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Safety of aromatase inhibitors in the adjuvant setting

Safety of aromatase inhibitors in the adjuvant setting Breast Cancer Res Treat (2007) 105:75–89 DOI 10.1007/s10549-007-9704-7 REVIEW Edith A. Perez Received: 28 February 2007 / Accepted: 17 July 2007 Springer Science+Business Media, LLC 2007 Abstract The third-generation aromatase inhibitors (AIs) Introduction letrozole, anastrozole, and exemestane are replacing tamoxifen as adjuvant therapy in most postmenopausal Tamoxifen became the standard adjuvant therapy for women with early breast cancer. Although AIs have dem- women with early breast cancer following the first dem- onstrated superior efficacy and better overall safety onstration of efficacy more than 20 years ago [1]. compared with tamoxifen in randomized controlled trials, Administration of tamoxifen for 5 years has been shown to they may not provide the cardioprotective effects of reduce breast cancer recurrence by 41% and mortality by tamoxifen, and bone loss may be a concern with their long- 34% in women with hormone-responsive tumors [2]. term adjuvant use. Patients require regular bone mineral Nevertheless, many limitations of tamoxifen have emerged density monitoring, and prophylactic bisphosphonates are with widespread use. In the landmark National Surgical being evaluated to determine whether they may protect Adjuvant Breast and Bowel Project B-14 trial, 66% of long-term bone health. AIs decrease the risks of thrombo- tamoxifen-treated patients experienced side effects com- embolic and cerebrovascular events compared with pared with 58% of patients given placebo [3]. Severe, tamoxifen, and the overall rate of cardiovascular events in potentially life-threatening events such as thrombosis were patients treated with AIs is within the range seen in age- more likely to occur in patients aged [60 years [3]. Long- matched, non-breast-cancer populations. AIs are also term adverse effects associated with 5 years’ adjuvant associated with a lower incidence of endometrial cancer tamoxifen include venous thromboembolic events, vaginal and fewer vaginal bleeding/discharge events than tamoxi- bleeding, vaginal discharge, ischemic cerebrovascular fen. Compared with tamoxifen, the incidence of hot flashes events, endometrial and uterine cancer, and hysterectomy is lower with anastrozole and letrozole but may be higher [3, 4]. Experiencing side effects significantly increases the with exemestane. Generally, adverse events with AIs are likelihood of patients discontinuing tamoxifen therapy predictable and manageable, whereas tamoxifen may be (odds ratio 4.0; 95% confidence interval [CI] 1.1, 13.9 in associated with life-threatening events in a minority of women aged ‡ 55 years) [5]. Over time, resistance to patients. Overall, the benefits of AIs over tamoxifen are tamoxifen may develop [6], and therapy beyond 5 years is achieved without compromising overall quality of life. not recommended because neither further disease-free survival nor survival benefit is gained [7]. Keywords Adjuvant therapy  Aromatase inhibitors  The third-generation aromatase inhibitors (AIs) letroz- Early breast cancer  Letrozole  Safety ole, anastrozole, and exemestane are rapidly replacing tamoxifen as initial adjuvant therapy [8, 9] or sequential adjuvant therapy after 2–5 years of tamoxifen [10–13]. By potently inhibiting the aromatase enzyme, which converts androgens to estrogen [14, 15], AIs achieve almost total E. A. Perez (&) suppression of total body aromatization and dramatic Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224, reductions in estrogen concentrations in postmenopausal USA women [16–18]. AIs are now recommended in e-mail: perez.edith@mayo.edu 123 76 Breast Cancer Res Treat (2007) 105:75–89 international guidelines for the management of breast The most serious consequence of CTIBL is an increased cancer [19–21]. In addition, guidance is being developed risk of fractures (Fig. 1)[35], which increase morbidity and for the management of common co-morbidities such as healthcare costs [40]. The presence of bone metastases can osteoporosis in postmenopausal women with hormone- contribute to CTIBL and lead to serious complications, sensitive breast cancer receiving AIs [20, 22]. This review including fractures, spinal compression, bone pain, and examines the safety of AIs and assesses their advantages hypercalcemia of malignancy [41]. and disadvantages compared with tamoxifen. It also con- siders the impact of treatment on co-morbidities commonly encountered in this population. Aromatase inhibitors and bone disease In a recent study, the bone health of 1,354 patients with Possible impact of treatment on common co-morbidities breast cancer receiving an AI (anastrozole, exemestane, or letrozole) was compared with 11,014 controls [39]. Treat- Adjuvant therapy should be individualized on the basis of ment with an AI increased the risk of bone loss (relative clinical and biologic risk factors [21], including the pres- risk 1.3; 95% CI 1.1, 1.6; P = 0.01) and bone fracture ence of co-morbidities [23–26]. The most prevalent co- (relative risk 1.4; 95% CI 1.2, 1.6; P = 0.001). The risks morbidities in the postmenopausal patient population are remained significantly higher for AI therapy after adjust- hypertension, arthritis, heart disease, diabetes, chronic ment for age and co-morbidities [39]. An increase in the obstructive pulmonary disease, eye problems, anemia, incidence of arthralgia is noted with all three AIs, when depression, fractures, hearing problems, osteoporosis, compared with tamoxifen. Parkinson’s disease, renal failure, and urinary tract prob- lems [25]. Understanding the long-term effects of aromatase inhibition on bone and cardiovascular health are Anastrozole particularly important to consider because of the potential effects of altering estrogen concentrations. Howell and colleagues reported fracture rates after a median follow-up of 68 months in the Arimidex, Tamox- ifen, Alone or in Combination (ATAC) trial [42]. Fractures Bone disease were reported in 577 (9.3%) of the 6,186 patients and were more common with anastrozole than with tamoxifen (11 vs. Bone health typically may deteriorate as women age, par- 8%, respectively; P \ 0.0001). The incidence of hip frac- ticularly after reaching menopause [27, 28]. A decline in tures was 1% in both groups. The rate of fractures was low estrogen concentrations accelerates postmenopausal bone at approximately 2% per year and decreased to baseline loss [29–31] while vitamin D deficiency also increases levels after completion of 5 years of treatment. The effects bone turnover and the risk of fracture [32, 33]. It is of anastrozole and tamoxifen on BMD were assessed in a important to note that bone health is compromised in women with breast cancer compared with the general 68.6 Breast cancer survivors population [34]. In the Women’s Health Initiative Obser- Reference group vational Study, breast cancer survivors had significantly 47.6 lower total body bone mineral density (BMD) and total hip BMD [34] and a significantly higher risk of clinical frac- tures [35]. Of concern, osteoporosis was undiagnosed in 150 more than three quarters of breast cancer survivors and the reference population [34]. Multiple factors contribute to the 17.4 increased risk of osteoporosis and fractures in postmeno- 50 7.3 -1.3 pausal women with breast cancer [34]. Furthermore, tumor cells can have a direct effect on bone remodeling [36], and Hip Clinical Lower arm All other Total vertebral or wrist breast cancer therapy can lead to cancer treatment-induced Fracture outcome bone loss (CTIBL) [37–39]. In a large cohort study, patients with early breast cancer who received anticancer Fig. 1 Age-standardized fracture incident rates by survivor status. Standardized rates were calculated using the age distribution of the therapy had a 30% higher risk for osteoporosis/osteopenia entire Women’s Health Initiative Observational Study cohort. Excess (odds ratio 1.29; 95% CI 1.13, 1.46) [38]. The study also numbers of fractures per 10,000 person-years are above each set of showed that other factors such as poor health status, history bars [35]. 2005 American Medical Association. Reproduced with of smoking, and alcohol abuse can contribute to CTIBL. permission Rate per 10,000 person-years Breast Cancer Res Treat (2007) 105:75–89 77 sub-analysis of 167 patients from the ATAC trial [43]. An- patient-reported diagnoses of new-onset osteoporosis (8% astrozole-treated patients had significant decreases in lumbar letrozole vs. 6% placebo, P = 0.003), and arthralgia and spine BMD (–8.1%; 95% CI –10.1, –6.1; P \ 0.0001) and myalgia were significantly more common with letrozole total hip BMD (–7.4%; 95% CI –9.6, –5.3; P \ 0.0001) rel- than placebo [10]. A companion study to MA.17 demon- ative to tamoxifen-treated patients, in whom small increases strated a significant decrease in lumbar spine BMD (–5.35 were observed. Bone loss was greatest in the first 2 years of vs. –0.70%; P = 0.008) and total hip BMD (–3.6 vs. anastrozole treatment, as reported previously [44], but the rate –0.71%; P = 0.044) over 2 years in patients treated with of loss appeared to slow down from years 2 to 5. In the updated letrozole compared with placebo, although no patient went analysis after a median follow-up of 68 months, osteopenia or below the threshold for osteoporosis in total hip BMD [47]. osteoporosis was reported in 11% of patients receiving anas- Data from this companion study suggest that women with a trozole compared with 7% receiving tamoxifen (P \ 0.0001) BMD score of –1.0 or greater when starting letrozole after [42, 45]. Another sub-analysis of the ATAC trial showed that tamoxifen are less vulnerable to enhanced bone resorption the majority of joint symptoms occur within 24 months of and may not require prophylactic bisphosphonate therapy. 