Adjuvant trials of aromatase inhibitors: determining the future landscape of adjuvant endocrine therapy

This review will discuss the role of aromatase inhibitors (AIs) in the adjuvant setting, and will summarize major strategies behind individual adjuvant trials using aromatase inhibitors. Studies with the third generation AIs including anastrozole, letrozole and exemestane, have shown better outcome and improved therapeutic ratio over second line hormonal approaches (i.e. progestins or aminoglutethimide) and, more recently, over tamoxifen also. These promising results have led recently to testing of AIs in the adjuvant setting for postmenopausal patients. Most trials now in progress are evaluating the role of new AIs versus tamoxifen (T) given×5 years, which in most institutions is currently the standard hormonal adjuvant therapy for breast cancer. Three adjuvant approaches are being tested. First is the use of AI+T×5 years in combination versus each agent alone, as reflected in the recently completed ATAC trial. Second is a sequential approach T first×2–3 years followed by AIs×2–3 years, or the other way round; and third, T×5 years followed by AIs for additional 5 years (i.e. total duration of adjuvant hormones of 10 years). Many patients in the above trials will survive their first cancer. Hence, the non-oncological outcomes known to be affected by hormones are of rising importance. Therefore, the assessment of lipids as surrogates for cardiovascular morbidity, and of bone mineral status, as a marker for osteoporosis/bone fractures, is an important component of these trials. Also discussed in this review are proposals for future studies of AIs with focus on hormone resistance, such as early alteration of multiple hormonal agents or their intermittent use, the impact of the new generation of SERMs or ‘pure’ antiestrogens on activity of AIs, and the rising importance of AIs interacting with biologicals, cytokines or hormone modulators.     

Future uses for aromatase inhibitors in breast cancer

Over recent years highly potent, well-tolerated aromatase inhibitors have been developed, which essentially obliterate peripheral aromatase activity in postmenopausal women. Their role as the optimal second-line agents (post-tamoxifen) for the treatment of advanced breast cancer has recently been established in large comparative clinical trials. Their testing as adjuvant therapy is warranted, but their eventual application in this (or the prophylactic) setting will be dependent on the currently unknown effects of profound oestrogen deprivation on the physiology of postmenopausal women as well as on its efficacy. It is also possible that these new compounds could suppress oestrogen synthesis in premenopausal women, but the consequences on ovarian folliculogenesis might prevent their widespread use in this group of patients.     

Aromatase inhibitors for therapy of advanced breast cancer

In postmenopausal women with advanced breast cancer, numerous phase III trials have been performed comparing the third-generation non-steroidal aromatase inhibitors (NS-AIs) anastrozole and letrozole and the steroidal AI (S-AI) exemestane in the “first-line” setting against tamoxifen and in the “second-line” setting against megestrol acetate. In both settings, the AIs were at least as efficacious or superior in some endpoints with a preferable toxicity profile including a lower incidence of thrombotic events. Relatively small differences in potency between the three AIs have been identified and it has not been demonstrated that these differences have clinical implications. The recent establishment of the value of AIs in the adjuvant setting for postmenopausal women will impact on their utilization in advanced disease. In premenopausal women the third-generation AIs have not been studied as monotherapy and there is a paucity of data in combination with ovarian function suppression in the advanced disease setting. The main area of future investigations for the AIs in premenopausal women will be in the adjuvant therapy setting in combination with suppression of ovarian function.     

Recent advances in the clinical application of aromatase inhibitors

Aromatase inhibitors have evolved over a period of 20 years to well tolerated agents that can effectively obliterate aromatase activity in postmenopausal women. Breast cancer is the predominant clinical application and here the newer agents have established themselves as the preferred second-line agent after tamoxifen in the treatment of advanced disease. Recent data indicate that they be more efficacious than tamoxifen and, therefore, may replace it as the first-line agent of choice in the near future. On-going clinical trials in the adjuvant setting and prospective prevention studies will elucidate whether these drugs have a yet greater role in breast cancer.     

