Aromatase inhibitors in breast cancer: review and possible benefits in premenopausal women

Inhibítory aromatázy v liečbe karcinómu prsníka: prehľad a možné prínosy u žien pred menopauzou

Nová generácia inhibítorov aromatázy predstavuje v súčasnosti prvú voľbu v endokrinnej liečbe pokročilého karcinómu prsníka u postmenopauzálnych pacientiek. Tieto farmaká sú rovnako účinné aj v adjuvantnej a neoadjuvantnej liečbe, výsledky niekoľkých prebiehajúcich štúdií môžu poukázať na ich úlohu v chemoprevencii rakoviny prsníka. Okrem toho sú potrebné dlhodobejšie štúdie, ktoré by dôsledne objasnili nežiaduce účinky inhibítorov aromatázy na ľudský organizmus. Účinnosť a bezpečnosť samostatne aplikovaných inhibítorov aromatázy u premenopauzálnych pacientiek s rakovinou prsníka je neznáma, v tejto oblasti bude potrebný ďalší výskum. Kombinované podávanie agonistov hormónu uvoľňujúceho luteinizačný hormón s inhibítormi aromatázy rozširuje využitie endokrinnej liečby rakoviny prsníka u premenopauzálnych žien či už s metastatickou alebo včasnou formou ochorenia. Výsledky našich štúdií chemoprevencie mamárnej karcinogenézy u samíc potkanov poukázali na potenciálnu výhodnosť aplikácie inhibítorov aromatázy – anastrozolu a letrozolu u premenopauzálnych žien postihnutých rakovinou prsníka.

Kľúčové slová:
inhibítory aromatázy – rakovina prsníka – premenopauzálne ženy – agonisti hormónu uvoľňujúceho luteinizačný hormón

Authors: P. Kubatkaihash2 ^{1,2 1,2}; K. Kajo ³; N. Stollárová ²; B. Bojková ⁴; M. Kassayová ⁴; P. Orendáš ⁴
Authors place of work: Department of Medical Biology, Jessenius Faculty of Medicine, Comenius University, Martin, Slovak Republic ¹; Department of Biology and Ecology, Faculty of Education, Catholic University, Ružomberok, Slovak Republic ²; Department of Pathology, Slovak Medical University and St. Elisabeth Oncology Institute, Bratislava, and BB Biocyt, Diagnostic Centre, Ltd., Banská Bystrica, Slovak Republic ³; Department of Animal Physiology, Institute of Biological and Ecological Sciences, Science Faculty, P. J. Šafárik University, Košice, Slovak Republic ⁴
Published in the journal: Prakt Gyn 2011; 15(3-4): 174-180
Category: Přehledová práce

Summary

The new generation of aromatase inhibitors has become the first choice of endocrine treatment of advanced breast cancer in postmenopausal patients. These compounds are also very effective as adjuvant and neoadjuvant treatment; results of several ongoing trials might elucidate their role in chemoprevention of breast cancer. Further studies with longer follow-up are required to provide a thorough evaluation of their safety profile. The effectiveness and safety of aromatase inhibitors as monotherapy in premenopausal breast cancer patients is unknown; this is an area for future research. Combined use of luteinising hormone releasing hormone agonists and aromatase inhibitors extends the use of endocrine therapy in premenopausal women with a metastatic or an early stage breast cancer. Our results of chemoprevention of mammary carcinogenesis in female rats have indicated potentially favourable effects of aromatase inhibitors – anastrozole and letrozole – in premenopausal women affected by breast cancer.

