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Toxicity of Aromatase Inhibitors
Toxicity of Aromatase Inhibitors Naimish Pandya and Gloria J. Morris Adjuvant hormonal therapy in hormone receptor–positive breast cancer is used for the prevention of disease recurrence and prolongation of survival. Aromatase inhibitors are increasingly being used for this purpose. Numerous studies now reveal their benefits over tamoxifen while demonstrating a markedly different toxicity profile. With greater use, a better understanding of the long-term effects of aromatase inhibitors on the prevention of cancer recurrence and on their long-term effects on chronic comorbid conditions will develop. Recognizing and understanding these toxicities, as well as the differences among the various aromatase inhibitors, will be crucial for all clinicians. When choosing the type of adjuvant hormonal therapy for each individual patient, comorbidities and quality-of-life parameters must be considered. In addition, ongoing studies evaluating these agents directly should reveal differences among them that may aid in determining the principal agent for use in this setting. In this article, we review the known toxicity profile of aromatase inhibitors and the current guidelines that exist in the diagnoses and management of these toxicities. Semin Oncol 33:688-695 © 2006 Elsevier Inc. All rights reserved.
I
t is estimated by the American Cancer Society that 214,640 women will develop breast cancer during 2006, of which 41,430 will die of the disease.1 Since the late 1980s, the incidence has stabilized and mortality has decreased, due in large part to aggressive prevention strategies and improved therapeutics. The Surveillance Epidemiology and End Results (SEER) data also reveal that with the increase in screening, breast cancer is being diagnosed more often in the early stages2 (Table 1). This has prompted efforts to determine the best breast conservation surgical approaches and the least toxic neoadjuvant and adjuvant therapies with the goal of improving longevity and the quality of life women lead afterwards. It has been estimated that more than one third of all breast carcinomas are estrogen-dependent and regress after estrogen deprivation.3 Therefore, reducing the levels of estrogen is important in the treatment of breast cancer in both premenopausal and postmenopausal women. Endocrine therapy, as a result, is important in the treatment of the patients to reduce recurrence of the primary carcinoma and to prevent further carcinoma development. Tamoxifen acts by blocking the effects of endogenous estrogen at the receptor level, but it also is associated with serious adverse events.4 Consequently, the
Division of Medical Oncology, Thomas Jefferson University Hospital, Philadelphia, PA. Address correspondence to Gloria Morris, MD, PhD, Department of Medical Oncology, Thomas Jefferson University Hospital, 111 South 11th St, Suite G-4240, Philadelphia, PA 19107. E-mail: [email protected]
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0093-7754/06/$-see front matter © 2006 Elsevier Inc. All rights reserved. doi:10.1053/j.seminoncol.2006.08.011
safety and tolerability of adjuvant endocrine agents must be considered when given over a prolonged period of time. Aromatase inhibitors, especially the newer third-generation agents, recently have been demonstrated to be superior to tamoxifen in the metastatic setting5-9 and are now proving to be efficacious in the adjuvant setting as well. Furthermore, recent data reveal that they have a slightly different toxicity profile than tamoxifen, one that can cause significant morbidity but markedly reduced mortality.10 In this review, we examine the available data on safety and toxicity of aromatase inhibitors and attempt to assess if any one agent is superior to another.
Principles of Aromatase Inhibitors In 1896, George Beatson successfully demonstrated tumor regression in a young woman with locally advance breast cancer by performing an oophorectomy, thereby concluding that breast cancer is hormonally responsive.11 With the introduction of an estrogen blocker, tamoxifen, in the 1970s, overall survivals for women with breast cancer improved markedly. Tamoxifen acts by directly blocking the estrogen receptor, which is essential in the signal pathway for growth and survival in breast carcinomas. However, tamoxifen also exerts partial estrogen agonist effects, which are detrimental and likely the cause of the increased risk of endometrial carcinoma, thromboembolism, and tamoxifen resistance.12 Aromatase inhibitors, in contrast, “block” the estrogen re-
Toxicity of aromatase inhibitors
689
Table 1 SEER Stage Distribution for Breast Cancer, All Ages, Females: SEER 9 Registries for 1975–79, 1985– 89, 1995–2001 Stage
1975–1979
1985–1989
1995–2001
Localized Regional Distant Unstaged
48% 41% 8% 4%
56% 34% 6% 4%
63% 29% 6% 2%
ceptor by reducing the levels of its ligand, endogenous estrogen. They target the aromatase enzyme, which converts testosterone and adrenal androgens to estrodiol and other estrogens. The aromatase enzyme is a P-450 cytochrome enzyme, which is present in adipose, liver, muscle, brain, placenta, and breast cancer tissue.13 Observational studies of adipose tissue adjacent to malignant cells within the breast have shown a greater aromatase enzymatic activity, consequently causing higher concentrations of estrogen within the tumor than in the circulation and promoting growth of malignant cells. aromatase inhibitors inhibit in situ aromatization in both the tumor and the nonmalignant cells within the breast tissue, and markedly suppress peripheral estrogen synthesis.14 There are two types of aromatase inhibitors, steroidal and nonsteroidal, and the third generation of these compounds demonstrates the greatest efficacy for breast cancer therapy (Table 2), Steroidal inhibitors compete with androstenedione and testosterone for the active site within the enzyme, and the metabolites of this reaction bind to the enzyme, causing irreversible enzyme inhibition. Alternatively, the nonsteroidal inhibitors compete with the endogenous ligands and form a strong but reversible bond to the heme iron atom of the active site of the enzyme, excluding both the ligands and oxygen from the enzyme (Fig 1). Although the method of inhibition differs, both classes of aromatase inhibitors exhibit potent suppression of the aromatase enzyme. Thus, the clinical relevance of these different mechanisms of inhibition remains to be established.4 Numerous studies have confirmed the benefit of aromatase inhibitors over tamoxifen in the estrogen receptor–positive advanced breast cancer patient, leading to their recommendation as first-line therapy in postmenopausal women.15-17 The goal in this setting is to increase the time to progression of the tumor and improve overall survival. However, the rationale of adjuvant therapy for early-stage breast cancer following primary therapy is to prevent or delay recurrence. Patients who receive adjuvant endocrine therapy tend to remain clinically disease-free for a much longer time (approximately five times longer) than metastatic breast cancer patients who also receive endocrine treatments.10 Therefore, it Table 2 Aromatase Inhibitors
First generation Second generation Third generation
Steroidal
Nonsteroidal
— Formestane Exemestane
Aminoglutehimide Fadrozole Anastrozole, letrozole
Figure 1 Mechanisms of action of tamoxifen and exemestane. Tumor growth in hormone-responsive breast cancer is propagated by intracellular signaling after estrogen engages with the estrogen receptor. Estrogen can originate from endogenous supply or as converted from androgens in non-ovarian sources such as adipose, muscle, and adrenal tissue by the action of the enzyme aromatase. Tamoxifen is a competitive blocker of the estrogen receptor from engaging with estrogen and does not allow growth signals to be induced by the receptor. In contrast, exemestane, a representative aromatase inhibitor, hinders the enzyme aromatase from converting peripheral (non-ovarian) androgen to estrogen, thereby not allowing further estrogens to engage their receptor. Oestrogen ⫽ estrogen. Reprinted by permission from Macmillan Publishers Ltd: British Journal of Cancer, Carpenter R, Miller WR: Role of aromatase inhibitors in breast cancer. 93(Suppl 1):S1-S5, 2005.
is imperative that the tolerability and safety profile of these agents be considered to determine methods to improve the risk/benefit ratio.
