Thürlimann B, Keshaviah A, Coates AS, Mouridsen H, Mauriac L, Forbes JF, Paridaens R, Castiglione-Gertsch M, Gelber RD, Rabaglio M, Smith I, Wardley A, Price KN, Goldhirsch A; Breast International Group (BIG) 1–98 Collaborative Group (2005) A comparison of letrozole and tamoxifen in postmenopausal women with early breast cancer. N Engl J Med 353:2747–2757. Erratum in: N Engl J Med (2006) 354:2200Google Scholar
  9. 9.
    Howell A, Cuzick J, Baum M, Buzdar A, Dowsett M, Forbes JF, Hoctin-Boes G, Houghton J, Locker GY, Tobias JS; ATAC Trialists’ Group (2005) Results of the ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial after completion of 5 years’ adjuvant treatment for breast cancer. Lancet 365:60–62PubMedGoogle Scholar
  10. 10.
    Goss PE, Ingle JN, Martino S, Robert NJ, Muss HB, Piccart MJ, Castiglione M, Tu D, Shepherd LE, Pritchard KI, Livingston RB, Davidson NE, Norton L, Perez EA, Abrams JS, Cameron DA, Palmer MJ, Pater JL (2005) Randomized trial of letrozole following tamoxifen as extended adjuvant therapy in receptor-positive breast cancer: updated findings from NCIC CTG MA.17. J Natl Cancer Inst 97:1262–1271PubMedGoogle Scholar
  11. 11.
    Coombes RC, Kilburn LS, Snowdon CF, Paridaens R, Coleman RE, Jones SE, Jassem J, Van de Velde CJ, Delozier T, Alvarez I, Del Mastro L, Ortmann O, Diedrich K, Coates AS, Bajetta E, Holmberg SB, Dodwell D, Mickiewicz E, Andersen J, Lonning PE, Cocconi G, Forbes J, Castiglione M, Stuart N, Stewart A, Fallowfield LJ, Bertelli G, Hall E, Bogle RG, Carpentieri M, Colajori E, Subar M, Ireland E, Bliss JM; Intergroup Exemestane Study (2007) Survival and safety of exemestane versus tamoxifen after 2–3 years’ tamoxifen treatment (Intergroup Exemestane Study): a randomised controlled trial. Lancet 17(369):559–570Google Scholar
  12. 12.
    Jakesz R, Jonat W, Gnant M, Mittlboeck M, Greil R, Tausch C, Hilfrich J, Kwasny W, Menzel C, Samonigg H, Seifert M, Gademann G, Kaufmann M, Wolfgang J; ABCSG, the GABG (2005) Switching of postmenopausal women with endocrine-responsive early breast cancer to anastrozole after 2 years’ adjuvant tamoxifen: combined results of ABCSG trial 8 and ARNO 95 trial. Lancet 366:455–462PubMedGoogle Scholar
  13. 13.
    Boccardo F, Rubagotti A, Puntoni M, Guglielmini P, Amoroso D, Fini A, Paladini G, Mesiti M, Romeo D, Rinaldini M, Scali S, Porpiglia M, Benedetto C, Restuccia N, Buzzi F, Franchi R, Massidda B, Distante V, Amadori D, Sismondi P (2005) Switching to anastrozole versus continued tamoxifen treatment of early breast cancer: preliminary results of the Italian Tamoxifen Anastrozole Trial. J Clin Oncol 23:5138–5147PubMedGoogle Scholar
  14. 14.
    Brodie A, Lu Q, Liu Y, Long B (1999) Aromatase inhibitors and their antitumor effects in model systems. Endocr Relat Cancer 6:205–210PubMedGoogle Scholar
  15. 15.
    Brodie AH, Jelovac D, Long B (2003) The intratumoral aromatase model: studies with aromatase inhibitors and antiestrogens. J Steroid Biochem Mol Biol 86:283–288PubMedGoogle Scholar
  16. 16.
    Dowsett M, Jones A, Johnston SR, Jacobs S, Trunet P, Smith IE (1995) In vivo measurement of aromatase inhibition by letrozole (CGS 20267) in postmenopausal patients with breast cancer. Clin Cancer Res 1:1511–1515PubMedGoogle Scholar
  17. 17.
    Geisler J, Haynes B, Anker G, Dowsett M, Lonning PE (2002) Influence of letrozole and anastrozole on total body aromatization and plasma estrogen levels in postmenopausal breast cancer women evaluated in a randomized, cross-over study. J Clin Oncol 20:751–757PubMedGoogle Scholar
  18. 18.
    Dixon JM, Renshaw L, Young O, Murray J, Macaskill EJ, McHugh M, Folkerd E, Cameron D, Dowsett M (2006) Letrozole suppresses plasma oestradiol (E2) levels more completely than anastrozole in postmenopausal women with breast cancer. J Clin Oncol 24(18S):15s. Abstract 552Google Scholar
  19. 19.
    National Comprehensive Cancer Network Practice Guidelines in Oncology v.1.2007. Breast Cancer Version 1.2007. Cited 6 Mar 2007
  20. 20.
    Winer EP, Hudis C, Burstein HJ, Wolff AC, Pritchard KI, Ingle JN, Chlebowski RT, Gelber R, Edge SB, Gralow J, Cobleigh MA, Mamounas EP, Goldstein LJ, Whelan TJ, Powles TJ, Bryant J, Perkins C, Perotti J, Braun S, Langer AS, Browman GP, Somerfield MR (2005) American Society of Clinical Oncology technology assessment on the use of aromatase inhibitors as adjuvant therapy for postmenopausal women with hormone receptor-positive breast cancer: status report 2004. J Clin Oncol 23:619–629PubMedGoogle Scholar
  21. 21.