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 Exemestane symptoms were mild in intensity, and 46% were reported as an exacerbation of a pre-existing condition. The incidence of In a model of ovariectomized rats, the steroidal AI exe- serious joint symptoms was similar for anastrozole and mestane was shown to prevent bone loss, presumably via tamoxifen (10.6 vs. 10.4%, respectively) and only 2.1 and its androgenic properties (both exemestane and its metab- 0.9%, respectively, discontinued treatment because of joint olite 17-hydro-exemestane demonstrate affinity for the symptoms. After a median follow-up of 68 months, muscle androgen receptor) [48]. However, a randomized study to cramps were less common with anastrozole than tamoxifen (4 compare the effects of progestins and AIs on bone vs. 8%, respectively; P \ 0.0001), whereas carpal-tunnel remodeling markers in patients with metastatic breast syndrome was more common with anastrozole (3 vs. 1%, cancer found that exemestane increased osteoclast activity respectively; P \ 0.0001) [42]. [49]. In the adjuvant treatment setting, a randomized trial These updated results from the ATAC trial confirm that AIs involving 147 patients with early breast cancer demon- are a well-tolerated initial treatment option in terms of bone strated a non-significant effect of exemestane compared health [43, 45, 46]. Although anastrozole is associated with with placebo on the annual rate of BMD loss in the lumbar BMD loss, no patient with normal bone at baseline became spine (2.17 vs. 1.84%; P = 0.568) and a small but signifi- osteoporotic after 5 years of treatment, and the rate of bone cant effect in the femoral neck (2.72 vs. 1.48%; P = 0.024) loss in the lumbar spine region slowed down in years 2–5. [50]. Of note was the finding that BMD may rapidly The ARNO/ABCSG8 trials investigated the efficacy and improve following AI discontinuation: this trial showed safety of switching to anastrozole after 2 years of tamox- that bone resorption markers returned to or below baseline ifen [12]. Although there were significantly more fractures values, and bone formation markers remained moderately in patients switching to anastrozole (2.1%) than in those increased within 6 months of stopping exemestane [51]. continuing on tamoxifen (1.0%) [12], the rate was lower In the Intergroup Exemestane Study (IES) of exemes- than that seen at a similar point in the ATAC trial [12]. In tane following 2–3 years of tamoxifen, fractures were the Italian Tamoxifen Anastrozole (ITA) trial, switching to reported more frequently with exemestane than with anastrozole after 2–3 years of tamoxifen was not associ- tamoxifen after a median follow-up of 30.6 months, ated with an increase in fracture rate, although differences although this difference was not statistically significant (3.1 may emerge with longer follow-up [13]. vs. 2.3%; P = 0.08) [52]. However, the difference in inci- dence of fractures was statistically significant (7.0% with exemestane vs. 4.9% with tamoxifen; P = 0.003) after a Letrozole median follow-up of 55.7 months [11]. The incidence of osteoporosis was also significantly higher with exemestane In the Breast International Group (BIG) 1–98 trial of initial than with tamoxifen (9.2 vs. 7.2%, respectively; P = 0.01). adjuvant therapy, there was a slight yet significant differ- Recent results from a 1-year sub-study revealed that ence in the incidence of fractures (5.7% with letrozole vs. patients on exemestane experienced a significant decrease 4.0% with tamoxifen; P \ 0.001) [8]. The MA.17 trial of in hip BMD, while patients on tamoxifen did not [53]. extended adjuvant therapy showed that when compared These results were confirmed by another recent study, with placebo, letrozole had no significant impact on frac- which evaluated the effects of exemestane on bone turn- tures [10]. There was a small but significant difference in over markers and BMD in 70 postmenopausal women 123 78 Breast Cancer Res Treat (2007) 105:75–89 (62.0 ± 8.9 years) with early breast cancer who were osteoporosis, and it is recommended that they have switched to exemestane after 2–3 years on tamoxifen [54]. baseline BMD evaluation and regular monitoring to Patients in the exemestane group had a significant decrease guide subsequent therapeutic interventions such as bis- in BMD and early parathyroid hormone (at month 6) and phosphonates [20, 58]. Preliminary results have been an increase in bone alkaline phosphatase (B-ALP) and reported from a small number of clinical trials of bis- the carboxy-terminal telopeptide of type I collagen phosphonates in women receiving adjuvant AI therapy. after 24 months. These studies suggest that switching In one trial, premenopausal breast cancer patients postmenopausal women from tamoxifen to exemestane receiving goserelin plus anastrozole or goserelin plus causes a marked increase in bone turnover markers with a tamoxifen were randomly assigned to the bisphosphonate consequent reduction in BMD. zoledronic acid (ZA) (4 mg IV every 6 months) or pla- Arthralgia was also significantly more common with cebo. After 36 months, it was shown that ZA given exemestane than with tamoxifen (5.4 vs. 3.6%, P = 0.01) every 6 months helped prevent bone loss in these pre- in the IES [52]. A study by Lønning et al. discovered a menopausal patients in both the lumbar spine and hip high prevalence of vitamin D deficiency in postmenopausal regardless of endocrine therapy [59]. Two randomized women treated with exemestane (52 of 59 patients) or trials have shown that bisphosphonates may be beneficial placebo (56 of 62 patients), and this could be the most in postmenopausal patients at a higher risk of osteopo- important factor causing bone loss in both groups [55]. rosis [60, 61]. In the Zometa-Femara Adjuvant Synergy Vitamin D substitution is therefore recommended for Trial (Z-FAST) (North American) trial, 602 postmeno- postmenopausal women, particularly those with breast pausal women with hormone-responsive breast cancer cancer receiving an AI. The incidence of carpal-tunnel starting adjuvant therapy with letrozole were randomized syndrome in the IES was higher in the exemestane arm to receive upfront ZA (4 mg IV infusion every (2.8%) than in the tamoxifen arm (0.4%; P \ 0.001) [11]. 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’ Comparative studies of aromatase inhibitors follow-up indicate that initial treatment with ZA may be used to prevent CTIBL, and results at 24 months confirm A randomized trial (Letrozole, Exemestane, and Anas- these initial findings [62, 63] although the rate of clinical trozole Pharmacodynamics [LEAP]) of healthy volunteers fractures was not changed. In addition, the small pro- demonstrated that letrozole, exemestane, and anastrozole portion of patients (8%) requiring ZA in the first year have similar effects on bone biochemical measurements highlights the short-term bone tolerability of letrozole and all result in increases in bone turnover [56]. There were [62]. Results from the similarly designed ZO-FAST no statistically significant differences between the AIs in (European; N = 1,065) trial also support the use of ZA changes from baseline to 24 weeks for B-ALP, serum C- to potentially manage CTIBL in postmenopausal women telopeptide crosslinks, and propeptide of type I procolla- with early breast cancer receiving adjuvant letrozole gen. The only difference in the bone remodeling markers [61]. was a greater decrease in parathyroid hormone with exe- Lipid metabolism: A cohort study demonstrated that mestane than with anastrozole (P = 0.04). total and low-density lipoprotein (LDL) cholesterol con- Thus, all AIs seem to have similar effects on bone centrations are positively correlated with years since health. The ATAC bone sub-study results are reassuring for diagnosis of breast cancer [64]. In addition, during meno- the entire AI class, and women with breast cancer who pause, women experience adverse changes in have normal BMD measurements at the onset of AI treat- cardiovascular risk factors, including declines in concen- ment may be able to undergo 5 years of therapy without the trations of high-density lipoprotein (HDL) cholesterol and risk of developing osteoporosis. Patients at risk of clini- increases in concentrations of total cholesterol, LDL cho- cally relevant BMD loss during treatment should be lesterol, HDL3 cholesterol, and triglycerides [65, 66]. identified and managed according to evolving clinical These changes are independent of age and body mass guidelines [20, 57]. index. Assessing the impact of AIs on lipid profiles is difficult in trials where tamoxifen is the comparator. The selective Bisphosphonates estrogen-receptor modulators (SERMs) such as tamoxifen are known to have lipid-lowering properties [67, 68]. What In the American Society of Clinical Oncology (ASCO) is clear is that the studies comparing AIs with tamoxifen guidelines postmenopausal patients with breast cancer indicate only that the AIs lack the lipid-lowering effects of whoreceiveAIs areidentified as beingathighriskfor tamoxifen. 123 Breast Cancer Res Treat (2007) 105:75–89 79 Aromatase inhibitors and lipid metabolism Another study examined the longitudinal changes in body composition and lipid profiles in 55 postmenopausal Anastrozole women with early breast cancer switched to exemestane after at least 2 years of tamoxifen treatment [70]. Fat In the ATAC trial, the incidence of hypercholesterolemia mass significantly decreased (P \ 0.01) while the fat-free was higher in patients receiving anastrozole than tamoxifen mass to fat mass ratio significantly increased (P \ 0.05) (9 vs. 3%, respectively; P \ 0.0001) [42]. In the ITA trial, by month 12 in the exemestane but not in the tamoxifen lipid metabolism disorders were reported in 9.3% of group. In addition, triglycerides and HDL cholesterol patients treated with anastrozole and 4.0% receiving significantly decreased (P \ 0.01 and P \ 0.05, respec- tamoxifen (P = 0.04) [13]. tively) in the exemestane group, while LDL cholesterol A recent multicenter study in patients with estrogen- significantly increased (P \ 0.01) at the end of the 1-year receptor positive breast cancer investigated the effects of study period. adjuvant anastrozole and toremifene, a SERM, on serum lipids [68]. Results showed that only toremifene had a ben- eficial effect on lipid profile, indicated by a decrease in total Aromatase inhibitors versus placebo cholesterol, LDL cholesterol, triglycerides, and apolipopro- tein B, and an increase in HDL cholesterol and When compared with placebo (the most accurate way to apolipoprotein A1. Changes in total cholesterol, HDL, LDL, assess the true impact of AIs on serum lipids), the final and apolipoproteins were significantly different between analysis of the MA.17 trial demonstrated the incidence of toremifene and anastrozole at 6 and 12 months (P \ 0.05). 