Abstract
Breast cancer is the most prevalent type of cancer in women and responsible for significant female cancer-related mortality worldwide. In the Western world, over 80% of breast cancers are hormone-receptor positive for which endocrine therapy is administered. The main anti-estrogen treatments in use consist of selective estrogen-receptor modulators, such as tamoxifen, and third-generation aromatase inhibitors (AIs), such as exemestane, letrozole, and anastrozole. In this review, the focus will lie on exemestane, its clinical use, and its side-effect profile. Exemestane is the only third-generation steroidal AI. Its efficacy as a first-line treatment in metastatic breast cancer has been demonstrated. Therefore, exemestane could be considered a valid first-line therapeutic option, but it also can be used in second-line or further situations. Exemestane is mostly used as part of sequential adjuvant treatment following tamoxifen, but in this setting it is also active in monotherapy. Furthermore, this AI has been studied in the neoadjuvant setting as presurgical treatment, and even as chemoprevention in high-risk healthy postmenopausal women. It may reverse side effects of tamoxifen, such as endometrial changes and thromboembolic disease but may also cause some inconvenient side effects itself. Additionally, there is a lack of total cross-resistance between exemestane and nonsteroidal AIs as far as their anti-tumoral efficacy is concerned; moreover the two classes of AIs display a nontotal overlapping toxicity profile. Taking together, exemestane can be considered as a useful treatment option at all stages of breast cancer.
Introduction
Breast cancer is the most common type of cancer in women and the main cause of female cancer-related deaths worldwide (Jemal et al. 2011). About 80% of primary breast cancers are hormone sensitive as they contain estrogen receptor (ER) and/or progesterone receptor-positive cells (Keen & Davidson 2003, Nadji et al. 2005). This type of breast cancer can be managed with endocrine therapy. The latter consists of either blocking the ER with an antagonist or reducing the endogenous production of estrogens.
Tamoxifen, a selective estrogen-receptor modulator (SERM), is one major type of endocrine treatment administered to women with hormone receptor (HR)-positive breast cancer. Adjuvant tamoxifen treatment can be administered for 5 years, whereby the rate of recurrence is lowered throughout the first decade, and breast cancer mortality is reduced by about a third throughout the first 15 years (Davies et al. 2011). The recent Adjuvant Tamoxifen: Longer Against Shorter (ATLAS) trial has found that continuing tamoxifen treatment up to 10 years further reduced recurrence and mortality compared with stopping therapy at 5 years (Davies et al. 2013). This has now also been confirmed by data from the adjuvant Tamoxifen–To offer more? (aTTom) trial presented at the 2013 ASCO meeting (Gray et al. 2013).
Another important type of anti-estrogen therapy is treatment with aromatase inhibitors (AIs). This hormone therapy is typically administered in postmenopausal breast cancer patients as it is contra-indicated in women with residual ovarian function because it indirectly increases estrogen production which can induce mammary tumor proliferation (Smith & Dowsett 2003). AIs can be subdivided in two major groups: steroidal AIs (SAIs) and nonsteroidal AIs (NSAIs). Both groups of AIs block aromatase activity. Aromatase is a member of the cytochrome P450 (CYP) family enzymes, which converts androstenedione to estrone and testosterone to estradiol (E2) (Dutta & Pant 2008). In this way, estrogen synthesis is inhibited.
According to the chronologic order of their clinical development, AIs are also classified as first-, second-, and third-generation inhibitors. Aminoglutethimide was a first-generation, fadrozole and rogletimide second-generation, and anastrozole and letrozole are third-generation NSAIs. In the SAI class, testolactone and formestane (4-hydroxyandrostenedione) are the first- and second-generation inhibitors respectively. Exemestane is the only representative of the third-generation steroidal inhibitors (Smith & Dowsett 2003).
Currently, the third-generation AIs such as, exemestane, letrozole, and anastrozole, are used in the treatment of HR-positive breast cancer. The focus of this report will be on exemestane, its clinical use, and its side effect profile, in line with the other AIs and tamoxifen.
Exemestane
Pharmacology
SAIs and NSAIs inhibit the enzyme aromatase in different ways (Lombardi 2002). SAIs such as exemestane are analogs of the natural aromatase substrate androstenedione. They bind covalently to the substrate-binding site of aromatase and hereby irreversibly inactivate the enzyme. NSAIs such as letrozole and anastrozole, on the other hand inhibit aromatase in a reversible manner by binding to the heme moiety of the enzyme. In this way, NSAIs prevent androgens from binding to the catalytic site. Clinical studies found 25 mg/day of exemestane, orally administered, to be the minimum effective dose producing maximum estrogen suppression (Evans et al. 1992, Johannessen et al. 1997, Paridaens et al. 1998). The mean maximum suppression of aromatase by exemestane is 97.9% (Geisler et al. 1998). For all third-generation AIs, 98% inhibition of total body aromatization has been reported whereas for first- and second-generation AIs only <90% has been achieved (Lønning & Eikesdal 2013).
An indirect comparison by Lønning & Geisler (2010) revealed that exemestane administered at 25 mg daily seemed to inhibit aromatization as efficiently as anastrozole administered at 1 mg daily. Furthermore 2.5 mg letrozole daily appeared to be a more potent inhibitor of aromatase compared with both alternatives (Geisler et al. 2002). Results, however, should be interpreted carefully considering plasma estrogen level measurements. To detect more than 90% inhibition in vivo, assays with a sensitivity limit of 5–7 pM for estrone and 1–2 pM for E2 are required. Consequently, methods to evaluate such low-plasma estrogen levels in patients require a high sensitivity which makes measurement in vivo very difficult. Our research group developed a sensitive liquid chromatography–tandem mass spectrometry method for measuring low-estrogen levels (Pauwels et al. 2013). The limit of quantification is 1.2 and 1.3 ng/l for estrone and E2 respectively. Exemestane, however, is metabolized into several steroidal compounds. These steroidal molecules may nonspecifically interact during the measurement of estrogen levels and consequently cause cross-contamination (Johannessen et al. 1997). As a result, chromatographic sample purification is required.
The question remains whether at very low levels of circulating estrogens, thus at more than 90% inhibition, there is a connection between anti-tumoral effect and hormonal suppression. Complicating this, however, are the potential roles of intratumoral aromatase activity/downregulation and drug metabolism in determining its efficacy for inhibiting tumor growth.
It is worth noting that breast cancer incidence in postmenopausal women is considered to be correlated with body fat. Adipose tissue physiologically expresses aromatase, but in obese women this expression is abnormally high. This leads to local overproduction of estrogens which stimulates tumor growth (Bulun et al. 2012). Consequently, obese patients may require higher AI dosages to achieve same efficacy, but results from previous studies seem to be inconsistent (Dixon et al. 2008, Goodwin & Pritchard 2010, Diorio et al. 2012).
Furthermore, estrogen levels, and particularly E2, in breast tumor tissue are significantly higher than plasma estrogen levels (Vermeulen et al. 1986). These elevated intratumor levels may reflect the high concentration of ERs which allow increased binding of circulating estrogen, or enhanced intratumoral hormone synthesis (Lønning & Geisler 2010, Lønning et al. 2011). One study ascribed elevated tissue E2 to a high concentration of ERs (Haynes et al. 2010). They, as well as other researchers, reported an increased E2:estrone ratio compared with normal tissue due to increased expression of an oxidative isoform of 17β-hydroxysteroid dehydrogenase (Reed et al. 1989, Haynes et al. 2010). The source of intratumoral estrogen is still in debate and further studies are warranted.
A limited amount of studies compared clinical efficacy of SAIs and NSAIs in patients with hormone-dependent metastatic breast cancer. In one trial, 130 postmenopausal women with advanced breast cancer were randomized to receive anastrozole or exemestane for at least 8 weeks. Another trial randomized 103 postmenopausal women with advanced breast cancer to anastrozole or exemestane until they had disease progression. Both studies showed no difference in clinical efficacy between exemestane and anastrozole (Campos et al. 2009, Llombart-Cussac et al. 2012). Riemsma et al. (2010) indirectly compared different AIs in postmenopausal patients with HR-positive advanced or metastatic breast cancer. The authors reported a higher objective response rate (ORR) for letrozole and exemestane than for anastrozole, although no significant differences between AI treatment arms were identified with regard to overall survival (OS) and progression-free survival (PFS).
Clinical use
Metastatic breast cancer
At first diagnosis, ∼6% of breast cancer patients present with metastatic disease. The remaining patients, diagnosed with apparently localized primary breast cancer, have a 20–50% chance of developing metastatic disease later, sometimes after more than two decades (Lu et al. 2009).
Treatment with endocrine therapy in metastatic breast cancer patients with HR-positive tumors is at least as efficacious as chemotherapy, if not more so (Glück 2009). Furthermore, it is generally better tolerated than chemotherapy. Exemestane, letrozole, and anastrozole have demonstrated clinical superiority when compared with conventional hormonal treatment, such as tamoxifen and first or second generation AIs (Smith & Dowsett 2003, Coombes et al. 2004, Lønning 2004, Howell et al. 2005, Jakesz et al. 2005, Thürlimann et al. 2005). In Table 1, all randomized trials are presented, in which third generation AIs were compared as first-line treatments with tamoxifen. Letrozole and anastrozole make up the treatment of choice in first-line therapy for metastatic disease (Winer et al. 2005). The Tamoxifen or Arimidex Randomized Group Efficacy and Tolerability (TARGET) study and the North American trial compared first-line anastrozole treatment with tamoxifen therapy (Bonneterre et al. 2000, Nabholtz et al. 2000). In the TARGET trial, 668 postmenopausal women were randomized to receive either anastrozole or tamoxifen monotherapy. In the North American trial, 353 postmenopausal patients were recruited and randomized to anastrozole monotherapy or tamoxifen monotherapy. Both trials confirmed that anastrozole was valid as a first treatment choice instead of tamoxifen. In a randomized phase III study, letrozole was found to be significantly superior to tamoxifen as a first-line treatment (Mouridsen et al. 2003).
Phase III clinical trials evaluating first-line aromatase inhibitors vs tamoxifen in advanced/metastatic breast cancer
| Study (follow-up)a | Patients (n)b | Treatment | Median TTP/PFS (P value) | TTP/PFS risk (95% CI) | ORR (%, P value) | CBR (%, P value) | OS (P value) |
|---|---|---|---|---|---|---|---|
| EORTC-BCCGc | E, 182 | E vs T | 9.9 vs 5.8 months (0.121) | 0.84 (0.67–1.08) | 46 vs 31 (0.005) | NR | 1 year, 82 vs 86% (0.821) |
| 29 months | T, 189 | ||||||
| TARGET studyd | T, 328 | T vs A | 8.3 vs 8.2 months (0.941) | 0.99 (NR) | 32.6 vs 32.9 (NR) | 55.5 vs 56.2 (NR) | NR |
| 19 months | A, 340 | ||||||
| The North American triale | T, 182 A, 171 | T vs A | 5.6 vs 11.1 months (0.005) | 1.44 (NR) | 17.0 vs 21.1 (NR) | 46 vs 59 (0.0098) | NR |
| 17.7 months | |||||||
| Phase III studyf | L, 453 | L vs T | 9.4 vs 6.0 months (<0.0001) | 0.72 (NR) | 32 vs 21 (0.0002) | 50 vs 38 (0.0004) | 34 vs 30 months (NS) |
| 32 months | T, 454 |
A, anastrozole; CBR, clinical benefit rate (CR+PR+SD for ≥6 months); E, exemestane; EORTC-BCCG, European Organisation for Research and Treatment of Cancer Breast Cancer Cooperative Group; HR, hazard ratio; L, letrozole; NR, not reported; NS, not significant; ORR, objective response rate (CR+PR); OS, overall survival; PFS, progression-free survival; T, tamoxifen; TARGET, Tamoxifen or Arimidex Randomized Group Efficacy and Tolerability; TTP, time to progression.
Median follow-up.
Patients analyzed.
Although exemestane is often used as a second-line treatment (Glück et al. 2013), its efficacy as a first-line treatment was also demonstrated in the European Organisation for the Research and Treatment of Cancer (EORTC) trial (Paridaens et al. 2008). The EORTC Breast Cancer Cooperative Group undertook a phase III randomized open-label clinical trial to investigate the efficacy and tolerability of exemestane in comparison with tamoxifen in 371 postmenopausal patients with hormone-dependent metastatic breast cancer. Overall response rate was greater for the exemestane treatment arm compared with the tamoxifen treatment arm whereas no significant difference in OS was detected between treatment arms. OS was not significantly different from that for tamoxifen in the different individual trials of the three third-generation AIs, but a meta-analysis showed an OS benefit of using AIs compared with tamoxifen as first-line therapy for HR-positive breast cancer (Mauri et al. 2006). AIs can thus be considered more efficacious than tamoxifen in first-line therapy, which is of prime importance for quality of life in a noncurable palliative setting. AIs are also superior to megestrol acetate, a progestin. Previously, megestrol acetate was used as a standard second-line hormonal therapy in patients with breast cancer resistant to tamoxifen, but according to a phase III trial, overall ORRs were higher with exemestane vs megestrol acetate as second-line treatment following tamoxifen failure (Kaufmann et al. 2000, Walker et al. 2013).