    Goldhirsch A, Glick JH, Gelber RD, Coates AS, Thurlimann B, Senn HJ; Panel members (2005) Meeting highlights: international expert consensus on the primary therapy of early breast cancer 2005. Ann Oncol 16:1569–1583PubMedGoogle Scholar
  22. 22.
    Theriault RL, Biermann JS, Brown E, Brufsky A, Demers L, Grewal RK, Guise T, Jackson R, McEnery K, Podoloff D, Ravdin P, Shapiro CL, Smith M, Van Poznak CH (2006) NCCN task force report: bone health and cancer care. J Natl Compr Canc Netw 4(Suppl 2):S1–S20Google Scholar
  23. 23.
    Siegelmann-Danieli N, Khandelwal V, Wood GC, Mainali R, Prichard J, Murphy TJ, Evans JF, Yumen O, Bernath AM (2006) Breast cancer in elderly women: outcome as affected by age, tumor features, co-morbidities, and treatment approach. Clin Breast Cancer 7:59–66PubMedGoogle Scholar
  24. 24.
    Nagel G, Rohrig B, Hoyer H, Wedding U, Katenkamp D (2003) A population-based study on variations in the use of adjuvant systemic therapy on postmenopausal patients with early stage breast cancer. J Cancer Res Clin Oncol 129:183–191PubMedGoogle Scholar
  25. 25.
    Yancik R, Wesley MN, Ries LA, Havlik RJ, Edwards BK, Yates JW (2001) Effect of age and comorbidity in postmenopausal breast cancer patients aged 55 years and older. JAMA 285:885–892PubMedGoogle Scholar
  26. 26.
    Ravdin PM, Siminoff LA, Davis GJ, Mercer MB, Hewlett J, Gerson N, Parker HL (2001) Computer program to assist in making decisions about adjuvant therapy for women with early breast cancer. J Clin Oncol 19:980–991PubMedGoogle Scholar
  27. 27.
    Siris ES, Miller PD, Barrett-Connor E, Faulkner KG, Wehren LE, Abbott TA, Berger ML, Santora AC, Sherwood LM (2001) Identification and fracture outcomes of undiagnosed low bone mineral density in postmenopausal women: results from the National Osteoporosis Risk Assessment. JAMA 286:2815–2822PubMedGoogle Scholar
  28. 28.
    Sirola J, Kroger H, Honkanen R, Jurvelin JS, Sandini L, Tuppurainen MT, Saarikoski S; OSTPRE Study Group (2003) Factors affecting bone loss around menopause in women without HRT: a prospective study. Maturitas 45:159–167PubMedGoogle Scholar
  29. 29.
    Guthrie JR, Lehert P, Dennerstein L, Burger HG, Ebeling PR, Wark JD (2004) The relative effect of endogenous estradiol and androgens on menopausal bone loss: a longitudinal study. Osteoporos Int 15:881–886PubMedGoogle Scholar
  30. 30.
    Hanna K, Wong J, Patterson C, O’Neill S, Lyons-Wall P (2004) Phytoestrogen intake, excretion and markers of bone health in Australian women. Asia Pac J Clin Nutr 13(Suppl):S74Google Scholar
  31. 31.
    Devine A, Dick IM, Dhaliwal SS, Naheed R, Beilby J, Prince RL (2005) Prediction of incident osteoporotic fractures in elderly women using the free estradiol index. Osteoporos Int 16:216–221PubMedGoogle Scholar
  32. 32.
    Prince RL, Dick I, Devine A, Price RI, Gutteridge DH, Kerr D, Criddle A, Garcia-Webb P, St John A (1995) The effects of menopause and age on calcitropic hormones: a cross-sectional study of 655 healthy women aged 35 to 90. J Bone Miner Res 10:835–842PubMedCrossRefGoogle Scholar
  33. 33.
    Brazier M, Kamel S, Maamer M, Agbomson F, Elesper I, Garabedian M, Desmet G, Sebert JL (1995) Markers of bone remodeling in the elderly subject: effect of vitamin D insufficiency and its correction. J Bone Miner Res 10:1753–1761PubMedGoogle Scholar
  34. 34.
    Chen Z, Maricic M, Pettinger M, Ritenbaugh C, Lopez AM, Barad DH, Gass M, Leboff MS, Bassford TL (2005) Osteoporosis and rate of bone loss among postmenopausal survivors of breast cancer. Cancer 104:1520–1530PubMedGoogle Scholar
  35. 35.
    Chen Z, Maricic M, Bassford TL, Pettinger M, Ritenbaugh C, Lopez AM, Barad DH, Gass M, Leboff MS (2005) Fracture risk among breast cancer survivors: results from the Women’s Health Initiative Observational Study. Arch Intern Med 165:552–558PubMedGoogle Scholar
  36. 36.
    Pederson L, Winding B, Foged NT, Spelsberg TC, Oursler MJ (1999) Identification of breast cancer cell line-derived paracrine factors that stimulate osteoclast activity. Cancer Res 59:5849–5855PubMedGoogle Scholar
  37. 37.
    Bruning PF, Pit MJ, de Jong-Bakker M, van den Ende A, Hart A, van Enk A (1990) Bone mineral density after adjuvant chemotherapy for premenopausal breast cancer. Br J Cancer 61:308–310PubMedGoogle Scholar
  38. 38.