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 Letrozole breast cancer treated for up to 36 months, letrozole (n = 183) does not significantly alter lipid profile (samples In the BIG 1–98 trial, according to the protocol, cholesterol drawn under fasting conditions) compared with placebo concentrations (fasting or non-fasting) were collected sys- (n = 164) [71]. In a placebo-controlled study involving 147 tematically in the case-report forms every 6 months and postmenopausal women with early breast cancer, exemes- even patients with only a single measurement above the tane had no major effect on lipid profile except for a upper limit of normal were defined as hypercholesterol- modest but significant decrease from baseline in HDL emic [8]. Hypercholesterolemia was reported in 5.4% of cholesterol (P \ 0.001) and apolipoprotein A1 (P = 0.004) the letrozole arm compared with 1.2% of the tamoxifen [50]. On the basis of these results, it is clear that when arm in patients with baseline values within normal limits, compared with placebo, AIs do not have a detrimental who then had an increase of 1.5 times the upper limit of effect on lipid profile. However, it should be noted that normal [69]. Hypercholesterolemia was typically a single there have been no placebo-controlled trials of adjuvant event and in the majority of these patients (80%) occurred anastrozole in women with breast cancer. at only grade 1 intensity (meaning a slight numerical increase above normal, not requiring medications). More- over, the majority of cases were single measurements collected in non-fasting patients. Furthermore, when Comparative studies of aromatase inhibitors looking at total serum cholesterol levels, there was a 12% median decrease from baseline in total cholesterol in the The LEAP trial directly compared safety parameters tamoxifen arm after 6 months, consistent with previous between the steroidal AI exemestane and the non-steroidal reports demonstrating the lipid-lowering effect of tamoxi- AIs anastrozole and letrozole in 90 healthy postmenopausal fen [67], while in the letrozole group total cholesterol women (Table 1)[72]. Initial results from the trial showed values remained stable [8]. Hypercholesterolemia was not that there were no significant differences between anas- predefined as an adverse event in the ATAC trial, and lipid trozole and letrozole in effects on LDL:HDL ratios, concentrations were not routinely assessed [42]. triglyceride concentrations, and non-HDL concentrations. Exemestane was associated with an increase in LDL:HDL ratio (+17) (P = 0.047) compared with anastrozole. There Exemestane was no median change from baseline in total serum cho- lesterol for letrozole, a slight increase for anastrozole Hypercholesterolemia was not reported in the IES trial of (+0.4), and a non-significant decrease for exemestane sequential exemestane after tamoxifen [11, 52]. (–3.9) (P = 0.164 vs. anastrozole) [72]. 123 80 Breast Cancer Res Treat (2007) 105:75–89 Table 1 Comparative effects of third-generation aromatase inhibitors on lipids [72] Percentage change Anastrozole Letrozole P value vs. Exemestane P value vs. from baseline (n = 29) (n = 29) anastrozole (n = 32) anastrozole Total cholesterol Week 12 –2.3 –3.8 0.617 –5.5 0.262 Week 24 +0.4 –0.0 0.900 –3.9 0.164 Triglycerides Week 12 –2.9 +9.6 0.037 –7.7 0.417 Week 24 +0.3 +5.4 0.550 +2.1 0.827 Ratio of LDL-C:HDL-C Week 12 –0.0 –3.1 0.486 +8.8 0.048 Week 24 +4.6 +3.4 0.847 +17.0 0.047 Non-HDL-C Week 12 –2.7 –4.2 0.667 –3.5 0.820 Week 24 +1.3 +1.2 0.975 –0.6 0.630 Ratio of apo B:apo A1 Week 12 –1.0 –3.3 0.452 +4.4 0.069 Week 24 +0.0 –0.8 0.842 +9.0 0.023 LDL-C low-density lipoprotein cholesterol, HDL-C high-density lipoprotein, apo B apolipoprotein B, apo A1 apolipoprotein A1 Cardiovascular disease meta-analysis, tamoxifen was associated with a significantly decreased incidence of myocardial infarction (relative risk Cardiovascular risk increases substantially and progressively 0.90) and death from myocardial infarction (relative risk in women aged ‡65 years [73–77]. Isolated systolic hyper- 0.62) [93]. This finding is consistent with results from an tension, associated with arterial stiffening, is predominant in earlier cohort study [94] and the Early Breast Cancer Trial- middle- and older-aged hypertensives [75] and predisposes ists’ Collaborative Group (EBCTCG) meta-analysis, which individuals to coronary heart disease, heart failure, stroke, demonstrated decreases in the risk of cardiac death and vascular dementia, and chronic kidney disease [73]. The risk overall mortality from vascular disease in patients receiving of cardiac disease is also influenced by ethnicity, smoking, tamoxifen compared with those receiving placebo [2]. obesity, physical inactivity, alcohol abuse, and the presence of co-morbid diseases such as diabetes. In patients with breast cancer the presence of co-mor- Aromatase inhibitors and cardiovascular disease bidities, including cardiovascular disease and diabetes, is associated with a poorer prognosis than when co-morbid Assessing the impact of different AIs on cardiovascular disease is absent [78] and may explain disparities in outcome disease in postmenopausal women with breast cancer is between different ethnic groups [79]. There is also evidence difficult and inter-trial comparisons are confounded by that breast cancer is associated with a higher prevalence of differences in data collection and end points; for example, hypertension compared with other tumor types [80]and a in the BIG 1–98 trial all potential adverse events were significantly increased risk of stroke compared with the predefined in the case-report forms whereas the ATAC trial general population (relative risk 1.12; 95% CI 1.07, 1.17) used non-specific case-report forms to report adverse [81]. Many breast cancer therapies increase the risk of car- events [8, 95]. Furthermore, comparisons with tamoxifen diovascular events [82–88]; tamoxifen, however, may have are complicated by its cardioprotective properties. Placebo- some cardio-protective effects [89, 90]. 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. Tamoxifen and cardiovascular disease Several studies have demonstrated the potential cardiopro- Anastrozole tective properties of tamoxifen, including a reduction in hospital admissions due to cardiac disease [89–91]and The ATAC trial provided data on the cardiovascular effects decreased mortality from cardiac disease [92]. In a of anastrozole as initial adjuvant therapy compared with 123 Breast Cancer Res Treat (2007) 105:75–89 81 tamoxifen. The incidence of ischemic cardiovascular dis- Aromatase inhibitors versus placebo ease was higher (but not significantly) with anastrozole than placebo (127/3092, 4.1% vs. 104/3094, 3.4%; Cardiovascular events occurred with similar frequency in P = 0.1). The incidence of angina was also higher with the letrozole and placebo arms in the MA.17 trial (5.8 vs. 5.6%, respectively; P = 0.76) [10]. Similar incidences anastrozole (71/3092, 2.3% vs. 51/3094, 1.6%; P = 0.07), while myocardial infarction occurred with similar fre- were reported in the letrozole and placebo arms for stroke/ transient ischemic attack (0.7 vs. 0.6%, respectively), quency (37/3092, 1.2% vs. 34/3094, 1.1%; P = 0.7 [42]. Hypertension was statistically significantly more common myocardial infarction (0.3 vs. 0.4%, respectively), new or worsening angina (1.2 vs. 0.9%), angina requiring coronary with anastrozole than with tamoxifen (13 vs. 11%, respectively; P = 0.04) [42]. In the ARNO95 trial vascular artery bypass graft (0.2 vs. 0.5%), and thromboembolic events, including hot flashes, ischemic cardiovascular events (0.4 vs. 0.2%, respectively) [10]. These results events, deep vein thrombosis, and ischemic cerebrovascu- clearly indicate that when compared with placebo, AIs do lar events, occurred in 9.2% of the anastrozole arm not have a detrimental effect on cardiovascular safety. compared with 8.8% of the tamoxifen arm [96]. Gynecologic health Letrozole The onset of menopause is characterized by numerous The BIG 1–98 trial demonstrated a similar incidence of adverse events associated with a decline in estrogen con- cardiac events in the letrozole and tamoxifen groups (4.1 centrations [100–102]. Early symptoms include abnormal vs. 3.8%, respectively; not significant). However, more vaginal bleeding, hot flashes, and mood changes, while women in the letrozole group had grade 3, 4, or 5 cardiac vaginal dryness and irritation, osteoporosis, and heart dis- events (2.1 vs. 1.1%, respectively; P \ 0.001), but these ease are late symptoms [29, 103, 104]. Vasomotor events remain rare [8]. Of note, a recent update of the symptoms, particularly hot flashes, are common during monotherapy arms of BIG 1–98 after a longer median transition to menopause [105–109] and may lead to dis- follow-up of 51 months showed that the overall incidence turbed sleep, depressive symptoms, and significant reductions in quality of life [110–115]. Cigarette smoking of cardiac events was comparable in the two groups (134 events [5.5%] in the letrozole group vs. 122 [5.0%] in the may be associated with increased risk of hot flashes in menopausal women [116]. Sexual dysfunction is also pre- tamoxifen arm), thus confirming the safe cardiac profile of letrozole reported at 26 months [97]. valent in menopausal women and is associated with vaginal atrophy, vaginal/genital dryness, dyspareunia (pain during sexual intercourse), vaginitis, cystitis, and urinary tract Exemestane infections [117]. In the IES, there was no significant difference between exemestane and tamoxifen in the incidence of combined Aromatase inhibitors and gynecologic health cardiovascular disease/thromboembolic events (22.1 vs. Anastrozole 20.9%, respectively; P = 0.34) after a median follow-up of 55.7 months [11]. The incidence of myocardial infarction In the ATAC trial, the incidence of hot flashes was sig- was higher with exemestane than with tamoxifen, although the difference between treatment groups was not significant nificantly lower with anastrozole than with tamoxifen (36 (1.3 vs. 0.8%, respectively; P = 0.08) [11]. vs. 41%; P \ 0.0001) [9]. In the latest analysis, anastrozole Overall, the rate of cardiovascular events in patients was associated with a significantly lower incidence of treated with AIs is well within the range seen in age-mat- gynecologic events (endometrial hyperplasia, endometrial ched, non-breast-cancer populations; for example, for neoplasia, cervical neoplasm, and enlarged uterine fibroids: women 57–65 years of age, the rates of fatal myocardial 3 vs. 10% with tamoxifen; P \ 0.0001) [42]. A quality-of- infarction and other fatal coronary artery disease are 1.1 life (QOL) analysis confirmed that vaginal discharge, and 0.81 per 1,000 patient-years, respectively [98]. Similar vaginal itching/irritation, and vaginal bleeding were less common with anastrozole but found that vaginal dryness, rates were recorded in the UK General Practice Research Database and Swedish MI register [99]. Currently, there is pain during intercourse, and loss of interest in sex were more common [118]. After 2 years of treatment there was a insufficient information to fully determine the effect of AIs on cardiovascular disease, especially coronary heart non-significant trend towards a lower incidence of endo- disease. metrial abnormalities with anastrozole than tamoxifen 123 82 Breast Cancer Res Treat (2007) 105:75–89 (odds ratio 0.44; 95% CI 0.146, 1.314; P = 0.14) [119]. (6 vs. 9%; P \ 0.001) [52]; however, vaginal dryness was The latest update of the ATAC trial revealed reduced libido significantly more common among women taking exe- in significantly more patients receiving anastrozole (1%) mestane than those taking tamoxifen, while vaginal than tamoxifen (\1%; P = 0.0001) [42]. Patients receiving discharge was significantly more common with tamoxifen anastrozole also experienced a significantly higher inci- [122]. Vaginal bleeding was significantly more common in dence of dyspareunia than those receiving tamoxifen the tamoxifen arm (7.1%) than in the exemestane group (1 vs. \ 1%, respectively; P = 0.002), whereas urinary (4.8%; P = 0.001) [11]. incontinence and urinary tract infection were significantly less common among patients receiving anastrozole (uri- nary incontinence: 2 vs. 4%, respectively, P \ 0.0001; Other adverse events urinary tract infection: 8 vs. 10%, respectively, P = 0.002). In a randomized study of postmenopausal women in Secondary cancer whom abnormal vaginal bleeding and/or asymptomatic endometrial thickening occurred during treatment with The association between tamoxifen and endometrial and tamoxifen, switching to anastrozole was associated with a uterine cancers is well-established [4] and is not observed significant reduction in mean endometrial thickness com- with AIs. However, a safety analysis of the ATAC trial pared with continuation of tamoxifen (P \ 0.0001) [120]. [42] showed a surprisingly higher incidence of head and Significantly fewer anastrozole patients required a repeat neck cancer with anastrozole compared with tamoxifen hysteroscopy and dilation and curettage compared with (10/3092 vs. 3/3094, respectively). Similarly, there was an those taking tamoxifen (4.8 vs. 33.0%, respectively; excess of lung cancer (25/3092 vs. 16/3094) and lung P \ 0.0001). 