Aromatase inhibitors versus tamoxifen for management of postmenopausal breast cancer in the advanced disease and neoadjuvant settings

The third-generation aromatase inhibitors anastrozole, exemestane and letrozole have become firmly established as the agents of choice in patients with tamoxifen-resistant tumors. Large, well-conducted, double-blind clinical trials directly comparing the non-steroidal aromatase inhibitors anastrozole and letrozole with tamoxifen in the advanced disease setting have matured. Based on these trials, there is sufficient evidence to choose one of these agents over tamoxifen because of a superior time to disease progression and acceptable toxicity which includes a lower incidence of thromboembolic complications. Information for the steroidal aromatase inhibitor exemestane will be forthcoming from a phase III trial which has completed accrual. Consistent with the findings in the advanced disease setting, a double-blind trial comparing letrozole with tamoxifen in the neoadjuvant setting revealed superiority for letrozole in terms of clinical response rate. This provides a strong impetus for further study of the aromatase inhibitors in the preoperative setting.     

Impact of aromatase inhibitors on bone health in breast cancer patients

Following the implementation of the third generation aromatase inhibitors in the treatment algorithms for early breast cancer, special attention has been given to the influence of these drugs on bone health. Due to their potent estrogen suppression, the aromatase inhibitors anastrozole and letrozole, as well as the aromatase inactivator exemestane, enhance bone loss in postmenopausal women reflected in decreasing levels of bone mineral density. Moreover, all major phase III trials involving aromatase inhibitors in the adjuvant setting have reported increased fracture rates. All in all, there is no hard evidence to suggest major differences between the individual compounds concerning their side-effects on bone. The consequences of AI therapy on bone are in addition modified by a variety of factors like the BMD level prior to therapy, time since menopause, and vitamin D status. Strategies to avoid bone loss during AI therapy have shown promising results. Thus, bisphosphonates have been shown to prohibit bone loss during AI therapy if used upfront. Novel treatment strategies, like antibodies against RANKL have been developed and promising preliminary results have been published from early trials. Standardized guidelines to avoid or minimize bone loss during AI therapy have been developed, in most countries involving calcium and vitamin D supplementation, as well as BMD measurements to identify patient subgroups demanding bisphosphonate therapy.     

A summary of second-line randomized studies of aromatase inhibitors

The new generation of selective aromatase inhibitors (anastrozole, letrozole and exemestane) offer a significant efficacy and safety advantage over both older agents in this class (aminoglutethimide) and the progestins (megestrol acetate (MA)), as second-line treatment for postmenopausal women with advanced hormone-dependent breast cancer who have failed on tamoxifen therapy. Exemestane, a steroidal aromatase inhibitor, has been shown to have activity after failure with the non-steroidal aromatase inhibitors, anastrozole and letrozole, and could be used as third-line treatment. Although the newer aromatase inhibitors belong to the same class and appear, from indirect comparisons, to have similar efficacy compared with the older therapies, they have different pharmacokinetic and pharmacodynamic profiles, suggesting the potential for clinical differences. Compared with exemestane and letrozole, anastrozole shows greater selectivity for aromatase, as it lacks any evidence of an effect on adrenal steroidogenesis and has no androgenic effects. Therefore, it is clear that these agents should not be considered to be similar in all respects. In summary, the introduction of the aromatase inhibitors represents a significant step forward in the treatment of advanced breast cancer in postmenopausal women. Studies in the adjuvant setting will ultimately determine whether the differences in pharmacokinetics and phamacodynamics will be of clinical relevance.     

Inhibition of aromatase: insights from recent studies

Aromatase is the rate limiting enzyme that catalyzes the conversion of androgens to estrogens. Blockade of this step allows treatment of diseases that are dependent upon estrogen. Over the past two decades, highly potent and specific aromatase inhibitors have been developed which block total body aromatization by over 99%. An important recent question is whether aromatase inhibitors are superior to the antiestrogens for treatment of hormone-dependent breast cancer. The third generation aromatase inhibitors have been compared to tamoxifen for the treatment of breast cancer in the advanced, adjuvant, and neoadjuvant settings. All of these studies suggest the superiority of aromatase inhibitors over tamoxifen. The mechanism responsible for the superiority of the aromatase inhibitors relates to the estrogen agonistic effects of tamoxifen. During exposure to estrogen deprived conditions and to tamoxifen, breast cancer cells adapt and upregulate the MAP kinase and PI-3 kinase pathways. These growth factor signaling pathways potentiate the estrogen agonistic properties of tamoxifen. Data from a large adjuvant therapy trial (ATAC trial) provide evidence that the aromatase inhibitors may also be superior for breast cancer prevention. The mechanism for superiority in this setting probably relates to the genotoxic effects of estradiol metabolites. The aromatase inhibitors may be also useful for the treatment of endometriosis and for ovulation induction as evidenced by preliminary data. The recent advances in development of the aromatase inhibitors clearly demonstrate the utility of these agents for treatment of breast cancer and potentially for other indications.     