    Boyce SP, Mincey AB, Duh M, Marynchenko M, Raut MK, Brandman J, Perez EA (2005) Risk of osteoporosis/osteopenia among women with breast cancer receiving anti-cancer therapy (ACT). J Clin Oncol 23(16S):44s. Abstract 665Google Scholar
  39. 39.
    Mincey BA, Duh MS, Thomas SK, Moyneur E, Marynchencko M, Boyce SP, Mallett D, Perez EA (2006) Risk of cancer treatment-associated bone loss and fractures among women with breast cancer receiving aromatase inhibitors. Clin Breast Cancer 7:127–132PubMedGoogle Scholar
  40. 40.
    Zhou Z, Redaelli A, Johnell O, Willke RJ, Massimini G (2004) A retrospective analysis of health care costs for bone fractures in women with early-stage breast carcinoma. Cancer 100:507–517PubMedGoogle Scholar
  41. 41.
    Kanis JA, McCloskey EV, Powles T, Paterson AH, Ashley S, Spector T (1999) A high incidence of vertebral fracture in women with breast cancer. Br J Cancer 79:1179–1181PubMedGoogle Scholar
  42. 42.
    The Arimidex, Tamoxifen, Alone or in Combination Trialists’ Group, Buzdar A, Howell A, Cuzick J, Wale C, Distler W, Hoctin-Boes G, Houghton J, Locker GY, Nabholtz JM (2006) Comprehensive side-effect profile of anastrozole and tamoxifen as adjuvant treatment for early-stage breast cancer: long-term safety analysis of the ATAC trial. Lancet Oncol 7:633–643Google Scholar
  43. 43.
    Coleman RE, on behalf of the ATAC Trialists’ Group (2006) Effect of anastrozole on bone mineral density: 5-year results from the ‘Arimidex’, Tamoxifen, Alone or in Combination (ATAC) trial. J Clin Oncol 24(18S):5s. Abstract 511Google Scholar
  44. 44.
    Howell A, on behalf of the ATAC Trialists’ Group (2003) Effect of anastrozole on bone mineral density: 2-year results of the ‘arimidex’ (anastrozole), tamoxifen, alone or in combination (ATAC) trial. Presented at the 26th Annual San Antonio Breast Cancer Symposium, 3–6 December 2003. Abstract 129Google Scholar
  45. 45.
    Howell A, on behalf of the ATAC Trialists’ Group (2006) Analysis of fracture risk factors from the ‘Arimidex’, Tamoxifen, Alone or in Combination (ATAC) trial: 5-year data. J Clin Oncol 24(18S):18s. Abstract 563Google Scholar
  46. 46.
    Buzdar A, on behalf of the ATAC Trialists’ Group (2006) Clinical features of joint symptoms observed in the ‘Arimidex’, Tamoxifen, Alone or in Combination (ATAC) trial. J Clin Oncol 24(18S):15s. Abstract 551Google Scholar
  47. 47.
    Perez EA, Josse RG, Pritchard KI, Ingle JN, Martino S, Findlay BP, Shenkier TN, Tozer RG, Palmer MJ, Shepherd LE, Liu S, Tu D, Goss PE (2006) Effect of letrozole versus placebo on bone mineral density in women with primary breast cancer completing ≥ 5 or more years of adjuvant tamoxifen: a companion study to NCIC CTG MA.17. J Clin Oncol 24:3629–3635PubMedGoogle Scholar
  48. 48.
    Goss PE, Qi S, Josse RG, Pritzker KP, Mendes M, Hu H, Waldman SD, Grynpas MD (2004) The steroidal aromatase inhibitor exemestane prevents bone loss in ovariectomized rats. Bone 34:384–392PubMedGoogle Scholar
  49. 49.
    Martinetti A, Zilembo N, Ferrari L, Massimini G, Polli A, La Torre I, Giovanazzi R, Pozzi P, Bidoli P, De Candis D, Seregni E, Bombardieri E, Bajetta E (2003) Bone turnover markers and insulin-like growth factor components in metastatic breast cancer: results from a randomised trial of exemestane vs megestrol acetate. Anticancer Res 23:3485–3491PubMedGoogle Scholar
  50. 50.
    Lønning PE, Geisler J, Krag LE, Erikstein B, Bremnes Y, Hagen AI, Schlichting E, Lien EA, Ofjord ES, Paolini J, Polli A, Massimini G (2005) Effects of exemestane administered for 2 years versus placebo on bone mineral density, bone biomarkers, and plasma lipids in patients with surgically resected early breast cancer. J Clin Oncol 23:5126–5137PubMedGoogle Scholar
  51. 51.
    Lonning PE, Geisler J, Krag LE, Ottestad L, Risberg T, Hagen AI, Schlichting E, Di Salle E, Polli A, Paolini J (2005) Changes in bone metabolism after 2 years treatment with exemestane in postmenopausal women with early breast cancer at low risk: follow-up results of a randomized placebo-controlled study. J Clin Oncol 23(16S):11s. Abstract 531Google Scholar
  52. 52.
    Coombes RC, Hall E, Gibson LJ, Paridaens R, Jassem J, Delozier T, Jones SE, Alvarez I, Bertelli G, Ortmann O, Coates AS, Bajetta E, Dodwell D, Coleman RE, Fallowfield LJ, Mickiewicz E, Andersen J, Lonning PE, Cocconi G, Stewart A, Stuart N, Snowdon CF, Carpentieri M, Massimini G, Bliss JM; Intergroup Exemestane Study (2004) A randomized trial of exemestane after two to three years of tamoxifen therapy in postmenopausal women with primary breast cancer. N Engl J Med 350:1081–1092. Erratum in: N Engl J Med (2004) 351:2461Google Scholar
  53. 53.
