Understanding the mechanisms of aromatase inhibitor resistance
© BioMed Central Ltd 2012
Published: 19 January 2012
Aromatase inhibitors (AIs) have a central role in the treatment of breast cancer; however, resistance is a major obstacle to optimal management. Evidence from endocrine, molecular and pathological measurements in clinical material taken before and after therapy with AIs and data from clinical trials in which AIs have been given as treatment either alone or in combination with other targeted agents suggest diverse causes for resistance. These include inherent tumour insensitivity to oestrogen, ineffective inhibition of aromatase, sources of oestrogenic hormones independent of aromatase, activation of signalling by non-endocrine pathways, enhanced cell survival and selection of hormone-insensitive cellular clones during treatment.
Some breast cancers require oestrogens for growth and, if deprived of these hormones, will regress. Consequently, oestrogen deprivation therapy is a major treatment strategy for hormone-dependent breast cancer. There are various forms of endocrine therapy but recently agents inhibiting the aromatase enzyme, which catalyzes the conversion of androgens to oestrogen, have been increasingly used . These have evolved from rational drug development, which has generated inhibitors with exceptional potency and specificity . In postmenopausal women, drugs such as letrozole, anastrozole and exemestane can inhibit aromatization of androgen in vivo by >99% , often decrease circulating oestrogens to undetectable levels [3, 4] and, in hormone-dependent breast cancers, reduce tumour proliferation [5, 6] and growth [7, 8]. Third-generation aromatase inhibitors (AIs) are now front-line treatments for breast cancer . However, response rates range between 35 and 70% in neoadjuvant studies [9, 10], and benefits may be lower in advanced disease . Acquired resistance after initial successful treatment also occurs . Consequently, resistance is a major obstacle and optimal clinical management would benefit from early identification of resistance and the mechanisms by which resistance occurs. Patients with clinically resistant cancers could then be spared unnecessary side effects and ineffective treatment. Knowledge of the underlying reason for resistance would also facilitate the development and implementation of new therapies by which to bypass or reverse resistance. The present review will address these issues by i) distinguishing between different types of resistance and identifying potential complications and confounders, ii) summarizing key clinical observations and iii) integrating these with biological/molecular studies performed on tumours clinically resistant to AIs.
Types of resistance
Before considering specific issues relating to resistance, some brief definitions of di erent forms of resistance are presented.
Clinical versus other forms of resistance
Clinical 'resistance' to AIs is usually perceived as a lack of growth inhibition by AI treatment in that the therapy is ineffective in causing a decrease in tumour size. However, AI treatment often results in molecular (and pathological) changes in clinically resistant tumours [13, 14]. Clinical resistance therefore needs to be distinguished from other forms of resistance, including that in which AI therapy fails to elicit any form of response (in the same way as dependence should be separated from sensitivity).
Primary versus acquired resistance
Resistance may be subdivided into primary (or de novo) and secondary to an initial treatment response (or acquired). Although having clinical implications, primary and acquired resistance may not be separate entities and underlying mechanisms of resistance may be shared. However, the inference is that 'acquired' resistance is the result of inductive changes or clonal selection caused by treatment. Molecular changes that could impact on e ectiveness of therapy have been observed following AI treatment [15, 16].
Cross-resistance and non-cross-resistance
Some tumours resistant to AIs also appear non-responsive to other forms of endocrine therapy (that is, they are cross-resistant ); other AI resistant tumours are sensitive to other endocrine therapies (that is, there is no cross-resistance [18, 19]). Non-cross-resistance can be subtle where, for example, tumours may be resistant to one AI (or class of AIs) but respond to another [20, 21].
Observations from clinical trials
Knowledge contributing to the understanding of resistance to AI may be derived from i) randomised clinical trials comparing AIs with other forms of endocrine therapies, ii) randomised studies in which AIs have been compared with a combination of AIs plus a targeted agent and iii) studies in which patients with AI-resistant tumours have been given further treatment.
Comparison of AIs with other forms of endocrine therapies
Novel, third generation AIs (anastrozole, letrozole and exemestane) have greater efficacy and improved safety profiles compared with their predecessors when employed as treatment for hormone-responsive postmenopausal breast cancers [2, 3, 8]. Randomized clinical trials also show that third generation AIs are equivalent or superior in efficacy to tamoxifen [9–11, 22, 23] and may be effective in tamoxifen-resistant advanced breast cancer [24, 25]. Despite the latter observation, prior resistance to other forms of endocrine therapy is associated with a decreased probability of response to an AI .