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 Letrozole events exemestane vs. 107 tamoxifen) or in the BIG 1–98 trial (69 letrozole vs. 82 tamoxifen) [8, 11]. In the BIG 1–98 trial [8], endometrial biopsies were sig- A meta-analysis showed that tamoxifen is associated nificantly less common in patients receiving letrozole than with a modest but statistically significant increase in the tamoxifen (2.3 vs. 9.1%, respectively; P \ 0.001), and risk of developing gastrointestinal cancer (relative risk there was a trend towards fewer invasive endometrial 1.31; 95% CI 1.01, 1.69), particularly for postmenopausal cancers (0.1 vs. 0.3%, respectively; not significant). There women (relative risk 1.77) [93]. was a significantly lower incidence of vaginal bleeding with letrozole than with tamoxifen (3.3 vs. 6.6%, respec- tively; P \ 0.001), and the incidence of hot flashes was Gastrointestinal health also significantly lower (33.5 vs. 38.0%, respectively; P \ 0.001). In another study in patients intolerant of Diarrhea was significantly more common among patients tamoxifen, switching to letrozole for 6 weeks was associ- receiving the steroidal AI exemestane than in those taking ated with a 53.7% decrease in hot flashes (hot-flash score tamoxifen (4.2 vs. 2.2%, respectively) [123] but is not a 97.0–52.1; P = 0.001) [121]. In the MA.17 trial, letrozole typical side effect of the non-steroidal AIs letrozole and was associated with less vaginal bleeding than placebo (6 anastrozole. However, an updated safety analysis of the vs. 8%, respectively; P = 0.005) but a greater incidence of ATAC trial showed that anastrozole was associated with an hot flashes (58 vs. 54%, respectively; P = 0.003) [10]. increased incidence of diarrhea compared with tamoxifen There was no significant difference in the incidence of (9 vs. 7%; P = 0.02) [42]. vaginal dryness between letrozole and placebo. Neurologic effects and visual disturbance Exemestane It has been suggested that endocrine therapy may affect In the IES, there were no significant differences between cognitive function in patients with breast cancer [124]. In a the exemestane and tamoxifen treatment arms in the inci- study comparing patients from the ATAC trial with healthy dence of endometrial cancer (0.4 vs. 0.7%, respectively; controls, anastrozole was associated with significant P = 0.17) [11], or the incidence of hot flashes (42 vs. 40%, impairments in a processing speed task and on a measure of respectively; P = 0.28) [52]. Overall, gynecologic symp- immediate verbal memory [125]. Another study conducted toms were lower with exemestane than with tamoxifen in healthy, estrogen-treated postmenopausal women treated 123 Breast Cancer Res Treat (2007) 105:75–89 83 with testosterone did not reveal any effects of aromatase The authors concluded that the benefits of anastrozole are inhibition on cognition [126]. achieved without detrimental effects on QOL. However, The impact of adjuvant AI therapy on cognition and another study conducted in Japanese patients demonstrated other neurologic processes is clearly an important issue that that FACT-G, FACT-B, and FACT-ES scores were sig- will require further studies in the future. Neurologic effects nificantly better with tamoxifen than with anastrozole reported with exemestane, including dizziness and vertigo (P = 0.012, P = 0.010, and P = 0.015, respectively) [132]. [127] and significantly more visual disturbances compared with tamoxifen [52], are not characteristic of non-steroidal AIs. Letrozole The MA.17 and BIG 1–98 trials have demonstrated that Dry mouth adjuvant letrozole is well-tolerated compared with placebo [10] and better tolerated than tamoxifen [8]. In another The latest analysis of the ATAC trial demonstrated a sig- study of postmenopausal women who were experiencing nificantly greater incidence of dry mouth in patients distressing side effects while taking adjuvant tamoxifen receiving anastrozole (4%) compared with tamoxifen (2%; and were switched to letrozole, after 6 weeks 66% of P = 0.003) [42]. 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 signifi- Cosmetic effects cantly improved outcomes and did not impair overall QOL [133] (Fig. 2). Minor differences seen in some domains Weight gain is common after breast cancer therapy and (physical functioning, bodily pain, vitality, vasomotor, and increases the risk of recurrence, cardiovascular disease, and sexual) were consistent with a minority of patients expe- diabetes [64]. A study of Japanese patients showed that riencing changes in QOL compatible with a reduction in more women reported weight gain in the anastrozole group estrogen synthesis. A sub-analysis of US subjects in MA.17 than in the tamoxifen group (35.8 vs. 12.5%, respectively; demonstrated no significant differences between letrozole P £ 0.0036) [128], but no difference was seen among and placebo in overall QOL summary scores (mental and patients from the ATAC trial included in a QOL sub- physical) and five of eight sub-domains of SF-36 [134]. analysis [118]. There were no differences in SF-36 mental and physical The androgen structure of exemestane may lead to androgenic side effects. Hypertrichosis, hair loss, hoarse- ness, and acne were reported in about 10% of patients treated with daily exemestane doses of 200 mg or more in Placebo Letrozole dose-finding studies [129, 130], but have not emerged as a significant issue in phase II or phase III trials with this agent. 1,353 1,289 779 353 -10 Anastrozole treatment was associated with a lower 1,315 1,282 750 333 -20 incidence of nail disorders (2 vs. 3%; P = 0.002) and Baseline 6 Month 12 Month 24 Month 36 Month fungal infection (1 vs. 1%; p = 0.01) compared with Assessment tamoxifen [42]. Placebo Letrozole Quality of life and patient preference 1,353 1,289 779 353 -10 Anastrozole 1,315 1,282 750 333 -20 Baseline 6 Month 12 Month 24 Month 36 Month The QOL of patients treated in the ATAC trial was studied Assessment during a 5-year follow-up period [118, 131]. Anastrozole and tamoxifen had similar overall effects on QOL (Func- Fig. 2 Mean change score in Short Form 36-item Health Survey. A positive score indicates a favorable change in quality of life. (A) tional Assessment of Cancer Therapy-Breast [FACT-B] Physical component summary; P = not significant for all time points. trial outcome index plus endocrine sub-scale) in the first (B) Mental component summary; P = not significant for all time 2 years of treatment [118], and an initial worsening of points. [133]. 2005 American Society of Clinical Oncology. endocrine symptoms gradually improved over time [131]. Reproduced with permission Mean change score Mean change score 84 Breast Cancer Res Treat (2007) 105:75–89 QOL scores and MENQOL (menopause symptom scale) in assessing and reporting risk of cardiovascular disease [8, psychosocial and physical domains [134]. 52, 95, 138]. Current information is insufficient to determine the effects of AIs on cardiovascular disease and coronary heart Exemestane disease risk [20]. Similarly, further follow-up is required to determine the late consequences of AI therapy [20]. Results from the IES QOL sub-protocol indicate that Despite these provisos, ASCO now recommends that switching to exemestane from tamoxifen improves out- optimal adjuvant hormonal therapy for a postmenopausal come without a significant detrimental impact upon QOL woman with receptor-positive breast cancer includes an AI [135]. At entry, there was a high prevalence of severe as initial therapy or after treatment with tamoxifen. Results endocrine symptoms (vasomotor complaints and sexual from several ongoing trials, including the Femara versus problems), and these persisted with exemestane and Anastrozole Clinical Evaluation, MA.27, the National tamoxifen during the study. No significant differences Surgical Adjuvant Breast and Bowel Project, LATER, and between groups were seen for any endocrine symptoms MILER, should provide more information on the long-term apart from vaginal discharge, which was more pronounced tolerance and the optimal duration of adjuvant AI therapy with tamoxifen (P \ 0.001). and help determine which strategy has the best ratio of efficacy to tolerance. In conclusion, the efficacy benefits of AIs outweigh the Conclusions risks when AIs are used as adjuvant therapy in postmen- opausal women with early breast cancer. Safety, QOL, and Clinical trials show that the third-generation AIs lack the patient preference must all be considered in the determi- serious risks of thromboembolism and endometrial cancers nation of the optimal strategy for long-term endocrine associated with tamoxifen and are generally well tolerated, therapy, bearing in mind that patients may require treat- with the majority of adverse events occurring at mild to ment for 10 years or more. Every patient is unique, and moderate intensity [8–11]. endocrine therapy must be individualized according to AIs are associated with a mild to modest increased risk clinical, biologic, and patient factors such as lifestyle, the of osteoporosis compared with tamoxifen, and it is there- presence of significant co-morbidities, and use of con- fore essential that patients have regular BMD assessments comitant medications. Tolerability should no longer be an and be monitored proactively to minimize the risk of obstacle to effective, long-term endocrine therapy. clinical fractures [20, 57]. The increased risk of fractures with an AI compared with tamoxifen needs to be balanced References against the increased risk of endometrial and cerebrovas- cular/thromboembolic morbidity with tamoxifen [136]. Of 1. Nolvadex Adjuvant Trial Organization (1983) Controlled trial of note, the updated ATAC analysis shows that the majority tamoxifen as adjuvant agent in management of early breast of excess adverse events associated with tamoxifen cancer. Interim analysis at four years by Nolvadex Adjuvant occurred during the first 2.5 years of treatment; there were Trial Organisation. Lancet 1:257–261 2. Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) 142 (8%) fewer predefined adverse events in the anas- (2005) Effects of chemotherapy and hormonal therapy for early trozole arm [137]. 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Safety of aromatase inhibitors in the adjuvant setting

Breast Cancer Research and Treatment , Volume 105 (Suppl 1) – Oct 3, 2007