Managing Bone Health in Breast Cancer

ObjectiveOsteoporosis is a common condition that can be caused or exacerbated by estrogen deficiency.MethodsThis narrative review will discuss optimizing bone health in the setting of adjuvant endocrine treatments for hormone receptor–positive breast cancer and the current use of antiresorptive agents as adjuvant therapy and as bone modifying agents.ResultsAdjuvant endocrine treatments for hormone receptor–positive breast cancer (tamoxifen and aromatase inhibitors) affect bone health. The exact effect depends on the agent used and the menopausal state of the woman. Antiresorptive medications for osteoporosis, bisphosphonates and denosumab, lower the risk of bone loss from aromatase inhibitors. Use of bisphosphonates as adjuvant treatment in breast cancer, regardless of hormone receptor status, is increasing because of benefits seen to cancer relapse and survival.ConclusionOptimizing bone health in women with breast cancer during and after cancer treatment is informed by an understanding of breast cancer treatment and its skeletal effect.     

Where do selective estrogen receptor modulators (SERMs) and aromatase inhibitors (AIs) now fit into breast cancer treatment algorithms?

The agents used for endocrine therapy in patients with breast cancer have changed markedly over the past decade. Tamoxifen remains the anti-oestrogen of choice, but could be replaced by the oestrogen receptor down-regulator ICI 182780 or by the fixed ring triphenylethylene arzoxifene (previously SERM III) soon. Whilst aminoglutethimide and 4-OH androstenedione were the aromatase inhibitors of choice, they have been replaced by non-steroidal (anastrozole and letrozole) and steroidal (exemestane) inhibitors of high potency and low side effect profile. Previously, often used treatments such as progestogens (megestrol acetate and medroxyprogesterone acetate) and androgens are now rarely used or confined to fourth or fifth line treatments. The LHRH agonist, goserelin, remains the treatment of choice for pre-menopausal patients with advanced breast cancer although recent randomised trials indicate a response, time to progression and survival advantage for the combination of goserelin and tamoxifen compared with goserelin alone.

The newer treatments have led to questions concerning the optimum sequence of agents to use in advanced breast cancer and as neo-adjuvant and adjuvant therapy in relation to surgery. Two trials of anastrozole compared with tamoxifen and one trial of letrozole compared with tamoxifen indicate that the new triazole aromatase inhibitors have a significant advantage over the anti-oestrogen with respect to time to progression and survival. Similarly, triazole aromatase inhibitors give faster and more complete responses compared with tamoxifen when used in post-menopausal women before surgery.

Major research questions remain with respect to the aromatase inhibitors used as adjuvant therapy. Anastrozole is being tested alone or in combination with tamoxifen compared with tamoxifen in the ‘so-called’ ATAC trial. Over 9000 patients have been randomised to this important study: the results will be available late-2001. A similar study comparing letrozole and tamoxifen started recently under the auspices of the Breast International Group. Importantly, this trial is also comparing the sequence of tamoxifen followed by letrozole (or vice versa). A similar trial of exemestane given after 2–3 years of tamoxifen compared with 5 years of tamoxifen is recruiting well as is a study comparing letrozole (or placebo) for 5 years after 5 years of adjuvant tamoxifen. These studies may show that aromatase inhibitors are superior to tamoxifen or that a sequence is preferable.

ICI 182780 causes complete oestrogen receptor down-regulation leading to a the lack of agonist activity of the drug. Two trials of ICI 182780 compared with anastrozole for advanced disease will report later this year and a comparison with tamoxifen next year. Arzoxifene (SERM III) is being tested against tamoxifen. These studies are likely to result in new anti-oestrogens being introduced into the clinic.

Most of our endocrine treatments deprived the tumour cell of oestradiol. In vitro experiments with MCF-7 cells indicate that tumour cells can adapt and then grow in response to low oestrogen concentrations in the tissue—culture medium. Importantly, the cells were shown to apoptose in response to high oestrogen concentrations. A recent clinical trial has demonstrated a high response rate to stilboestrol given after a median of four previous oestrogen depriving endocrine therapies. These data and the newer treatments available indicate a need to re-think our general approach to endocrine therapy and endocrine prevention.     