    Jones SE, Cantrell J, Vukelja S, Pippen SJ, O’Shaughnessy J, Blum JL, Brooks R, Mull S, Ilegbodu D, Asmar L (2005) The effect of tamoxifen (T) or exemestane (E) on bone mineral density (BMD) after 1 year of adjuvant treatment of postmenopausal women with early breast cancer. J Clin Oncol 23(16S):31S. Abstract 610Google Scholar
  54. 54.
    Gonnelli S, Cadirni A, Caffarelli C, Petrioli R, Montagnani A, Franci MB, Lucani B, Francini G, Nuti R (2007) Changes in bone turnover and in bone mass in women with breast cancer switched from tamoxifen to exemestane. Bone 40:205–210PubMedGoogle Scholar
  55. 55.
    Lønning P, Geisler J, Krag LE, Løkkevik E, Risberg T, Hagen AI, Schlichting E, Eide GE, Di Salle E (2006) Vitamin D deficiency: a threat to bone health in breast cancer patients during adjuvant treatment with aromatase inhibitors. J Clin Oncol 24(18S):16s. Abstract 554Google Scholar
  56. 56.
    McCloskey E, Hannon R, Lakner G, Clack G, Miyamoto A, Eastell R (2006) The letrozole (L), exemestane (E), and anastrozole (A) pharmacodynamics (LEAP) trial: a direct comparison of bone biochemical measurements between aromatase inhibitors (AIs) in healthy postmenopausal women. J Clin Oncol 24(18S):16s. Abstract 555Google Scholar
  57. 57.
    U.S. Preventive Services Task Force (2005) Hormone therapy for the prevention of chronic conditions in postmenopausal women: recommendations from the U.S. Preventive Services Task Force. Ann Intern Med 142:855–860Google Scholar
  58. 58.
    Hillner BE, Ingle JN, Chlebowski RT, Gralow J, Yee GC, Janjan NA, Cauley JA, Blumenstein BA, Albain KS, Lipton A, Brown S; American Society of Clinical Oncology (2003) American Society of Clinical Oncology 2003 update on the role of bisphosphonates and bone health issues in women with breast cancer. J Clin Oncol 21:4042–4057PubMedGoogle Scholar
  59. 59.
    Gnant MF, Mlineritsch B, Luschin-Ebengreuth G, Grampp S, Kaessmann H, Schmid M, Menzel C, Piswanger-Soelkner JC, Galid A, Mittlboeck M, Hausmaninger H, Jakesz R; Austrian Breast and Colorectal Cancer Study Group (2007) Zoledronic acid prevents cancer treatment-induced bone loss in premenopausal women receiving adjuvant endocrine therapy for hormone-responsive breast cancer: a report from the Austrian Breast and Colorectal Cancer Study Group. J Clin Oncol 25:820–828PubMedGoogle Scholar
  60. 60.
    Brufsky A, Harker WG, Beck JT, Carroll R, Tan-Chiu E, Seidler C, Hohneker J, Lacerna L, Petrone S, Perez EA (2007) Zoledronic acid inhibits adjuvant letrozole-induced bone loss in postmenopausal women with early breast cancer. J Clin Oncol 25:829–836PubMedGoogle Scholar
  61. 61.
    Bundred N, Campbell I, Coleman R, DeBoer R, Eidtmann H, Frassolati A, Llomobart A, Monnier A, Neven P, Dias R (2006) Zoledronic acid in the prevention of cancer treatment-induced bone loss in postmenopausal women receiving letrozole as adjuvant therapy for early breast cancer (ZO-FAST study). Eur J Cancer Suppl 4:48. Abstract 12Google Scholar
  62. 62.
    Brufsky A (2006) Management of cancer-treatment-induced bone loss in postmenopausal women undergoing adjuvant breast cancer therapy: a Z-FAST update. Semin Oncol 33(Suppl 7):S13–S17PubMedGoogle Scholar
  63. 63.
    Brufsky A, Dong M, Lunk K, Warsi G, Cobb P, Eisenberg P, Papish S, Lacerna L, Perez E (2006) Twenty-four month follow-up of the effect of zoledronic acid (ZA) on aromatase inhibitor associated bone loss (AIBL) in postmenopausal women (PMW) with early breast cancer (BCa) receiving adjuvant letrozole (LET). Breast Cancer Res Treat 100(Suppl 1):S233. Abstract 5060Google Scholar
  64. 64.
    Herman DR, Ganz PA, Petersen L, Greendale GA (2005) Obesity and cardiovascular risk factors in younger breast cancer survivors: The Cancer and Menopause Study (CAMS). Breast Cancer Res Treat 93:13–23PubMedGoogle Scholar
  65. 65.
    Matthews KA, Wing RR, Kuller LH, Meilahn EN, Plantinga P (1994) Influence of the perimenopause on cardiovascular risk factors and symptoms of middle-aged healthy women. Arch Intern Med 154:2349–2355PubMedGoogle Scholar
  66. 66.
    Stevenson JC, Crook D, Godsland IF (1993) Influence of age and menopause on serum lipids and lipoproteins in healthy women. Atherosclerosis 98:83–90PubMedGoogle Scholar
  67. 67.
    Chang J, Powles TJ, Ashley SE, Gregory RK, Tidy VA, Treleaven JG, Singh R (1996) The effect of tamoxifen and hormone replacement therapy on serum cholesterol, bone mineral density and coagulation factors in healthy postmenopausal women participating in a randomised, controlled tamoxifen prevention study. Ann Oncol 7:671–675PubMedGoogle Scholar
  68. 68.