It is worth commenting on the time taken to elicit clinical response. Several neoadjuvant protocols show that longer treatment with an AI results in additional clinical benefit [27, 28]. It is thus possible that a minority of apparently resistant tumours may be sensitive to the action of AIs but extended treatment is required before clinical response becomes manifest. This contrasts with the speed of response generally observed following chemotherapy.
Comparison of AIs with a combination of AIs plus a targeted agent
Clues to potential resistance mechanisms may be gleaned from studying agents that significantly change response rates when given in combination with AIs. The most informative studies are those involving selected targeted agents for which there is a rationale related to AI resistance. Targets include type I growth factor receptors, epidermal growth factor receptor, human epidermal growth factor receptor (HER)2 and phosphoinositide 3-kinase/mammalian target of rapamycin (mTOR) inhibitors. Results from several of these clinical trials have recently been reported. For example, a preoperative study of letrozole with or without the mTOR inhibitor everolimus reported greater tumour shrinkage for the combination . Furthermore, marked antiproliferative responses occurred in 57% of patients in the combination everolimus arm compared with 30% in the letrozole alone arm. This suggests that, in some tumours, AKT signalling is associated with letrozole resistance, an influence that may be abrogated by phosphoinositide 3-kinase/mTOR inhibitors.
Other combinations involve therapies that target the HER family of growth factor receptors using either antigrowth factor-receptor antibodies (for example, trastuzumab) or small molecule tyrosine-kinase inhibitors (such as gefitinib and lapatinib). A randomized trial of first-line gefitinib plus anastrozole versus anastrozole alone in women with oestrogen receptor (ER)-positive advanced breast cancer reported that patients who received the combination therapy experienced significantly longer progression-free survival (PFS) and an improvement in clinical benefit rate, but a lower response rate [30, 31]. In neither of the mentioned trials using the combination of gefitinib plus anastrozole were patients selected on the basis of overexpression of growth factor receptors. However, two studies have included HER-2 status in selection criteria. Thus, in patients with known ER-positive/HER2-positive tumours, the addition of lapatinib to letrozole significantly reduced the risk of progression and improved median PFS; clinical benefit rate was also significantly greater for the combination ; a preplanned analysis was also able to show an impact of combination therapy on PFS in the HER2-negative population. Finally, a randomized phase III trial in patients with known hormone receptor- positive/HER2-positive metastatic breast cancer recently reported a doubling of PFS with the addition of trastuzumab to anastrozole compared with anastrozole alone . In these combination studies, it is possible that the additional benefit of targeted therapy is separate from the endocrine e ects of AIs. However, preclinical studies and measurements of biological markers suggest synergy or cross-talk between signalling systems. The hypothesis is therefore that acquired resistance to AIs in patients with ER-positive/HER2-negative tumours may be caused by adaptive epidermal growth factor receptor or HER2 upregulation and this might be prevented or delayed by agents directed against these targets.
Further treatment in patients with AI-resistant tumours
Sequential treatment using different classes of aromatase inhibitors
Time to progression
Anastrozole or letrozole
Anastrozole or letrozole
Anastrozole or letrozole
Anastrozole or letrozole
Anastrozole or letrozole
Anastrozole or letrozole
Anastrozole or letrozole
Endocrine and molecular markers
The understanding of mechanisms of AI resistance has also been furthered by identification of i) molecular and endocrine markers that might distinguish between resistant and responsive cancers, ii) changes induced by AI therapy that might be associated with an AI-resistant phenotype and iii) genetic signatures and patterns that illustrate diversity of resistance.
Endocrine and molecular markers
A major cause of resistance to AIs and other endocrine therapies is absence of functional ER in tumours. For example, in the P024 neoadjuvant trial of letrozole versus tamoxifen , a small number of ER-negative tumours (protocol violators) were entered into the study and none responded to either drug. Patients with ER-negative tumours should not be o ered therapy. However, many ER-positive tumours also do not respond to AIs. The challenge is how to discriminate accurately and on an individual basis which ER-positive tumours respond to treatment and those that do not.