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© Springer Science+Business Media, LLC 2007
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Abstract

Breast Cancer Res Treat (2007) 105:75–89 DOI 10.1007/s10549-007-9704-7 REVIEW Edith A. Perez Received: 28 February 2007 / Accepted: 17 July 2007 Springer Science+Business Media, LLC 2007 Abstract The third-generation aromatase inhibitors (AIs) Introduction letrozole, anastrozole, and exemestane are replacing tamoxifen as adjuvant therapy in most postmenopausal Tamoxifen became the standard adjuvant therapy for women with early breast cancer. Although AIs have dem- women with early breast cancer following the first dem- onstrated superior efficacy and better overall safety onstration of efficacy more than 20 years ago [1]. compared with tamoxifen in randomized controlled trials, Administration of tamoxifen for 5 years has been shown to they may not provide the cardioprotective effects of reduce breast cancer recurrence by 41% and mortality by tamoxifen, and bone loss may be a concern with their long- 34% in women with hormone-responsive tumors [2]. term adjuvant use. Patients require regular bone mineral Nevertheless, many limitations of tamoxifen have emerged density monitoring, and prophylactic bisphosphonates are with widespread use. In the landmark National Surgical being evaluated to determine whether they may protect Adjuvant Breast and Bowel Project B-14 trial, 66% of long-term bone health. AIs decrease the risks of thrombo- tamoxifen-treated patients experienced side effects com- embolic and cerebrovascular events compared with pared with 58% of patients given placebo [3]. Severe, tamoxifen, and the overall rate of cardiovascular events in potentially life-threatening events such as thrombosis were patients treated with AIs is within the range seen in age- more likely to occur in patients aged [60 years [3]. Long- matched, non-breast-cancer populations. AIs are also term adverse effects associated with 5 years’ adjuvant associated with a lower incidence of endometrial cancer tamoxifen include venous thromboembolic events, vaginal and fewer vaginal bleeding/discharge events than tamoxi- bleeding, vaginal discharge, ischemic cerebrovascular fen. Compared with tamoxifen, the incidence of hot flashes events, endometrial and uterine cancer, and hysterectomy is lower with anastrozole and letrozole but may be higher [3, 4]. Experiencing side effects significantly increases the with exemestane. Generally, adverse events with AIs are likelihood of patients discontinuing tamoxifen therapy predictable and manageable, whereas tamoxifen may be (odds ratio 4.0; 95% confidence interval [CI] 1.1, 13.9 in associated with life-threatening events in a minority of women aged ‡ 55 years) [5]. Over time, resistance to patients. Overall, the benefits of AIs over tamoxifen are tamoxifen may develop [6], and therapy beyond 5 years is achieved without compromising overall quality of life. not recommended because neither further disease-free survival nor survival benefit is gained [7]. Keywords Adjuvant therapy  Aromatase inhibitors  The third-generation aromatase inhibitors (AIs) letroz- Early breast cancer  Letrozole  Safety ole, anastrozole, and exemestane are rapidly replacing tamoxifen as initial adjuvant therapy [8, 9] or sequential adjuvant therapy after 2–5 years of tamoxifen [10–13]. By potently inhibiting the aromatase enzyme, which converts androgens to estrogen [14, 15], AIs achieve almost total E. A. Perez (&) suppression of total body aromatization and dramatic Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224, reductions in estrogen concentrations in postmenopausal USA women [16–18]. AIs are now recommended in e-mail: perez.edith@mayo.edu 123 76 Breast Cancer Res Treat (2007) 105:75–89 international guidelines for the management of breast The most serious consequence of CTIBL is an increased cancer [19–21]. In addition, guidance is being developed risk of fractures (Fig. 1)[35], which increase morbidity and for the management of common co-morbidities such as healthcare costs [40]. The presence of bone metastases can osteoporosis in postmenopausal women with hormone- contribute to CTIBL and lead to serious complications, sensitive breast cancer receiving AIs [20, 22]. This review including fractures, spinal compression, bone pain, and examines the safety of AIs and assesses their advantages hypercalcemia of malignancy [41]. and disadvantages compared with tamoxifen. It also con- siders the impact of treatment on co-morbidities commonly encountered in this population. Aromatase inhibitors and bone disease In a recent study, the bone health of 1,354 patients with Possible impact of treatment on common co-morbidities breast cancer receiving an AI (anastrozole, exemestane, or letrozole) was compared with 11,014 controls [39]. Treat- Adjuvant therapy should be individualized on the basis of ment with an AI increased the risk of bone loss (relative clinical and biologic risk factors [21], including the pres- risk 1.3; 95% CI 1.1, 1.6; P = 0.01) and bone fracture ence of co-morbidities [23–26]. The most prevalent co- (relative risk 1.4; 95% CI 1.2, 1.6; P = 0.001). The risks morbidities in the postmenopausal patient population are remained significantly higher for AI therapy after adjust- hypertension, arthritis, heart disease, diabetes, chronic ment for age and co-morbidities [39]. An increase in the obstructive pulmonary disease, eye problems, anemia, incidence of arthralgia is noted with all three AIs, when depression, fractures, hearing problems, osteoporosis, compared with tamoxifen. Parkinson’s disease, renal failure, and urinary tract prob- lems [25]. Understanding the long-term effects of aromatase inhibition on bone and cardiovascular health are Anastrozole particularly important to consider because of the potential effects of altering estrogen concentrations. Howell and colleagues reported fracture rates after a median follow-up of 68 months in the Arimidex, Tamox- ifen, Alone or in Combination (ATAC) trial [42]. Fractures Bone disease were reported in 577 (9.3%) of the 6,186 patients and were more common with anastrozole than with tamoxifen (11 vs. Bone health typically may deteriorate as women age, par- 8%, respectively; P \ 0.0001). The incidence of hip frac- ticularly after reaching menopause [27, 28]. A decline in tures was 1% in both groups. The rate of fractures was low estrogen concentrations accelerates postmenopausal bone at approximately 2% per year and decreased to baseline loss [29–31] while vitamin D deficiency also increases levels after completion of 5 years of treatment. The effects bone turnover and the risk of fracture [32, 33]. It is of anastrozole and tamoxifen on BMD were assessed in a important to note that bone health is compromised in women with breast cancer compared with the general 68.6 Breast cancer survivors population [34]. In the Women’s Health Initiative Obser- Reference group vational Study, breast cancer survivors had significantly 47.6 lower total body bone mineral density (BMD) and total hip BMD [34] and a significantly higher risk of clinical frac- tures [35]. Of concern, osteoporosis was undiagnosed in 150 more than three quarters of breast cancer survivors and the reference population [34]. Multiple factors contribute to the 17.4 increased risk of osteoporosis and fractures in postmeno- 50 7.3 -1.3 pausal women with breast cancer [34]. Furthermore, tumor cells can have a direct effect on bone remodeling [36], and Hip Clinical Lower arm All other Total vertebral or wrist breast cancer therapy can lead to cancer treatment-induced Fracture outcome bone loss (CTIBL) [37–39]. In a large cohort study, patients with early breast cancer who received anticancer Fig. 1 Age-standardized fracture incident rates by survivor status. Standardized rates were calculated using the age distribution of the therapy had a 30% higher risk for osteoporosis/osteopenia entire Women’s Health Initiative Observational Study cohort. Excess (odds ratio 1.29; 95% CI 1.13, 1.46) [38]. The study also numbers of fractures per 10,000 person-years are above each set of showed that other factors such as poor health status, history bars [35]. 2005 American Medical Association. Reproduced with of smoking, and alcohol abuse can contribute to CTIBL. permission Rate per 10,000 person-years Breast Cancer Res Treat (2007) 105:75–89 77 sub-analysis of 167 patients from the ATAC trial [43]. An- patient-reported diagnoses of new-onset osteoporosis (8% astrozole-treated patients had significant decreases in lumbar letrozole vs. 6% placebo, P = 0.003), and arthralgia and spine BMD (–8.1%; 95% CI –10.1, –6.1; P \ 0.0001) and myalgia were significantly more common with letrozole total hip BMD (–7.4%; 95% CI –9.6, –5.3; P \ 0.0001) rel- than placebo [10]. A companion study to MA.17 demon- ative to tamoxifen-treated patients, in whom small increases strated a significant decrease in lumbar spine BMD (–5.35 were observed. Bone loss was greatest in the first 2 years of vs. –0.70%; P = 0.008) and total hip BMD (–3.6 vs. anastrozole treatment, as reported previously [44], but the rate –0.71%; P = 0.044) over 2 years in patients treated with of loss appeared to slow down from years 2 to 5. In the updated letrozole compared with placebo, although no patient went analysis after a median follow-up of 68 months, osteopenia or below the threshold for osteoporosis in total hip BMD [47]. osteoporosis was reported in 11% of patients receiving anas- Data from this companion study suggest that women with a trozole compared with 7% receiving tamoxifen (P \ 0.0001) BMD score of –1.0 or greater when starting letrozole after [42, 45]. Another sub-analysis of the ATAC trial showed that tamoxifen are less vulnerable to enhanced bone resorption the majority of joint symptoms occur within 24 months of and may not require prophylactic bisphosphonate therapy. 