Effects on Bone Loss The pathogenesis of osteoporosis is multifactorial in women with breast cancer. Estrogen deficiency is probably the most important factor contributing to osteoporosis, and marked reductions in circulating estrogen occur after ovarian suppression in premenopausal women and after aromatase inhibition in postmenopausal women. The most significant reductions in bone mineral density (BMD) are due to
N. Pandya and G.J. Morris
690 Table 3 Causes of Bone Loss Among Breast Cancer Patients Treatment Chemotherapy Indirect effect
Study Shapiro et al20 Vehmanen et al21
Direct effect
Wheeler et al22
No. of Patients 49 148 69
Subjects Premenopausal women Premenopausal women Rats
Outcome 4% 2 Spine BMD within 6 months 7.5% 2 Spine BMD within 36 months 2 Bone volume, 2 mineralizing surface, 1 osteoclast surface, P <.05 No significant change in T score, but significant changes in Z score at lumbar spine, BMD 2 0.6, P ⴝ .05 1.44% 2 Spine BMD within 12 months, P <.001
Greep et al23
130
Postmenopausal women
Tamoxifen
Powles et al24
125
Premenopausal women
Ovarian ablation Drug induced
Leather et al25
19
Premenopausal women Premenopausal women
4.8% 2 Spine BMD in 6 months, P <.001
Postmenopausal women Postmenopausal women Postmenopausal women Postmenopausal women
2.6% 2 Spine BMD in 12 months
Surgical Aromatase inhibitors Anastrozole
Hashimoto et al26
244
Eastell et al27
308
Letrozole
Goss et al28
5187
Exemestane
Coombes et al29
4742
Lonning et al30
147
10.7% 2 Spine BMD in 12 months
1 Osteoporosis in letrozole arm v placebo, 5.8% v 4.5%, P ⴝ .07 1 Osteoporosis in exemestane arm v tamoxifen arm, 7.4% v 5.7%, P ⴝ .05 Annual rate of 2.17% 2 spine BMD
Reprinted by permission from Macmillan Publishers Ltd: British Journal of Cancer, Lester J, Coleman R: Bone loss and aromatase inhibitors. 93(Suppl 1):S16 –S22, 2005.
treatment-induced bone loss, as a result of oophorectomy, irradiation, luteinizing hormone–releasing hormone (LHRH) analogues, or chemotherapy, leading to significant clinical sequelae and increased fracture risk.18 Table 3 summarizes the various causes of bone loss among breast cancer patients.19 Chemotherapy has been shown to have direct toxicity on bone proliferation and mineralization and indirect toxicity by a sudden decrease in estrogen production from treatment-induced ovarian failure (in premenopausal women), resulting on average 4.0% loss of lumbar spine BMD in just 6 months.20,22 Tamoxifen, which has a complex mechanism of action with antiestrogenic effect on breast tissue, conversely has a partial estrogenic effect on the bone, uterus, and lipids. These partial agonist effects on bone metabolism may protect postmenopausal women from developing osteoporosis, with one study documenting an increase in lumbar spine BMD by 0.61% per year.31 Nevertheless, with studies showing improved cancer outcomes, aromatase inhibitors are replacing the use of tamoxifen, and the American Society of Clinical Oncology (ASCO) guidelines encourage their primary role in the treatment regimen for postmenopausal women in the adjuvant setting.32 Consequently, the use of aromatase inhibitors in the adjuvant setting, causing further marked reduction in endogenous estrogen production, will have profound effects on bone physiology. Aromatase inhibitors, in general, tend to induce bone loss and increase fracture risk to a higher degree, when compared
to tamoxifen or placebo. Although head-to-head trials have not been performed, the steroidal inhibitor, exemestane, seems to have less of an effect on bone than the nonsteroidal agents, letrozole and anastrozole.33 The Intergroup Exemestane Study (IES) evaluated more than 4,000 patients in a randomized, double-blinded, phase III trial comparing 5 years of either tamoxifen or exemestane in postmenopausal women in the adjuvant setting. There was a nonsignificant increase in osteoporosis in both arms, with a 1.7% increase in the exemestane arm, and a corresponding nonsignificant increase in fractures, with a trend not in favor of the steroidal aromatase inhibitors by 0.8%.29 More recently, a smaller study by the Norwegian Breast Cancer Group demonstrated in low-risk early breast cancer or ductal carcinoma-in-situ (DCIS) patients an increase in BMD loss in the exemestane arm when compared to placebo in the adjuvant setting. The results demonstrated a statistically significant bone loss when measured at the femoral neck but not in the lumbar spine. In addition, it also demonstrated an increase in bone resorption biomarkers (C-telopeptide and N-telopeptide) and bone formation markers (bone alkaline phosphatase, pro-collagen type I amino-terminal propeptide, and osteocalcin).33 Although bone turnover has been suggested to be associated with an increased fracture risk, a prospective study showed that an increase in markers of bone resorption and not of bone formation is related with fracture risk.34 Exemestane, unlike the nonsteroidal aromatase inhibitors, expresses an-
Toxicity of aromatase inhibitors drogenic effects through its metabolite, 17-hydroxy-exemestane, which could elevate bone formation markers.35 It is possibly this difference leads to less bone loss when compared to nonsteroidal inhibitors, but long-term direct comparisons between the compounds are necessary to differentiate the full effects on bone metabolism and overall fracture risk. In contrast, the nonsteroidal aromatase inhibitors have shown marked bone loss with their use. The ATAC trial (Arimidex, Tamoxifen Alone or in Combination Trial), which compared anastrozole to tamoxifen in 9,000 postmenopausal women with early-stage breast cancer in the adjuvant setting, showed a statistically significant increase in all fractures in the anastrozole arm as compared to those in the tamoxifen arm (11.0% v 7.7%) after 68 months of follow-up.36 The bone sub-protocol of the ATAC group demonstrated a decrease in BMD by 4% in the lumbar spine and 3.2% in the hip, with an increase in the bone resorption and formation markers in the anastrozole arm compared to those in the tamoxifen arm.37 The Italian Tamoxifen Anastrozole (ITA) trial, a randomized, phase III, multicenter study among postmenopausal women who were either treated with 5 years of tamoxifen or 2 to 3 years of tamoxifen followed by to 2 to 3 years of anastrozole therapy, showed no statistical variation in the fracture risk between the arms after a median follow-up of 36 months.38 Nevertheless, these results are premature, based on few events, and include 2 years of tamoxifen therapy, so significant differences may require longer follow-up to discern. The National Cancer Institute of Canada Cancer Treatment Group (NCIC CTG) MA.17 trial, which compared the use of letrozole against a placebo after 5 years of adjuvant tamoxifen therapy among 5,000 postmenopausal early-stage breast cancer patients, showed a statistically significant increase in reported diagnoses of osteoporosis but a nonsignificant rise in fractures in the letrozole arm after a median follow-up of 30 months.39 A bone sub-protocol analysis revealed a markedly significant decrease in BMD in the lumbar spine and the hip,40 with an increase in the bone resorption markers and decrease in the bone formation markers in the letrozole arm.41 The Breast International Group (BIG) 1-98 study, which compared head-to-head and in combination use of letrozole against tamoxifen in 8,000 postmenopausal women with early-stage breast cancer, also showed a statistically significant increase in number of fractures in the letrozole-only arm. This trial also revealed a significantly shorter time interval to first fracture in the letrozole arm.42 Clearly, these large trials reveal a noteworthy rise in the development of osteoporosis and fracture risk among recipients of nonsteroidal aromatase inhibitors, for which increased screening and aggressive treatment strategies will need to be developed in concordance with their use. ASCO has released recommendations for monitoring postmenopausal breast cancer patients who are receiving aromatase inhibitor therapy. These women should have a baseline dual-energy x-ray absorptiometry (DEXA) scan performed and treatment initiated as per the results of BMD testing. No standard recommendations currently exist regarding baseline measurement and serial follow-up of either bone resorp-