Key words:
aromatase inhibitors – breast cancer – premenopausal women – luteinising hormone releasing hormone agonists

Introduction

Most breast cancers occurring in women older than 50 years are oestrogen- and/or progesterone-receptor positive [1]. In these patients, oestrogens and their metabolites have been implicated in both, the initiation and progression of the disease [2]. The aim of endocrine therapy is to prevent breast cancer cells from endogenous oestrogen stimulation and thus to prevent hormone-positive cells from proliferation and spreading. More than a century ago, oophorectomy was the first therapy to be shown to cause regression of advanced breast cancer [3] and, at present, oestrogen deprivation remains an important therapeutic approach. In the early 1970s, selective oestrogen receptor modulator tamoxifen was introduced in clinical practice. Tamoxifen inhibits the breast cancer growth by competitive antagonism of oestrogen at its receptor site. Tamoxifen became the „gold standard” of adjuvant endocrine therapy in postmenopausal women with oestrogen receptor-positive breast cancer. Moreover, tamoxifen was approved for chemoprevention of breast cancer in high-risk women [4]. However, tamoxifen also exhibits partial oestrogen-agonist effects. This is associated with beneficial influence on the organism, such as a prevention of bone demineralization in postmenopausal women, as well as with some detrimental properties, such as elevated risk of uterine carcinogenesis or thromboembolism [5].

The enzyme aromatase catalyzesthe last step of oestrogen synthesis and is primarily found in adipose tissue, muscle and skin, as well as in breast tissue. Aromatase inhibitors (AIs) are effective suppressors of aromatase enzyme activity that decrease circulating levels of oestrogens in postmenopausal women to nearly undetectable levels. Therefore, AIs are primarily used in the treatment of hormone-sensitive breast cancer in postmenopausal women. AIs are now the first choice endocrine therapyin postmenopausal women with metastatic breast cancer. These endocrine agents become a standard adjuvant therapy for postmenopausal patients with hormone-responsive breast cancer, either alone or in sequence with tamoxifen. Some trials showed that AIs reduced the incidence of contralateral breast cancer [6,7]. In direct comparisons with tamoxifen in adjuvant therapy, AIs have a better toxicity profile with fewer patients stopping therapy because of drug-related adverse effects. These data have prompted breast cancer chemoprevention trials with AIs. Results of ongoing trials using exemestane and anastrozole may elucidate the role for AIs in the prevention of breast cancer. Research on the use of AIs in premenopausal women with a hormone receptor-sensitive disease, is only starting to emerge. For these women, combination strategies with gonadotropin agonists and AIs are being investigated [8].

In the present paper, the current clinical status of AIs in breast cancer treatment will be reviewed. We will discuss advantages and disadvantages of AIs administration in postmenopausal and premenopausal population. Finally, future research directions will be outlined.

Aromatase inhibitors in the treatment of breast cancer

The third-generation AIs (anastrozole, letrozole, exemestane) have become the first-choice endocrine drugs for postmenopausal breast cancer women. The drugs are associated with superior activity and better general tolerability when compared with tamoxifen in both metastatic and adjuvant settings. A number of clinical trials have evaluated the efficacy and safety of these agents in metastatic, adjuvant, neoadjuvant or prevention settings.