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 Exemestane symptoms were mild in intensity, and 46% were reported as an exacerbation of a pre-existing condition. The incidence of In a model of ovariectomized rats, the steroidal AI exe- serious joint symptoms was similar for anastrozole and mestane was shown to prevent bone loss, presumably via tamoxifen (10.6 vs. 10.4%, respectively) and only 2.1 and its androgenic properties (both exemestane and its metab- 0.9%, respectively, discontinued treatment because of joint olite 17-hydro-exemestane demonstrate affinity for the symptoms. After a median follow-up of 68 months, muscle androgen receptor) [48]. However, a randomized study to cramps were less common with anastrozole than tamoxifen (4 compare the effects of progestins and AIs on bone vs. 8%, respectively; P \ 0.0001), whereas carpal-tunnel remodeling markers in patients with metastatic breast syndrome was more common with anastrozole (3 vs. 1%, cancer found that exemestane increased osteoclast activity respectively; P \ 0.0001) [42]. [49]. In the adjuvant treatment setting, a randomized trial These updated results from the ATAC trial confirm that AIs involving 147 patients with early breast cancer demon- are a well-tolerated initial treatment option in terms of bone strated a non-significant effect of exemestane compared health [43, 45, 46]. Although anastrozole is associated with with placebo on the annual rate of BMD loss in the lumbar BMD loss, no patient with normal bone at baseline became spine (2.17 vs. 1.84%; P = 0.568) and a small but signifi- osteoporotic after 5 years of treatment, and the rate of bone cant effect in the femoral neck (2.72 vs. 1.48%; P = 0.024) loss in the lumbar spine region slowed down in years 2–5. [50]. Of note was the finding that BMD may rapidly The ARNO/ABCSG8 trials investigated the efficacy and improve following AI discontinuation: this trial showed safety of switching to anastrozole after 2 years of tamox- that bone resorption markers returned to or below baseline ifen [12]. Although there were significantly more fractures values, and bone formation markers remained moderately in patients switching to anastrozole (2.1%) than in those increased within 6 months of stopping exemestane [51]. continuing on tamoxifen (1.0%) [12], the rate was lower In the Intergroup Exemestane Study (IES) of exemes- than that seen at a similar point in the ATAC trial [12]. In tane following 2–3 years of tamoxifen, fractures were the Italian Tamoxifen Anastrozole (ITA) trial, switching to reported more frequently with exemestane than with anastrozole after 2–3 years of tamoxifen was not associ- tamoxifen after a median follow-up of 30.6 months, ated with an increase in fracture rate, although differences although this difference was not statistically significant (3.1 may emerge with longer follow-up [13]. vs. 2.3%; P = 0.08) [52]. However, the difference in inci- dence of fractures was statistically significant (7.0% with exemestane vs. 4.9% with tamoxifen; P = 0.003) after a Letrozole median follow-up of 55.7 months [11]. The incidence of osteoporosis was also significantly higher with exemestane In the Breast International Group (BIG) 1–98 trial of initial than with tamoxifen (9.2 vs. 7.2%, respectively; P = 0.01). adjuvant therapy, there was a slight yet significant differ- Recent results from a 1-year sub-study revealed that ence in the incidence of fractures (5.7% with letrozole vs. patients on exemestane experienced a significant decrease 4.0% with tamoxifen; P \ 0.001) [8]. The MA.17 trial of in hip BMD, while patients on tamoxifen did not [53]. extended adjuvant therapy showed that when compared These results were confirmed by another recent study, with placebo, letrozole had no significant impact on frac- which evaluated the effects of exemestane on bone turn- tures [10]. There was a small but significant difference in over markers and BMD in 70 postmenopausal women 123 78 Breast Cancer Res Treat (2007) 105:75–89 (62.0 ± 8.9 years) with early breast cancer who were osteoporosis, and it is recommended that they have switched to exemestane after 2–3 years on tamoxifen [54]. baseline BMD evaluation and regular monitoring to Patients in the exemestane group had a significant decrease guide subsequent therapeutic interventions such as bis- in BMD and early parathyroid hormone (at month 6) and phosphonates [20, 58]. Preliminary results have been an increase in bone alkaline phosphatase (B-ALP) and reported from a small number of clinical trials of bis- the carboxy-terminal telopeptide of type I collagen phosphonates in women receiving adjuvant AI therapy. after 24 months. These studies suggest that switching In one trial, premenopausal breast cancer patients postmenopausal women from tamoxifen to exemestane receiving goserelin plus anastrozole or goserelin plus causes a marked increase in bone turnover markers with a tamoxifen were randomly assigned to the bisphosphonate consequent reduction in BMD. zoledronic acid (ZA) (4 mg IV every 6 months) or pla- Arthralgia was also significantly more common with cebo. After 36 months, it was shown that ZA given exemestane than with tamoxifen (5.4 vs. 3.6%, P = 0.01) every 6 months helped prevent bone loss in these pre- in the IES [52]. A study by Lønning et al. discovered a menopausal patients in both the lumbar spine and hip high prevalence of vitamin D deficiency in postmenopausal regardless of endocrine therapy [59]. Two randomized women treated with exemestane (52 of 59 patients) or trials have shown that bisphosphonates may be beneficial placebo (56 of 62 patients), and this could be the most in postmenopausal patients at a higher risk of osteopo- important factor causing bone loss in both groups [55]. rosis [60, 61]. In the Zometa-Femara Adjuvant Synergy Vitamin D substitution is therefore recommended for Trial (Z-FAST) (North American) trial, 602 postmeno- postmenopausal women, particularly those with breast pausal women with hormone-responsive breast cancer cancer receiving an AI. The incidence of carpal-tunnel starting adjuvant therapy with letrozole were randomized syndrome in the IES was higher in the exemestane arm to receive upfront ZA (4 mg IV infusion every (2.8%) than in the tamoxifen arm (0.4%; P \ 0.001) [11]. 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’ Comparative studies of aromatase inhibitors follow-up indicate that initial treatment with ZA may be used to prevent CTIBL, and results at 24 months confirm A randomized trial (Letrozole, Exemestane, and Anas- these initial findings [62, 63] although the rate of clinical trozole Pharmacodynamics [LEAP]) of healthy volunteers fractures was not changed. In addition, the small pro- demonstrated that letrozole, exemestane, and anastrozole portion of patients (8%) requiring ZA in the first year have similar effects on bone biochemical measurements highlights the short-term bone tolerability of letrozole and all result in increases in bone turnover [56]. There were [62]. Results from the similarly designed ZO-FAST no statistically significant differences between the AIs in (European; N = 1,065) trial also support the use of ZA changes from baseline to 24 weeks for B-ALP, serum C- to potentially manage CTIBL in postmenopausal women telopeptide crosslinks, and propeptide of type I procolla- with early breast cancer receiving adjuvant letrozole gen. The only difference in the bone remodeling markers [61]. was a greater decrease in parathyroid hormone with exe- Lipid metabolism: A cohort study demonstrated that mestane than with anastrozole (P = 0.04). total and low-density lipoprotein (LDL) cholesterol con- Thus, all AIs seem to have similar effects on bone centrations are positively correlated with years since health. The ATAC bone sub-study results are reassuring for diagnosis of breast cancer [64]. In addition, during meno- the entire AI class, and women with breast cancer who pause, women experience adverse changes in have normal BMD measurements at the onset of AI treat- cardiovascular risk factors, including declines in concen- ment may be able to undergo 5 years of therapy without the trations of high-density lipoprotein (HDL) cholesterol and risk of developing osteoporosis. Patients at risk of clini- increases in concentrations of total cholesterol, LDL cho- cally relevant BMD loss during treatment should be lesterol, HDL3 cholesterol, and triglycerides [65, 66]. identified and managed according to evolving clinical These changes are independent of age and body mass guidelines [20, 57]. index. Assessing the impact of AIs on lipid profiles is difficult in trials where tamoxifen is the comparator. The selective Bisphosphonates estrogen-receptor modulators (SERMs) such as tamoxifen are known to have lipid-lowering properties [67, 68]. What In the American Society of Clinical Oncology (ASCO) is clear is that the studies comparing AIs with tamoxifen guidelines postmenopausal patients with breast cancer indicate only that the AIs lack the lipid-lowering effects of whoreceiveAIs areidentified as beingathighriskfor tamoxifen. 123 Breast Cancer Res Treat (2007) 105:75–89 79 Aromatase inhibitors and lipid metabolism Another study examined the longitudinal changes in body composition and lipid profiles in 55 postmenopausal Anastrozole women with early breast cancer switched to exemestane after at least 2 years of tamoxifen treatment [70]. Fat In the ATAC trial, the incidence of hypercholesterolemia mass significantly decreased (P \ 0.01) while the fat-free was higher in patients receiving anastrozole than tamoxifen mass to fat mass ratio significantly increased (P \ 0.05) (9 vs. 3%, respectively; P \ 0.0001) [42]. In the ITA trial, by month 12 in the exemestane but not in the tamoxifen lipid metabolism disorders were reported in 9.3% of group. In addition, triglycerides and HDL cholesterol patients treated with anastrozole and 4.0% receiving significantly decreased (P \ 0.01 and P \ 0.05, respec- tamoxifen (P = 0.04) [13]. tively) in the exemestane group, while LDL cholesterol A recent multicenter study in patients with estrogen- significantly increased (P \ 0.01) at the end of the 1-year receptor positive breast cancer investigated the effects of study period. adjuvant anastrozole and toremifene, a SERM, on serum lipids [68]. Results showed that only toremifene had a ben- eficial effect on lipid profile, indicated by a decrease in total Aromatase inhibitors versus placebo cholesterol, LDL cholesterol, triglycerides, and apolipopro- tein B, and an increase in HDL cholesterol and When compared with placebo (the most accurate way to apolipoprotein A1. Changes in total cholesterol, HDL, LDL, assess the true impact of AIs on serum lipids), the final and apolipoproteins were significantly different between analysis of the MA.17 trial demonstrated the incidence of toremifene and anastrozole at 6 and 12 months (P \ 0.05). 