Sequential adjuvant hormone therapy in postmenopausal breast cancer: rationale and clinical results

For the past 15 years tamoxifen has been the standard adjuvant hormone therapy for women with early-stage breast cancer and estrogen receptor (ER)-positive tumors, irrespective of nodal status and other clinicopathological parameters. Recent studies provided evidence that the optimal duration of tamoxifen treatment is 5 years. Based on the positive clinical results obtained with the administration of aromatase inhibitors (AIs) in the metastatic setting, several controlled clinical trials have evaluated the efficacy and side effects of AIs versus standard tamoxifen also as adjuvant therapy in postmenopausal breast cancer patients. The results of the above studies, suggest a therapeutic advantage of AIs over tamoxifen with regard to relapse-free survival and the risk of metachronous contralateral breast cancer. We review the rationale and the available clinical data on initial or sequential hormone treatment with AIs and we propose a novel scenario for possible therapeutic strategies based on the clinicopathological characteristics of the patients and on the biology of each single tumor.     

Surgical issues surrounding use of aromatase inhibitors

There are important surgical issues related to the use of the third generation aromatase inhibitors in both the neoadjuvant and adjuvant settings. Neoadjuvant hormone therapy is effective at downstaging tumours, particularly large tumours initially thought to be inoperable or requiring mastectomy. Randomised trials have shown that the newer aromatase inhibitors letrozole and anastrozole increase the numbers of women who are suitable for breast-conservation compared with tamoxifen, and that letrozole is superior to tamoxifen in terms of clinical response.

Aromatase inhibitors are most effective in ER-rich tumours and are clinically and biologically effective in both HER2 positive and negative tumours, whereas HER2 positive tumours show a level of resistance to tamoxifen.

In neoadjuvant studies comparing aromatase inhibitors with tamoxifen, the duration of use has been 3–4 months, by which time any response is usually evident but longer treatment periods produce continued shrinkage and response. The re-excision rate following breast conservation surgery after neoadjuvant hormone therapy is favourable compared with the rates following immediate wide local excision. Local recurrence rates are acceptable in patients undergoing neoadjuvant therapy and breast-conserving surgery providing post-operative radiotherapy is given.

Adjuvant aromatase inhibitors, as well as having an effect on metastatic disease and survival, reduce local and regional recurrence.     

Intracellular aromatase and its relevance to the pharmacological efficacy of aromatase inhibitors

An important feature of the pharmacological profile of aromatase inhibitors is the ability of the various inhibitors to inhibit intracellular aromatase. It is now well documented that a large proportion of breast tumors express their own aromatase. This intratumoral aromatase produces estrogen in situ and therefore may contribute significantly to the amount of estrogen to which the cell is exposed. Thus it is not only important that aromatase inhibitors potently inhibit the peripheral production of estrogen and eliminate the external supply of estrogen to the tumor cell, but that they in addition potently inhibit intratumoral aromatase and prevent the tumor cell from making its own estrogen within the cell. To study the inhibition of intracellular aromatase we have compared the aromatase-inhibiting potency of the non-steroidal aromatase inhibitors, letrozole, anastrozole and fadrozole in a variety of model cellular endocrine and tumor systems which contain aromatase. We have used hamsters ovarian tissue fragments, adipose tissue fibroblasts from normal human breast, the MCF-7Ca human breast cancer cell line transfected with the human aromatase gene and the JEG-3 human choriocarcinoma cell line. Although letrozole and anastrozole are approximately equipotent in a cell-free aromatase system (human placental microsomes), letrozole is consistently 10–30 times more potent than anastrozole in inhibiting intracellular aromatase in intact rodent cells, normal human adipose fibroblasts and human cancer cell lines. Whether these differences between letrozole and anastrozole are seen in the clinical setting will have to await the results of clinical trials which are currently in progress.     