In the Evaluation of Faslodex vs Exemestane Clinical Trial (EFECT), the time to progression for exemestane and fulvestrant (Faslodex), a complete ER antagonist, was demonstrated to be similar as well as the adverse event profile in a setting where tumors were refractory to a NSAI (Chia et al. 2008). It is noteworthy that in the EFECT trial, the conventional dose of fulvestrant (250 mg) was administered. Later in another trial it was found that with the present advised dose (500 mg), fulvestrant is at least as efficacious as exemestane as a second-line treatment in postmenopausal women with advanced breast cancer (Cope et al. 2013).
As a result of the order in which they were developed, third-generation NSAIs instead of SAIs are more often used as first-line treatment in metastatic disease. Upon progression of metastatic disease following treatment with NSAIs, exemestane may be effective as sequential hormone therapy (Lønning et al. 2000, Bertelli & Paridaens 2006, Steele et al. 2006, Lønning 2009, Lønning & Geisler 2010, Kim et al. 2012). Several trials have found that breast cancer patients who have become resistant to NSAIs may experience benefit from SAIs (Table 2; Thürlimann et al. 1997, Lønning et al. 2000, Bertelli et al. 2005, Iaffaioli et al. 2005, Gennatas et al. 2006, Mayordomo et al. 2006, Steele et al. 2006, Carlini et al. 2007, Chin et al. 2007, Mauriac et al. 2009). On average, 25–30% of patients in these cross-over studies experienced objective response or stable disease for 6 months or more. Conversely, administration of NSAIs seems to be effective after failing SAIs as well (Table 2; Bertelli et al. 2005, Mayordomo et al. 2006). Several potential mechanisms underlying this nontotal cross-resistance have been suggested, but studies exploring which mechanisms are actually responsible are eagerly awaited.
Cross-over clinical trials in advanced/metastatic breast cancer
| Patients (n)a | First AI | Second AI | TTP | ORR (%) | CBR (%) | References |
|---|---|---|---|---|---|---|
| 78 | AG | E | 21 weeks | 26 | 39 | Thürlimann et al. (1997) |
| 241 | AG, A, L, V | E | 14.7 weeks | 6.6 | 24.3 | Lønning et al. (2000) |
| 18 | E | L (A) | 9.3 months | 22.2 | 55.6 | Bertelli et al. (2005) |
| 23 | A, L | E | 5.1 months | 8.7 | 43.5 | Bertelli et al. (2005) |
| 50 | A | E | 5 months | 8 | 44 | Iaffaioli et al. (2005) |
| 60 | A, L | E | 3.2 weeks | 20.0 | 38.3 | Gennatas et al. (2006) |
| 12 | A | E | 4.4 months | NR | NR | Mayordomo et al. (2006) |
| 11 | E | A | 1.9 months | NR | NR | Mayordomo et al. (2006) |
| 108 | A, L | E | 18 months | 5 | 46 | Steele et al. (2006) |
| 30 | A, L | E | 4 months | NR | 46.6 | Carlini et al. (2007) |
| 31 | A, L | E | 3.2 months | 19.4 | 54.8 | Chin et al. (2007) |
| 184b | A, L | E | 2.8 months | 4.4 | 27.2 | Mauriac et al. (2009) |
| 239 | A, L | E | 4.1 months | 0.4 | 64.8 | Baselga et al. (2012) |
A, anastrozole; AG, aminoglutethimide; CBR, clinical benefit rate (CR+PR+SD for ≥6 months); E, exemestane; L, letrozole; NR, not reported; ORR, objective response rate (CR+PR); TTP, time to progression; V, vorozole.
Patients analyzed.
Patients with visceral metastases.
Taking all these data into account, one can conclude that exemestane as first-line treatment is effective, well tolerated, and can be considered, like NSAIs, as a valid first-line option for treatment of HR-positive cancers in postmenopausal women (Glück 2009). As far as hormonal suppression is concerned, exemestane seems slightly less efficacious when compared with the other AIs, whereas the clinical anti-tumoral efficacy of NSAIs and SAIs seems to be similar. In second-line treatment, the sequence of AIs does not seem to matter as a result of nontotal cross-resistance.
Adjuvant setting
Upfront treatment
As stated above, 5 years of treatment with tamoxifen remained for more than two decennia the standard adjuvant anti-hormonal treatment for postmenopausal patients. The first trials aiming at integrating AIs into the adjuvant setting explored various schedules, compared with 5 years tamoxifen which was considered to be the standard reference treatment.
The first schedule was 5 years treatment with AIs instead of 5 years of tamoxifen, in which mainly NSAIs were studied. The Arimidex, Tamoxifen Alone or in Combination (ATAC) trial compared the safety and efficacy of tamoxifen monotherapy, anastrozole monotherapy, and tamoxifen–anastrozole combination therapy for 5 years (Baum et al. 2002). We learned from this trial that tamoxifen should not be combined with AIs and that NSAIs were slightly but significantly superior to tamoxifen.
Further, switch strategies were explored for all three AIs in which 2–3 years of tamoxifen are followed by 2–3 years of AI therapy. The Intergroup Exemestane Study (IES) conducted a trial to compare 5 years tamoxifen with a sequential therapy consisting of a sequence of tamoxifen followed by exemestane (called the exemestane ‘switch’) for a total of 5 years in postmenopausal patients with early, HR-positive breast cancer (Coombes et al. 2004). After 2–3 years of tamoxifen treatment, patients were randomized in an intent-to-treat analysis to receive either tamoxifen or exemestane. A significantly higher disease-free survival (DFS) was reported in the exemestane treatment arm. Based on these results, the exemestane ‘switch’ was considered a valuable adjuvant option. Later on, the Tamoxifen Exemestane Adjuvant Multinational (TEAM) phase III trial investigated the potential of 5 years exemestane as an alternative to 5 years tamoxifen. The trial had to be modified because the results of the IES were published while the TEAM trial was still ongoing, indicating that 5 years adjuvant tamoxifen might be considered as a suboptimal adjuvant treatment. The modified TEAM design compared long-term effects of exemestane monotherapy for 5 years with the tamoxifen/exemestane ‘switch’ strategy in postmenopausal women with HR-positive breast cancer (van de Velde et al. 2011). Results showed no significant differences in DFS and OS between both groups.
The Breast International Group (BIG) 1–98 trial was conducted to ascertain the efficacy of the switch strategy vs 5 years of AI therapy (Regan et al. 2011). The BIG 1–98 trial was a four-arm trial wherein 5 years of letrozole or tamoxifen monotherapy or sequences of 2 years of one followed by 3 years of the other were compared with each other. The authors found that efficacy with sequential therapy was not significantly different from that with letrozole monotherapy, while tamoxifen only was inferior to the three arms including an AI. The investigators, however, found that DFS and OS in the sequential treatment arm were, although nonsignificant, inferior in comparison with monotherapy at a median follow-up of 71 months. The results concerning DFS and OS between ‘switch’ strategy and monotherapy contrast with what was observed in the TEAM trial. Thus, so far, it is not yet known whether AI monotherapy or sequential therapy should be preferred.
Taken together, AI treatment should be preferred as standard adjuvant endocrine therapy, but the question remains which AI should be given preference as first-line therapy. This was addressed in the MA.27 trial which compared exemestane with anastrozole as a 5 years initial adjuvant treatment in postmenopausal women (Goss et al. 2013). The authors reported similar efficacy for both treatment options and thus suggested exemestane also as a safe and effective option as first-line adjuvant treatment in postmenopausal women with HR-positive breast cancer.
Based on the above results, AIs have become a standard adjuvant endocrine therapy for postmenopausal breast cancer patients and have proven superiority to tamoxifen monotherapy (Coombes et al. 2004, van de Velde et al. 2010, Rao & Cobleigh 2012, Boccardo et al. 2013).
Extended treatment
Studies have shown that an endocrine therapy schedule of 5 years is more efficacious than one of 2 or 3 years (Abram et al. 1996, Swedish Breast Cancer Cooperative Group 1996). The question remains, however, whether extending therapy with an additional 5 years of adjuvant treatment is more efficacious in comparison with the standard 5 years anti-estrogen therapy.
As stated earlier, the ATLAS and the aTTom trials demonstrated that extending therapy to 10 years of tamoxifen instead of 5 years for patients with HR-positive breast cancer further reduces recurrence and mortality (Davies et al. 2013, Gray et al. 2013).
There are studies which investigated the effects of prolonging 5 years tamoxifen treatment with 5 years of treatment with an AI. The National Surgical Adjuvant Breast and Bowel Project B-33 trial (NASBP-B33) randomly assigned postmenopausal breast cancer patients who were disease-free after 5 years of tamoxifen treatment to one of two treatment arms comprising either 5 years of exemestane treatment or 5 years of placebo treatment (Mamounas et al. 2008). This study showed a nonsignificant improvement in DFS for the exemestane group. A significant improvement in relapse-free survival was seen at a median follow-up of 30 months. Letrozole following 5 years of tamoxifen treatment also improves DFS and distant-free survival in patients with HR-positive breast cancer according to the MA.17 trial (Goss et al. 2005). Extended letrozole treatment is well-tolerated. The Study of Letrozole Extension (SOLE) in postmenopausal women with breast cancer is a currently ongoing randomized trial wherein extended continuous letrozole treatment is compared with intermittent letrozole treatment following 4–6 years of prior adjuvant endocrine therapy (Colleoni 2011). The Adjuvant post-Tamoxifen Exemestane vs Nothing Applied (ATENA) trial was an open-label trial in which postmenopausal patients were randomized to 5 years of exemestane treatment or 5 years of observation after 5–7 years of tamoxifen administration (Markopoulos et al. 2009a). This trial, however, was prematurely ended because results of the MA.17 trial were published. Furthermore, to date, no trials have, to our knowledge, investigated the efficacy of 10 years of AI treatment instead of 5 years.
Neoadjuvant setting
Neoadjuvant therapy makes conservative surgery possible in a high percentage of breast cancer patients and its use is increasing. Chemotherapy is mostly applied in this setting, although AIs may also play an important role. In a randomized phase II trial, the effects of presurgical treatment with letrozole, anastrozole, or exemestane in postmenopausal women with ER-rich stage 2 or 3 breast cancer were investigated (Ellis et al. 2011). Results showed improved surgical outcomes in patients treated with neoadjuvant AI therapy and that these AIs are biologically equivalent.
In a phase II study investigating presurgical treatment with exemestane for 6 months in postmenopausal patients with ER-positive breast cancer, a beneficial effect of this therapy was observed (Barnadas et al. 2009). Treatment for conservative surgery appeared to be effective and well tolerated.
Another randomized phase II trial, PTEX46, investigated the optimal duration of neoadjuvant exemestane treatment (Hojo et al. 2013). Fifty-one postmenopausal women with HR-positive invasive breast cancer were randomized to neoadjuvant exemestane treatment for 4 or 6 months. No difference in the outcome of breast-conserving surgery was observed between the different treatment-duration groups. Thus, a 4-months treatment with exemestane appears to be warranted in postmenopausal patients awaiting breast-conserving surgery. Based on these results, exemestane should be considered a valid option in the neoadjuvant setting.
Breast cancer-off label use
Premenopause
AIs are mainly used as adjuvant treatment for early HR-positive breast cancer in postmenopausal patients (Nordman et al. 2005). In premenopausal patients, standard of care in the adjuvant setting is 5–10 years treatment with tamoxifen (Rao & Cobleigh 2012). Tamoxifen combined with ovarian function suppression or ablation is deemed superior to first-line tamoxifen monotherapy in the case of metastatic disease (Paridaens et al. 2010). Aromatase inhibition is not recommended in premenopausal women, because inhibition of the hypothalamus pituitary aromatase induces an increase in gonadotropins which in turn stimulate ovarian follicular growth, producing high levels of circulating estrogen which can thereby induce mammary tumor proliferation (Simpson 2003). As proof of this, let us remember that AIs in young women are also used for the stimulation of ovaries, as treatment of infertility (Polyzos et al. 2009). For these reasons, AIs are formally contra-indicated in women with residual ovarian function. They can, however, safely be given in combination with reversible or irreversible ovarian ablation.
In 1803 premenopausal women with early breast cancer, the Austrian Breast and Colorectal Cancer Study (ABCSG-12) tested the addition of AIs to ovarian suppression achieved by goserelin, a gonadotropin-releasing hormone (GNRH) agonist (Gnant et al. 2009). All patients received goserelin and were randomly assigned to either tamoxifen or anastrozole for 5 years, with or without zoledronic acid for 3 years. DFS was similar in all groups, but OS was inferior in the anastrozole monotherapy group (Gnant et al. 2011).
Currently, two ongoing trials are investigating adjuvant exemestane in premenopausal women combined with suppression of their ovarian function. In the Suppression of Ovarian Function Trial (SOFT), 5 years tamoxifen treatment – the reference for premenopausal patients – is compared with tamoxifen plus ovarian function suppression or exemestane plus ovarian function suppression. The latter is accomplished by administering 5 years of treatment with the GNRH analog triptorelin, surgical oophorectomy, or ovarian irradiation (Zickl et al. 2012). The Tamoxifen and Exemestane Trial (TEXT) compares 5-year treatment with triptorelin plus tamoxifen with 5 years triptorelin plus exemestane (Zickl et al. 2012). Results from both studies, which have completed their accrual, are eagerly awaited.