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 Letrozole breast cancer treated for up to 36 months, letrozole (n = 183) does not significantly alter lipid profile (samples In the BIG 1–98 trial, according to the protocol, cholesterol drawn under fasting conditions) compared with placebo concentrations (fasting or non-fasting) were collected sys- (n = 164) [71]. In a placebo-controlled study involving 147 tematically in the case-report forms every 6 months and postmenopausal women with early breast cancer, exemes- even patients with only a single measurement above the tane had no major effect on lipid profile except for a upper limit of normal were defined as hypercholesterol- modest but significant decrease from baseline in HDL emic [8]. Hypercholesterolemia was reported in 5.4% of cholesterol (P \ 0.001) and apolipoprotein A1 (P = 0.004) the letrozole arm compared with 1.2% of the tamoxifen [50]. On the basis of these results, it is clear that when arm in patients with baseline values within normal limits, compared with placebo, AIs do not have a detrimental who then had an increase of 1.5 times the upper limit of effect on lipid profile. However, it should be noted that normal [69]. Hypercholesterolemia was typically a single there have been no placebo-controlled trials of adjuvant event and in the majority of these patients (80%) occurred anastrozole in women with breast cancer. at only grade 1 intensity (meaning a slight numerical increase above normal, not requiring medications). More- over, the majority of cases were single measurements collected in non-fasting patients. Furthermore, when Comparative studies of aromatase inhibitors looking at total serum cholesterol levels, there was a 12% median decrease from baseline in total cholesterol in the The LEAP trial directly compared safety parameters tamoxifen arm after 6 months, consistent with previous between the steroidal AI exemestane and the non-steroidal reports demonstrating the lipid-lowering effect of tamoxi- AIs anastrozole and letrozole in 90 healthy postmenopausal fen [67], while in the letrozole group total cholesterol women (Table 1)[72]. Initial results from the trial showed values remained stable [8]. Hypercholesterolemia was not that there were no significant differences between anas- predefined as an adverse event in the ATAC trial, and lipid trozole and letrozole in effects on LDL:HDL ratios, concentrations were not routinely assessed [42]. triglyceride concentrations, and non-HDL concentrations. Exemestane was associated with an increase in LDL:HDL ratio (+17) (P = 0.047) compared with anastrozole. There Exemestane was no median change from baseline in total serum cho- lesterol for letrozole, a slight increase for anastrozole Hypercholesterolemia was not reported in the IES trial of (+0.4), and a non-significant decrease for exemestane sequential exemestane after tamoxifen [11, 52]. (–3.9) (P = 0.164 vs. anastrozole) [72]. 123 80 Breast Cancer Res Treat (2007) 105:75–89 Table 1 Comparative effects of third-generation aromatase inhibitors on lipids [72] Percentage change Anastrozole Letrozole P value vs. Exemestane P value vs. from baseline (n = 29) (n = 29) anastrozole (n = 32) anastrozole Total cholesterol Week 12 –2.3 –3.8 0.617 –5.5 0.262 Week 24 +0.4 –0.0 0.900 –3.9 0.164 Triglycerides Week 12 –2.9 +9.6 0.037 –7.7 0.417 Week 24 +0.3 +5.4 0.550 +2.1 0.827 Ratio of LDL-C:HDL-C Week 12 –0.0 –3.1 0.486 +8.8 0.048 Week 24 +4.6 +3.4 0.847 +17.0 0.047 Non-HDL-C Week 12 –2.7 –4.2 0.667 –3.5 0.820 Week 24 +1.3 +1.2 0.975 –0.6 0.630 Ratio of apo B:apo A1 Week 12 –1.0 –3.3 0.452 +4.4 0.069 Week 24 +0.0 –0.8 0.842 +9.0 0.023 LDL-C low-density lipoprotein cholesterol, HDL-C high-density lipoprotein, apo B apolipoprotein B, apo A1 apolipoprotein A1 Cardiovascular disease meta-analysis, tamoxifen was associated with a significantly decreased incidence of myocardial infarction (relative risk Cardiovascular risk increases substantially and progressively 0.90) and death from myocardial infarction (relative risk in women aged ‡65 years [73–77]. Isolated systolic hyper- 0.62) [93]. This finding is consistent with results from an tension, associated with arterial stiffening, is predominant in earlier cohort study [94] and the Early Breast Cancer Trial- middle- and older-aged hypertensives [75] and predisposes ists’ Collaborative Group (EBCTCG) meta-analysis, which individuals to coronary heart disease, heart failure, stroke, demonstrated decreases in the risk of cardiac death and vascular dementia, and chronic kidney disease [73]. The risk overall mortality from vascular disease in patients receiving of cardiac disease is also influenced by ethnicity, smoking, tamoxifen compared with those receiving placebo [2]. obesity, physical inactivity, alcohol abuse, and the presence of co-morbid diseases such as diabetes. In patients with breast cancer the presence of co-mor- Aromatase inhibitors and cardiovascular disease bidities, including cardiovascular disease and diabetes, is associated with a poorer prognosis than when co-morbid Assessing the impact of different AIs on cardiovascular disease is absent [78] and may explain disparities in outcome disease in postmenopausal women with breast cancer is between different ethnic groups [79]. There is also evidence difficult and inter-trial comparisons are confounded by that breast cancer is associated with a higher prevalence of differences in data collection and end points; for example, hypertension compared with other tumor types [80]and a in the BIG 1–98 trial all potential adverse events were significantly increased risk of stroke compared with the predefined in the case-report forms whereas the ATAC trial general population (relative risk 1.12; 95% CI 1.07, 1.17) used non-specific case-report forms to report adverse [81]. Many breast cancer therapies increase the risk of car- events [8, 95]. Furthermore, comparisons with tamoxifen diovascular events [82–88]; tamoxifen, however, may have are complicated by its cardioprotective properties. Placebo- some cardio-protective effects [89, 90]. 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. Tamoxifen and cardiovascular disease Several studies have demonstrated the potential cardiopro- Anastrozole tective properties of tamoxifen, including a reduction in hospital admissions due to cardiac disease [89–91]and The ATAC trial provided data on the cardiovascular effects decreased mortality from cardiac disease [92]. In a of anastrozole as initial adjuvant therapy compared with 123 Breast Cancer Res Treat (2007) 105:75–89 81 tamoxifen. The incidence of ischemic cardiovascular dis- Aromatase inhibitors versus placebo ease was higher (but not significantly) with anastrozole than placebo (127/3092, 4.1% vs. 104/3094, 3.4%; Cardiovascular events occurred with similar frequency in P = 0.1). The incidence of angina was also higher with the letrozole and placebo arms in the MA.17 trial (5.8 vs. 5.6%, respectively; P = 0.76) [10]. Similar incidences anastrozole (71/3092, 2.3% vs. 51/3094, 1.6%; P = 0.07), while myocardial infarction occurred with similar fre- were reported in the letrozole and placebo arms for stroke/ transient ischemic attack (0.7 vs. 0.6%, respectively), quency (37/3092, 1.2% vs. 34/3094, 1.1%; P = 0.7 [42]. Hypertension was statistically significantly more common myocardial infarction (0.3 vs. 0.4%, respectively), new or worsening angina (1.2 vs. 0.9%), angina requiring coronary with anastrozole than with tamoxifen (13 vs. 11%, respectively; P = 0.04) [42]. In the ARNO95 trial vascular artery bypass graft (0.2 vs. 0.5%), and thromboembolic events, including hot flashes, ischemic cardiovascular events (0.4 vs. 0.2%, respectively) [10]. These results events, deep vein thrombosis, and ischemic cerebrovascu- clearly indicate that when compared with placebo, AIs do lar events, occurred in 9.2% of the anastrozole arm not have a detrimental effect on cardiovascular safety. compared with 8.8% of the tamoxifen arm [96]. Gynecologic health Letrozole The onset of menopause is characterized by numerous The BIG 1–98 trial demonstrated a similar incidence of adverse events associated with a decline in estrogen con- cardiac events in the letrozole and tamoxifen groups (4.1 centrations [100–102]. Early symptoms include abnormal vs. 3.8%, respectively; not significant). However, more vaginal bleeding, hot flashes, and mood changes, while women in the letrozole group had grade 3, 4, or 5 cardiac vaginal dryness and irritation, osteoporosis, and heart dis- events (2.1 vs. 1.1%, respectively; P \ 0.001), but these ease are late symptoms [29, 103, 104]. Vasomotor events remain rare [8]. Of note, a recent update of the symptoms, particularly hot flashes, are common during monotherapy arms of BIG 1–98 after a longer median transition to menopause [105–109] and may lead to dis- follow-up of 51 months showed that the overall incidence turbed sleep, depressive symptoms, and significant reductions in quality of life [110–115]. Cigarette smoking of cardiac events was comparable in the two groups (134 events [5.5%] in the letrozole group vs. 122 [5.0%] in the may be associated with increased risk of hot flashes in menopausal women [116]. Sexual dysfunction is also pre- tamoxifen arm), thus confirming the safe cardiac profile of letrozole reported at 26 months [97]. valent in menopausal women and is associated with vaginal atrophy, vaginal/genital dryness, dyspareunia (pain during sexual intercourse), vaginitis, cystitis, and urinary tract Exemestane infections [117]. In the IES, there was no significant difference between exemestane and tamoxifen in the incidence of combined Aromatase inhibitors and gynecologic health cardiovascular disease/thromboembolic events (22.1 vs. Anastrozole 20.9%, respectively; P = 0.34) after a median follow-up of 55.7 months [11]. The incidence of myocardial infarction In the ATAC trial, the incidence of hot flashes was sig- was higher with exemestane than with tamoxifen, although the difference between treatment groups was not significant nificantly lower with anastrozole than with tamoxifen (36 (1.3 vs. 0.8%, respectively; P = 0.08) [11]. vs. 41%; P \ 0.0001) [9]. In the latest analysis, anastrozole Overall, the rate of cardiovascular events in patients was associated with a significantly lower incidence of treated with AIs is well within the range seen in age-mat- gynecologic events (endometrial hyperplasia, endometrial ched, non-breast-cancer populations; for example, for neoplasia, cervical neoplasm, and enlarged uterine fibroids: women 57–65 years of age, the rates of fatal myocardial 3 vs. 10% with tamoxifen; P \ 0.0001) [42]. A quality-of- infarction and other fatal coronary artery disease are 1.1 life (QOL) analysis confirmed that vaginal discharge, and 0.81 per 1,000 patient-years, respectively [98]. Similar vaginal itching/irritation, and vaginal bleeding were less common with anastrozole but found that vaginal dryness, rates were recorded in the UK General Practice Research Database and Swedish MI register [99]. Currently, there is pain during intercourse, and loss of interest in sex were more common [118]. After 2 years of treatment there was a insufficient information to fully determine the effect of AIs on cardiovascular disease, especially coronary heart non-significant trend towards a lower incidence of endo- disease. metrial abnormalities with anastrozole than tamoxifen 123 82 Breast Cancer Res Treat (2007) 105:75–89 (odds ratio 0.44; 95% CI 0.146, 1.314; P = 0.14) [119]. (6 vs. 9%; P \ 0.001) [52]; however, vaginal dryness was The latest update of the ATAC trial revealed reduced libido significantly more common among women taking exe- in significantly more patients receiving anastrozole (1%) mestane than those taking tamoxifen, while vaginal than tamoxifen (\1%; P = 0.0001) [42]. Patients receiving discharge was significantly more common with tamoxifen anastrozole also experienced a significantly higher inci- [122]. Vaginal bleeding was significantly more common in dence of dyspareunia than those receiving tamoxifen the tamoxifen arm (7.1%) than in the exemestane group (1 vs. \ 1%, respectively; P = 0.002), whereas urinary (4.8%; P = 0.001) [11]. incontinence and urinary tract infection were significantly less common among patients receiving anastrozole (uri- nary incontinence: 2 vs. 4%, respectively, P \ 0.0001; Other adverse events urinary tract infection: 8 vs. 10%, respectively, P = 0.002). In a randomized study of postmenopausal women in Secondary cancer whom abnormal vaginal bleeding and/or asymptomatic endometrial thickening occurred during treatment with The association between tamoxifen and endometrial and tamoxifen, switching to anastrozole was associated with a uterine cancers is well-established [4] and is not observed significant reduction in mean endometrial thickness com- with AIs. However, a safety analysis of the ATAC trial pared with continuation of tamoxifen (P \ 0.0001) [120]. [42] showed a surprisingly higher incidence of head and Significantly fewer anastrozole patients required a repeat neck cancer with anastrozole compared with tamoxifen hysteroscopy and dilation and curettage compared with (10/3092 vs. 3/3094, respectively). Similarly, there was an those taking tamoxifen (4.8 vs. 33.0%, respectively; excess of lung cancer (25/3092 vs. 16/3094) and lung P \ 0.0001). 