Riemsma et al [9] systematically reviewed the first-line treatments (letrozole, anastrozole and exemestane) of postmenopausal women with hormone-sensitive advanced or metastatic breast cancer. They included randomised controlled clinical trials assessing the safety and efficacy of first-line AIs in postmenopausal women with hormone receptor-positive and with or without ErbB2 (HER2)-positive metastatic breast cancer who have not received prior therapy for advanced or metastatic disease. The available evidence enabled a comparison of the three AIs with tamoxifen. In addition, by using a network meta-analysis, it was possible to compare the three AIs with each other. Based on the direct evidence, letrozole seemed to be significantly better than tamoxifen in terms of time-to-progression, objective response rate and quality-adjusted time without symptoms or toxicity. Exemestane seemed significantly superior to tamoxifen in terms of objective response rate. Anastrozole seemed significantly superior to tamoxifen in terms of time-to-progression in one trial, but not in the other. In terms of adverse events, no significant differences were found between letrozole and tamoxifen. Tamoxifen was associated with significantly more serious adverse events in comparison with exemestane, while exemestane was associated with significantly more arthralgia in comparison to tamoxifen. Anastrozole was associated with significantly more total adverse events and hot flushes in comparison to tamoxifen in one trial; however, the other trial showed no significant differences in adverse events between anastrozole and tamoxifen. The indirect comparison of AIs in women with post-menopausal, hormone-sensitive advanced or MBC (Metastatic Breast Cancer) showed that letrozole and exemestane were better in terms of objective response rate than anastrozole; while the more clinically relevant outcomes including overall survival and progression-free survival showed no significant differences between AIs. Even though these are the best data available, the results need to be interpreted with caution. AIs are also recommended as the second-line therapy in postmenopausal women with recurrent invasive breast cancer who have received anti-oestrogen treatment within the past 12 months [10]. Several studies have evaluated sequential hormone therapy and found small but consistent response of aromatese inhibitors in advanced breast cancer [11,12]. AIs have a different toxicity profile than other endocrine therapies in postmenopausal women with advanced breast cancer. Similar proportions of patients had hot flushes and arthralgia, an increased risks of rash, nausea, diarrhoea and vomiting but the risk of vaginal bleeding was reduced by 71% and thromboembolic events by 47% compared to other endocrine therapies [13].

Clinical trials with AIs in adjuvant treatment are designed as comparisons with tamoxifen in postmenopausal women with breast cancer. The Arimidex, Tamoxifen Alone or in Combination (ATAC) trial was the first to show that anastrozole was more effective than tamoxifen as initial adjuvant therapy for early-stage breast cancer [14]. BIG 1-98 is a randomized Phase III trial that compared tamoxifen and letrozole monotherapy and sequences of both with letrozole monotherapy. Sequential therapy was not superior to letrozole monotherapy. However, lack of statistical significance does not imply that patients should be switched to tamoxifen after 2 years of treatment with the AI [15]. The findings of the Intergroup Exemestane Study (IES) challenge the standard adjuvant endocrine therapy consisting of 5 years of tamoxifen therapy in women with estrogen receptor-positive breast cancer. The IES study confirmed that switching postmenopausal women to exemestane after 2–3 years of tamoxifen therapy relative to 5 years of tamoxifen alone resulted in improved survival [16]. Two German and Austrian Cooperative groups reported results of The Austrian Breast Cancer Study Group (ABCSG-8) and Arimidex-Nolvadex (ARNO-95) studies. Trials were similar in design, and both were conducted to determine whether switching postmenopausal women with oestrogen receptor-positive early breast cancer to anastrozole after 2 years of tamoxifen administration was more effective than continuing tamoxifen for the remaining 3 years of adjuvant therapy. Women whose therapy was switched had an improved overall survival compared to tamoxifen alone [17]. Five-year therapy with tamoxifen, followed with a second adjuvant therapy with letrozole was investigated in the MA-17 study of the National Cancer Institute of the Canada’s Clinical Trial Group. Results suggested that letrozole treatment should also be considered for all disease-free women for periods up to 5 years following completion of adjuvant tamoxifen [18]. AIs were well tolerated in all the above mentioned studies in adjuvant setting. In adition, patients who received AIs experienced fewer thrombolic events and had lower incidence of endometrial cancer, hot flashes, night sweats and vaginal bleeding compared to patients who received tamoxifen. However, patients who received tamoxifen had fewer skeletal events compared to women who received AIs.