In some premenopausal women with chemotherapy-induced amenorrhea, however, recovery of ovarian function occurs when these patients are treated with AIs (Smith et al. 2006, Ortmann et al. 2009). Ten percent of patients experienced resumed bleeding within the subsequent 3 years (Sukumvanich et al. 2010). Chemotherapy-induced amenorrhea in premenopausal breast cancer patients is thus not always irreversible, and hormonal assays are not predictive in this regard, so that one should be careful when administering adjuvant AIs in younger women. The question remains, from what age adjuvant treatment with an AI should be considered safe. In practice, tamoxifen could first be given for several years, allowing an AI switch later, eventually to be delayed beyond the age of 50 years. In addition, the practical guideline produced by De Vos et al. (2012) could be used to establish a patient's menopausal status.
In summary, AIs are contra-indicated in premenopausal breast cancer patients with hormonally active gonads. Preliminary results of the randomized ABCSG-12 trial comparing GNRH analogs with either tamoxifen or anastrazole show no significant difference in relapse rates, but many more events are necessary to make powerful comparisons. Likewise, the results of the SOFT and the TEXT study are eagerly awaited.
Aromatase inhibition in men
In Europe, 1 out of 100 000 men/year will develop breast cancer (Fentiman et al. 2006), which represents 1% of all breast cancer patients. A family history of breast cancer, exogenous estrogens, and therapeutic or diagnostic radiation are the risk factors for men to develop breast cancer (Fentiman et al. 2006).
The treatment options include surgery, adjuvant loco-regional radiotherapy, and/or systemic therapy (Fentiman et al. 2006). Up to 90% of male breast cancers are HR-positive (Rayson et al. 1998) and therefore, adjuvant endocrine therapy or combined endocrine and chemotherapy are mainly administered (Agrawal et al. 2007). Herein tamoxifen is the standard of care. AIs, however, are suggested to have survival benefit compared with tamoxifen in female postmenopausal breast cancer patients with metastatic HR-positive breast cancer. In contrast, OS in men was significantly increased with tamoxifen compared with AIs (Eggemann et al. 2013). This could be explained by the ‘feedback loop’ hypothesis. Testicular production of estrogen in men accounts for ∼20% of circulating estrogens and this part is independent of aromatase; the remaining 80% of circulating estrogen in men is formed by peripheral aromatization of androgens (Agrawal et al. 2007). Chronic administration of AIs causes a significant decrease in plasma E2, but testicular production of estrogen is not inhibited. Therefore, estrogen levels are suboptimally decreased and there is less suppression in men compared with women. Furthermore, testosterone and follicle-stimulating hormone are increased with long-term AI treatment. Taken together, the changes in hormone levels via this feedback loop could lead to an increase in substrate for aromatization (Giordano & Hortobagyi 2006, Doyen et al. 2010).
Additionally, increased testosterone levels caused by exemestane treatment seem to stimulate tumor growth in men with prostate carcinoma (Bonomo et al. 2003). As a result, tamoxifen should be considered the treatment of choice for men with HR-positive breast cancer in the adjuvant setting. For treating metastatic disease, AIs may be helpful, but should be only administered in combination with agents blocking the testicular production of steroid hormones, e.g. GNRH analogs (Zagouri et al. 2013).
Side effects
Many women undergoing natural menopause experience inconveniences caused by a decrease in estrogen levels (Shanafelt et al. 2002). These side effects may be particularly pronounced in young women when menopause is abruptly induced by chemotherapy or ovarian ablation. Similar troubles arise in breast cancer patients treated with AIs due to further estrogen synthesis suppression. Therefore, several AI-induced side effects such as hot flashes, musculoskeletal symptoms, cardiovascular events, and sexual dysfunction are believed to be associated with the AI-induced estrogen deficiency (Ahlborg et al. 2003).
Hot flashes
Hot flashes are one of the most common side effects reported under tamoxifen and AI therapies (Kittaneh & Glück 2011), with a frequency up to 50% (Shanafelt et al. 2002).
Both randomized adjuvant IES and TEAM trials reported high numbers of hot flashes among postmenopausal breast cancer patients treated with exemestane (Coombes et al. 2004, 2007, van de Velde et al. 2011). In a TEAM substudy, hot flashes complaints were compared between the first year of either adjuvant exemestane or tamoxifen treatment (Jones et al. 2007). The mean hot flash score of both groups peaked at 3 months of therapy, and subsequently decreased. After 12 months, a lower hot flash frequency was found with exemestane then with tamoxifen.
One prospective, cross-over study scored hot flashes after switching to letrozole or exemestane in postmenopausal women who already experienced hot flashes on adjuvant tamoxifen (Thomas et al. 2008). The authors found a significant improvement following treatment with AIs. The intensity of hot flashes was slightly lower if patients were treated with exemestane compared with letrozole.
The NCIC CTG MA.27 randomized controlled phase III trial evaluated vasomotor symptoms of anastrozole-treated and exemestane-treated patients (Goss et al. 2013). No significant differences were seen between the two treatment groups. Taking these data together, it can be concluded that fewer hot flashes occur for treatment with AIs compared with treatment with tamoxifen. To reduce symptomatic hot flashes and if conventional lifestyle measures fail, nonhormonal treatments, e.g. clonidine, venlafaxine, or gabapentine are generally administered (Shanafelt et al. 2002). In contrast to concomitant tamoxifen use, SSRIs are generally not contra-indicated during AI treatment.
Bone metabolism
Owing to its estrogen-like effect on bone, tamoxifen inhibits bone resorption in postmenopausal women thereby exerting a protective effect against osteoporosis. On the other hand, as a consequence of the estrogen-lowering effect of AIs, rate of bone turnover, loss of bone mineral density (BMD), and the incidence of fractures increase in postmenopausal breast cancer patients treated with these agents, as suggested in the ATAC trial, BIG 1–98 study and the IES (Coleman et al. 2010, Eastell et al. 2011, Zaman et al. 2012).
Anastrozole accelerates bone loss as a result of increased bone turnover leading to reduced BMD (Eastell et al. 2008). Similarly, exemestane causes an increase in bone turnover markers and reduces BMD (Lønning et al. 2005). The same decrease was recorded when patients were treated with letrozole (Perez et al. 2006) or after completing 5 years of adjuvant tamoxifen therapy (Gonnelli et al. 2007). For the latter study, bone loss could be explained firstly by the estrogen-reducing effect of exemestane and secondly by the loss of the protective effect of tamoxifen as well. This is attested by a significant increase in bone turnover markers already detected after 6 months tamoxifen withdrawal and exemestane initiation. Bone turnover markers were significantly increased at 6 months with respect to tamoxifen withdrawal and exemestane initiation.
The annual fracture incidences in women treated with anastrozole or letrozole were 21.6 and 22.0/1000 women-years, respectively, according to the ATAC and BIG 1–98 trials. Under exemestane, this was 19.2/1000 women-years (Coleman et al. 2007). Reassuringly, increased bone loss was found to be reversed after discontinuing the anti-aromatase treatment (Coleman et al. 2010).
To prevent and treat AI-induced bone loss, patients typically receive calcium and vitamin D supplements. BMD should also be monitored every 2 years as long as AI treatment is continued. Additionally, bisphosphonate therapy or treatment with receptor activator for nuclear factor-κB ligand (RANKL) inhibitors, such as denosumab, could be administered to patients at increased risk of fractures or osteoporosis, smokers and patients taking oral corticosteroids for more than 6 months (Gnant et al. 2007, Eastell et al. 2008, Hadji et al. 2008, Gaillard & Stearns 2011). In conclusion, exemestane, like other AIs, is associated with increased bone turnover, loss of BMD, and an increased incidence of fractures, thus requiring close observation and, if needed, treatment.
Musculoskeletal symptoms
Although the reported incidences of AI-induced musculoskeletal symptoms range from 5–36.0% in the large clinical trials (Howell et al. 2005, Coombes et al. 2007, Crew et al. 2007, Gaillard & Stearns 2011), more than half of patients complain of these adverse events in the clinical setting (Presant et al. 2007, Lintermans & Neven 2011). The lowest incidence has been reported for exemestane-treated patients in the IES. However, other reports did not show differences in incidences of musculoskeletal symptoms between the three AIs (Crew et al. 2007). These conflicting results are due to the variable definitions used in the several trials.
Musculoskeletal symptoms often lead to a decreased quality of life and, consequently, compromise adherence and lead to therapy discontinuation. The most encountered symptoms include new or worsened carpal tunnel syndrome; trigger finger; morning stiffness; and pain of wrists, hands, knees, hips, back, ankles, feet, and shoulders (Henry et al. 2008, Mao et al. 2009, Gaillard & Stearns 2011). A retrospective evaluation of the IES showed higher rates of carpal tunnel syndrome in patients treated with exemestane when compared with those treated with tamoxifen (Mieog et al. 2012). In most patients, symptoms occur rapidly, generally, within the first 3 months of AI therapy (Henry et al. 2008, Mao et al. 2009), though delayed onset can also occur in some patients.
There is a growing interest in defining proper biomarkers in order to identify patients at risk of developing these bothers. Reported clinical risk factors include prior taxane-based chemotherapy, time since menopause, low BMI, and baseline arthralgia (Crew et al. 2007, Mao et al. 2009).
Underlying mechanisms still remain not fully understood. Our group and others demonstrated tenosynovial changes and intra-articular fluid accumulation, on magnetic resonance imaging and ultrasonography in patients who reported severe AI-induced musculoskeletal pain (Morales et al. 2007, Henry et al. 2010, Lintermans et al. 2011, 2013). The etiology is still largely unknown and improvement of symptoms is rarely seen after administration of nonsteroidal anti-inflammatory drugs, the most commonly used strategy to tackle these problems. As a consequence, up to one out of four patients may discontinue treatment (Lintermans & Neven 2011).
Another emerging hypothesis proposes a role for vitamin D. Indeed vitamin D deficiency is common in postmenopausal breast cancer patients and is associated with worse outcome (Hatse et al. 2012). Consequently, recent studies have reported that daily vitamin D supplements may have a protective effect on pathogenesis (Khan et al. 2010, Rastelli et al. 2011). This observation may represent a promising possibility for maintaining quality of life and for preventing discontinuation of a potentially life-saving adjuvant anticancer treatment.
Lipid metabolism
Natural or induced menopause, with low levels of circulating estrogens, frequently leads to increased levels of LDL cholesterol and decreased HDL cholesterol levels. These changes are considered to increase the risk of the development of coronary heart disease (Gorodeski 2002). Tamoxifen has a favorable effect on lipids (mainly by decreasing levels of LDL, the atherogenic fraction of cholesterol), whereas AIs may have a further negative effect on these lipid parameters.
In contrast with tamoxifen, NSAIs do not have a protective effect on lipid metabolism. Most studies, however, did not show marked changes in lipid parameters induced by letrozole or anastrozole (Nabholtz 2008). In addition, no detrimental effect on atherogenic indices was seen for exemestane. Exemestane has no effect on levels of total cholesterol or its fractions, nor on lipoprotein levels (Atalay et al. 2004). A TEAM substudy compared the effect of exemestane on lipid metabolism to that of tamoxifen (Markopoulos et al. 2005). For triglyceride levels, no significant mean difference across time was seen between tamoxifen and exemestane (Markopoulos et al. 2009a). Another randomized study in early breast cancer patients showed no major effect of exemestane on serum lipids compared with placebo (Lønning et al. 2005). Both treatments decreased total cholesterol levels. The ATENA trial evaluated the effect of extending adjuvant therapy with exemestane for 2 years after completion of 5 years of tamoxifen treatment. This extended regimen did not induce significant effects on lipid profiles during the 24 months of the study (Markopoulos et al. 2009b). Consequently, data from both trials were reassuring.
As can be concluded from these studies, exemestane seems to have an almost neutral effect on lipids. Whether it will translate into an increased risk of cardiovascular disease remains to be shown by long-term follow-up data in adjuvant trials, as is also the case for NSAIs.
Cardiovascular adverse events
With advancing age, the heart undergoes subtle physiological changes and subsequently cardiovascular diseases such as hypertension, coronary heart disease, heart valve disease, and rhythm disorders, become increasingly common (Young et al. 2000). Consequently, among postmenopausal women, cardiovascular diseases occur more frequently (Ewer & Glück 2009).
Owing to its cholesterol-lowering effect, tamoxifen therapy has beneficial effects on the cardiovascular system. However, it is well-known that tamoxifen increases the risk of thromboembolic events (Meier & Jick 1998), as was demonstrated by the higher frequency of thromboembolic disease in patients who received tamoxifen in the IES-control arm compared with exemestane users (Coombes et al. 2004, 2007). Hypertension was increased in the latter group, which may explain why the overall incidence of cardiovascular events was similar in the two groups. Similar findings were reported in the TEAM trial (van de Velde et al. 2011).
In the MA.27 trial, myocardial infarction, stroke, and transient ischemic attacks were compared between patients receiving anastrozole or exemestane (Goss et al. 2013). For these events, no difference was observed between both treatment groups. However, atrial fibrillation was more frequently reported among exemestane users.
In summary, mild increases in cardiovascular risk have been observed with AI treatment compared with tamoxifen. This may reflect the fact that AIs do not display the well-known protective effect of tamoxifen, although no evidence is present of any increase as compared with placebo (Jakesz et al. 2005, Kaufmann et al. 2007, Forbes et al. 2008, Colleoni et al. 2011, Bliss et al. 2012, Dubsky et al. 2012, Boccardo et al. 2013).