691 tion or bone formation markers.32 Recently, results from the Zometa-Femara Adjuvant Synergy Trial (Z-FAST), which evaluates the use of upfront zoledronic acid given semi-annually in postmenopausal women on adjuvant letrozole therapy against delayed treatment at the time of fracture or diagnosis of osteoporosis by DEXA scan, were presented at the 2004 San Antonio Breast Cancer Symposium and updated at the 2005 ASCO meeting.43,44 The study showed a significant difference in favor of early initiation of zoledronic acid, with an increase in BMD and suppression of bone turnover markers. This supports the use of aggressive preventive strategies with bisphosphonate therapy as prophylaxis and annual DEXA scans for BMD screening. Further studies are needed to validate this strategy for long-term use, provide data with other aromatase inhibitors, and determine the safety and tolerability of bisphosphonate use in conjunction with aromatase inhibitors. Initiation of bisphosphonate therapy is recommended for any woman treated for breast cancer whose BMD score falls within the osteoporotic range (T score ⱕ⫺2.5).45 ASCO also recommends lifestyle modification and calcium with vitamin D supplementation for women whose BMD score falls in the osteopenic range (T score between ⫺1 and ⫺2.5).45
Effects on Lipids Clinical evidence shows that the low-density lipoprotein (LDL) particle is the key atherogenic cholesterol in the pathogenesis of atherosclerosis and coronary heart disease (CHD), whereas the high-density lipoprotein (HDL) particle exerts a protective effect. Although women tend to have higher levels of HDL than men, the difference between the sexes is reduced in the postmenopausal state.46 High levels of triglycerides also have been suggested to be a predictor of CHD in women more so than in men.47 Moreover, high levels of lipoprotein (a) [Lp(a)] have been shown to be more atherogenic in women as well.48 Estrogen is known to exert a protective effect on the lipid profile of an individual. High levels of HDL and low levels of atherogenic particles [LDL, Lp(a)] are associated with high estrogen levels. A reduction in the endogenous estrogen levels during menopause reverses this cholesterol lipid profile, thereby increasing the risk of CHD.49 Although doubts remain regarding the relationship between estrogen levels and CHD risk, there is evidence that lowering the estrogen levels with adjuvant therapy for breast cancer may lead to a more atherogenic lipid profile and increased CHD risk. This is of utmost importance, as the most common cause of death in women with early-stage breast cancer is cardiovascular disease.50 Although aromatase inhibitors have a different mode of action from tamoxifen, their effects on lipids should be considered when fully evaluating and screening patients in the adjuvant setting. Among the very few studies that exist that detail the effects of aromatase inhibitors on lipids, many show conflicting results. Different aromatase inhibitors exert differing effects on lipid profiles51 (Table 4). Exemestane appears to be the most studied aromatase inhibitor in this regard. The European Organization for Research and Treatment of Cancer (EORTC) phase II trial 10951 randomized more than 100
N. Pandya and G.J. Morris
692 Table 4 Effects of Aromatase Inhibitors on Lipids
Tamoxifen Anastrozole Letrozole Exemestane
LDL Cholesterol
HDL Cholesterol
Total Cholesterol
2 1/– 1/– 2/–
– 1/– – 2/–
2 1/– 1/– 2/–
Triglycerides ? – – 2
Total:HDL Cholesterol
Lp(a)
apo B
? – 1/– ?
2 1/– ? –
2 1/– 1/– –
Symbols: 1 ⴝ increased; 2 ⴝ decreased; ⴚ ⴝ no change; ? ⴝ unknown. Reprinted by permission from Macmillan Publishers Ltd: British Journal of Cancer, Bundred NJ: The effects of aromatase inhibitors on lipids and thrombosis. 93(Suppl 1):S23-S27, 2005.
postmenopausal women to either tamoxifen or exemestane in the adjuvant setting with a 48-week follow-up. The results revealed no differences in total cholesterol, HDL, apolipoprotein (apo) A1, apo B, or Lp(a) in either arm, although exemestane proved to decrease serum triglyceride levels when compared to tamoxifen.52 The Tamoxifen and Exemestane Adjuvant Multicenter (TEAM) Greek sub-study is a phase III randomized trial that evaluated changes in lipid profile in 176 postmenopausal women receiving exemestane or tamoxifen in the adjuvant setting with a 12-month follow-up. Tamoxifen produced a statistically significant reduction of total cholesterol at 12 months when compared to baseline values and to the effects by exemestane. The tamoxifen group also demonstrated a significant rise in HDL and decrease in LDL at 6 months when compared to baseline. Triglycerides did not change from baseline with either treatment. This study reveals the beneficial effects of tamoxifen and the indifference of exemestane to serum lipids.53 Although the IES trial did not systematically measure any lipid markers, the Norwegian Breast Cancer Group study meticulously measured all lipid particles with a mean follow-up of 24 months. However, both studies showed no significant change in lipids or in incidence of myocardial infarction between arms.29,33 Although previously several smaller studies involving anastrozole showed no marked effects on the serum lipid profile, the ATAC study revealed a statistically nonsignificant increase in the incidences of high cholesterol and ischemic cardiomyopathy.36 The ITA trial found anastrozole to be harmful by raising cholesterol levels (8.1% v 2.7%) when compared to the tamoxifen arm after 2 years.38 In addition, a recent smaller study showed a significant rise in total cholesterol, LDL, HDL, apo A1, apo B, and Lp(a).54 However, the BIG 1-98 trial, comparing letrozole with tamoxifen, found that almost 44% of letrozole patients had mild to moderate increases in cholesterol levels compared to 18% of tamoxifentreated patients at 2 years. However, this difference did not translate into a higher incidence of cardiovascular events.42 Lipid profiles were not followed in the MA.17 trial, but no statistical difference was noted in either arm for cardiovascular events.39 It is not feasible to assess fully the changes in lipid profiles with the use of the various aromatase inhibitors, due largely to limited data and small studies. When changes are detected, they are generally minor and do not correlate to any significant clinical cardiovascular events. This is likely due to the short follow-up periods in all of these studies, as clinical
cardiovascular events could take years to manifest after the detection of elevated lipids. However, despite the lack of a consensus statement on this issue in breast cancer patients, it is generally accepted that lipid-lowering treatment needs to be initiated when a change in the lipid profile causes the patient’s risk for cardiovascular events to increase. The benefits of aromatase inhibitor therapy far outweigh any lipid or CHD risk known to date. Again, although no formal guidelines exist, a baseline and periodic monitoring of the fasting lipid profile, as well as early institution of diet control, exercise, and statin therapy, would be prudent in conjunction with aromatase inhibitor use. Clearly, more data are needed to determine the full effects of the increased lipid levels associated with the use of aromatase inhibitors on cardiovascular morbidity and mortality. Trials currently being initiated include, as part of their protocol, the measurement of lipid profiles and assessment of overall clinical outcome. Also, it would be important to determine if additional comorbidities, such as diabetes mellitus, hypertension, smoking, and/or the use of anthracycline-based chemotherapy prior to aromatase inhibitor use, increase the risk of developing cardiomyopathy and symptomatic heart failure or other cardiovascular events.51
Effects on the Musculoskeletal System Besides the already discussed effects on the skeletal system, studies have shown a link between low serum levels of estrogen and arthralgias. The most compelling evidence linking decreased estrogen and arthralgias emanates from aromatase inhibitor trials in which women experienced joint pain and other musculoskeletal aches, with some requiring cessation of treatment due to their severity.55 Joint pain is perceived by the nociceptive fibers innervating the articular structures and inflammatory mediators, such as prostaglandins and bradykinin, which activate these nociceptors, augmenting their sensitivity to pain with mechanical stimuli. Inflammation also leads to an expansion of the nociceptor’s receptor field, increasing neural transmission and overall pain perception.56 Although no specific effects on articular structures or on joint inflammation are known, estrogen effects inflammatory cytokines and enhances nociception with its depletion. Low estrogen levels directly affect opioid pain fibers in the central