Benefit with aromatase inhibitors in the adjuvant setting for postmenopausal women with breast cancer

The third-generation aromatase inhibitors, letrozole, anastrozole, and exemestane, have been shown to be effective both as alternatives to tamoxifen in first-line treatment of hormone-sensitive advanced breast cancer in postmenopausal women and following failure of first-line tamoxifen for endocrine therapy. These 3 agents are now being investigated as adjuvant therapy of early breast cancer, as alternative or complementary treatments to the standard, tamoxifen. Three treatment strategies are under investigation: replacement of tamoxifen as adjuvant therapy for 5 years (early adjuvant therapy), sequencing of tamoxifen before or after an aromatase inhibitor during the first 5 years (early sequential adjuvant therapy), or following 5 years of tamoxifen (extended adjuvant therapy). In the first adjuvant trial (Arimidex, Tamoxifen Alone or in Combination [ATAC]), anastrozole was significantly superior to tamoxifen in reducing risk of disease recurrence, and recently, the Breast International Group (BIG) trial BIG 1-98 demonstrated the significant superiority of letrozole over tamoxifen in improving disease-free survival. A large trial (International Collaborative Cancer Group [ICCG] trial 96) investigated sequencing of 2 to 3 years of exemestane after 2 to 3 years of tamoxifen and found that switching to exemestane was significantly superior in disease-free survival compared with continuing on tamoxifen. The Arimidex or Nolvadex (ARNO) and the small ITA (Italian Tamoxifen Arimidex) trials similarly sequenced anastrozole after tamoxifen and also found that sequencing reduced the hazard of recurrence compared with remaining on tamoxifen. Trial MA.17 evaluated extended adjuvant therapy with letrozole vs placebo following 5 years of tamoxifen. Disease-free survival was significantly improved with letrozole vs placebo, irrespective of whether patients had lymph node-positive or node-negative tumors. All 3 aromatase inhibitors were generally well tolerated. Results of these trials indicate that aromatase inhibitors provide important benefits relative to tamoxifen in each of these adjuvant treatment settings, but the optimal approach still needs to be defined. Other trials continue to investigate some of these adjuvant treatment strategies.     

Endocrine effects of aromatase inhibitors and inactivators in vivo: review of data and method limitations

The so-called “third-generation” aromatase inhibitors/inactivators have become standard first-line endocrine therapy for postmenopausal women in the metastatic setting. In addition, these compounds, administered as monotherapy or in sequence with tamoxifen, are likely to become standard adjuvant therapy in most countries in the near future. In contrast to the SERMs, aromatase inhibitors may be assessed for their biochemical efficacy in vivo either by measuring their ability to suppress plasma and tissue estrogen levels or, alternatively, by measuring their ability to inhibit the conversion of tracer-labelled androstenedione into estrone. While contemporary methods for estrogen measurement (with the exception of estrone sulphate) lack the sensitivity to measure plasma estrogen levels during treatment with the most potent compounds, in vivo aromatase inhibition can be determined with a much better sensitivity. Thus, in a joint program conducted by the Royal Marsden Hospital, London and our team in Bergen, we were able to reveal profound differences between first- and second-generation aromatase inhibitors, causing 50–90% aromatase inhibition, and the three third-generation compounds, causing >98% inhibition of total body aromatization.     

Aromatase inhibitors--socioeconomical issues

With costs of health care in general and for cancer therapy in particular escalating due to implementation of novel compounds, there is an increasing focus on therapy costs in most countries. A common way of assessing therapeutic utility versus cost is by assessing cost per additional life year gained or cost per additional quality-adjusted life year (QALY) gained with a novel therapy. While endocrine therapy in general is associated with low costs, the fact that aromatase inhibitors are administered over several years to each patient in the adjuvant setting, together with the substantial number of postmenopausal breast cancer patients that are candidates for adjuvant treatment with aromatase inhibitors, advocates critical examination of cost–utilities related to implementation of such therapy in the adjuvant setting. While cost–utility estimates for treatment with aromatase inhibitors in the adjuvant setting look favorable, the estimates are sensitive to variations with respect to long-term benefits but also side effects. For patient groups with a low-risk of relapse but also patients with a limited life expectancy due to high age, cost–utility estimates may exceed the upper limits generally proposed for costs per quality-adjusted life year gained.     

Aromatase inhibitors--socio-economical issues

Novel, third-generation aromatase inhibitors are currently implemented for treatment of postmenopausal breast cancer in the metastatic and adjuvant setting and, potentially, for breast cancer prevention. Introduction of novel therapeutic strategies to large patient groups may add significant costs to health care budgets, forcing institutions to focus entirely on costs or the cost-utility of implementing such novel strategies. Breast cancer is the most frequent cancer in the female population in western societies, and its incidence is currently increasing in other parts of the world as well. Due to the proven efficacy and limited side effects of endocrine therapy in the adjuvant setting, the indications for use have been successively broadened. Currently, the majority of postmenopausal women treated for an estrogen-receptor positive breast cancer will be offered adjuvant endocrine therapy; thus, a general change of practice may cause significant implications to healthcare costs. This may relate to direct drug costs as well as indirect costs related to prevention of side effects, like additional use of bisphosphonates to prevent enhanced bone loss. The aim of this paper is to overview these considerations and put them into perspective by simple illustrations taken from current cost estimates.     