Vaginal side effects
A TEAM substudy compared menopausal symptoms during the first year of adjuvant exemestane treatment vs tamoxifen treatment (Jones et al. 2007). No significant difference in vaginal bleeding was detected, but exemestane patients reported more vaginal dryness whereas tamoxifen users had significantly more vaginal discharge. The latter has also been reported in an IES substudy (Fallowfield et al. 2006); however, a difference in vaginal dryness could not be corroborated.
An increased vaginal dryness incidence was similarly reported for anastrozole in the ATAC substudy (Fallowfield et al. 2006). Letrozole therapy, when compared with placebo, showed no significant difference in vaginal dryness, as observed in the MA.17 trial (Goss et al. 2005). AI treatment has also been associated with a higher incidence of dyspareunia compared with individuals not treated with AIs (Wiggins & Dizon 2008, Mortimer 2010).
Cognition
ERs have been found in many parts of the brain involved in cognition suggest a role for estrogen in cognitive function (Gasbarri et al. 2011, Phillips et al. 2011a). Some reports indicate that estrogen supplementation has a beneficial effect on cognitive function, although results are still conflicting (Sherwin 2012). Accordingly, adjuvant endocrine therapy in postmenopausal breast cancer may influence cognitive function. Tamoxifen was negatively associated with cognitive functions in some reports (Paganini-Hill & Clark 2000, Collins et al. 2009) and the TEAM trial confirmed these findings by showing that tamoxifen is significantly associated with lower functioning in verbal memory and executive functioning (Schilder et al. 2010). Exemestane, on the other hand, did not show significantly worse outcomes for any cognitive domain compared with healthy controls.
The BIG 1–98 trial, comparing tamoxifen to letrozole, indicated that, during the fifth year of treatment, the cognitive function of the letrozole-treated group was better than that of the tamoxifen-treated group. It is noteworthy that cognitive function improved consistently after cessation of treatment (Phillips et al. 2011b).
The International Breast Intervention Study II (IBIS II) found no significant difference between the anastrozole-treated and placebo groups in high-risk women (Jenkins et al. 2008). In contrast, one pilot study of the ATAC trial showed that both anastrozole-treated and tamoxifen-treated patients had decreased verbal memory and processing speed compared with patients that had received placebo (Jenkins et al. 2004). Consequently, results about the effect of AIs on cognition are still conflicting; they seem anyhow less pronounced than the effects of tamoxifen but more studies are warranted to ascertain this.
Perspectives
Predicting response
About 30% of breast cancer patients receiving endocrine treatment relapse or become resistant to their therapy (Beelen et al. 2012). Therefore, biomarkers capable of predicting resistance are of major clinical interest. Tumor cell characteristics like nuclear receptor status, ERα modifications, variation in cofactor expression, and cell cycle regulation may be very relevant parameters. Also, activated growth-factor pathways such as phosphoinositide 3 kinase (PI3K), epidermal growth factor receptor 1 (HER1) and HER2, and estrogen and drug metabolism could be involved in the development of resistance as well (Beelen et al. 2012). The development of resistance to anti-estrogen treatment in breast cancer has been linked to activation of the PI3K–Akt–mTOR signaling pathway. Inhibition of proliferation could then be synergistically enhanced by the addition of a mTOR inhibitor to the endocrine treatment (Boulay et al. 2005). The Breast Cancer Trials of Oral Everolimus-2 (BOLERO-2) study investigated the safety and efficacy of adding the mTOR inhibitor, everolimus, to exemestane therapy in breast cancer patients who had been previously treated with NSAIs (Baselga et al. 2012). The study showed that concomitant use prolonged PFS. Nonetheless, combination therapy was associated with a higher incidence of adverse events when compared with exemestane monotherapy as well as a higher percentage of treatment discontinuation (Dhillon 2013). Despite its prolonged PFS, cost-effectiveness of this combination therapy is still under debate due to the amount of side effects of mTOR inhibitors (Peterson 2013).
The BALLET study is a similar study which is currently ongoing. In this trial everolimus–exemestane combination therapy is administered to postmenopausal women with ER-positive locally advanced or metastatic breast cancer resistant to NSAIs. The primary objective is to evaluate the safety of everolimus treatment. As the study is ongoing, no data are available yet. Furthermore, efficacy of letrozole plus the mTOR inhibitor, temsirolimus, was investigated in another randomized phase III trial (Wolff et al. 2013). In this study, the combination was administered as a first-line treatment to postmenopausal women with AI-naïve locally advanced or metastatic breast cancer. Results showed that letrozole plus temsirolimus did not improve PFS. These findings are in contrast to the findings from the BOLERO2 trial. The lack of complete cross-resistance between the different AI classes was confirmed in these phase III trials as SAIs were administered to patients who experienced recurrence after treatment with NSAIs and this resulted in a prolonged PFS.
It has been found that changing from one AI-class to another, regardless of the sequence, can result in 0–26% ORR and that 50–62% of these patients achieve stable disease (Thürlimann et al. 1997, Zilembo et al. 2004, Bertelli et al. 2005, Chia et al. 2008, Miller et al. 2008). The exact mechanism of nontotal cross-resistance however is not yet known. One explanation could be the variance in AIs which results in different sensitivity. Polymorphisms in the aromatase gene such as single nucleotide polymorphisms (SNPs) could predict response of AIs in breast cancer. For instance, two tightly linked SNPs in CYP19 were significantly associated with improved efficacy of letrozole (Wang et al. 2010). In contrast, a polymorphism at the 3′-UTR region of the aromatase gene defines a subgroup of patients refractory to neoadjuvant letrozole associated with poor prognosis (Garcia-Casado et al. 2010). Another possible explanation is the in vivo androgen agonistic effects of 17-hydro-exemestane, a metabolite of exemestane. Most breast tumors contain more than 10 fmol/mg protein androgen receptors (Lea et al. 1989). When estrogen levels are reduced, breast cancer cells are more sensitive to the protecting effect of androgens and consequently their proliferation can be inhibited by androgens or androgen agonists (Macedo et al. 2006, Suzuki et al. 2007). This anti-tumor effect might also occur with AIs because of their estrogen-suppressive effect, and as a result, this sensitizes tumor cells to androgen growth inhibition. However, further investigations remain necessary to clarify this topic, because the exact reason for lack of complete cross-resistance is still unknown and could be explained by the different mechanisms of action.
Currently, the influence on therapy efficacy is being investigated after the addition of several other signal transduction inhibitors such as inhibitors of the Ras–Raf- MEK–MAPK pathway, insulin-like growth factor 1 receptor, gamma secretase/Notch, cyclin-dependent kinase 4/6 (CDK4/6), histone deacetylase, and Src/Abl a.o., to AI treatment (Fedele et al. 2012).
In addition, biomarkers able to accurately discriminate responders and nonresponders to endocrine therapy are warranted, as they would play a major role in personalized medicine.
Chemoprevention
The three major options for reducing breast cancer occurrence in high-risk women are screening, chemoprevention, and prophylactic surgery. SERMs are considered a preventive treatment for breast cancer. Prophylactic use of tamoxifen reduces the risk of breast cancer development in women at high-risk by about 50% (Cuzick et al. 2002, Waters et al. 2010). In the adjuvant setting, 5 years of tamoxifen reduces recurrence, contralateral disease, and mortality by 30–50%. Additionally, AIs could be used as chemoprevention. The Mammary Prevention 3 (MAP.3) trial was implemented based on the fact that AIs have been shown to be more effective than tamoxifen at reducing contralateral breast cancer incidence as adjuvant therapy (Coombes et al. 2007, Goss et al. 2011, Dunn et al. 2013). This double-blind, placebo-controlled trial examined exemestane as a chemoprevention agent for breast cancer in postmenopausal women. Results demonstrated exemestane administration for at least 3 years to be superior to placebo for the prevention of breast cancer in high-risk postmenopausal women (Goss et al. 2011, DeCensi et al. 2012). The incidence of breast cancer with exemestane compared with placebo was reduced by 65% (Goss et al. 2011, Litton et al. 2012). No serious toxic effects were reported with exemestane and quality of life was minimally changed, while long-term administration of tamoxifen could be associated with serious side effects such as venous thromboembolism and endometrial malignancy (Goss et al. 2011, Walker et al. 2013). An increased risk of osteoporosis with exemestane should be taken into account (Zhang et al. 2012). Further long-term follow-up studies are still needed.
New indications
Benign diseases: endometriosis and uterine myomas
Endometriosis is an estrogen-dependent inflammatory disease associated with chronic pelvic pain, dysmenorrhea, dyspareunia, and infertility which mostly occurs in premenopausal women (Pavone & Bulun 2012). Aromatase levels in the endometrium are elevated in women experiencing this gynecological disease and therefore, AIs could be considered as a treatment option (Bulun et al. 2005, Attar & Bulun 2006, Bedaiwy et al. 2009). Additionally, concurrent therapy such as AIs combined with progesterone or progestin, GNRH analogs, or oral contraceptives, has been suggested by several studies (Pavone & Bulun 2012). In postmenopausal women, endometriosis occurs rarely. In general, it is treated surgically because of risk of malignancy. As surgery is not always possible, systemic drugs are administered (Pavone & Bulun 2012). Treatment options are GnRH analogs, progestin, and AIs.
Several studies have indicated letrozole and anastrozole to be effective for treating endometriosis (Pavone & Bulun 2012). One case report documented therapy with exemestane in a postmenopausal woman with endometriosis, but exemestane was not able to improve symptoms. Switching to letrozole, however, relieved the pain (Mousa et al. 2007).
AIs can be associated with adverse effects such as osteoporosis and follicular cyst formation (Bedaiwy et al. 2009). Therefore, AIs are not recommended as monotherapy, but in combination with a therapy that reduces adverse effects.
Furthermore, uterine myoma is the most common benign tumor in women. Abnormal uterine bleeding and pelvic pressure often occur. The standard of care is surgery because no inexpensive and safe long-term medical treatment is available (Bedaiwy et al. 2009). Like endometriosis, myomas are associated with elevated aromatase and estrogen production, creating another indication to be treated with AIs. Letrozole and anastrozole have been reported to be effective at improving symptoms of uterine myomas, but, to our knowledge, no cases involving exemestane have been documented yet (Bedaiwy et al. 2009).
Endometrial changes
One of the main adverse effects that tamoxifen-treated breast cancer patients experience is an increased risk of developing endometrial hyperplasia, polyps, and carcinoma (Fornander et al. 1989, Neven et al. 1989, Rutqvist & Johansson 2007). Patients treated with tamoxifen have a two- to three-times higher risk of developing endometrial cancer compared with individuals receiving placebo (Fisher et al. 1998). One study compared changes in double endometrial thickness (DET) and uterine volume (UV) between third-generation AIs and tamoxifen (Morales et al. 2005). DET in patients previously treated with tamoxifen was significantly higher at 3 months compared with baseline, while in patients treated with AIs no significant difference was seen. In addition, exemestane following tamoxifen treatment was found to decrease DET and UV significantly. It can be concluded that endometrial changes induced by tamoxifen can be reversed by AIs, which is a safety argument for sequential use in a curative adjuvant setting.
Conclusion
Exemestane is the only third-generation SAI. It is well-tolerated and used as a standard second-line treatment in postmenopausal patients with metastatic breast cancer. Additionally, its efficacy as a first choice therapy for metastatic disease has been reported. Furthermore, exemestane is considered to be a valid option for chemoprevention, presurgical treatment, or as adjuvant treatment. In the latter setting, many options are possible, including monotherapy for 5 years, tamoxifen/exemestane switch, or extended therapy with exemestane beyond 5 years adjuvant treatment. As far as anti-tumoral efficacy in advanced disease is concerned, exemestane is not totally cross-resistant with NSAIs like letrozole and anastrozole, thus yielding an additional therapeutic window of opportunity in any sequence. Moreover, they also display toxicity profiles that are not totally overlapping, useful for patients complaining of major side-effects. Importantly exemestane as its NSAI congeners may reverse tamoxifen side effects like undesirable endometrial changes and risks of thromboembolic disease. Optimal duration and scheduling still have to be explored in the adjuvant setting. In conclusion, exemestane can be considered a valuable addition to the current arsenal for the treatment at all stages of breast cancer.
Declaration of interest
The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the review reported.
Funding
This review did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.
References
Abram P, Baum M, Berstock D, Cawthorn S, Coibion M, Fennessy M, Houghton J, Kissin M, Lee D & Mac-Rae K et al. 1996 Preliminary results from the cancer research campaign trial evaluating tamoxifen duration in women aged fifty years or older with breast cancer. Journal of the National Cancer Institute 88 1834–1839. (doi:10.1093/jnci/88.24.1834).
Agrawal A, Ayantunde AA, Rampaul R & Robertson JF 2007 Male breast cancer: a review of clinical management. Breast Cancer Research and Treatment 103 11–21. (doi:10.1007/s10549-006-9356-z).
Ahlborg HG, Johnell O, Turner CH, Rannevik G & Karlsson MK 2003 Bone loss and bone size after menopause. New England Journal of Medicine 349 327–334. (doi:10.1056/NEJMoa022464).
Atalay G, Dirix L, Biganzoli L, Beex L, Nooij M, Cameron D, Lohrisch C, Cufer T, Lobelle JP & Mattiaci MR et al. 2004 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 exemestane or tamoxifen in postmenopausal patients’. Annals of Oncology 15 211–217. (doi:10.1093/annonc/mdh064).
Attar E & Bulun SE 2006 Aromatase and other steroidogenic genes in endometriosis: translational aspects. Human Reproduction Update 12 49–56. (doi:10.1093/humupd/dmi034).