Neoadjuvant endocrine therapy in hormone receptor positive postmenopausal women is an alternative in patients with larger tumours when chemotherapy is not feasible due to medical contraindications or a surgery is delayed for a variety of reasons. The Immediate Preoperative Anastrozole, Tamoxifen, or Combined with Tamoxifen (IMPACT) trial involved 330 postmenopausal women with oestrogen receptor–positive, invasive and operable breast cancer. Preoperative treatment with anastrozole, tamoxifen or both lasted 3 months. There was a significantly greater proportion of patients undergoing breast-conserving surgery in the anastrozole group in comparison to those on tamoxifen [19]. The efficacy of treatment with anastrozole versus tamoxifen as neoadjuvant therapy lasting 12 weeks was evaluated in 451 postmenopausal women with hormone receptor-positive breast cancer involved in the phase III Preoperative Arimidex Compared with Tamoxifen (PROACT) trial. In a subset of patients who received hormonal therapy only, 43% of those treated with anastrozole received breast-conserving surgery compared to 31% of those treated with tamoxifen [20]. Anastrozole appears to be at least as effective as tamoxifen in this setting, and more effective than tamoxifen in certain clinically relevant subgroups. Treatments in both trials were well tolerated. The P024trial, led by Eiermann et al. [21], compared 4 months of neoadjuvant letrozole with tamoxifen therapy in postmenopausal women with untreated, hormone receptor-positive primary breast cancer in the neoadjuvant setting. All 337 women had large breast tumours that either required mastectomy or were deemed to be inoperable. Letrozole produced a significantly higher clinical response rate than tamoxifen. The clinical response rate was measured primarily by palpation or ultrasonography and mammography. Furthermore, significantly more women in the letrozole group were able to undergo breast-conserving surgery than in the tamoxifen group (45% vs. 35%).

Adjuvant studies with AIs, which demonstrated a greater reduction in contralateral breast cancers than tamoxifen without increased incidence in thromboembolic events or uterine cancer, have led to an initiation of primary prevention trials in high-risk postmenopausal women without prior breast cancer. There are some ongoing prevention studies with AIs [22]. The IBIS-2 randomised phase III trial compares anastrozole versus placebo over 5 years in 6,000 women at high risk. A further 4,000 women, who have been previously treated for DCIS, are randomised to receive tamoxifen or anastrozole. In addition to the incidence of breast cancer as the primary endpoint, this trial is also investigating disease-specific mortality along withbone mineral density and other end-organ functions. Following the Intergroup Exemestane Study, incorporating data on the use of coxibs (cyclooxygenase-2 selective inhibitors) in the prevention, the National Cancer Institute of Canada Clinical Trials Group MAP.3 Breast Cancer Prevention Trial was launched. Women were randomized to exemestane with or without celecoxib versus placebo. Consequent to the recent publication of data on increased cardiac death associated with coxibs, the celecoxib arm has closed. Aromasin Prevention Study evaluates exemestane in postmenopausal women with known BRCA1/2 gene mutations compared to placebo over 3 years.

Premenopausal versus postmenopausal administration of aromatase inhibitors

AIs have revolutionized treatment of postmenopausal women with hormone receptor-positive breast cancer. On the other hand, the role of AI therapy in premenopausal breast cancer women has not been established. However, approximately 22% of all cases of breast cancer in North America are diagnosed in women below the age of 50 and a substantial proportion of these women are premenopausal. For that reason, research on the use of AIs in premenopausal population with oestrogen receptor–positive breast cancer is required.

Aromatase-catalyzed aromatization in peripheral tissues serves as the main source of oestrogen in postmenopausal women. Consequently, AIs are very effective in the treatment of postmenopausal breast cancer. Aromatase-catalyzed conversion of androstendione and testosterone to oestrogen in the ovaries under a pulsative influence of hormones of the hypothalamus is the main source of oestrogen in premenopausal women. Peripheral aromatization contributes approximately 20% of oestradiol to premenopausal serum oestradiol levels. In premenopausal women, monotherapy with AIs leads to highly variable effects on oestradiol and significant increase in plasma testosterone and androstendione levels; this is probably partly due to reflex rise in gonadotropins [23]. The relative resistance of a premenopausal ovary to AI blockade results from the dual effect of high androstendione tissue concentrations as an ovarian substrate and reflex rises in LH and FSH, occurring as a consequence of reduced oestradiol levels [2]. Consequently, LH stimulates a production of androstendione and FSH induces increased levels of aromatase. These conditions allow continuous oestradiol synthesis by the ovaries.