    Mitsuyama S, Yanagida Y, Doihara H, Komaki K, Kusama M, Ikeda T, Kimura M, Sano M, Miyauchi K (2006) A multi-center study of the effects of toremifene (TOR) and anastrozole (ANA) on serum lipids and bone metabolism in postmenopausal patients with estrogen receptor (ER) positive breast cancer: interim report. J Clin Oncol 24(18S):39s. Abstract 645Google Scholar
  69. 69.
    Femara Prescribing Information (2005) NovartisGoogle Scholar
  70. 70.
    Francini G, Petrioli R, Montagnani A, Cadirni A, Campagna S, Francini E, Gonnelli S (2006) Exemestane after tamoxifen as adjuvant hormonal therapy in postmenopausal women with breast cancer: effects on body composition and lipids. Br J Cancer 95:153–158PubMedGoogle Scholar
  71. 71.
    Wasan KM, Goss PE, Pritchard PH, Shepherd L, Palmer MJ, Liu S, Tu D, Ingle JN, Heath M, Deangelis D, Perez EA (2005) The influence of letrozole on serum lipid concentrations in postmenopausal women with primary breast cancer who have completed 5 years of adjuvant tamoxifen (NCIC CTG MA.17L). Ann Oncol 16:707–715PubMedGoogle Scholar
  72. 72.
    McCloskey E, Eastell R, Lakner G, Miyamoto A, Clack G (2005) Initial results from the LEAP study: the first direct comparison of safety parameters between aromatase inhibitors in healthy postmenopausal women. Breast Cancer Res Treat 94(Suppl 1):S101. Abstract 2052Google Scholar
  73. 73.
    Franklin SS (2006) Hypertension in older people: part 1. J Clin Hypertens (Greenwich) 8:444–449Google Scholar
  74. 74.
    Franklin SS, Pio JR, Wong ND, Larson MG, Leip EP, Vasan RS, Levy D (2005) Predictors of new-onset diastolic and systolic hypertension: the Framingham Heart Study. Circulation 111:1121–1127PubMedGoogle Scholar
  75. 75.
    Franklin SS, Jacobs MJ, Wong ND, L’Italien GJ, Lapuerta P (2001) Predominance of isolated systolic hypertension among middle-aged and elderly US hypertensives: analysis based on National Health and Nutrition Examination Survey (NHANES) III. Hypertension 37:869–874PubMedGoogle Scholar
  76. 76.
    Franklin SS, Gustin W 4th, Wong ND, Larson MG, Weber MA, Kannel WB, Levy D (1997) Hemodynamic patterns of age-related changes in blood pressure. The Framingham Heart Study. Circulation 96:308–315PubMedGoogle Scholar
  77. 77.
    American Heart Association. (2007) Heart disease and stroke statistics–2007 update. American Heart Association, DallasGoogle Scholar
  78. 78.
    Louwman WJ, Janssen-Heijnen ML, Houterman S, Voogd AC, van der Sangen MJ, Nieuwenhuijzen GA, Coebergh JW (2005) Less extensive treatment and inferior prognosis for breast cancer patient with comorbidity: a population-based study. Eur J Cancer 41:779–785PubMedGoogle Scholar
  79. 79.
    Tammemagi CM, Nerenz D, Neslund-Dudas C, Feldkamp C, Nathanson D (2005) Comorbidity and survival disparities among black and white patients with breast cancer. JAMA 294:1765–1772PubMedGoogle Scholar
  80. 80.
    Coebergh JW, Janssen-Heijnen ML, Post PN, Razenberg PP (1999) Serious comorbidity among unselected cancer patients newly diagnosed in the southeastern part of The Netherlands in 1993–1996. J Clin Epidemiol 52:1131–1136PubMedGoogle Scholar
  81. 81.
    Nilsson G, Holmberg L, Garmo H, Terent A, Blomqvist C (2005) Increased incidence of stroke in women with breast cancer. Eur J Cancer 41:423–429PubMedGoogle Scholar
  82. 82.
    Geiger AM, Fischberg GM, Chen W, Bernstein L (2004) Stroke risk and tamoxifen therapy for breast cancer. J Natl Cancer Inst 96:1528–1536PubMedGoogle Scholar
  83. 83.
    Doyle JJ, Neugut AI, Jacobson JS, Grann VR, Hershman DL (2005) Chemotherapy and cardiotoxicity in older breast cancer patients: a population-based study. J Clin Oncol 23:8597–8605PubMedGoogle Scholar
  84. 84.
    Fumoleau P, Roche H, Kerbrat P, Bonneterre J, Romestaing P, Fargeot P, Namer M, Monnier A, Montcuquet P, Goudier MJ, Luporsi E; French Adjuvant Study Group (2006) Long-term cardiac toxicity after adjuvant epirubicin-based chemotherapy in early breast cancer: French Adjuvant Study Group results. Ann Oncol 17:85–92PubMedGoogle Scholar
  85. 85.
    Darby S, McGale P, Peto R, Granath F, Hall P, Ekbom A (2003) Mortality from cardiovascular disease more than 10 years after radiotherapy for breast cancer: nationwide cohort study of 90,000 Swedish women. BMJ 326:256–257PubMedGoogle Scholar
  86. 86.
    Paszat LF, Mackillop WJ, Groome PA, Schulze K, Holowaty E (1999) Mortality from myocardial infarction following postlumpectomy radiotherapy for breast cancer: a population-based study in Ontario, Canada. Int J Radiat Oncol Biol Phys 43:755–762PubMedGoogle Scholar
  87. 87.