Barnadas A, Gil M, González S, Tusquets I, Muñoz M, Arcusa A, Prieto L, Margelí-Vila M & Moreno A 2009 Exemestane as primary treatment of oestrogen receptor-positive breast cancer in postmenopausal women: a phase II trial. British Journal of Cancer 100 442–449. (doi:10.1038/sj.bjc.6604868).
Baselga J, Campone M, Piccart M, Burris HA, Rugo HS, Sahmoud T, Noguchi S, Gnant M, Pritchard KI & Lebrun F et al. 2012 Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer. New England Journal of Medicine 366 520–529. (doi:10.1056/NEJMoa1109653).
Baum M, Budzar AU, Cuzick J, Forbes J, Houghton JH, Klijn JG & Sahmoud T 2002 Anastrozole alone or in combination with tamoxifen versus tamoxifen alone for adjuvant treatment of postmenopausal women with early breast cancer: first results of the ATAC randomised trial. Lancet 359 2131–2139. (doi:10.1016/S0140-6736(02)09088-8).
Bedaiwy MA, Mousa NA & Casper RF 2009 Aromatase inhibitors: potential reproductive implications. Journal of Minimally Invasive Gynecology 16 533–539. (doi:10.1016/j.jmig.2009.05.009).
Beelen K, Zwart W & Linn SC 2012 Can predictive biomarkers in breast cancer guide adjuvant endocrine therapy? Nature Reviews. Clinical Oncology 9 529–541. (doi:10.1038/nrclinonc.2012.121).
Bertelli G & Paridaens R 2006 Optimal sequence of hormonotherapy in advanced breast cancer. Current Opinion in Oncology 18 572–577. (doi:10.1097/01.cco.0000245313.97638.1d).
Bertelli G, Garrone O, Merlano M, Occelli M, Bertolotti L, Castiglione F, Pepi F, Fusco O, Del Mastro L & Leonard RC 2005 Sequential treatment with exemestane and non-steroidal aromatase inhibitors in advanced breast cancer. Oncology 69 471–477. (doi:10.1159/000090985).
Bliss JM, Kilburn LS, Coleman RE, Forbes JF, Coates AS, Jones SE, Jassem J, Delozier T, Andersen J & Paridaens R et al. 2012 Disease-related outcomes with long-term follow-up: an updated analysis of the Intergroup Exemestane Study. Journal of Clinical Oncology 30 709–717. (doi:10.1200/JCO.2010.33.7899).
Boccardo F, Guglielmini P, Bordonaro R, Fini A, Massidda B, Porpiglia M, Roagna R, Serra P, Orzalesi L & Ucci G et al. 2013 Switching to anastrozole versus continued tamoxifen treatment of early breast cancer: long term results of the Italian Tamoxifen Anastrozole Trial. European Journal of Cancer 49 1546–1554. (doi:10.1016/j.ejca.2012.12.025).
Bonneterre J, Thürlimann B, Robertson JF, Krzakowski M, Mauriac L, Koralewski P, Vergote I, Webster A, Steinberg M & von Euler M 2000 Anastrozole versus tamoxifen as first-line therapy for advanced breast cancer in 668 postmenopausal women: results of the tamoxifen or arimidex randomized group efficacy and tolerability study. Journal of Clinical Oncology 18 3748–3757.
Bonomo M, Mingrone W, Brauchli P, Hering F & Goldhirsch A 2003 Exemestane seems to stimulate tumour growth in men with prostate carcinoma. European Journal of Cancer 39 2111–2112. (doi:10.1016/S0959-8049(03)00486-6).
Boulay A, Rudloff J, Ye J, Zumstein-Mecker S, Reilly TO, Evans DB, Chen S & Lane HA 2005 Dual inhibition of mTOR and estrogen receptor signaling in vitro induces cell death in models of breast cancer. Clinical Cancer Research 11 5319–5328. (doi:10.1158/1078-0432.CCR-04-2402).
Bulun SE, Imir G, Utsunomiya H, Thung S, Gurates B, Tamura M & Lin Z 2005 Aromatase in endometriosis and uterine leiomyomata. Journal of Steroid Biochemistry and Molecular Biology 95 57–62. (doi:10.1016/j.jsbmb.2005.04.012).
Bulun SE, Chen D, Moy I, Brooks DC & Zhao H 2012 Aromatase, breast cancer and obesity: a complex interaction. Trends in Endocrinology and Metabolism 23 83–89. (doi:10.1016/j.tem.2011.10.003).
Campos SM, Guastalla JP, Subar M, Abreu P, Winer EP & Cameron DA 2009 A comparative study of exemestane versus anastrozole in patients with postmenopausal breast cancer with visceral metastases. Clinical Breast Cancer 9 39–44. (doi:10.3816/CBC.2009.n.007).
Carlini P, Michelotti A, Ferretti G, Ricci S, Giannarelli D, Pellegrini M, Cresti N, Di Cosimo S, Bria E & Papaldo P et al. 2007 Clinical evaluation of the use of exemestane as further hormonal therapy after nonsteroidal aromatase inhibitors in postmenopausal metastatic breast cancer patients. Cancer Investigation 25 102–105. (doi:10.1080/07357900701224789).
Chia S, Gradishar W, Mauriac L, Bines J, Amant F, Federico M, Fein L, Romieu G, Buzdar A & Robertson JFR et al. 2008 Double-blind, randomized placebo controlled trial of fulvestrant compared with exemestane after prior nonsteroidal aromatase inhibitor therapy in postmenopausal women with hormone receptor-positive, advanced breast cancer: results from EFECT. Journal of Clinical Oncology 26 1664–1670. (doi:10.1200/JCO.2007.13.5822).
Chin YS, Beresford MJ, Ravichandran D & Makris A 2007 Exemestane after non-steroidal aromatase inhibitors for post-menopausal women with advanced breast cancer. Breast 16 436–439. (doi:10.1016/j.breast.2007.02.002).
Coleman RE, Banks LM, Girgis SI, Kilburn LS, Vrdoljak E, Fox J, Cawthorn SJ, Patel A, Snowdon CF & Hall E et al. 2007 Skeletal effects of exemestane on bone-mineral density, bone biomarkers, and fracture incidence in postmenopausal women with early breast cancer participating in the Intergroup Exemestane Study (IES): a randomised controlled study. Lancet Oncology 8 119–127. (doi:10.1016/S1470-2045(07)70003-7).
Coleman RE, Banks LM, Girgis SI, Vrdoljak E, Fox J, Cawthorn SJ, Patel A, Bliss JM, Coombes RC & Kilburn LS 2010 Reversal of skeletal effects of endocrine treatments in the Intergroup Exemestane Study. Breast Cancer Research and Treatment 124 153–161. (doi:10.1007/s10549-010-1121-7).
Colleoni M 2011 The SOLE trial: International Breast Cancer Study Group (IBCSG 35–07) and Breast International Group (BIG 1–07) study of letrozole extension. Cancer Research 71 (Suppl 3) OT2-02-01 doi:10.1158/0008-5472.SABCS11-OT2-02-01).
Colleoni M, Giobbie-Hurder A, Regan MM, Thürlimann B, Mouridsen H, Mauriac L, Forbes JF, Paridaens R, Láng I & Smith I et al. 2011 Analyses adjusting for selective crossover show improved overall survival with adjuvant letrozole compared with tamoxifen in the BIG 1–98 study. Journal of Clinical Oncology 29 1117–1124. (doi:10.1200/JCO.2010.31.6455).
Collins B, Mackenzie J, Stewart A, Bielajew C & Verma S 2009 Cognitive effects of hormonal therapy in early stage breast cancer patients: a prospective study. Psycho-oncology 18 811–821. (doi:10.1002/pon.1453).
Coombes RC, Hall E, Gibson LJ, Phil M, Paridaens RJ, Jassem J, Delozier T, Jones SE, Alvare I & Bertelli G et al. 2004 A randomized trial of exemestane after two to three years of tamoxifen therapy in postmenopausal women with primary breast cancer. New England Journal of Medicine 350 1081–1092. (doi:10.1056/NEJMoa040331).
Coombes RC, Kilburn LS, Snowdon CF, Paridaens R, Coleman RE, Jones SE, Jassem J, van de Velde CJ, Delozier T & Alvarez I et al. 2007 Survival and safety of exemestane versus tamoxifen after 2–3 years' tamoxifen treatment (Intergroup Exemestane Study): a randomised controlled trial. Lancet 369 559–570. (doi:10.1016/S0140-6736(07)60200-1).
Cope S, Ouwens MJ, Jansen JP & Schmid P 2013 Progression-free survival with fulvestrant 500 mg and alternative endocrine therapies as second-line treatment for advanced breast cancer: a network meta-analysis with parametric survival models. Value in Health 16 403–417. (doi:10.1016/j.jval.2012.10.019).
Crew KD, Greenlee H, Capodice J, Raptis G, Brafman L, Fuentes D, Sierra A & Hershman DL 2007 Prevalence of joint symptoms in postmenopausal women taking aromatase inhibitors for early-stage breast cancer. Journal of Clinical Oncology 25 3877–3883. (doi:10.1200/JCO.2007.10.7573).
Cuzick J, Forbes J, Edwards R, Baum M, Cawthorn S, Coates A, Hamed A, Howell A & Powles T 2002 First results from the International Breast Cancer Intervention Study (IBIS-i): a randomised prevention trial. Lancet 360 817–824. (doi:10.1016/S0140-6736(02)09962-2).
Davies C, Godwin J, Gray R, Clarke M, Cutter D, Darby S, McGale P, Pan HC, Taylor C & Wang YC et al. 2011 Relevance of breast cancer hormone receptors and other factors to the efficacy of adjuvant tamoxifen: patient-level meta-analysis of randomised trials. Lancet 378 771–784. (doi:10.1016/S0140-6736(11)60993-8).
Davies C, Pan H, Godwin J, Gray R, Arriagada R, Raina V, Abraham M, Alencar VH, Badran A & Bonfill X et al. 2013 Long-term effects of continuing adjuvant tamoxifen to 10 years versus stopping at 5 years after diagnosis of oestrogen receptor-positive breast cancer: ATLAS, a randomised trial. Lancet 381 805–816. (doi:10.1016/S0140-6736(12)61963-1).
DeCensi A, Dunn BK, Puntoni M, Gennari A & Ford LG 2012 Exemestane for breast cancer prevention: a critical shift? Cancer Discovery 2 25–40. (doi:10.1158/2159-8290.CD-11-0248).
De Vos FY, van Laarhoven HW, Laven JS, Themmen AP, Beex LV, Sweep CG, Seynaeve C & Jager A 2012 Menopausal status and adjuvant hormonal therapy for breast cancer patients: a practical guideline. Critical Reviews in Oncology/Hematology 84 252–260. (doi:10.1016/j.critrevonc.2012.06.005).
Dhillon S 2013 Everolimus in combination with exemestane: a review of its use in the treatment of patients with postmenopausal hormone receptor-positive, HER2-negative advanced breast cancer. Drugs 73 475–485. (doi:10.1007/s40265-013-0034-2).
Diorio C, Lemieux J, Provencher L, Hogue J-C & Vachon E 2012 Aromatase inhibitors in obese breast cancer patients are not associated with increased plasma estradiol levels. Breast Cancer Research and Treatment 136 573–579. (doi:10.1007/s10549-012-2278-z).
Dixon JM, Renshaw L, Young O, Murray J, Macaskill EJ, McHugh M, Folkerd E, Cameron DA, A'Hern RP & Dowsett M 2008 Letrozole suppresses plasma estradiol and estrone sulphate more completely than anastrozole in postmenopausal women with breast cancer. Journal of Clinical Oncology 26 1671–1676. (doi:10.1200/JCO.2007.13.9279).
Doyen J, Italiano A, Largillier R, Ferrero J-M, Fontana X & Thyss A 2010 Aromatase inhibition in male breast cancer patients: biological and clinical implications. Annals of Oncology 21 1243–1245. (doi:10.1093/annonc/mdp450).
Dubsky PC, Jakesz R, Mlineritsch B, Pöstlberger S, Samonigg H, Kwasny W, Tausch C, Stöger H, Haider K & Fitzal F et al. 2012 Tamoxifen and anastrozole as a sequencing strategy: a randomized controlled trial in postmenopausal patients with endocrine-responsive early breast cancer from the Austrian Breast and Colorectal Cancer Study Group. Journal of Clinical Oncology 30 722–728. (doi:10.1200/JCO.2011.36.8993).
Dunn BK, Cazzaniga M & Decensi A 2013 Exemestane: one part of the chemopreventive spectrum for ER-positive breast cancer. Breast 22 1–13. (doi:10.1016/j.breast.2013.02.015).
Dutta U & Pant K 2008 Aromatase inhibitors: past, present and future in breast cancer therapy. Medical Oncology 25 113–124. (doi:10.1007/s12032-007-9019-x).
Eastell R, Adams JE, Coleman RE, Howell A, Hannon RA, Cuzick J, Mackey JR, Beckmann MW & Clack G 2008 Effect of anastrozole on bone mineral density: 5-year results from the anastrozole, tamoxifen, alone or in combination trial 18233230. Journal of Clinical Oncology 26 1051–1057. (doi:10.1200/JCO.2007.11.0726).
Eastell R, Adams J, Clack G, Howell A, Cuzick J, Mackey J, Beckmann MW & Coleman RE 2011 Long-term effects of anastrozole on bone mineral density: 7-year results from the ATAC trial. Annals of Oncology 22 857–862. (doi:10.1093/annonc/mdq541).