HER signalling can result in ER phosphorylation (a critical step in ER activation) even in the absence of oestrogen . However, the situation with regard to tumour HER2 overexpression and resistance to AIs is complicated. In the neoadjuvant setting, clinical response rates to AIs are similar in HER2-positive and -negative tumours [41, 42]. At the same time, AIs often fail to reduce proliferation in ER-positive/HER2-positive breast cancers even amongst those that display a clinical response [41, 43]; this suggests that growth factors other than oestrogen are driving proliferation, limiting the benefits of AIs in HER2-overexpressing tumours (this observation would also account for the poorer long-term outcomes in HER2-overexpressing breast cancer as reported in adjuvant trials with AIs [44, 45]). Further-more, numbers of ER-positive/HER2-positive breast cancers are small  and the pathway is unlikely to account for AI resistance in most tumours.
Other potential markers
Genetic polymorphisms have been identified and characterised in the aromatase gene and may have functional influences on the interaction between the enzyme protein, its substrate and inhibitors . Thus, it is of interest that Wang and colleagues , examining tumour from breast cancer patients, reported that two tightly linked SNPs (rs6493497 and rs7176005) were significantly associated with a greater change in aromatase activity after AI treatment and that, in a separate group of cases, these two same SNPs were associated with higher plasma oestradiol levels in patients pre-AI and post-AI treatment. The authors hypothesised that SNPs in the CYP19 gene may alter the effectiveness of AI therapy in the neoadjuvant setting. Others have reported interesting findings with regard to a SNP (rs4646) located in the 3' untranslated region of the aromatase CYP19 gene. Thus, Colomer and colleagues  found that in patients with hormone receptor-positive metastatic breast cancer treated with the aromatase inhibitor letrozole, time to progression was significantly improved in patients with the rs4646 variant compared with the wild-type gene (17.2 versus 6.4 months; P = 0.02). In contrast, Garcia-Casado and colleagues  analysed DNA from peripheral blood of patients offered neoadjuvant letrozole; they showed that those carrying genetic variants of rs4646 had a lower PFS than patients homozygous for the reference variant. Ribosomal proteins have also been associated with resistance to an AI. Thus, mRNA expression of several ribosomal proteins has been reported to be significantly lower in letrozole-resistant tumours compared with responsive cases . A study using letrozole alone or in combination with chemotherapy  examined a group of tumour proteins involved in apoptosis, cell survival, hypoxia, angiogenesis, and growth factor and hormone signalling; increased hypoxia-inducible factor-1 alpha and P44/42 mitogen-activated protein kinase (MAPK) were associated with resistance. Lastly, overexpression of low-molecular-weight cyclin E has been claimed to bypass letrozole-induced G1 arrest and thereby produce resistance . Whilst all these studies are potentially important, being derived from appropriate clinical material and involving markers that could functionally impact on resistance mechanism for AIs, it should be noted that results have usually been based on a single series of breast cancers; there is an immediate need for independent confirmation using different cohorts of tumours.
Changes induced by aromatase inhibitor therapy
Mello-Grande and colleagues  examined gene expression profiling and response to neoadjuvant treatment with anastrozole and observed an enrichment of induction of T-cell anergy, positive regulation of androgen signalling, synaptic transmission and vehicle tracking in non-responding tumours. In a further study, upregulation of ER coactivator mRNA and HER2 was observed during neoadjuvant treatment with either letrozole or anastrozole . This is of interest since these are factors that influence oestrogen signalling and could potentially mediate acquired resistance to AIs.
It is self-evident that to differentiate between responsive and resistant tumours on the basis of changes on treatment, it will be necessary to sample tumours on multiple occasions. A further corollary is that if adaptive changes during treatment result in resistance, it is likely that there will be a necessity for a re-biopsy at time of recurrence/resistance to elucidate the nature/mechanism of resistance.
Molecular diversity of aromatase inhibitor resistance
The authors suggest that a systematic molecular characterisation of changes in expression of classical oestrogen-regulated and proliferation-associated genes with short-term exposure to AIs will provide fundamental information relating to underlying mechanism of resistance and allow a more rational clinical management in individual patients. A prospective study is recommended for the future.