Toxicity of aromatase inhibitors nervous system (CNS) and prevent inhibition of nociceptive neurons.57 The impetus for the preliminary research elucidating these pain pathways and mechanisms was the clinical observation of increased joint pain in women who were using aromatase inhibitors. An increased rate of arthralgias was noted in women treated with an aromatase inhibitor when compared to tamoxifen or placebo, despite their low rate of bone metastases. In the ATAC trial, there was a statistically significant increase in arthralgias (35.6% v 29.4%) in the anastrozole arm when compared to the tamoxifen arm.36 The NCIC CTG MA.17 also revealed marked statistically significant increases in arthralgias (25% v 21%) and myalgias (15% v 12%) in patients in the letrozole arm when compared with placebo.39 Finally, the IES trial also confirmed the link of arthralgias with exemestane when compared to tamoxifen (5.4% v 3.6%).29 Although the arthralgias in these studies were not disabling, a smaller study evaluating early-stage breast cancer patients on adjuvant anastrozole treatment noted that 5% of patients required discontinuation, with resolution of the arthralgias after withdrawal of the aromatase inhibitor.58 The historical descriptions of “menopausal arthritis” likely were due to marked reductions in serum estrogen levels in the postmenopausal state. Clearly, more studies are needed to define these syndromes of arthralgias, diffuse body pain, and myalgias, and to characterize clearly the role of estrogen. Based on clinical experience, it is obvious that aromatase inhibitors worsen these symptoms when compared to either placebo or tamoxifen. However, the overall clinical significance of this in relation to the quality of life and associated morbidity still needs to be determined in large, multicenter clinical trials.55
Effects on Cognition Estrogen receptors also have been found throughout the brain, particularly in the hippocampus and amygdala, which serve important learning and memory functions. Furthermore, enzymes related to estrogen biosynthesis have been discovered in the same regions of the brain, adding evidence to the importance of its role in the CNS.59 Additionally, improvement in cognitive impairment has been documented when treated with estrogen in early phases of dementia.60 Preliminary data comparing patients from the ATAC trial and healthy women revealed a statistically significant impairment in verbal memory and task processing speed in the trial patients, despite controlling for age and hormone replacement therapy.61 Moreover, preliminary data from the TEAM trial also indicate a significantly higher incidence of impaired word finding in patients treated with exemestane when compared to those taking tamoxifen.62 Therefore, there is growing evidence to support that cognitive impairment may be a late toxicity of aromatase inhibition in adjuvant hormonal treatment. With a rising number of younger women requiring adjuvant hormonal therapy and the overall increase in longevity in the United States, delayed toxicities leading to dementia can contribute to a marked reduction in the quality
693 of life and overall function after adjuvant therapy. It will be important to determine the true incidence rates of and to quantify the reductions in cognition, activities of daily living, and independence with the use of aromatase inhibitors. Consequently, an effort to assess and follow the cognitive status of patients on aromatase inhibitors should be included in future prospective clinical trials.63
Conclusions The purpose of adjuvant hormonal therapy is to prevent cancer recurrence and prolong overall survival in early-stage, hormone receptor–positive breast cancer. As such, a minimum of 5 years’ duration of therapy is considered optimal. It is therefore imperative for the clinician to evaluate the risk/ benefit ratio when choosing the type of therapy for individual patients, evaluating comorbidities and quality-of-life parameters. Although tamoxifen has generally been effective in this setting, long-term use significantly increases the risk of endometrial cancer and thromboembolism. Newer agents, especially third-generation aromatase inhibitors, have been proven to provide superior efficacy to tamoxifen, albeit with a different toxicity profile. Clearly, adverse events from these agents increase morbidity; however, long-term follow-up is needed to determine if this translates to changes in mortality as well. The adverse effects profiles discussed here reveal that the toxicities from aromatase inhibitors will have a significant impact on the quality of life of these individuals, who are essentially disease-free from their cancer. Although to date no head-to-head trials have compared the various aromatase inhibitors, data from the trials reviewed herein point to less severity of adverse events associated with the use of steroidal inhibitors, especially as regards the effects on bone loss. Direct comparative studies with long-term follow-up are needed to evaluate fully the spectrum of toxicities of each individual aromatase inhibitor. Specifically, the NCIC MA-27 trial, which randomizes postmenopausal breast cancer patients to anatrozole or exemestane for 5 years’ duration, may provide insight into the specific toxicity profiles of aromatase inhibitors. From that point, conclusions as to the optimal therapy can be made while accounting for associated comorbidities, with the goal not only to prolong survival, but also to maintain an enhanced quality of life during these years. In the interim, improved screening, perpetual vigilance for adverse events, and early aggressive treatment of symptoms, as well as prophylaxis, should be the objective when treating breast cancer patients with adjuvant aromatase inhibitors.
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premenopausal and postmenopausal women. J Clin Oncol 14:7884, 1996 Leather AT, Studd JW, Watson NR, et al: The prevention of bone loss in young women treated with GnRH analogues with ‘add back’ estrogen therapy. Obstet Gynecol 81:104-107, 1993 Hashimoto K, Nozaki M, Inoue Y, et al: The chronological change of vertebral bone loss following oophroectomy using dual energy x-ray absorptiometry: The correlation with specific markers of bone metabolism. Maturitas 22:185-192, 1995 Eastell R, Hannon RA, Cuzick J, et al: Effect of anastrozole on bone density and bone turnover: results of the ‘Arimidex’ (anastrozole), Tamoxifen Alone or in Combination (ATAC) trial bone sub-protocol. 24th Annual Meeting American Society for Bone and Mineral Research, San Antonio, TX, 2002 (abstr 1170) Goss PE, Ingle JN, Martino S, et al: A randomized trial of letrozole in postmenopausal women after five years of tamoxifen therapy for earlystage breast cancer. N Engl J Med 349:1793-1802, 2003 Coombes RC, Hall E, Gibson LJ, et al: Intergroup Exemestane Study. 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, 2004 Lonning PE, Geisler J, Krag LE, et al: Effect of exemestane on bone: A randomized placebo controlled study in postmenopausal women with early breast cancer at low risk. J Clin Onco 22(14S):518, 2004 (abstr) Love RR, Mazess RB, Barden HS, et al: Effects of tamoxifen on bone mineral density in postmenopausal women with breast cancer. N Engl J Med 326:852-856, 1992 Winer EP, Hudis C, Burstein HJ, et al: American Society of Clinical Oncology technology assessment on the use of aromatase inhibitors as adjuvant therapy for postmenopausal women with hormone receptorpositive breast cancer: Status report 2004. J Clin Oncol 23:619629, 2005 Lonning PE, Jurgen G, Krag LE, et al: 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 23:5126-5137, 2005 Looker AC, Bauer DC, Chestnut CH, et al: Clinical use of biochemical markers of bone remodeling: Current status and future directions. Osteoporos Int 11:467-480, 2000 Johannessen DC, Engan T, diSalle E, et al: Endocrine and clinical effects of exemestane (PNU 155971), a novel steroidal aromatase inhibitor, in postmenopausal breast cancer patients. A phase I study. Clin Cancer Res 3:1101-1108, 1997 ATAC Trialists’ Group: Results of the ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial after completion of 5 years’ adjuvant treatment for breast cancer. Lancet 365:60-62, 2005 Eastell R, Hannon RA, Cuzick J, et al: Effect of anastrozole on bone density and bone turnover: Results of the ‘Arimidex’ (anastrozole), Tamoxifen Alone or in Combination (ATAC) trial bone sub-protocol. 24th Annual Meeting American Society for Bone and Mineral Research, San Antonio, TX, 2002 (abstr 1170) Boccardo F, Rubagotti A, Puntoni M, et al: Switching to anastrozole versus continued tamoxifen treatment of early breast cancer: Preliminary results of the Italian tamoxifen anastrozole trial. J Clin Oncol 23:5138-5147, 2005 Goss PE, Ingle JN, Martino S, et al: 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 97:1262-1271, 2005 Perez EA, Josse RG, Pritchard KI, et al: Effect of letrozole versus placebo on bone mineral density in women completing ⱖ5 years of adjuvant tamoxifen: NCIC CTG MA.17b. 27th Annual San Antonio Breast Cancer Symposium, San Antonio, TX, 2004 (abstr 404) Goss P, Thompsen T, Banke-Bochita J: A randomized, placebo-controlled, explorative study to investigate the effect of low estrogen plasma levels on markers of bone turnover in healthy postmenopausal women during the 12-week treatment with exemestane or letrozole. Breast Cancer Res Treat 76:S76, 2002 (suppl 1, abstr 267) The Breast International Group (BIG) 1-98 Collaborative Group: A
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43.