AIs in postmenopausal women would also lower the tissue oestradiol levels. No reflex effects on negative feedback would be observed. The plasma oestradiol levels also fall, as has been shown in women treated with AIs. However, consequences such as potential acceleration of osteoporosis, urogenital atrophy and vasomotor instability would be expected in these women. These issues have not been addressed specifically for women with advanced breast cancer with relatively short duration of AIs treatment. Similarly, AIs may represent a logical alternative to tamoxifen in adjuvant treatment of postmenopausal women in whom endometrial cancer risk, thromboembolism and urogenital dysfunction are the most pronounced [24].

Luteinising hormone releasing hormone agonists and aromatase inhibitors

In premenopausal women, luteinising hormone releasing hormone agonists (LH-RHa) induce ovarian suppression that is usually reversible on cessation of therapy. Their binding to pituitary LH-RH receptors results in downregulation of the receptors and subsequent suppression of luteinising hormone and oestrogens. The role of LH-RHa in premenopausal women is still under investigation. Combination of LHRHa with AIs seems to be very promising in reducing plasma levels of oestrogens. In a study with premenopausal women with advanced breast cancer, ovarian suppression induced by goserelin combined with an AI reduced circulating oestrogen levels by an additional 76% compared to ovarian suppression combined with tamoxifen [25]. In a recent study, a combination of ovarian function suppression using goserelin and AIs produced sustained clinical benefit and minimal side effects in premenopausal women with advanced breast cancer with significant reduction in oestradiol levels [26]. A phase II parallel group study demonstrated comparable efficacy between premenopausal metastatic breast cancer women treated with letrozole plus goserelin and postmenopausal women treated with letrozole alone [27].

Also available is direct comparison of efficacy of goserelin combined with tamoxifen and goserelin combined with anastrozole (with or without zoledronic acid) administered in the adjuvant setting in premenopausal women with oestrogen receptor-positive breast cancer [28]. At a median follow-up of 3.9 years, there was no significant difference in the disease-free survival between groups. However, a higher rate of distant metastases was observed in the anastrozole group. The small number of events and short follow-up in this study did not allow precise determination of potential benefits or risks for patients. Rossi et al [29] assessed the effect of adjuvant treatment with triptorelin plus letrozole or triptorelin plus tamoxifen in premenopausal women with early breast cancer. The combination of LH-RHawith an AI induced a significant reduction of median serum oestradiol compared to LH-RHa plus tamoxifen. Median FSH was suppressed in both groups but significantly lower suppression was observed in the group with an AI.

The data from the International Breast Cancer Study Group suggested that the treatment with LH-RHa might not be useful in inducing complete suppression of ovarian function in a small group of premenopausal women. In these women, concomitant treatment with an AI can stimulate the residual ovarian function and lead to a short-lasting increase in plasma oestrogen levels [30]. The results from large phase III studies comparing LH-RHa plus tamoxifen or AI are being awaited. Based on the available data, the combination of LH-RHa and an AI should be avoided in routine clinical practice.

The optimal duration of LH-RHa administration has not been determined yet. In clinical practice, the usual duration of treatment with LH-RHa in premenopausal patients receiving AIs is 5 years, while it may range from 2 to 5 years in women receiving tamoxifen [31].