Eggemann H, Ignatov A, Smith BJ, Altmann U, von Minckwitz G, Röhl FW, Jahn M & Costa S-D 2013 Adjuvant therapy with tamoxifen compared to aromatase inhibitors for 257 male breast cancer patients. Breast Cancer Research and Treatment 137 465–470. (doi:10.1007/s10549-012-2355-3).
Ellis MJ, Suman VJ, Hoog J, Lin L, Snider J, Prat A, Parker JS, Luo J, DeSchryver K & Allred DC et al. 2011 Randomized phase II neoadjuvant comparison between letrozole, anastrozole, and exemestane for postmenopausal women with estrogen receptor-rich stage 2 to 3 breast cancer: clinical and biomarker outcomes and predictive value of the baseline PAM50-based intrinsic subtype – ACOSOG Z1031. Journal of Clinical Oncology 29 2342–2349. (doi:10.1200/JCO.2010.31.6950).
Evans TRJ, Salle E, Di Ornati G, Lassus M, Benedetti MS, Pianezzola E & Coombes RC 1992 Phase I and endocrine study of exemestane (FCE 24304), a new aromatase inhibitor, in postmenopausal women. Cancer Research 52 5933–5939.
Ewer MS & Glück S 2009 A woman's heart: the impact of adjuvant endocrine therapy on cardiovascular health. Cancer 115 1813–1826. (doi:10.1002/cncr.24219).
Fallowfield LJ, Bliss JM, Porter LS, Price MH, Snowdon CF, Jones SE, Coombes RC & Hall E 2006 Quality of life in the Intergroup Exemestane Study: a randomized trial of exemestane versus continued tamoxifen after 2 to 3 years of tamoxifen in postmenopausal women with primary breast cancer. Journal of Clinical Oncology 24 910–917. (doi:10.1200/JCO.2005.03.3654).
Fedele P, Calvani N, Marino A, Orlando L, Schiavone P, Quaranta A & Cinieri S 2012 Targeted agents to reverse resistance to endocrine therapy in metastatic breast cancer: where are we now and where are we going? Critical Reviews in Oncology/Hematology 84 243–251. (doi:10.1016/j.critrevonc.2012.03.004).
Fentiman IS, Fourquet A & Hortobagyi GN 2006 Male breast cancer. Lancet 367 595–604. (doi:10.1016/S0140-6736(06)68226-3).
Fisher B, Costantino JP, Wickerham LD, Redmond CK, Kavanah M, Cronin WM, Vogel VG & Wickerham DL 1998 Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study. Journal of the National Cancer Institute 90 1371–1388. (doi:10.1093/jnci/90.18.1371).
Forbes JF, Cuzick J, Buzdar A, Howell A, Tobias JS & Baum M 2008 Effect of anastrozole and tamoxifen as adjuvant treatment for early-stage breast cancer: 100-month analysis of the ATAC trial. Lancet Oncology 9 45–53. (doi:10.1016/S1470-2045(07)70385-6).
Fornander T, Cedermark RN, Mattsson A, Skoog L, Glas U, Silfversw C, Somell A, Wilking N & Hjalmar M 1989 Adjuvant tamoxifen in early breast cancer: occurrence of new primary cancers. Lancet 1 117–119. (doi:10.1016/S0140-6736(89)91141-0).
Gaillard S & Stearns V 2011 Aromatase inhibitor-associated bone and musculoskeletal effects: new evidence defining etiology and strategies for management. Breast Cancer Research 13 1–11. (doi:10.1186/bcr2818).
Garcia-Casado Z, Guerrero-Zotano A, Llombart-Cussac A, Calatrava A, Fernandez-Serra A, Ruiz-Simon A, Gavila J, Climent MA, Almenar S & Cervera-Deval J et al. 2010 A polymorphism at the 3′-UTR region of the aromatase gene defines a subgroup of postmenopausal breast cancer patients with poor response to neoadjuvant letrozole. BMC Cancer 10 1–11. (doi:10.1186/1471-2407-10-36).
Gasbarri A, Pompili A, Arnone B, Cavicchio A, Patrono E, Amico D, Tavares MC & Tomaz C 2011 Sex steroid hormone estrogen and cognition. Neurobiologia 74 121–138.
Geisler J, King N, Anker G, Ornati G, Di Salle E, Lønning PE & Dowsett M 1998 In vivo inhibition of aromatization by exemestane, a novel irreversible aromatase inhibitor, in postmenopausal breast cancer patients. Clinical Cancer Research 4 2089–2093. (doi:10.1016/0959-8049(95)00623-0).
Geisler J, Haynes B, Anker G, Dowsett M & Lønning PE 2002 Influence of letrozole and anastrozole on total body aromatization and plasma estrogen levels in postmenopausal breast cancer patients evaluated in a randomized, cross-over study. Journal of Clinical Oncology 20 751–757. (doi:10.1200/JCO.20.3.751).
Gennatas C, Michalaki V, Carvounis E, Psychogios J, Poulakaki N, Katsiamis G, Voros D, Kouloulias V, Mouratidou D & Tsavaris N 2006 Third-line hormonal treatment with exemestane in postmenopausal patients with advanced breast cancer progressing on letrozole or anastrozole. A phase II trial conducted by the Hellenic Group of Oncology (HELGO). Tumori 92 13–17.
Giordano SH & Hortobagyi GN 2006 Leuprolide acetate plus aromatase inhibition for male breast cancer. Journal of Clinical Oncology 24 e42–e43. (doi:10.1200/JCO.2006.07.2397).
Glück S 2009 Exemestane as first-line therapy in postmenopausal women with recurrent or metastatic breast cancer. American Journal of Clinical Oncology 33 314–319. (doi:10.1097/COC.0b013e31819fdf9b).
Glück S, von Minckwitz G & Untch M 2013 Aromatase inhibitors in the treatment of elderly women with metastatic breast cancer. Breast 22 142–149. (doi:10.1016/j.breast.2012.12.015).
Gnant MFX, Mlineritsch B, Luschin-Ebengreuth G, Grampp S, Kaessmann H, Schmid M, Menzel C, Piswanger-Soelkner JC, Galid A & Mittlboeck M et al. 2007 Zoledronic acid prevents cancer treatment-induced bone loss in premenopausal women receiving adjuvant endocrine therapy for hormone-responsive breast cancer: a report from the Austrian Breast and Colorectal cancer Study Group. Journal of Clinical Oncology 25 820–828. (doi:10.1200/JCO.2005.02.7102).
Gnant M, Mlineritsch B, Schippinger W, Luschin-Ebengreuth G, Pöstlberger S, Menzel C, Jakesz R, Seifert M, Hubalek M & Bjelic-Radisic V et al. 2009 Endocrine therapy plus zoledronic acid in premenopausal breast cancer. New England Journal of Medicine 360 679–691. (doi:10.1056/NEJMoa0806285).
Gnant M, Mlineritsch B, Stoeger H, Luschin-Ebengreuth G, Heck D, Menzel C, Jakesz R, Seifert M, Hubalek M & Pristauz G et al. 2011 Adjuvant endocrine therapy plus zoledronic acid in premenopausal women with early-stage breast cancer: 62-month follow-up from the ABCSG-12 randomised trial. Lancet Oncology 12 631–641. (doi:10.1016/S1470-2045(11)70122-X).
Gonnelli S, Cadirni A, Caffarelli C, Petrioli R, Montagnani A, Franci MB, Lucani B, Francini G & Nuti R 2007 Changes in bone turnover and in bone mass in women with breast cancer switched from tamoxifen to exemestane. Bone 40 205–210. (doi:10.1016/j.bone.2006.06.027).
Goodwin PJ & Pritchard KI 2010 Obesity and hormone therapy in breast cancer: an unfinished puzzle. Journal of Clinical Oncology 28 3405–3407. (doi:10.1200/JCO.2010.29.5113).
Gorodeski GI 2002 Update on cardiovascular disease in post-menopausal women. Best Practice & Research. Clinical Obstetrics & Gynaecology 16 329–355. (doi:10.1053/beog.2002.0282).
Goss PE, Ingle JN, Martino S, Robert NJ, Muss HB, Piccart MJ, Castiglione M, Tu D, Shepherd LE & Pritchard KI et al. 2005 Randomized trial of letrozole following tamoxifen as extended adjuvant therapy in receptor-positive breast cancer: updated findings from NCIC CTG MA.17. Journal of the National Cancer Institute 97 1262–1271. (doi:10.1093/jnci/dji250).
Goss PE, Ingle JN, Alés-Martinez JE, Cheung AM, Chlebowski RT, Wactawski-Wende J, Mctiernan A, Robbins J, Johnson KC & Martin LW et al. 2011 Exemestane for breast-cancer prevention in postmenopausal women. New England Journal of Medicine 364 2381–2391. (doi:10.1056/NEJMoa1103507).
Goss PE, Ingle JN, Pritchard KI, Ellis MJ, Sledge GW, Budd GT, Rabaglio M, Ansari RH, Johnson DB & Tozer R et al. 2013 Exemestane versus anastrozole in postmenopausal women with early breast cancer: NCIC CTG MA.27 – a randomized controlled phase III trial. Journal of Clinical Oncology 31 1398–1404. (doi:10.1200/JCO.2012.44.7805).
Gray R, Rea D, Handley K, Bowden SJ, Perry P, Earl HM, Poole CJ, Bates T, Chetiyawardana S & Dewar JA et al. 2013 aTTom: long-term effects of continuing adjuvant tamoxifen to 10 years versus stopping at 5 in 6,953 women with early breast cancer. Journal of Clinical Oncology 31 Abstr 5. (doi:10.1200/JCO.2012.47.5301).
Hadji P, Body J-J, Aapro MS, Brufsky A, Coleman RE, Guise T, Lipton A & Tubiana-Hulin M 2008 Practical guidance for the management of aromatase inhibitor-associated bone loss. Annals of Oncology 19 1407–1416. (doi:10.1093/annonc/mdn164).
Hatse S, Lambrechts D, Verstuyf A, Smeets A, Brouwers B, Vandorpe T, Brouckaert O, Peuteman G, Laenen A & Verlinden L et al. 2012 Vitamin D status at breast cancer diagnosis: correlation with tumor characteristics, disease outcome, and genetic determinants of vitamin D insufficiency. Carcinogenesis 33 1319–1326. (doi:10.1093/carcin/bgs187).
Haynes BP, Straume AH, Geisler J, A'Hern R, Helle H, Smith IE, Lønning PE & Dowsett M 2010 Intratumoral estrogen disposition in breast cancer. Clinical Cancer Research 16 1790–1801. (doi:10.1158/1078-0432.CCR-09-2481).
Henry NL, Giles JT, Ang D, Mohan M, Dadabhoy D, Robarge J, Hayden J, Lemler S, Shahverdi K & Powers P et al. 2008 Prospective characterization of musculoskeletal symptoms in early stage breast cancer patients treated with aromatase inhibitors. Breast Cancer Research and Treatment 111 365–372. (doi:10.1007/s10549-007-9774-6).
Henry NL, Jacobson JA, Banerjee M, Hayden J, Smerage JB, Van Poznak C, Storniolo AM, Stearns V & Hayes DF 2010 A prospective study of aromatase inhibitor-associated musculoskeletal symptoms and abnormalities on serial high-resolution wrist ultrasonography. Cancer 116 4360–4367. (doi:10.1002/cncr.25385).
Hojo T, Kinoshita T, Imoto S, Shimizu C, Isaka H, Ito H, Imi K, Wada N, Ando M & Fujiwara Y 2013 Use of the neo-adjuvant exemestane in post-menopausal estrogen receptor-positive breast cancer: a randomized phase II trial (PTEX46) to investigate the optimal duration of preoperative endocrine therapy. Breast 22 263–267. (doi:10.1016/j.breast.2013.03.002).
Howell PA, Cuzick J, Baum M, Buzdar A, Anderson M, Dowsett M, Forbes JD, Hoctin-Boes G, Houghton J & Locker GY et al. 2005 Results of the ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial after completion of 5 years' adjuvant treatment for breast cancer. Lancet 365 60–62. (doi:10.1016/S0140-6736(05)74803-0).
Iaffaioli RV, Formato R, Tortoriello A, Del Prete S, Caraglia M, Pappagallo G, Pisano A, Gebbia V, Fanelli F & Ianniello G et al. 2005 Phase II study of sequential hormonal therapy with anastrozole/exemestane in advanced and metastatic breast cancer. British Journal of Cancer 92 1621–1625. (doi:10.1038/sj.bjc.6602579).
Jakesz R, Jonat W, Gnant M, Mittlboeck M, Greil R, Tausch C, Hilfrich J, Kwasny W, Menzel C & Samonigg H et al. 2005 Switching of postmenopausal women with endocrine-responsive early breast cancer to anastrozole after 2 years' adjuvant tamoxifen: combined results of ABCSG trial 8 and ARNO 95 trial. Lancet 366 455–462. (doi:10.1016/S0140-6736(05)67059-6).
Jemal A, Bray F, Center MM, Ferlay J, Ward E & Forman D 2011 Global cancer statistics. CA: A Cancer Journal for Clinicians 61 69–90. (doi:10.3322/caac.20107).