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 Letrozole events exemestane vs. 107 tamoxifen) or in the BIG 1–98 trial (69 letrozole vs. 82 tamoxifen) [8, 11]. In the BIG 1–98 trial [8], endometrial biopsies were sig- A meta-analysis showed that tamoxifen is associated nificantly less common in patients receiving letrozole than with a modest but statistically significant increase in the tamoxifen (2.3 vs. 9.1%, respectively; P \ 0.001), and risk of developing gastrointestinal cancer (relative risk there was a trend towards fewer invasive endometrial 1.31; 95% CI 1.01, 1.69), particularly for postmenopausal cancers (0.1 vs. 0.3%, respectively; not significant). There women (relative risk 1.77) [93]. was a significantly lower incidence of vaginal bleeding with letrozole than with tamoxifen (3.3 vs. 6.6%, respec- tively; P \ 0.001), and the incidence of hot flashes was Gastrointestinal health also significantly lower (33.5 vs. 38.0%, respectively; P \ 0.001). In another study in patients intolerant of Diarrhea was significantly more common among patients tamoxifen, switching to letrozole for 6 weeks was associ- receiving the steroidal AI exemestane than in those taking ated with a 53.7% decrease in hot flashes (hot-flash score tamoxifen (4.2 vs. 2.2%, respectively) [123] but is not a 97.0–52.1; P = 0.001) [121]. In the MA.17 trial, letrozole typical side effect of the non-steroidal AIs letrozole and was associated with less vaginal bleeding than placebo (6 anastrozole. However, an updated safety analysis of the vs. 8%, respectively; P = 0.005) but a greater incidence of ATAC trial showed that anastrozole was associated with an hot flashes (58 vs. 54%, respectively; P = 0.003) [10]. increased incidence of diarrhea compared with tamoxifen There was no significant difference in the incidence of (9 vs. 7%; P = 0.02) [42]. vaginal dryness between letrozole and placebo. Neurologic effects and visual disturbance Exemestane It has been suggested that endocrine therapy may affect In the IES, there were no significant differences between cognitive function in patients with breast cancer [124]. In a the exemestane and tamoxifen treatment arms in the inci- study comparing patients from the ATAC trial with healthy dence of endometrial cancer (0.4 vs. 0.7%, respectively; controls, anastrozole was associated with significant P = 0.17) [11], or the incidence of hot flashes (42 vs. 40%, impairments in a processing speed task and on a measure of respectively; P = 0.28) [52]. Overall, gynecologic symp- immediate verbal memory [125]. Another study conducted toms were lower with exemestane than with tamoxifen in healthy, estrogen-treated postmenopausal women treated 123 Breast Cancer Res Treat (2007) 105:75–89 83 with testosterone did not reveal any effects of aromatase The authors concluded that the benefits of anastrozole are inhibition on cognition [126]. achieved without detrimental effects on QOL. However, The impact of adjuvant AI therapy on cognition and another study conducted in Japanese patients demonstrated other neurologic processes is clearly an important issue that that FACT-G, FACT-B, and FACT-ES scores were sig- will require further studies in the future. Neurologic effects nificantly better with tamoxifen than with anastrozole reported with exemestane, including dizziness and vertigo (P = 0.012, P = 0.010, and P = 0.015, respectively) [132]. [127] and significantly more visual disturbances compared with tamoxifen [52], are not characteristic of non-steroidal AIs. Letrozole The MA.17 and BIG 1–98 trials have demonstrated that Dry mouth adjuvant letrozole is well-tolerated compared with placebo [10] and better tolerated than tamoxifen [8]. In another The latest analysis of the ATAC trial demonstrated a sig- study of postmenopausal women who were experiencing nificantly greater incidence of dry mouth in patients distressing side effects while taking adjuvant tamoxifen receiving anastrozole (4%) compared with tamoxifen (2%; and were switched to letrozole, after 6 weeks 66% of P = 0.003) [42]. 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 signifi- Cosmetic effects cantly improved outcomes and did not impair overall QOL [133] (Fig. 2). Minor differences seen in some domains Weight gain is common after breast cancer therapy and (physical functioning, bodily pain, vitality, vasomotor, and increases the risk of recurrence, cardiovascular disease, and sexual) were consistent with a minority of patients expe- diabetes [64]. A study of Japanese patients showed that riencing changes in QOL compatible with a reduction in more women reported weight gain in the anastrozole group estrogen synthesis. A sub-analysis of US subjects in MA.17 than in the tamoxifen group (35.8 vs. 12.5%, respectively; demonstrated no significant differences between letrozole P £ 0.0036) [128], but no difference was seen among and placebo in overall QOL summary scores (mental and patients from the ATAC trial included in a QOL sub- physical) and five of eight sub-domains of SF-36 [134]. analysis [118]. There were no differences in SF-36 mental and physical The androgen structure of exemestane may lead to androgenic side effects. Hypertrichosis, hair loss, hoarse- ness, and acne were reported in about 10% of patients treated with daily exemestane doses of 200 mg or more in Placebo Letrozole dose-finding studies [129, 130], but have not emerged as a significant issue in phase II or phase III trials with this agent. 1,353 1,289 779 353 -10 Anastrozole treatment was associated with a lower 1,315 1,282 750 333 -20 incidence of nail disorders (2 vs. 3%; P = 0.002) and Baseline 6 Month 12 Month 24 Month 36 Month fungal infection (1 vs. 1%; p = 0.01) compared with Assessment tamoxifen [42]. Placebo Letrozole Quality of life and patient preference 1,353 1,289 779 353 -10 Anastrozole 1,315 1,282 750 333 -20 Baseline 6 Month 12 Month 24 Month 36 Month The QOL of patients treated in the ATAC trial was studied Assessment during a 5-year follow-up period [118, 131]. Anastrozole and tamoxifen had similar overall effects on QOL (Func- Fig. 2 Mean change score in Short Form 36-item Health Survey. A positive score indicates a favorable change in quality of life. (A) tional Assessment of Cancer Therapy-Breast [FACT-B] Physical component summary; P = not significant for all time points. trial outcome index plus endocrine sub-scale) in the first (B) Mental component summary; P = not significant for all time 2 years of treatment [118], and an initial worsening of points. [133]. 2005 American Society of Clinical Oncology. endocrine symptoms gradually improved over time [131]. Reproduced with permission Mean change score Mean change score 84 Breast Cancer Res Treat (2007) 105:75–89 QOL scores and MENQOL (menopause symptom scale) in assessing and reporting risk of cardiovascular disease [8, psychosocial and physical domains [134]. 52, 95, 138]. Current information is insufficient to determine the effects of AIs on cardiovascular disease and coronary heart Exemestane disease risk [20]. Similarly, further follow-up is required to determine the late consequences of AI therapy [20]. Results from the IES QOL sub-protocol indicate that Despite these provisos, ASCO now recommends that switching to exemestane from tamoxifen improves out- optimal adjuvant hormonal therapy for a postmenopausal come without a significant detrimental impact upon QOL woman with receptor-positive breast cancer includes an AI [135]. At entry, there was a high prevalence of severe as initial therapy or after treatment with tamoxifen. Results endocrine symptoms (vasomotor complaints and sexual from several ongoing trials, including the Femara versus problems), and these persisted with exemestane and Anastrozole Clinical Evaluation, MA.27, the National tamoxifen during the study. No significant differences Surgical Adjuvant Breast and Bowel Project, LATER, and between groups were seen for any endocrine symptoms MILER, should provide more information on the long-term apart from vaginal discharge, which was more pronounced tolerance and the optimal duration of adjuvant AI therapy with tamoxifen (P \ 0.001). and help determine which strategy has the best ratio of efficacy to tolerance. In conclusion, the efficacy benefits of AIs outweigh the Conclusions risks when AIs are used as adjuvant therapy in postmen- opausal women with early breast cancer. Safety, QOL, and Clinical trials show that the third-generation AIs lack the patient preference must all be considered in the determi- serious risks of thromboembolism and endometrial cancers nation of the optimal strategy for long-term endocrine associated with tamoxifen and are generally well tolerated, therapy, bearing in mind that patients may require treat- with the majority of adverse events occurring at mild to ment for 10 years or more. Every patient is unique, and moderate intensity [8–11]. endocrine therapy must be individualized according to AIs are associated with a mild to modest increased risk clinical, biologic, and patient factors such as lifestyle, the of osteoporosis compared with tamoxifen, and it is there- presence of significant co-morbidities, and use of con- fore essential that patients have regular BMD assessments comitant medications. Tolerability should no longer be an and be monitored proactively to minimize the risk of obstacle to effective, long-term endocrine therapy. clinical fractures [20, 57]. The increased risk of fractures with an AI compared with tamoxifen needs to be balanced References against the increased risk of endometrial and cerebrovas- cular/thromboembolic morbidity with tamoxifen [136]. Of 1. Nolvadex Adjuvant Trial Organization (1983) Controlled trial of note, the updated ATAC analysis shows that the majority tamoxifen as adjuvant agent in management of early breast of excess adverse events associated with tamoxifen cancer. Interim analysis at four years by Nolvadex Adjuvant occurred during the first 2.5 years of treatment; there were Trial Organisation. Lancet 1:257–261 2. Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) 142 (8%) fewer predefined adverse events in the anas- (2005) Effects of chemotherapy and hormonal therapy for early trozole arm [137]. 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Published: Oct 3, 2007

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