    Giordano SH, Kuo YF, Freeman JL, Buchholz TA, Hortobagyi GN, Goodwin JS (2005) Risk of cardiac death after adjuvant radiotherapy for breast cancer. J Natl Cancer Inst 97:419–424PubMedGoogle Scholar
  88. 88.
    Tan-Chiu E, Yothers G, Romond E, Geyer CE Jr, Ewer M, Keefe D, Shannon RP, Swain SM, Brown A, Fehrenbacher L, Vogel VG, Seay TE, Rastogi P, Mamounas EP, Wolmark N, Bryant J (2005) Assessment of cardiac dysfunction in a randomized trial comparing doxorubicin and cyclophosphamide followed by paclitaxel, with or without trastuzumab as adjuvant therapy in node-positive, human epidermal growth factor receptor 2-overexpressing breast cancer: NSABP B-31. J Clin Oncol 23:7811–7819PubMedGoogle Scholar
  89. 89.
    Conti E, Marchese N, Andreotti F (2004) Favorable cardiac risk among elderly breast carcinoma survivors. Cancer 100:878–879PubMedGoogle Scholar
  90. 90.
    Bradbury BD, Lash TL, Kaye JA, Jick SS (2005) Tamoxifen-treated breast carcinoma patients and the risk of acute myocardial infarction and newly-diagnosed angina. Cancer 103:1114–1121PubMedGoogle Scholar
  91. 91.
    Rutqvist LE, Mattsson A (1993) Cardiac and thromboembolic morbidity among postmenopausal women with early-stage breast cancer in a randomized trial of adjuvant tamoxifen. The Stockholm Breast Cancer Study Group. J Natl Cancer Inst 85:1398–1406PubMedGoogle Scholar
  92. 92.
    Nordenskjold B, Rosell J, Rutqvist LE, Malmstrom PO, Bergh J, Bengtsson NO, Hatschek T, Wallgren A, Carstensen J (2005) Coronary heart disease mortality after 5 years of adjuvant tamoxifen therapy: results from a randomized trial. J Natl Cancer Inst 97:1609–1610PubMedCrossRefGoogle Scholar
  93. 93.
    Braithwaite RS, Chlebowski RT, Lau J, George S, Hess R, Col NF (2003) Meta-analysis of vascular and neoplastic events associated with tamoxifen. J Gen Intern Med 18:937–947PubMedGoogle Scholar
  94. 94.
    McDonald CC, Alexander FE, Whyte BW, Forrest AP, Stewart HJ (1995) Cardiac and vascular morbidity in women receiving adjuvant tamoxifen for breast cancer in a randomised trial. The Scottish Cancer Trials Breast Group. BMJ 311:977–980Google Scholar
  95. 95.
    Baum M, Budzar AU, Cuzick J, Forbes J, Houghton JH, Klijn JG, Sahmoud T; ATAC Trialists’ Group (2002) Anastrozole alone or in combination with tamoxifen versus tamoxifen alone for adjuvant treatment of postmenopausal women with early breast cancer: first results of the ATAC randomised trial. Lancet 359:2131–2139. Erratum in: Lancet (2002) 360:1520Google Scholar
  96. 96.
    Kaufmann M, Jonat W, Hilfrich J, Eidtmann H, Gademann G, Zuna I, Von Minckwitz G; on behalf of the German Adjuvant Breast Cancer Group (2006) Survival benefit of switching to anastrozole after 2 years’ treatment with tamoxifen versus continued tamoxifen therapy: the ARNO 95 study. J Clin Oncol 24(18S):14s. Abstract 547Google Scholar
  97. 97.
    Coates AS, Keshaviah A, Thurlimann B, Mouridsen H, Mauriac L, Forbes JF, Paridaens R, Castiglione-Gertsch M, Gelber RD, Colleoni M, Lang I, Del Mastro L, Smith I, Chirgwin J, Nogaret JM, Pienkowski T, Wardley A, Jakobsen EH, Price KN, Goldhirsch A (2007) Five years of letrozole compared with tamoxifen as initial adjuvant therapy for postmenopausal women with endocrine-responsive early breast cancer: update of study BIG 1–98. J Clin Oncol 25:486–492PubMedGoogle Scholar
  98. 98.
    Sourander L, Rajala T, Raiha I, Makinen J, Erkkola R, Helenius H (1998) Cardiovascular and cancer morbidity and mortality and sudden cardiac death in postmenopausal women on oestrogen replacement therapy (ERT). Lancet 352:1965–1969. Erratum in: Lancet (1999) 353:330Google Scholar
  99. 99.
    Medicines and Healthcare Products Regulatory Agency (MHRA) Publication Assessment Report (2005) Femara 2.5 mg tablet. Cited 13 Jul 2006
  100. 100.
    Chakravarti S, Collins WP, Forecast JD, Newton JR, Oram DH, Studd JW (1976) Hormonal profiles after the menopause. Br Med J 2:784–787PubMedGoogle Scholar
  101. 101.
    Hutton JD, Jacobs HS, Murray MAF, James VHT (1978) Relation between plasma esterone and estradiol and climacteric symptoms. Lancet 1:678–681PubMedGoogle Scholar
  102. 102.
    Barnabei VM, Cochrane BB, Aragaki AK, Nygaard I, Williams RS, McGovern PG, Young RL, Wells EC, O’Sullivan MJ, Chen B, Schenken R, Johnson SR; Women’s Health Initiative Investigators (2005) Menopausal symptoms and treatment-related effects of estrogen and progestin in the Women’s Health Initiative. Obstet Gynecol 105(5 Pt 1):1063–1073Google Scholar
  103. 103.