Jenkins V, Shilling V, Fallowfield L, Howell A & Hutton S 2004 Does hormone therapy for the treatment of breast cancer have a detrimental effect on memory and cognition? A pilot study. Psycho-oncology 13 61–66. (doi:10.1002/pon.709).
Jenkins VA, Ambroisine LM, Atkins L, Cuzick J, Howell A & Fallowfield LJ 2008 Effects of anastrozole on cognitive performance in postmenopausal women: a randomised, double-blind chemoprevention trial (IBIS II). Lancet Oncology 9 953–961. (doi:10.1016/S1470-2045(08)70207-9).
Johannessen DC, Engan T, Di Salle E, Zurlo MG, Paolini J, Ornati G, Piscitelli G, Kvinnsland S & Lonning PE 1997 Endocrine and clinical effects of exemestane (PNU 155971), a novel steroidal aromatase inhibitor, in postmenopausal breast cancer patients: a phase I study. Clinical Cancer Research 3 1101–1108.
Jones SE, Cantrell J, Vukelja S, Pippen J, O'Shaughnessy J, Blum JL, Brooks R, Hartung NL, Negron AG & Richards DA et al. 2007 Comparison of menopausal symptoms during the first year of adjuvant therapy with either exemestane or tamoxifen in early breast cancer: report of a tamoxifen exemestane adjuvant multicenter trial substudy. Journal of Clinical Oncology 25 4765–4771. (doi:10.1200/JCO.2007.10.8274).
Kaufmann M, Bajetta E, Dirix LY, Fein LE, Jones SE, Zilembo N, Dugardyn J, Nasurdi C, Mennel RG & Cervek J et al. 2000 Exemestane is superior to megestrol acetate after tamoxifen failure in postmenopausal women with advanced breast cancer: results of a phase III randomized double-blind trial. Journal of Clinical Oncology 18 1399–1411.
Kaufmann M, Jonat W, Hilfrich J, Eidtmann H, Gademann G, Zuna I & von Minckwitz G 2007 Improved overall survival in postmenopausal women with early breast cancer after anastrozole initiated after treatment with tamoxifen compared with continued tamoxifen: the ARNO 95 study. Journal of Clinical Oncology 25 2664–2670. (doi:10.1200/JCO.2006.08.8054).
Keen JC & Davidson NE 2003 The biology of breast carcinoma. Cancer 97 825–833. (doi:10.1002/cncr.11126).
Khan QJ, Reddy PS, Kimler BF, Sharma P, Baxa SE, O'Dea AP, Klemp JR & Fabian CJ 2010 Effect of vitamin D supplementation on serum 25-hydroxy vitamin D levels, joint pain, and fatigue in women starting adjuvant letrozole treatment for breast cancer. Breast Cancer Research and Treatment 119 111–118. (doi:10.1007/s10549-009-0495-x).
Kim SH, Park IH, Lee H, Lee KS, Nam B-H & Ro J 2012 Efficacy of exemestane after nonsteroidal aromatase inhibitor use in metastatic breast cancer patients. Asian Pacific Journal of Cancer Prevention 13 979–983. (doi:10.7314/APJCP.2012.13.3.979).
Kittaneh M & Glück S 2011 Exemestane in the adjuvant treatment of breast cancer in postmenopausal women. Breast Cancer: Basic and Clinical Research 5 209–226. (doi:10.4137/BCBCR.S6234).
Lea OA, Kvinnsland S, Thorsen T & Stener K 1989 Improved measurement of androgen receptors in human breast cancer. Cancer Research 49 7162–7167.
Lintermans A & Neven P 2011 Pharmacology of arthralgia with estrogen deprivation. Steroids 76 781–785. (doi:10.1016/j.steroids.2011.02.034).
Lintermans A, Van Calster B, Van Hoydonck M, Pans S, Verhaeghe J, Westhovens R, Henry NL, Wildiers H, Paridaens R & Dieudonné AS et al. 2011 Aromatase inhibitor-induced loss of grip strength is body mass index dependent: hypothesis-generating findings for its pathogenesis. Annals of Oncology 22 1763–1769. (doi:10.1093/annonc/mdq699).
Lintermans A, Laenen A, Van Calster B, Van Hoydonck M, Pans S, Verhaeghe J, Westhovens R, Henry NL, Wildiers H & Paridaens R et al. 2013 Prospective study to assess fluid accumulation and tenosynovial changes in the aromatase inhibitor-induced musculoskeletal syndrome: 2-year follow-up data. Annals of Oncology 24 350–355. (doi:10.1093/annonc/mds290).
Litton JK, Bevers TB & Arun BK 2012 Exemestane in the prevention setting. Therapeutic Advances in Medical Oncology 4 107–112. (doi:10.1177/1758834012438214).
Llombart-Cussac A, Ruiz A, Antón A, Barnadas A, Antolín S, Alés-Martínez JE, Alvarez I, Andrés R, García Saenz JA & Lao J et al. 2012 Exemestane versus anastrozole as front-line endocrine therapy in postmenopausal patients with hormone receptor-positive, advanced breast cancer: final results from the Spanish Breast Cancer Group 2001–03 Phase 2 Randomized Trial. Cancer 118 241–247. (doi:10.1002/cncr.26299).
Lombardi P 2002 Exemestane, a new steroidal aromatase inhibitor of clinical relevance. Biochimica et Biophysica Acta 1587 326–337. (doi:10.1016/S0925-4439(02)00096-0).
Lønning PE 2004 Aromatase inhibitors in breast cancer. Endocrine-Related Cancer 11 179–189. (doi:10.1677/erc.0.0110179).
Lønning PE 2009 Lack of complete cross-resistance between different aromatase inhibitors; a real finding in search for an explanation? European Journal of Cancer 45 527–535. (doi:10.1016/j.ejca.2008.10.019).
Lønning PE & Eikesdal HP 2013 Aromatase inhibition 2013: clinical state of the art and questions that remain to be solved. Endocrine-Related Cancer 20 R183–R201. (doi:10.1530/ERC-13-0099).
Lønning PE & Geisler J 2010 Evaluation of plasma and tissue estrogen suppression with third-generation aromatase inhibitors: of relevance to clinical understanding? Journal of Steroid Biochemistry and Molecular Biology 118 288–293. (doi:10.1016/j.jsbmb.2009.09.013).
Lønning PE, Bajetta E, Murray R, Tubiana-Hulin M, Eisenberg PD, Mickiewicz E, Celio L, Pitt P, Mita M & Aaronson NK et al. 2000 Activity of exemestane in metastatic breast cancer after failure of nonsteroidal aromatase inhibitors: a phase II trial. Journal of Clinical Oncology 18 2234–2244.
Lønning PE, Geisler J, Krag LE, Erikstein B, Bremnes Y, Hagen AI, Schlichting E, Lien EA, Ofjord ES & Paolini J et al. 2005 Effects of exemestane administered for 2 years versus placebo on bone mineral density, bone biomarkers, and plasma lipids in patients with surgically resected early breast cancer. Journal of Clinical Oncology 23 5126–5137. (doi:10.1200/JCO.2005.07.097).
Lønning PE, Haynes BP, Straume AH, Dunbier A, Helle H, Knappskog S & Dowsett M 2011 Exploring breast cancer estrogen disposition: the basis for endocrine manipulation. Clinical Cancer Research 17 4948–4958. (doi:10.1158/1078-0432.CCR-11-0043).
Lu J, Steeg PS, Price JE, Krishnamurthy S, Mani SA, Reuben J, Cristofanilli M, Dontu G, Bidaut L & Valero V et al. 2009 Breast cancer metastasis: challenges and opportunities. Cancer Research 69 4951–4953. (doi:10.1158/0008-5472.CAN-09-0099).
Macedo LF, Guo Z, Tilghman SL, Sabnis GJ, Qiu Y & Brodie A 2006 Role of androgens on MCF-7 breast cancer cell growth and on the inhibitory effect of letrozole. Cancer Research 66 7775–7782. (doi:10.1158/0008-5472.CAN-05-3984).
Mamounas EP, Jeong J-H, Wickerham DL, Smith RE, Ganz PA, Land SR, Eisen A, Fehrenbacher L, Farrar WB & Atkins JN et al. 2008 Benefit from exemestane as extended adjuvant therapy after 5 years of adjuvant tamoxifen: intention-to-treat analysis of the national surgical Adjuvant Breast and Bowel Project B-33 trial. Journal of Clinical Oncology 26 1965–1971. (doi:10.1200/JCO.2007.14.0228).
Mao J, Stricker C, Bruner D, Xie S, Bowman M, Farrar J, Greene B & DeMichele A 2009 Patterns and risk factors associated with aromatase inhibitor related arthralgia among breast cancer survivors. Cancer 115 3631–3639. (doi:10.1002/cncr.24419).
Markopoulos C, Polychronis A, Zobolas V, Xepapadakis G, Papadiamantis J, Koukouras D, Lappas H & Gogas H 2005 The effect of exemestane on the lipidemic profile of postmenopausal early breast cancer patients: preliminary results of the team Greek sub-study. Breast Cancer Research and Treatment 93 61–66. (doi:10.1007/s10549-005-3783-0).
Markopoulos C, Dafni U, Misitzis J, Zobolas V, Tzoracoleftherakis E, Koukouras D, Xepapadakis G, Papadiamantis J, Venizelos B & Antonopoulou Z et al. 2009a Extended adjuvant hormonal therapy with exemestane has no detrimental effect on the lipid profile of postmenopausal breast cancer patients: final results of the ATENA lipid substudy. Breast Cancer Research 11 1–9. (doi:10.1186/bcr2320).
Markopoulos C, Polychronis A, Dafni U, Koukouras D, Zobolas V, Tzorakoleftherakis E, Xepapadakis G & Gogas H 2009b Lipid changes in breast cancer patients on exemestane treatment: final results of the TEAM Greek substudy. Annals of Oncology 20 49–55. (doi:10.1093/annonc/mdn545).
Mauri D, Pavlidis N, Polyzos NP & Ioannidis JPA 2006 Survival with aromatase inhibitors and inactivators versus standard hormonal therapy in advanced breast cancer: meta-analysis. Journal of the National Cancer Institute 98 1285–1291. (doi:10.1093/jnci/djj357).
Mauriac L, Romieu G & Bines J 2009 Activity of fulvestrant versus exemestane in advanced breast cancer patients with or without visceral metastases: data from the EFECT trial. Breast Cancer Research and Treatment 117 69–75. (doi:10.1007/s10549-008-0141-z).
Mayordomo J, Llombart A, Martin M, Antón A, Barnadas A, Antolin S, Alés-Martinez J & Alvarez I 2006 Randomized, multicenter, crossover phase II trial to compare exemestane (E) vs. anastrozole (A) in postmenopausal patients (pt) with advanced breast cancer (ABC) and positive hormone receptors (HR). Final efficacy analysis of GEICAM 2001–03 study. Journal of Clinical Oncology 24 (Suppl 18S) 638.
Meier CR & Jick H 1998 Tamoxifen and risk of idiopathic venous thromboembolism. British Journal of Clinical Pharmacology 45 608–612. (doi:10.1046/j.1365-2125.1998.00733.x).
Mieog JS, Morden JP, Bliss JM, Coombes RC & van de Velde CJ 2012 Carpal tunnel syndrome and musculoskeletal symptoms in postmenopausal women with early breast cancer treated with exemestane or tamoxifen after 2–3 years of tamoxifen: a retrospective analysis of the Intergroup Exemestane Study. Lancet Oncology 13 420–432. (doi:10.1016/S1470-2045(11)70328-X).
Miller WR, Bartlett J, Brodie AM, Brueggemeier RW, di Salle E, Lønning PE, Llombart A, Maass N, Maudelonde T & Sasano H et al. 2008 Aromatase inhibitors: are there differences between steroidal and nonsteroidal aromatase inhibitors and do they matter? Oncologist 13 829–837. (doi:10.1634/theoncologist.2008-0055).
Morales L, Timmerman D, Neven P, Konstantinovic ML, Carbonez A, Van Huffel S, Ameye L, Weltens C, Christiaens MR & Vergote I et al. 2005 Third generation aromatase inhibitors may prevent endometrial growth and reverse tamoxifen-induced uterine changes in postmenopausal breast cancer patients. Annals of Oncology 16 70–74. (doi:10.1093/annonc/mdi021).
Morales L, Pans S, Paridaens R, Westhovens R, Timmerman D, Verhaeghe J, Wildiers H, Leunen K, Amant F & Berteloot P et al. 2007 Debilitating musculoskeletal pain and stiffness with letrozole and exemestane: associated tenosynovial changes on magnetic resonance imaging. Breast Cancer Research and Treatment 104 87–91. (doi:10.1007/s10549-006-9394-6).
Mortimer JE 2010 Managing the toxicities of the aromatase inhibitors. Current Opinion in Obstetrics & Gynecology 22 56–60. (doi:10.1097/GCO.0b013e328334e44e).
Mouridsen H, Gershanovich M, Sun Y, Perez-Carrion R, Boni C, Monnier A, Apffelstaedt J, Smith R, Sleeboom HP & Jaenicke F et al. 2003 Phase III study of letrozole versus tamoxifen as first-line therapy of advanced breast cancer in postmenopausal women: analysis of survival and update of efficacy from the international letrozole breast cancer group. Journal of Clinical Oncology 21 2101–2109. (doi:10.1200/JCO.2003.04.194).
Mousa NA, Bedaiwy MA & Casper RF 2007 Aromatase inhibitors in the treatment of severe endometriosis. Obstetrics and Gynecology 109 1421–1423. (doi:10.1097/01.AOG.0000265807.19397.6d).