44.
45.
46.
47. 48. 49.
50. 51. 52.
comparison of letrozole and tamoxifen in postmenopausal women with early breast cancer. N Engl J Med 353:2747-2757, 2005 Brufsky A, Harker G, Beck T, et al: Z-FAST Study Group. Zoledronic acid (ZA) for prevention of cancer treatment-induced bone loss (CTIBL) in postmenopausal women with early breast cancer receiving adjuvant Letrozole: Preliminary results of the Z-FAST trial. 27th Annual San Antonio Breast Cancer Symposium, 2004 (abstr 1114) Brufsky A, Harker W, Beck J, et al: Z-FAST Study Group. Zoledronic acid (ZA) effectively inhibits cancer treatment-induced bone loss (CTIBL) in postmenopausal women with early breast cancer receiving adjuvant letrozole: 12 mos BMD results of the Z-FAST trial. 2005 ASCO Annual Meeting Proceedings. J Clin Oncol 23:533, 2005 (suppl, abstr) Hillner BE, Ingle JN, Chlebowski RT, et al: American Society of Clinical Oncology 2003 update on the role of bisphosphonates and bone health issues in women with breast cancer. J Clin Oncol 21:4042-4057, 2003 Miller-Bass K, Newschaffer CJ, Klag MJ, et al: Plasma lipoprotein levels as predictors of cardiovascular death in women. Arch Intern Med 154: 2349-2355, 1994 La Rosa JC: Triglycerides and coronary risk in women and the elderly. Arch Intern Med 157:961-968, 1997 Danesh J, Collins R, Peto R: Lipoprotein (a) and coronary heart disease: Meta-analysis of prospective studies. Circulation 102:1082-1085, 2000 deAloysio D, Gambacciani M, Meschia M, et al: The Icarus Study Group. The effect of menopause on blood lipid and lipoprotein levels. Atherosclerosis 147:147-153, 1999 Levi F, Randimbison L, Te VC, et al: Long-term mortality of women with a diagnosis of breast cancer. Oncology 63:266-269, 2002 Bundred NJ: The effects of aromatase inhibitors on lipids and thrombosis. Br J Cancer 93:S23-S27, 2005 (suppl 1) Atalay G, Dirix L, Biganzoli L, et al: The effect of exemestane on serum lipid profile in postmenopausal women with metastatic breast cancer: A companion study to EORTC trial 10951, ‘Randomized phase II study in first line hormonal treatment for metastatic breast cancer with exemes-
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53.
54.
55.
56.
57. 58. 59. 60.
61.
62.
63.
tane or tamoxifen in postmenopausal patients. Ann Oncol 15:211-217, 2004 Markopoulos C, Polychronis A, Zobolas V, et al: The effect of exemestane on the lipidemic profile of postmenopausal early breast cancer patients: Preliminary results of the TEAM Greek sub-study. Breast Cancer Res Treat 93:61-66, 2005 Hozumi Y, Saito T, Inoue K, et al: Effects of anastrozole on the lipid profile in postmenopausal breast cancer patients—A preliminary study. Fourth European Breast Cancer Conference, Hamburg, Germany, 2004 (abstr 300) Felson DT, Cummings SR: Aromatase inhibitors and the syndrome of arthralgias with estrogen deprivation. Arthritis Rheum 52:25942598, 2005 Kidd BL, Photiou A, Inglis JJ: The role of inflammatory mediators on nociception and pain in arthritis. Novartis Found Symp 260:122-133, 2004 Blomqvist A: Sex hormones and pain: A new role for brain aromatas? J Comp Neurol 423:549-551, 2000 Donnellan PP, Douglas SL, Cameron DA, et al: Aromatase inhibitors and arthralgia. J Clin Oncol 19:2767, 2001 (letter) Stoffel-Wagner B: Neurosteroid metabolism in the human brain. Eur J Endocrinol 145:669-679, 2001 McEwen BS: Clinical review 108: The molecular and neuroanatomical basis for estrogen effects in the central nervous system. J Clin Endocrinol Metab 84:1790-1797, 1999 Jenkins VA, Schiling V, Fallowfield LJ, et al: Does hormone therapy for the treatment of breast cancer have a detrimental effect on memory and cognition? A pilot study. Psychooncology 13:61-66, 2004 Jones J, Vukelja S, Cantrell J, et al: A planned comparison of menopausal symptoms during year 1 in patients receiving either exemestane or tamoxifen in a double-blind adjuvant hormonal study. Breast Cancer Res Treat 82:S31, 2003 Tralongo P, DiMari A, Ferrau F: Cognitive impairment, aromatase inhibitors and age. J Clin Oncol 23:4243, 2005
I
t is estimated by the American Cancer Society that 214,640 women will develop breast cancer during 2006, of which 41,430 will die of the disease.1 Since the late 1980s, the incidence has stabilized and mortality has decreased, due in large part to aggressive prevention strategies and improved therapeutics. The Surveillance Epidemiology and End Results (SEER) data also reveal that with the increase in screening, breast cancer is being diagnosed more often in the early stages2 (Table 1). This has prompted efforts to determine the best breast conservation surgical approaches and the least toxic neoadjuvant and adjuvant therapies with the goal of improving longevity and the quality of life women lead afterwards. It has been estimated that more than one third of all breast carcinomas are estrogen-dependent and regress after estrogen deprivation.3 Therefore, reducing the levels of estrogen is important in the treatment of breast cancer in both premenopausal and postmenopausal women. Endocrine therapy, as a result, is important in the treatment of the patients to reduce recurrence of the primary carcinoma and to prevent further carcinoma development. Tamoxifen acts by blocking the effects of endogenous estrogen at the receptor level, but it also is associated with serious adverse events.4 Consequently, the
Division of Medical Oncology, Thomas Jefferson University Hospital, Philadelphia, PA. Address correspondence to Gloria Morris, MD, PhD, Department of Medical Oncology, Thomas Jefferson University Hospital, 111 South 11th St, Suite G-4240, Philadelphia, PA 19107. E-mail: [email protected]
688
0093-7754/06/$-see front matter © 2006 Elsevier Inc. All rights reserved. doi:10.1053/j.seminoncol.2006.08.011
safety and tolerability of adjuvant endocrine agents must be considered when given over a prolonged period of time. Aromatase inhibitors, especially the newer third-generation agents, recently have been demonstrated to be superior to tamoxifen in the metastatic setting5-9 and are now proving to be efficacious in the adjuvant setting as well. Furthermore, recent data reveal that they have a slightly different toxicity profile than tamoxifen, one that can cause significant morbidity but markedly reduced mortality.10 In this review, we examine the available data on safety and toxicity of aromatase inhibitors and attempt to assess if any one agent is superior to another.