Mechanisms of resistance
Ineffective inhibition of aromatase
There are several reasons by which AI may fail to inhibit aromatase effectively and residual oestrogen may maintain tumour growth. These include poor drug potency, adverse pharmocokinetics/pharmacogenetics, compensatory endocrine loops and altered aromatase phenotype. Early-generation AIs did not completely block oestrogen biosynthesis [3, 4] whereas later generation AIs were potent and able to produce clinical responses in tumours resistant to inferior inhibitors (see  for details). Although measurable differences in potency are apparent between the current generation of inhibitors, there is no direct evidence to suggest that this is associated with cross-resistance. Furthermore, in the absence of confounding factors, effective inhibition of aromatase by third generation inhibitors appears to occur in most postmenopausal patients [59, 60], suggesting that ineffective suppression of oestrogen is only likely to be the cause of resistance in occasional cases.
Pharmacokinetics/pharmacogenomics may have adverse influences on AIs . Th ere are drug interactions between tamoxifen and some AIs; concomitant administration of tamoxifen with either anastrozole or letrozole decreases plasma levels of the AIs (letrozole by 30 to 40% and anastrozole by 20 to 30%). However, oestrogen suppression does not seem to be compromised [62, 63] and clinical relevance is likely to be limited. High/raised levels of aromatase may prevent effective blockade by inhibitors. For example, high levels of aromatase in the premenopausal ovary and compensatory feedback loops, which increase levels of gonadotrophins, are associated with ine effective inhibition of ovarian aromatase by AIs. Consequently, in premenopausal women, AIs are generally used with a luteinizing hormone releasing hormone (LHRH) agonist to block the rise in gonado-trophins . SNPs in the aromatase gene have been associated with resistance to AIs, suggesting an aromatase phenotype that is resistant to AIs. Differential sensitivity to AIs has been observed in some breast cancers, but it is comparatively rare and has not been associated with mutations in aromatase . Finally, ineffective aromatase inhibition may be related to treatment compliance issues.
Alternative sources of oestrogen/oestrogenic hormones
AIs block endogenous synthesis of oestrogen but have no effects on the synthesis of other steroid classes, which can interact with ER (such as adrenal androgens) , and on exogenous oestrogens/oestrogenic compounds, including synthetic estrogens, industrial pollutants, and phytoestrogens. However, if these alternative sources of oestrogenic factors were a common cause of resistance to AIs, it might be expected that anti-oestrogens (which block the action of oestrogenic factors irrespective of source) would have superior clinical benefits to AIs whereas generally they do not [9–11, 66]. Moreover, there is evidence that tamoxifen can act as an oestrogen to compromise the action of AIs. Thus, the experience of combining tamoxifen with anastrozole in the Arimidex, Tamoxifen Alone or in Combination (ATAC) trial was that disease-free survival in patients taking the combination of anastrozole plus tamoxifen was significantly less than in those taking anastrozole alone (and similar to tamoxifen alone) . The basis for this probably resides in the accentuation of the oestrogen agonist properties of tamoxifen [67–69], which become apparent in the low oestrogen environment produced by AIs.
Inherent oestrogen insensitivity (non-functional ER)
Stimulatory effects of oestrogen on the growth of hormone-dependent breast cancers are mostly mediated through ERs. It is confirmed by the fact that AIs are unlikely to produce responses in ER-negative tumours . However, many tumours resistant to AIs have ER-positive phenotypes , and the major challenge is to comprehend why, if AIs produce effective oestrogen deprivation, they do not result in tumour regression. One possibility is that ER is non-functional. RNAs encoding variant and mutant ERs have been reported in breast cancer ; abnormal receptors may bind oestrogens but not transmit a signal. Tumours with non-functional ERs would be inherently insensitive to hormone stimulation (and refractory to AI therapy) despite being ER-positive. Other critical components of ER signalling are co-regulators . Coregulator abnormalities or imbalance may dislocate signalling so that growth is independent of oestrogen and not susceptible to AIs.
Ligand-independent activation/stimulation of oestrogen signalling pathways
ER signalling may be activated independently of oestrogen . For example, HER2 signalling can result in ligand-independent ER phosphorylation . Although numbers of ER-positive HER2-positive tumours are small , other kinases such as MAPKs and insulin-like growth factor 1 receptor/AKT are capable of activating and supersensitizing ER signalling . It is thus relevant that overexpression of MAPK has been found in breast cancers resistance to letrozole . These considerations underpin the proposed use of appropriate signal transduction inhibitors in combination or sequence with AIs [12, 52]. Involvement of ligand-independent ER signalling may also explain cases with lack of cross-resistance between AIs and anti-oestrogens.