    Guthrie JR, Taffe JR, Lehert P, Burger HG, Dennerstein L (2004) Association between hormonal changes at menopause and the risk of a coronary event: a longitudinal study. Menopause 11:315–322PubMedGoogle Scholar
  104. 104.
    Morales L, Neven P, Timmerman D, Christiaens MR, Vergote I, Van Limbergen E, Carbonez A, Van Huffel S, Ameye L, Paridaens R (2004) Acute effects of tamoxifen and third-generation aromatase inhibitors on menopausal symptoms of breast cancer patients. Anticancer Drugs 15:753–760PubMedGoogle Scholar
  105. 105.
    Avis NE, Crawford SL, McKinlay SM (1997) Psychosocial, behavioral, and health factors related to menopause symptomatology. Womens Health 3:103–120PubMedGoogle Scholar
  106. 106.
    Feldman BM, Voda A, Groseth E (1985) The prevalence of hot flash and associated variables among perimenopausal women. Res Nurs Health 8:261–268PubMedGoogle Scholar
  107. 107.
    Freedman RR (2005) Pathophysiology and treatment of menopausal hot flashes. Semin Reprod Med 23:117–125PubMedGoogle Scholar
  108. 108.
    Randolph JF Jr, Sowers M, Bondarenko I, Gold EB, Greendale GA, Bromberger JT, Brockwell SE, Matthews KA (2005) The relationship of longitudinal change in reproductive hormones and vasomotor symptoms during the menopausal transition. J Clin Endocrinol Metab 90:6106–6112PubMedGoogle Scholar
  109. 109.
    Larson B, Collins A, Landgren BM (1997) Urogenital and vasomotor symptoms in relation to menopausal status and the use of hormone replacement therapy (HRT) in healthy women during transition to menopause. Maturitas 28:99–105PubMedGoogle Scholar
  110. 110.
    Ohayon MM (2006) Severe hot flashes are associated with chronic insomnia. Arch Intern Med 166:1262–1268PubMedGoogle Scholar
  111. 111.
    Bachmann GA (2005) Menopausal vasomotor symptoms: a review of causes, effects and evidence-based treatment options. J Reprod Med 50:155–165PubMedGoogle Scholar
  112. 112.
    Kumari M, Stafford M, Marmot M (2005) The menopausal transition was associated in a prospective study with decreased health functioning in women who report menopausal symptoms. J Clin Epidemiol 58:719–727PubMedGoogle Scholar
  113. 113.
    Baker A, Simpson S, Dawson D (1997) Sleep disruption and mood changes associated with menopause. J Psychosom Res 43:359–369PubMedGoogle Scholar
  114. 114.
    Dennerstein L, Dudley EC, Hopper JL, Guthrie JR, Burger HG (2000) A prospective population-based study of menopausal symptoms. Obstet Gynecol 96:351–358PubMedGoogle Scholar
  115. 115.
    Owens JF, Matthews KA (1998) Sleep disturbance in healthy middle-aged women. Maturitas 30:41–50PubMedGoogle Scholar
  116. 116.
    Staropoli CA, Flaws JA, Bush TL, Moulton AW (1998) Predictors of menopausal hot flashes. J Womens Health 7:1149–1155PubMedCrossRefGoogle Scholar
  117. 117.
    Rosen RC, Taylor JF, Leiblum SR, Bachmann GA (1993) Prevalence of sexual dysfunction in women: results of a survey study of 329 women in an outpatient gynecological clinic. J Sex Marital Ther 19:171–188PubMedGoogle Scholar
  118. 118.
    Fallowfield L, Cella D, Cuzick J, Francis S, Locker G, Howell A (2004) Quality of life of postmenopausal women in the Arimidex, Tamoxifen, Alone or in Combination (ATAC) Adjuvant Breast Cancer Trial. J Clin Oncol 22:4261–4271PubMedGoogle Scholar
  119. 119.
    Duffy S, Jackson TL, Lansdown M, Philips K, Wells M, Pollard S, Clack G, Coibion M, Bianco AR (2006) The ATAC (‘Arimidex’, Tamoxifen, Alone or in Combination) adjuvant breast cancer trial: first results of the endometrial sub-protocol following 2 years of treatment. Hum Reprod 21:545–553PubMedGoogle Scholar
  120. 120.
    Gerber B, Krause A, Reimer T, Mylonas I, Makovitzky J, Kundt G, Janni W (2006) Anastrozole versus tamoxifen treatment in postmenopausal women with endocrine-responsive breast cancer and tamoxifen-induced endometrial pathology. Clin Cancer Res 12:1245–1250PubMedGoogle Scholar
  121. 121.
    Thomas RJ, Marshall CJ, Williams M, Walker LG (2006) Switching to adjuvant letrozole improves hot flushes, mood and quality of life in the tamoxifen intolerant subgroup. Ann Oncol 17(Suppl 9):ix93. Abstract 264PGoogle Scholar
  122. 122.
    Jones S, Vukelja S, Cantrell J, O’ Shaughnessy J, Pippen J, Brooks R, Blum J, Canfield V, Chittoor S, Gore I, Mull S, Guo H, Asmar L (2003) A planned comparison of menopausal symptoms during year 1 in patients receiving either exemestane or tamoxifen in a double-blind adjuvant hormonal study. Presented at the 26th Annual San Antonio Breast Cancer Symposium, 3–6 December 2003. Abstract 141Google Scholar
  123. 123.