Aromatase inhibitors in the premenopausal breast cancer model

Preclinical research indicates that usefulness of AIs in premenopausal breast cancer depends on the primary source of breast tissue oestradiol levels. If local aromatization is crucial, AIs would block this in situ oestradiol biosynthesis. Several experimental methods have been used to determine the biological importance of in situ oestrogen production by breast tissue. Using immunohistochemical techniques, high focal levels of aromatase in breast tumours were found, supporting the concept that aromatase might act in an autocrine or paracrine fashion in breast tissue [32,33]. Other data also supported the biological importance of aromatase in breast cancer tissue [34]. In another experiment, administration of the aromatase substrate androstendione stimulated growth of aromatase-positive MCF-7 cells implanted in ovariectomized nude mice but did not causegrowth stimulation in aromatase-negative MCF-7 cells [35]. The same authors designed an additional experiment where the relative importance of in situ production versus uptake of plasma estradiol was found using silastic implants that produced plasma oestradiol in castrated rats [35]. These results led to the hypothesis that an important determinant of tissue oestradiol levels (and consequently oestradiol-induced carcinogenesis) is its local production in the mammary gland. This fact may explain the poor correlation between plasma oestrogen levels and breast cancer development [36]. Based on this hypothesis, the concentration of oestradiol in breast tissue itself would be a more precise predictor of later breast cancer development. This hypothesis, while not proven, is attractive since it suggests that AIs can lower breast tissue oestradiol levels without causing a reduction in plasma oestradiol levels. This would protect a premenopausal patient treated with AIs from developing osteoporosis, urogenital atrophy and vasomotor instability while still reducing the incidence of breast cancer.

The above described concept provides a rationale for the use of AIs in the treatment and prevention of breast cancer in women with functional ovaries. The design of our recent experiments evaluating antineoplastic effects of dietary administered AIs in chemoprevention of N-methyl-N-nitrosourea-induced premenopausal mammary carcinogenesis in female rats was based on this concept. The animals received AIs for about 15 weeks after they were administered a carcinogen. In our first experiment, anastrozole used in premenopausal breast cancer animal model demonstrated a significant antineoplastic effect [37]. Moreover, anastrozole did not cause any changes in serum concentrations of oestradiol or other steroids compared to untreated animals. Therefore, since anastrozole treatment led in rats to a suppression of mammary gland carcinogenesis and did not affect plasma levels of oestradiol, the results of our study clearly confirm the hypothesis of the crucial role of in situ oestradiol biosynthesis in breast tissue. In our similarly designed experiment, a remarkable tumour-suppressive effect of letrozole was detected [38]. In this experiment, an atrophy of the genital system in rats observed after letrozole treatment was dose-dependent. Contrary to the antineoplastic effects of anastrozole and letrozole, the results of our study with steroidal AI exemestane demonstrated its significant tumour-promoting activity in rat mammary carcinogenesis [39]. It is postulated that the effects of exemestane and its metabolite 17-hydroexemestane, with the chemical structure related to the natural oestrogen precursor androstenedione, may be a result of their androgenic action through the androgen receptor [40]. This may have implications for several end organ effects of exemestane, including its mitotic activity on rat mammary gland observed in our study. The remarkable difference in the effects of exemestane observed in postmenopausal women with breast cancer and female rats in our experiment are probably caused by species-dependent dissimilarities in the structure of gene regulation areas (promotors) of responsible genes. The results of our evaluation of the effects of anastrozole, letrozole and exemestane in a premenopausal breast cancer model are summarised in tab. 1 [37–39].

**Tab. 1. Effects of anastrozole, letrozole and exemestane in the premenopausal breast cancer model in female rats [36–38].**

Conclusions

AIs have been proven to provide the most effective endocrine therapy in metastatic, adjuvant and neoadjuvant setting for postmenopausal women with breast cancer. Questions remain about longterm side-effects and safety profile of AIs. Results of ongoing studies might elucidate the role of AIs in the prevention of breast cancer. The effectiveness and safety of therapy with AIs alone or in combination with LH-RHa in premenopausal patients with breast cancer is unknown; this is an area for future research. Our model of premenopausal breast cancer in female rats demonstrated a significant antineoplastic effect of anastrozole and letrozole and these results provided a rationale for the use of non-steroidal AIs in breast cancer research in premenopausal women.

Doručeno do redakce: 12. 5. 2011

Přijato po recenzi: 12. 7. 2011

Peter Kubatka, Assoc. Prof., RNDr., PhD.

Department of Medical Biology,

Jessenius Faculty of Medicine,

Comenius University, Martin,

Slovak Republic

kubatka@jfmed.uniba.sk

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