Principles of Aromatase Inhibitors In 1896, George Beatson successfully demonstrated tumor regression in a young woman with locally advance breast cancer by performing an oophorectomy, thereby concluding that breast cancer is hormonally responsive.11 With the introduction of an estrogen blocker, tamoxifen, in the 1970s, overall survivals for women with breast cancer improved markedly. Tamoxifen acts by directly blocking the estrogen receptor, which is essential in the signal pathway for growth and survival in breast carcinomas. However, tamoxifen also exerts partial estrogen agonist effects, which are detrimental and likely the cause of the increased risk of endometrial carcinoma, thromboembolism, and tamoxifen resistance.12 Aromatase inhibitors, in contrast, “block” the estrogen re-
Toxicity of aromatase inhibitors
689
Table 1 SEER Stage Distribution for Breast Cancer, All Ages, Females: SEER 9 Registries for 1975–79, 1985– 89, 1995–2001 Stage
1975–1979
1985–1989
1995–2001
Localized Regional Distant Unstaged
48% 41% 8% 4%
56% 34% 6% 4%
63% 29% 6% 2%
ceptor by reducing the levels of its ligand, endogenous estrogen. They target the aromatase enzyme, which converts testosterone and adrenal androgens to estrodiol and other estrogens. The aromatase enzyme is a P-450 cytochrome enzyme, which is present in adipose, liver, muscle, brain, placenta, and breast cancer tissue.13 Observational studies of adipose tissue adjacent to malignant cells within the breast have shown a greater aromatase enzymatic activity, consequently causing higher concentrations of estrogen within the tumor than in the circulation and promoting growth of malignant cells. aromatase inhibitors inhibit in situ aromatization in both the tumor and the nonmalignant cells within the breast tissue, and markedly suppress peripheral estrogen synthesis.14 There are two types of aromatase inhibitors, steroidal and nonsteroidal, and the third generation of these compounds demonstrates the greatest efficacy for breast cancer therapy (Table 2), Steroidal inhibitors compete with androstenedione and testosterone for the active site within the enzyme, and the metabolites of this reaction bind to the enzyme, causing irreversible enzyme inhibition. Alternatively, the nonsteroidal inhibitors compete with the endogenous ligands and form a strong but reversible bond to the heme iron atom of the active site of the enzyme, excluding both the ligands and oxygen from the enzyme (Fig 1). Although the method of inhibition differs, both classes of aromatase inhibitors exhibit potent suppression of the aromatase enzyme. Thus, the clinical relevance of these different mechanisms of inhibition remains to be established.4 Numerous studies have confirmed the benefit of aromatase inhibitors over tamoxifen in the estrogen receptor–positive advanced breast cancer patient, leading to their recommendation as first-line therapy in postmenopausal women.15-17 The goal in this setting is to increase the time to progression of the tumor and improve overall survival. However, the rationale of adjuvant therapy for early-stage breast cancer following primary therapy is to prevent or delay recurrence. Patients who receive adjuvant endocrine therapy tend to remain clinically disease-free for a much longer time (approximately five times longer) than metastatic breast cancer patients who also receive endocrine treatments.10 Therefore, it Table 2 Aromatase Inhibitors
First generation Second generation Third generation
Steroidal
Nonsteroidal
— Formestane Exemestane
Aminoglutehimide Fadrozole Anastrozole, letrozole
Figure 1 Mechanisms of action of tamoxifen and exemestane. Tumor growth in hormone-responsive breast cancer is propagated by intracellular signaling after estrogen engages with the estrogen receptor. Estrogen can originate from endogenous supply or as converted from androgens in non-ovarian sources such as adipose, muscle, and adrenal tissue by the action of the enzyme aromatase. Tamoxifen is a competitive blocker of the estrogen receptor from engaging with estrogen and does not allow growth signals to be induced by the receptor. In contrast, exemestane, a representative aromatase inhibitor, hinders the enzyme aromatase from converting peripheral (non-ovarian) androgen to estrogen, thereby not allowing further estrogens to engage their receptor. Oestrogen ⫽ estrogen. Reprinted by permission from Macmillan Publishers Ltd: British Journal of Cancer, Carpenter R, Miller WR: Role of aromatase inhibitors in breast cancer. 93(Suppl 1):S1-S5, 2005.
is imperative that the tolerability and safety profile of these agents be considered to determine methods to improve the risk/benefit ratio.
Effects on Bone Loss The pathogenesis of osteoporosis is multifactorial in women with breast cancer. Estrogen deficiency is probably the most important factor contributing to osteoporosis, and marked reductions in circulating estrogen occur after ovarian suppression in premenopausal women and after aromatase inhibition in postmenopausal women. The most significant reductions in bone mineral density (BMD) are due to
N. Pandya and G.J. Morris
690 Table 3 Causes of Bone Loss Among Breast Cancer Patients Treatment Chemotherapy Indirect effect
Study Shapiro et al20 Vehmanen et al21
Direct effect
Wheeler et al22
No. of Patients 49 148 69
Subjects Premenopausal women Premenopausal women Rats
Outcome 4% 2 Spine BMD within 6 months 7.5% 2 Spine BMD within 36 months 2 Bone volume, 2 mineralizing surface, 1 osteoclast surface, P <.05 No significant change in T score, but significant changes in Z score at lumbar spine, BMD 2 0.6, P ⴝ .05 1.44% 2 Spine BMD within 12 months, P <.001
Greep et al23
130
Postmenopausal women
Tamoxifen
Powles et al24
125
Premenopausal women
Ovarian ablation Drug induced
Leather et al25
19
Premenopausal women Premenopausal women
4.8% 2 Spine BMD in 6 months, P <.001
Postmenopausal women Postmenopausal women Postmenopausal women Postmenopausal women
2.6% 2 Spine BMD in 12 months
Surgical Aromatase inhibitors Anastrozole
Hashimoto et al26
244
Eastell et al27
308
Letrozole
Goss et al28
5187
Exemestane
Coombes et al29
4742
Lonning et al30
147
10.7% 2 Spine BMD in 12 months
1 Osteoporosis in letrozole arm v placebo, 5.8% v 4.5%, P ⴝ .07 1 Osteoporosis in exemestane arm v tamoxifen arm, 7.4% v 5.7%, P ⴝ .05 Annual rate of 2.17% 2 spine BMD
Reprinted by permission from Macmillan Publishers Ltd: British Journal of Cancer, Lester J, Coleman R: Bone loss and aromatase inhibitors. 93(Suppl 1):S16 –S22, 2005.
treatment-induced bone loss, as a result of oophorectomy, irradiation, luteinizing hormone–releasing hormone (LHRH) analogues, or chemotherapy, leading to significant clinical sequelae and increased fracture risk.18 Table 3 summarizes the various causes of bone loss among breast cancer patients.19 Chemotherapy has been shown to have direct toxicity on bone proliferation and mineralization and indirect toxicity by a sudden decrease in estrogen production from treatment-induced ovarian failure (in premenopausal women), resulting on average 4.0% loss of lumbar spine BMD in just 6 months.20,22 Tamoxifen, which has a complex mechanism of action with antiestrogenic effect on breast tissue, conversely has a partial estrogenic effect on the bone, uterus, and lipids. These partial agonist effects on bone metabolism may protect postmenopausal women from developing osteoporosis, with one study documenting an increase in lumbar spine BMD by 0.61% per year.31 Nevertheless, with studies showing improved cancer outcomes, aromatase inhibitors are replacing the use of tamoxifen, and the American Society of Clinical Oncology (ASCO) guidelines encourage their primary role in the treatment regimen for postmenopausal women in the adjuvant setting.32 Consequently, the use of aromatase inhibitors in the adjuvant setting, causing further marked reduction in endogenous estrogen production, will have profound effects on bone physiology. Aromatase inhibitors, in general, tend to induce bone loss and increase fracture risk to a higher degree, when compared