    Aromasin Prescribing Information (2005) Pfizer, IncGoogle Scholar
  124. 124.
    Paganini-Hill A, Clark LJ (2000) Preliminary assessment of cognitive function in breast cancer patients treated with tamoxifen. Breast Cancer Res Treat 64:165–176PubMedGoogle Scholar
  125. 125.
    Jenkins V, Shilling V, Fallowfield L, Howell A, Hutton S (2004) Does hormone therapy for the treatment of breast cancer have a detrimental effect on memory and cognition? A pilot study. Psychooncology 13:61–66PubMedGoogle Scholar
  126. 126.
    Shah S, Bell RJ, Savage G, Goldstat R, Papalia MA, Kulkarni J, Donath S, Davis SR (2006) Testosterone aromatization and cognition in women: a randomized, placebo-controlled trial. Menopause 13:600–608PubMedGoogle Scholar
  127. 127.
    Takei H, Suemasu K, Inoue K, Saito T, Okubo K, Koh J, Sato K, Tsuda H, Kurosumi M, Tabei T (2006) Multicenter phase II trial of neoadjuvant exemestane for postmenopausal patients with hormone-sensitive, operable, breast cancer: Saitama Breast Cancer Clinical Study Group (SBCCSG-03). Eur J Cancer Suppl 4:154. Abstract 368Google Scholar
  128. 128.
    Hori Y, Akizuki M, Nishimura R (2006) Comparison of adverse effects on lipid metabolism of anastrozole with tamoxifen in the adjuvant setting for postmenopausal women with early breast cancer. Eur J Cancer Suppl 4:94. Abstract 172Google Scholar
  129. 129.
    Lønning PE, Paridaens R, Thurlimann B, Piscitelli G, di Salle E (1997) Exemestane experience in breast cancer treatment. J Steroid Biochem Mol Biol 61:151–155PubMedGoogle Scholar
  130. 130.
    Paridaens R, Thomas J, Wildiers J, Vermeiren P, Lobelle JP, di Salle E, Ornati G, Zurlo MG, Polli A, Lanzalone S, de Belder K (1998) Safety, activity and estrogen inhibition by exemestane in postmenopausal women with advanced breast cancer: a phase I study. Anticancer Drugs 9:675–683PubMedGoogle Scholar
  131. 131.
    Cella D, Fallowfield L, on behalf of the ATAC Trialists’ Group (2005) Five-year quality of life (QOL) follow-up of adjuvant endocrine therapy for postmenopausal women in the Arimidex (A), Tamoxifen (T), Alone or in Combination (ATAC) Trial. J Clin Oncol 23(16S):23S. Abstract 577Google Scholar
  132. 132.
    Ohsumi S, Shimozuma K, Ohashi Y, Nishiuchi H, Aihara T, Takatsuka Y (2005) Health-related quality-of-life and psychological distress of breast cancer patients after surgery during phase III randomized trial comparing further tamoxifen with switching to anastrozole after adjuvant tamoxifen for 1 to 4 years: N-SAS BC 03. Breast Cancer Res Treat 94(Suppl 1):S99. Abstract 2044Google Scholar
  133. 133.
    Whelan TJ, Goss PE, Ingle JN, Pater JL, Tu D, Pritchard K, Liu S, Shepherd LE, Palmer M, Robert NJ, Martino S, Muss HB (2005) Assessment of quality of life in MA.17: a randomized, placebo-controlled trial of letrozole after 5 years of tamoxifen in postmenopausal women. J Clin Oncol 23:6931–6940PubMedGoogle Scholar
  134. 134.
    Abetz L, Barghout V, Thomas S, Arbuckle R (2005) Letrozole did not worsen quality of life relative to placebo in postmenopausal women with early breast cancer: results from the US subjects of the MA-17 study. Breast Cancer Res Treat 94(Suppl 1):S100. Abstract 2047Google Scholar
  135. 135.
    Fallowfield LJ, Bliss JM, Porter LS, Price MH, Snowdon CF, Jones SE, Coombes RC, Hall E (2006) Quality of life in the intergroup exemestane study: a randomized trial of exemestane versus continued tamoxifen after 2 to 3 years of tamoxifen in postmenopausal women with primary breast cancer. J Clin Oncol 24:910–917PubMedGoogle Scholar
  136. 136.
    Houghton J, on behalf of the ATAC Trialists’ Group (2005) Using anastrozole as initial adjuvant treatment prevents early recurrences and reduces adverse events: updated data from the ATAC (‘Arimidex, Tamoxifen, Alone or in Combination’) trial. J Clin Oncol 23(16S):24S. Abstract 582Google Scholar
  137. 137.
    Houghton J (2006). Initial adjuvant therapy with anastrozole (A) reduces rates of early breast cancer recurrence and adverse events compared with tamoxifen (T) – data reported on behalf of the ATAC (‘Arimidex, tamoxifen, alone or in combination’) trialists’ group. Ann Oncol 17(Suppl 9):ix94. Abstract 243PDGoogle Scholar
  138. 138.
    Goss PE, Ingle JN, Martino S, Robert NJ, Muss HB, Piccart MJ, Castiglione M, Tu D, Shepherd LE, Pritchard KI, Livingston RB, Davidson NE, Norton L, Perez EA, Abrams JS, Therasse P, Palmer MJ, Pater JL (2003) A randomized trial of letrozole in postmenopausal women after five years of tamoxifen therapy for early-stage breast cancer. N Engl J Med 349:1793–1802PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2007

Authors and Affiliations

  1. 1.Mayo ClinicJacksonvilleUSA

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