Development and evolution of therapies targeted to the estrogen receptor for the treatment and prevention of breast cancer

This article describes the origins and evolution of "antiestrogenic" medicines for the treatment and prevention of breast cancer. Developing drugs that target the estrogen receptor (ER) either directly (tamoxifen) or indirectly (aromatase inhibitors) has improved the prognosis of breast cancer and significantly advanced healthcare. The development of the principles for treatment and the success of the concept, in practice, has become a model for molecular medicine and presaged the current testing of numerous targeted therapies for all forms of cancer. The translational research with tamoxifen to target the ER with the appropriate duration (5 years) of adjuvant therapy has contributed to the falling national death rates from breast cancer. Additionally, exploration of the endocrine pharmacology of tamoxifen and related nonsteroidal antiestrogen (e.g. keoxifene now known as raloxifene) resulted in the laboratory recognition of selective ER modulation and the translation of the concept to use raloxifene for the prevention of osteoporosis and breast cancer. However, the extensive evaluation of tamoxifen treatment revealed small but significant side effects such as endometrial cancer, blood clots and the development of acquired resistance. The solution was to develop drugs that targeted the aromatase enzyme specifically to prevent the conversion of androstenedione to estrone and subsequently estradiol. The successful translational research with the suicide inhibitor 4-hydroxyandrostenedione (known as formestane) pioneered the development of a range of oral aromatase inhibitors that are either suicide inhibitors (exemestane) or competitive inhibitors (letrozole and anastrozole) of the aromatase enzyme. Treatment with aromatase inhibitors is proving effective and is associated with reduction in the incidence of endometrial cancer and blood clots when compared with tamoxifen and there is also limited cross resistance so treatment can be sequential. Current clinical trials are addressing the value of aromatase inhibitors as chemopreventive agents for postmenopausal women.     

Aromatase inhibitors continue their ATAC on tamoxifen

The breast cancer drug tamoxifen, the best-known and most widely prescribed anticancer drug in the world, is facing a stiff challenge from an exciting group of compounds called aromatase inhibitors. ‘Tamoxifen is under threat,’ says Anthony Howell, Professor of Medical Oncology at Manchester's Christie Hospital, and Principal Investigator of the largest breast cancer trial ever undertaken. The initial results of this trial suggest that for postmenopausal women, the aromatase inhibitor anastrozole (Arimidex®) is more successful than tamoxifen as an adjuvant (i.e. treatment given to patients after surgery to prevent their cancer returning). ‘If this result holds up, which I think it will undoubtedly, tamoxifen will be ousted from its first-line setting for postmenopausal women,’ he says.     

Aromatase, aromatase inhibitors, and breast cancer

Estrogens are known to be important in the growth of breast cancers in both pre and postmenopausal women. As the number of breast cancer patients increases with age, the majority of breast cancer patients are postmenopausal women. Although estrogens are no longer made in the ovaries after menopause, peripheral tissues produce sufficient concentrations to stimulate tumor growth. As aromatase catalyzes the final and rate-limiting step in the biosynthesis of estrogen, inhibitors of this enzyme are effective targeted therapy for breast cancer. Three aromatase inhibitors (AIs) are now FDA approved and have been shown to be more effective than the antiestrogen tamoxifen and are well tolerated. AIs are now a standard treatment for postmenopausal patients. AIs are effective in adjuvant and first-line metastatic setting. This review describes the development of AIs and their current use in breast cancer. Recent research focuses on elucidating mechanisms of acquired resistance that may develop in some patients with long term AI treatment and also in innate resistance. Preclinical data in resistance models demonstrated that the crosstalk between ER and other signaling pathways particularly MAPK and PI3K/Akt is an important resistant mechanism. Blockade of these other signaling pathways is an attractive strategy to circumvent the resistance to AI therapy in breast cancer. Several clinical trials are ongoing to evaluate the role of these novel targeted therapies to reverse resistance to AIs. Article from the special issue on 'Targeted Inhibitors'.