to tamoxifen or placebo. Although head-to-head trials have not been performed, the steroidal inhibitor, exemestane, seems to have less of an effect on bone than the nonsteroidal agents, letrozole and anastrozole.33 The Intergroup Exemestane Study (IES) evaluated more than 4,000 patients in a randomized, double-blinded, phase III trial comparing 5 years of either tamoxifen or exemestane in postmenopausal women in the adjuvant setting. There was a nonsignificant increase in osteoporosis in both arms, with a 1.7% increase in the exemestane arm, and a corresponding nonsignificant increase in fractures, with a trend not in favor of the steroidal aromatase inhibitors by 0.8%.29 More recently, a smaller study by the Norwegian Breast Cancer Group demonstrated in low-risk early breast cancer or ductal carcinoma-in-situ (DCIS) patients an increase in BMD loss in the exemestane arm when compared to placebo in the adjuvant setting. The results demonstrated a statistically significant bone loss when measured at the femoral neck but not in the lumbar spine. In addition, it also demonstrated an increase in bone resorption biomarkers (C-telopeptide and N-telopeptide) and bone formation markers (bone alkaline phosphatase, pro-collagen type I amino-terminal propeptide, and osteocalcin).33 Although bone turnover has been suggested to be associated with an increased fracture risk, a prospective study showed that an increase in markers of bone resorption and not of bone formation is related with fracture risk.34 Exemestane, unlike the nonsteroidal aromatase inhibitors, expresses an-
Toxicity of aromatase inhibitors drogenic effects through its metabolite, 17-hydroxy-exemestane, which could elevate bone formation markers.35 It is possibly this difference leads to less bone loss when compared to nonsteroidal inhibitors, but long-term direct comparisons between the compounds are necessary to differentiate the full effects on bone metabolism and overall fracture risk. In contrast, the nonsteroidal aromatase inhibitors have shown marked bone loss with their use. The ATAC trial (Arimidex, Tamoxifen Alone or in Combination Trial), which compared anastrozole to tamoxifen in 9,000 postmenopausal women with early-stage breast cancer in the adjuvant setting, showed a statistically significant increase in all fractures in the anastrozole arm as compared to those in the tamoxifen arm (11.0% v 7.7%) after 68 months of follow-up.36 The bone sub-protocol of the ATAC group demonstrated a decrease in BMD by 4% in the lumbar spine and 3.2% in the hip, with an increase in the bone resorption and formation markers in the anastrozole arm compared to those in the tamoxifen arm.37 The Italian Tamoxifen Anastrozole (ITA) trial, a randomized, phase III, multicenter study among postmenopausal women who were either treated with 5 years of tamoxifen or 2 to 3 years of tamoxifen followed by to 2 to 3 years of anastrozole therapy, showed no statistical variation in the fracture risk between the arms after a median follow-up of 36 months.38 Nevertheless, these results are premature, based on few events, and include 2 years of tamoxifen therapy, so significant differences may require longer follow-up to discern. The National Cancer Institute of Canada Cancer Treatment Group (NCIC CTG) MA.17 trial, which compared the use of letrozole against a placebo after 5 years of adjuvant tamoxifen therapy among 5,000 postmenopausal early-stage breast cancer patients, showed a statistically significant increase in reported diagnoses of osteoporosis but a nonsignificant rise in fractures in the letrozole arm after a median follow-up of 30 months.39 A bone sub-protocol analysis revealed a markedly significant decrease in BMD in the lumbar spine and the hip,40 with an increase in the bone resorption markers and decrease in the bone formation markers in the letrozole arm.41 The Breast International Group (BIG) 1-98 study, which compared head-to-head and in combination use of letrozole against tamoxifen in 8,000 postmenopausal women with early-stage breast cancer, also showed a statistically significant increase in number of fractures in the letrozole-only arm. This trial also revealed a significantly shorter time interval to first fracture in the letrozole arm.42 Clearly, these large trials reveal a noteworthy rise in the development of osteoporosis and fracture risk among recipients of nonsteroidal aromatase inhibitors, for which increased screening and aggressive treatment strategies will need to be developed in concordance with their use. ASCO has released recommendations for monitoring postmenopausal breast cancer patients who are receiving aromatase inhibitor therapy. These women should have a baseline dual-energy x-ray absorptiometry (DEXA) scan performed and treatment initiated as per the results of BMD testing. No standard recommendations currently exist regarding baseline measurement and serial follow-up of either bone resorp-
691 tion or bone formation markers.32 Recently, results from the Zometa-Femara Adjuvant Synergy Trial (Z-FAST), which evaluates the use of upfront zoledronic acid given semi-annually in postmenopausal women on adjuvant letrozole therapy against delayed treatment at the time of fracture or diagnosis of osteoporosis by DEXA scan, were presented at the 2004 San Antonio Breast Cancer Symposium and updated at the 2005 ASCO meeting.43,44 The study showed a significant difference in favor of early initiation of zoledronic acid, with an increase in BMD and suppression of bone turnover markers. This supports the use of aggressive preventive strategies with bisphosphonate therapy as prophylaxis and annual DEXA scans for BMD screening. Further studies are needed to validate this strategy for long-term use, provide data with other aromatase inhibitors, and determine the safety and tolerability of bisphosphonate use in conjunction with aromatase inhibitors. Initiation of bisphosphonate therapy is recommended for any woman treated for breast cancer whose BMD score falls within the osteoporotic range (T score ⱕ⫺2.5).45 ASCO also recommends lifestyle modification and calcium with vitamin D supplementation for women whose BMD score falls in the osteopenic range (T score between ⫺1 and ⫺2.5).45
Effects on Lipids Clinical evidence shows that the low-density lipoprotein (LDL) particle is the key atherogenic cholesterol in the pathogenesis of atherosclerosis and coronary heart disease (CHD), whereas the high-density lipoprotein (HDL) particle exerts a protective effect. Although women tend to have higher levels of HDL than men, the difference between the sexes is reduced in the postmenopausal state.46 High levels of triglycerides also have been suggested to be a predictor of CHD in women more so than in men.47 Moreover, high levels of lipoprotein (a) [Lp(a)] have been shown to be more atherogenic in women as well.48 Estrogen is known to exert a protective effect on the lipid profile of an individual. High levels of HDL and low levels of atherogenic particles [LDL, Lp(a)] are associated with high estrogen levels. A reduction in the endogenous estrogen levels during menopause reverses this cholesterol lipid profile, thereby increasing the risk of CHD.49 Although doubts remain regarding the relationship between estrogen levels and CHD risk, there is evidence that lowering the estrogen levels with adjuvant therapy for breast cancer may lead to a more atherogenic lipid profile and increased CHD risk. This is of utmost importance, as the most common cause of death in women with early-stage breast cancer is cardiovascular disease.50 Although aromatase inhibitors have a different mode of action from tamoxifen, their effects on lipids should be considered when fully evaluating and screening patients in the adjuvant setting. Among the very few studies that exist that detail the effects of aromatase inhibitors on lipids, many show conflicting results. Different aromatase inhibitors exert differing effects on lipid profiles51 (Table 4). Exemestane appears to be the most studied aromatase inhibitor in this regard. The European Organization for Research and Treatment of Cancer (EORTC) phase II trial 10951 randomized more than 100
N. Pandya and G.J. Morris
692 Table 4 Effects of Aromatase Inhibitors on Lipids
Tamoxifen Anastrozole Letrozole Exemestane
LDL Cholesterol
HDL Cholesterol
Total Cholesterol
2 1/– 1/– 2/–
– 1/– – 2/–
2 1/– 1/– 2/–
Triglycerides ? – – 2
Total:HDL Cholesterol
Lp(a)
apo B
? – 1/– ?
2 1/– ? –
2 1/– 1/– –
Symbols: 1 ⴝ increased; 2 ⴝ decreased; ⴚ ⴝ no change; ? ⴝ unknown. Reprinted by permission from Macmillan Publishers Ltd: British Journal of Cancer, Bundred NJ: The effects of aromatase inhibitors on lipids and thrombosis. 93(Suppl 1):S23-S27, 2005.