Nabholtz J-M 2008 Long-term safety of aromatase inhibitors in the treatment of breast cancer. Therapeutics and Clinical Risk Management 4 189–204. (doi:10.2147/TCRM.S1566).
Nabholtz J-M, Buzdar A, Pollak M, Harwin W, Burton G, Mangalik A, Steinberg M, Webster A & von Euler M 2000 Anastrozole is superior to tamoxifen as first-line therapy for advanced breast cancer in postmenopausal women: results of a North American multicenter randomized trial. Journal of Clinical Oncology 18 3758–3767.
Nadji M, Gomez-Fernandez C, Ganjei-Azar P & Morales AR 2005 Immunohistochemistry of estrogen and progesterone receptors reconsidered. American Journal of Clinical Pathology 123 21–27. (doi:10.1309/4WV79N2GHJ3X1841).
Neven P, De Muylder X, Van Belle Y, Vanderick G & De Muylder E 1989 Tamoxifen and the uterus and endometrium. Lancet 1 375. (doi:10.1016/S0140-6736(89)91741-8).
Nordman IC, Spillane AJ & Hamilton AL 2005 The aromatase inhibitors in early breast cancer: who, when, and why? Medical Journal of Australia 183 24–27.
Ortmann O, Cufer T, Dixon JM, Maass N, Marchetti P, Pagani O, Pronzato P, Semiglazov V, Spano J-P & Vrdoljak E et al. 2009 Adjuvant endocrine therapy for perimenopausal women with early breast cancer. Breast 18 2–7. (doi:10.1016/j.breast.2008.10.002).
Paganini-Hill A & Clark LJ 2000 Preliminary assessment of cognitive function in breast cancer patients treated with tamoxifen. Breast Cancer Research and Treatment 64 165–176. (doi:10.1023/A:1006426132338).
Paridaens R, Thomas J, Wildiers J, Vermeiren P, Lobelle JP, di Salle E, Ornati G, Zurlo MG, Polli A & Lanzalone S et al. 1998 Safety, activity and estrogen inhibition by exemestane in postmenopausal women with advanced breast cancer: a phase I study. Anti-Cancer Drugs 9 675–683. (doi:10.1097/00001813-199809000-00002).
Paridaens RJ, Dirix LY, Beex LV, Nooij M, Cameron DA, Cufer T, Piccart MJ, Bogaerts J & Therasse P 2008 Phase III study comparing exemestane with tamoxifen as first-line hormonal treatment of metastatic breast cancer in postmenopausal women: the European Organisation for Research and Treatment of Cancer Breast Cancer Cooperative Group. Journal of Clinical Oncology 26 4883–4890. (doi:10.1200/JCO.2007.14.4659).
Paridaens RJ, Gelber S, Cole BF, Gelber RD, Thürlimann B, Price KN, Holmberg SB, Crivellari D, Coates AS & Goldhirsch A 2010 Adjuvant! online estimation of chemotherapy effectiveness when added to ovarian function suppression plus tamoxifen for premenopausal women with estrogen-receptor-positive breast cancer. Breast Cancer Research and Treatment 123 303–310. (doi:10.1007/s10549-010-0794-2).
Pauwels S, Antonio L, Jans I, Lintermans A, Neven P, Claessens F, Decallonne B, Billen J, Vanderschueren D & Vermeersch P 2013 Sensitive routine liquid chromatography–tandem mass spectrometry method for serum estradiol and estrone without derivatization. Analytical and Bioanalytical Chemistry 405 8569–8577. (doi:10.1007/s00216-013-7259-5).
Pavone ME & Bulun SE 2012 Aromatase inhibitors for the treatment of endometriosis. Fertility and Sterility 98 1370–1379. (doi:10.1016/j.fertnstert.2012.08.053).
Perez EA, Josse RG, Pritchard KI, Ingle JN, Martino S, Findlay BP, Shenkier TN, Tozer RG, Palmer MJ & Shepherd LE et al. 2006 Effect of letrozole versus placebo on bone mineral density in women with primary breast cancer completing 5 or more years of adjuvant tamoxifen: a companion study to NCIC CTG MA.17. Journal of Clinical Oncology 24 3629–3635. (doi:10.1200/JCO.2005.05.4882).
Peterson ME 2013 Management of adverse events in patients with hormone receptor-positive breast cancer treated with everolimus: observations from a phase III clinical trial. Supportive Care in Cancer 21 2341–2349. (doi:10.1007/s00520-013-1826-3).
Phillips KA, Ribi K & Fisher R 2011a Do aromatase inhibitors have adverse effects on cognitive function? Breast Cancer Research 13 1–7. (doi:10.1186/bcr2806).
Phillips KA, Aldridge J, Ribi K, Sun Z, Thompson A, Harvey V, Thürlimann B, Cardoso F, Pagani O & Coates AS et al. 2011b Cognitive function in postmenopausal breast cancer patients one year after completing adjuvant endocrine therapy with letrozole and/or tamoxifen in the BIG 1–98 trial. Breast Cancer Research and Treatment 126 221–226. (doi:10.1007/s10549-010-1235-y).
Polyzos NP, Tzioras S, Badawy AM, Valachis A, Dritsas C & Mauri D 2009 Aromatase inhibitors for female infertility: a systematic review of the literature. Reproductive Biomedicine Online 19 456–471. (doi:10.1016/j.rbmo.2009.06.008).
Presant CA, Bosserman L, Young T, Vakil M, Horns R, Upadhyaya G, Ebrahimi B, Yeon C & Howard F 2007 Aromatase inhibitor-associated arthralgia and/or bone pain: frequency and characterization in non-clinical trial patients. Clinical Breast Cancer 7 775–778. (doi:10.3816/CBC.2007.n.038).
Rao BR & Cobleigh MA 2012 Adjuvant endocrine therapy for breast cancer. Oncology 26 1–12.
Rastelli AL, Taylor ME, Gao F, Armamento-Villareal R, Jamalabadi-Majidi S, Napoli N & Ellis MJ 2011 Vitamin D and aromatase inhibitor-induced musculoskeletal symptoms (AIMSS): a phase II, double-blind, placebo-controlled, randomized trial. Breast Cancer Research and Treatment 129 107–116. (doi:10.1007/s10549-011-1644-6).
Rayson D, Erlichman C, Suman VJ, Roche PC, Wold LE, Ingle JN & Donohue JH 1998 Molecular markers in male breast carcinoma. Cancer 83 1947–1955. (doi:10.1002/(SICI)1097-0142(19981101)83:9<1947::AID-CNCR10>3.0.CO;2-J).
Reed MJ, Owen AM, Lai LC, Coldham NG, Ghilchik MW, Shaikh NA & James VH 1989 In situ oestrone synthesis in normal breast and breast tumour tissues: effect of treatment with 4-hydroxyandrostenedione. International Journal of Cancer 44 233–237. (doi:10.1002/ijc.2910440208).
Regan MM, Price KN, Giobbie-Hurder A, Thürlimann B & Gelber RD 2011 Interpreting breast international group (BIG) 1–98: a randomized, double-blind, phase III trial comparing letrozole and tamoxifen as adjuvant endocrine therapy for postmenopausal women with hormone receptor-positive, early breast cancer. Breast Cancer Research 13 209. (doi:10.1186/bcr2837).
Riemsma R, Forbes CA, Kessels A, Lykopoulos K, Amonkar MM, Rea DW & Kleijnen J 2010 Systematic review of aromatase inhibitors in the first-line treatment for hormone sensitive advanced or metastatic breast cancer. Breast Cancer Research and Treatment 123 9–24. (doi:10.1007/s10549-010-0974-0).
Rutqvist LE & Johansson H 2007 Long-term follow-up of the randomized Stockholm trial on adjuvant tamoxifen among postmenopausal patients with early stage breast cancer. Acta Oncologica 46 133–145. (doi:10.1080/02841860601034834).
Schilder CM, Seynaeve C, Beex LV, Boogerd W, Linn SC, Gundy CM, Huizenga HM, Nortier JW, van de Velde CJ & van Dam FS et al. 2010 Effects of tamoxifen and exemestane on cognitive functioning of postmenopausal patients with breast cancer: results from the neuropsychological side study of the tamoxifen and exemestane adjuvant multinational trial. Journal of Clinical Oncology 28 1294–1300. (doi:10.1200/JCO.2008.21.3553).
Shanafelt TD, Barton DL, Adjei AA & Loprinzi CL 2002 Pathophysiology and treatment of hot flashes. Mayo Clinic Proceedings 77 1207–1218. (doi:10.4065/77.11.1207).
Sherwin BB 2012 Estrogen and cognitive functioning in women: lessons we have learned. Behavioral Neuroscience 126 123–127. (doi:10.1037/a0025539).
Simpson E 2003 Sources of estrogen and their importance. Journal of Steroid Biochemistry and Molecular Biology 86 225–230. (doi:10.1016/S0960-0760(03)00360-1).
Smith IE & Dowsett M 2003 Aromatase inhibitors in breast cancer. New England Journal of Medicine 348 2431–2442. (doi:10.1056/NEJMra023246).
Smith IE, Dowsett M, Yap Y-S, Walsh G, Lønning PE, Santen RJ & Hayes D 2006 Adjuvant aromatase inhibitors for early breast cancer after chemotherapy-induced amenorrhoea: caution and suggested guidelines. Journal of Clinical Oncology 24 2444–2447. (doi:10.1200/JCO.2005.05.3694).
Steele N, Zekri J, Coleman R, Leonard R, Dunn K, Bowman A, Manifold I, Kunkler I, Purohit O & Cameron D 2006 Exemestane in metastatic breast cancer: effective therapy after third-generation non-steroidal aromatase inhibitor failure. Breast 15 430–436. (doi:10.1016/j.breast.2005.08.032).
Sukumvanich P, Case LD, Van Zee K, Singletary SE, Paskett ED, Petrek JA, Naftalis E & Naughton MJ 2010 Incidence and time course of bleeding after long-term amenorrhea after breast cancer treatment: a prospective study. Cancer 116 3102–3111. (doi:10.1002/cncr.25106).
Suzuki T, Miki Y, Moriya T, Akahira J, Ishida T, Hirakawa H, Yamaguchi Y, Hayashi S & Sasano H 2007 5α-Reductase type 1 and aromatase in breast carcinoma as regulators of in situ androgen production. International Journal of Cancer 120 285–291. (doi:10.1002/ijc.22317).
Swedish Breast Cancer Cooperative Group Randomized trial of two versus five years of adjuvant tamoxifen for postmenopausal early stage breast cancer Journal of the National Cancer Institute 88 1996 1543–1549. (doi:10.1093/jnci/88.21.1543).
Thomas R, Williams M, Marshall C & Walker L 2008 Switching to letrozole or exemestane improves hot flushes, mood and quality of life in tamoxifen intolerant women. British Journal of Cancer 98 1494–1499. (doi:10.1038/sj.bjc.6604323).
Thürlimann B, Paridaens R, Serin D, Bonneterre J, Rochc H, Murray R, Salle E, Lanzalone S, Zurlo MG & Piscitelli G 1997 Third-line hormonal treatment with exemestane in postmenopausal patients with advanced breast cancer progressing on aminoglutethimide: a phase II multicentre multinational study. European Journal of Cancer 33 1767–1773. (doi:10.1016/S0959-8049(97)00283-9).
Thürlimann B, Keshavia A, Coates AS, Mouridsen H, Mauriac L, Forbes JF, Paridaens R, Vastiglione-Gertsch M, Gelber RD & Rabaglio M et al. 2005 A comparison of letrozole and tamoxifen in postmenopausal women with early breast cancer. New England Journal of Medicine 353 2747–2757. (doi:10.1056/NEJMoa052258).
van de Velde CJ, Verma S, van Nes JG, Masterman C & Pritchard KI 2010 Switching from tamoxifen to aromatase inhibitors for adjuvant endocrine therapy in postmenopausal patients with early breast cancer. Cancer Treatment Reviews 36 54–62. (doi:10.1016/j.ctrv.2009.10.003).
van de Velde CJ, Rea D, Seynaeve C, Putter H, Hasenburg A, Vannetzel J-M, Paridaens R, Markopoulos C, Hozumi Y & Hille ETM et al. 2011 Adjuvant tamoxifen and exemestane in early breast cancer (TEAM): a randomised phase 3 trial. Lancet 377 321–331. (doi:10.1016/S0140-6736(10)62312-4).
Vermeulen A, Deslypere JP & Paridaens R 1986 Steroid dynamics carcinomatous in the normal and mammary gland. Journal of Steroid Biochemistry 25 799–802. (doi:10.1016/0022-4731(86)90311-0).
Walker G, Xenophontos M, Chen L & Cheung K 2013 Long-term efficacy and safety of exemestane in the treatment of breast cancer. Patient Preference and Adherence 7 245–258. (doi:10.2147/PPA.S42223).
Wang L, Ellsworth KA, Moon I, Pelleymounter LL, Eckloff BW, Martin YN, Fridley BL, Jenkins GD, Batzler A & Suman VJ et al. 2010 Functional genetic polymorphisms in the aromatase gene CYP19 vary the response of breast cancer patients to neoadjuvant therapy with aromatase inhibitors. Cancer Research 70 319–328. (doi:10.1158/0008-5472.CAN-09-3224).
Waters EA, Cronin KA,