Oestrogen signalling disconnected from tumour proliferation and growth
Certain breast cancers appear clinically resistant despite fully functional ER and effective oestrogen deprivation. However, it may be that proliferation and growth are stimulated by oestrogen-independent pathways. In this setting, AI treatment would reduce expression of classically oestrogen-regulated genes but not those associated with cellular proliferation. The phenotype has been described in some breast cancers clinically resistant to neoadjuvant treatment with letrozole [13, 58].
Most tumours that appear clinically resistant to AI are nevertheless molecularly sensitive to the drugs insofar as the expression of both oestrogen-regulated and proliferation-associated genes and proteins decreases with treatment [13, 14, 58]. To explain this form of resistance, it is necessary to suggest that the therapeutic reduction in proliferation leaves residual cell cycling which, together with efficient cell survival mechanisms, maintains tumour growth.
Adaption with treatment/outgrowth of hormone-insensitive cellular clones
This scenario suggests that at the outset of treatment, tumours may have a responsive phenotype or be composed of a mixture of AI-responsive and -resistant cells. Under the pressure of treatment either adaptive intracellular changes occur (transforming a responsive phenotype into one with resistant characteristics) or there is an outgrowth of resistant cellular clones (present at the outset of treatment) with a survival advantage over other cells that are susceptible to therapy. This type of mechanism would be particularly applicable to resistance secondary to an initial response or 'acquired' resistance. Adaptive changes with AI treatment, such as increased/changed expression of HER2 and ER co-regulators and loss of ER, have been described (although most breast cancers with acquired resistance to AIs remain ER-positive after treatment [12, 71]).
In order to understand the nature of resistance to AIs, this review has drawn upon endocrine, molecular and pathological measurements made in clinical material taken before and after therapy with AIs and upon observations from clinical trials in which AIs have been given as treatment either alone or in combination with other targeted agents. The major message from these studies is that no single reason can account for resistance in all cases and that there are multiple and diverse mechanisms by which breast cancers may avoid the restraints of AI therapy. The consequences of this are that a battery of tests and predictive markers may be needed in order to elucidate the nature of resistance in individual tumours and that if rational treatments to avoid or reverse resistance are based on an underlying mechanism, they also will be both varied and individually targeted.
In terms of general identification of resistance, assessment of ER is essential. However, in ER-positive tumours, additional markers are needed both to identify resistance and pinpoint its nature. Status of ER signalling may be directly assessed by measuring the degree/type of ER phosphorylation and levels of ER coactivators/corepressors, and indirectly by analyzing profiles of oestrogen-regulated genes. Measurement of proliferation markers, relevant growth factors, their receptors and kinase activity may complement the ER signalling assessment. Treatment adherence and efficiency of aromatase inhibition may be monitored by measuring blood levels of drugs, oestrogen and other hormones, aromatase activity, pharmacokinetics of AIs and pharmacogenetics of aromatase. As well as multiple assessments, dynamic measurements may be necessary - neoadjuvant studies indicate that most clinically resistant tumours show a variety of molecular responses and these may help identify more precisely the exact nature of resistance in individual tumours. This may entail sequential biopsies of tumour during treatment and, in the case of acquired resistance, at the time of recurrence.
If resistance to AIs occurs through a diverse set of mechanisms, it follows that therapy aimed at preventing or reversing resistance is to be designed rationally by targeting, and understanding of the specific cause of resistance in individual cases will be necessary. In this respect, the use of neoadjuvant and short-term preoperative protocols may be particularly informative - AIs and other signal-transduction modifying agents can be administered to patients and the primary tumour monitored for molecular and pathological effects. These approaches are particularly promising because they may be coupled with new pathological methodologies and molecular techniques. A future can be envisaged in which patients may be selected for specific treatment regimes after molecular profiling and phenotyping at genomic, transcriptomic and proteomic levels in tumour taken before treatment and after a short period of therapy. These results will be used to detect early evidence of resistance and to select rational treatments to avoid resistance (by using appropriate targeting drugs either in combination or in sequence with AIs). These measures can be expected to increase and prolong clinical benefits of AIs whilst circumventing resistance.
This article is part of a review series on Controversies in AI therapy, edited by Lewis Chodosh. Other articles in the series can be found online at http://breast-cancer-research.com/series/AI_controversies.
human epidermal growth factor receptor
mitogen-activated protein kinase
mammalian target of rapamycin
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