postmenopausal women to either tamoxifen or exemestane in the adjuvant setting with a 48-week follow-up. The results revealed no differences in total cholesterol, HDL, apolipoprotein (apo) A1, apo B, or Lp(a) in either arm, although exemestane proved to decrease serum triglyceride levels when compared to tamoxifen.52 The Tamoxifen and Exemestane Adjuvant Multicenter (TEAM) Greek sub-study is a phase III randomized trial that evaluated changes in lipid profile in 176 postmenopausal women receiving exemestane or tamoxifen in the adjuvant setting with a 12-month follow-up. Tamoxifen produced a statistically significant reduction of total cholesterol at 12 months when compared to baseline values and to the effects by exemestane. The tamoxifen group also demonstrated a significant rise in HDL and decrease in LDL at 6 months when compared to baseline. Triglycerides did not change from baseline with either treatment. This study reveals the beneficial effects of tamoxifen and the indifference of exemestane to serum lipids.53 Although the IES trial did not systematically measure any lipid markers, the Norwegian Breast Cancer Group study meticulously measured all lipid particles with a mean follow-up of 24 months. However, both studies showed no significant change in lipids or in incidence of myocardial infarction between arms.29,33 Although previously several smaller studies involving anastrozole showed no marked effects on the serum lipid profile, the ATAC study revealed a statistically nonsignificant increase in the incidences of high cholesterol and ischemic cardiomyopathy.36 The ITA trial found anastrozole to be harmful by raising cholesterol levels (8.1% v 2.7%) when compared to the tamoxifen arm after 2 years.38 In addition, a recent smaller study showed a significant rise in total cholesterol, LDL, HDL, apo A1, apo B, and Lp(a).54 However, the BIG 1-98 trial, comparing letrozole with tamoxifen, found that almost 44% of letrozole patients had mild to moderate increases in cholesterol levels compared to 18% of tamoxifentreated patients at 2 years. However, this difference did not translate into a higher incidence of cardiovascular events.42 Lipid profiles were not followed in the MA.17 trial, but no statistical difference was noted in either arm for cardiovascular events.39 It is not feasible to assess fully the changes in lipid profiles with the use of the various aromatase inhibitors, due largely to limited data and small studies. When changes are detected, they are generally minor and do not correlate to any significant clinical cardiovascular events. This is likely due to the short follow-up periods in all of these studies, as clinical
cardiovascular events could take years to manifest after the detection of elevated lipids. However, despite the lack of a consensus statement on this issue in breast cancer patients, it is generally accepted that lipid-lowering treatment needs to be initiated when a change in the lipid profile causes the patient’s risk for cardiovascular events to increase. The benefits of aromatase inhibitor therapy far outweigh any lipid or CHD risk known to date. Again, although no formal guidelines exist, a baseline and periodic monitoring of the fasting lipid profile, as well as early institution of diet control, exercise, and statin therapy, would be prudent in conjunction with aromatase inhibitor use. Clearly, more data are needed to determine the full effects of the increased lipid levels associated with the use of aromatase inhibitors on cardiovascular morbidity and mortality. Trials currently being initiated include, as part of their protocol, the measurement of lipid profiles and assessment of overall clinical outcome. Also, it would be important to determine if additional comorbidities, such as diabetes mellitus, hypertension, smoking, and/or the use of anthracycline-based chemotherapy prior to aromatase inhibitor use, increase the risk of developing cardiomyopathy and symptomatic heart failure or other cardiovascular events.51
Effects on the Musculoskeletal System Besides the already discussed effects on the skeletal system, studies have shown a link between low serum levels of estrogen and arthralgias. The most compelling evidence linking decreased estrogen and arthralgias emanates from aromatase inhibitor trials in which women experienced joint pain and other musculoskeletal aches, with some requiring cessation of treatment due to their severity.55 Joint pain is perceived by the nociceptive fibers innervating the articular structures and inflammatory mediators, such as prostaglandins and bradykinin, which activate these nociceptors, augmenting their sensitivity to pain with mechanical stimuli. Inflammation also leads to an expansion of the nociceptor’s receptor field, increasing neural transmission and overall pain perception.56 Although no specific effects on articular structures or on joint inflammation are known, estrogen effects inflammatory cytokines and enhances nociception with its depletion. Low estrogen levels directly affect opioid pain fibers in the central
Toxicity of aromatase inhibitors nervous system (CNS) and prevent inhibition of nociceptive neurons.57 The impetus for the preliminary research elucidating these pain pathways and mechanisms was the clinical observation of increased joint pain in women who were using aromatase inhibitors. An increased rate of arthralgias was noted in women treated with an aromatase inhibitor when compared to tamoxifen or placebo, despite their low rate of bone metastases. In the ATAC trial, there was a statistically significant increase in arthralgias (35.6% v 29.4%) in the anastrozole arm when compared to the tamoxifen arm.36 The NCIC CTG MA.17 also revealed marked statistically significant increases in arthralgias (25% v 21%) and myalgias (15% v 12%) in patients in the letrozole arm when compared with placebo.39 Finally, the IES trial also confirmed the link of arthralgias with exemestane when compared to tamoxifen (5.4% v 3.6%).29 Although the arthralgias in these studies were not disabling, a smaller study evaluating early-stage breast cancer patients on adjuvant anastrozole treatment noted that 5% of patients required discontinuation, with resolution of the arthralgias after withdrawal of the aromatase inhibitor.58 The historical descriptions of “menopausal arthritis” likely were due to marked reductions in serum estrogen levels in the postmenopausal state. Clearly, more studies are needed to define these syndromes of arthralgias, diffuse body pain, and myalgias, and to characterize clearly the role of estrogen. Based on clinical experience, it is obvious that aromatase inhibitors worsen these symptoms when compared to either placebo or tamoxifen. However, the overall clinical significance of this in relation to the quality of life and associated morbidity still needs to be determined in large, multicenter clinical trials.55
Effects on Cognition Estrogen receptors also have been found throughout the brain, particularly in the hippocampus and amygdala, which serve important learning and memory functions. Furthermore, enzymes related to estrogen biosynthesis have been discovered in the same regions of the brain, adding evidence to the importance of its role in the CNS.59 Additionally, improvement in cognitive impairment has been documented when treated with estrogen in early phases of dementia.60 Preliminary data comparing patients from the ATAC trial and healthy women revealed a statistically significant impairment in verbal memory and task processing speed in the trial patients, despite controlling for age and hormone replacement therapy.61 Moreover, preliminary data from the TEAM trial also indicate a significantly higher incidence of impaired word finding in patients treated with exemestane when compared to those taking tamoxifen.62 Therefore, there is growing evidence to support that cognitive impairment may be a late toxicity of aromatase inhibition in adjuvant hormonal treatment. With a rising number of younger women requiring adjuvant hormonal therapy and the overall increase in longevity in the United States, delayed toxicities leading to dementia can contribute to a marked reduction in the quality
693 of life and overall function after adjuvant therapy. It will be important to determine the true incidence rates of and to quantify the reductions in cognition, activities of daily living, and independence with the use of aromatase inhibitors. Consequently, an effort to assess and follow the cognitive status of patients on aromatase inhibitors should be included in future prospective clinical trials.63
Conclusions The purpose of adjuvant hormonal therapy is to prevent cancer recurrence and prolong overall survival in early-stage, hormone receptor–positive breast cancer. As such, a minimum of 5 years’ duration of therapy is considered optimal. It is therefore imperative for the clinician to evaluate the risk/ benefit ratio when choosing the type of therapy for individual patients, evaluating comorbidities and quality-of-life parameters. Although tamoxifen has generally been effective in this setting, long-term use significantly increases the risk of endometrial cancer and thromboembolism. Newer agents, especially third-generation aromatase inhibitors, have been proven to provide superior efficacy to tamoxifen, albeit with a different toxicity profile. Clearly, adverse events from these agents increase morbidity; however, long-term follow-up is needed to determine if this translates to changes in mortality as well. The adverse effects profiles discussed here reveal that the toxicities from aromatase inhibitors will have a significant impact on the quality of life of these individuals, who are essentially disease-free from their cancer. Although to date no head-to-head trials have compared the various aromatase inhibitors, data from the trials reviewed herein point to less severity of adverse events associated with the use of steroidal inhibitors, especially as regards the effects on bone loss. Direct comparative studies with long-term follow-up are needed to evaluate fully the spectrum of toxicities of each individual aromatase inhibitor. Specifically, the NCIC MA-27 trial, which randomizes postmenopausal breast cancer patients to anatrozole or exemestane for 5 years’ duration, may provide insight into the specific toxicity profiles of aromatase inhibitors. From that point, conclusions as to the optimal therapy can be made while accounting for associated comorbidities, with the goal not only to prolong survival, but also to maintain an enhanced quality of life during these years. In the interim, improved screening, perpetual vigilance for adverse events, and early aggressive treatment of symptoms, as well as prophylaxis, should be the objective when treating breast cancer patients with adjuvant aromatase inhibitors.
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