The Oncologist, Vol. 9, Suppl 3, 20–26,
June 3, 2004
© 2004 AlphaMed Press
Overcoming Endocrine Therapy Resistance by Signal Transduction Inhibition
Matthew Ellis
Siteman Cancer Center, Washington University, St. Louis, Missouri, USA
Correspondence:
Matthew Ellis, M.D., Ph.D., F.R.C.P., Washington University School of Medicine, 660 South Euclid Avenue, Campus Box 8056, Division of Oncology, St. Louis, Missouri 63110, USA. Telephone: 314-362-8866; Fax: 314-362-7086; e-mail: mellis{at}im.wustl.edu
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LEARNING OBJECTIVES
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After completing this course, the reader will be able to:
- Discuss patterns of resistance to endocrine therapy for breast cancer.
- Relate differences in resistance patterns in early and advanced disease settings.
- Identify potential treatment strategies to overcome resistance and/or restore endocrine therapy efficacy.
Access and take the CME test online and receive 1 hour of AMA PRA category 1 credit at CME.TheOncologist.com
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ABSTRACT
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Endocrine therapy is the most effective systemic treatment for patients with hormone-receptor-positive (HR+) breast cancer. Unfortunately, efficacy is often limited by the onset of resistance, which is almost inevitable for patients with advanced disease. Several patterns of endocrine resistance are recognizable clinically, including: A) tumors that are inherently insensitive to all attempts at estrogen receptor (ER) targeting despite expression of ER (pan-endocrine therapy resistance); B) tumors that are estrogen dependent but resistant to one or more specific endocrine therapies (agent-selective resistance); and C) tumors that initially respond but subsequently progress (acquired resistance). Current insights into the molecular basis for these resistance patterns are rudimentary, but are most clearly illuminated by investigations that focus on the crosstalk between the ErbB or HER peptide growth factor family and the ER. The data are sufficiently compelling to be addressed by ongoing clinical trials that examine combinations of endocrine agents and either trastuzumab (Herceptin®; Genentech, Inc.; South San Francisco, CA) or ErbB-specific tyrosine kinase (TK) inhibitors. Preliminary data from a small "proof of concept" phase II study of letrozole (Femara®; Novartis Pharmaceuticals Corporation; East Hanover, NJ) and trastuzumab demonstrated durable responses despite tamoxifen (Nolvadex®; AstraZeneca Pharmaceuticals; Wilmington, DE) resistance. Efficacy was variable, however, despite the selection of patients on the basis of ER and ErbB-2 coexpression. Complicating matters further, resistance often occurs in the absence of any evidence for ErbB TK family member expression. In the absence of a clear target, common downstream signal transduction proteins that are known to intersect with the ER pathway can be inhibited to address resistance, including G proteins with farnesyltransferase inhibitors and molecular target of rapamycin (mTOR) with rapamycin analogues. With a number of phase III clinical trials now under way, major advances in the endocrine treatment of advanced disease are possible.
Key Words. Breast cancer • Estrogen receptor • ErbB • HER-2 • Inhibition • Tyrosine kinase
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ENDOCRINE THERAPY RESISTANCE: A CRITICAL PROBLEM IN BREAST CANCER ONCOLOGY
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Estrogen deprivation therapy with a nonsteroidal third-generation aromatase inhibitor is more effective than tamoxifen (Nolvadex®; AstraZeneca Pharmaceuticals; Wilmington, DE) for the endocrine treatment of postmenopausal women with hormone-receptor-positive (HR+) advanced breast cancer [1, 2]. These agents are also more effective and/or better tolerated than megestol acetate for patients with tamoxifen-resistant disease [3–5]. While these developments are significant, the major limitation of endocrine therapy remains the nearly universal development of resistance. The problem of endocrine therapy resistance is also evident in the adjuvant setting where endocrine manipulations are only partially effective in reducing the death rate from breast cancer, even in populations of patients selected on the basis of tumor estrogen-receptor (ER) expression [6].
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DISTINCT PATTERNS OF ENDOCRINE THERAPY RESISTANCE
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From a biological and clinical standpoint, several patterns of resistance can be distinguished: A) tumors that are inherently insensitive to ER targeting despite ER expression (pan-endocrine therapy resistance); B) tumors that are estrogen dependent but resistant to one or more specific endocrine therapies (agent-selective resistance); and C) tumors that initially respond but subsequently progress (acquired resistance). Pan-endocrine resistance is nearly universal in breast cancers negative for both ER and progesterone receptor (PgR) content, but also occurs in a significant fraction of breast cancers that express HRs. The underlying mechanism of pan-endocrine resistance is obscure, but it is possible that critical connections between the ER and cell cycle or cell survival pathways are disrupted so that the cell is using other pathways to serve functions previously subject to master regulation by the ER [7]. The existence of agent-selective resistance mechanisms can be inferred from the clinical observation that acquired resistance to one endocrine agent does not preclude a response to another from a different therapeutic class. In addition, the superior efficacy of an aromatase inhibitor versus tamoxifen implies that some tumors with intrinsic tamoxifen resistance remain sensitive to estrogen deprivation (otherwise the two therapies would be equivalent as first-line therapy). This paradoxical phenotype is usually explained on the basis of tamoxifen "agonism," since any tumor whose growth is tamoxifen-dependent must also be estrogen-dependent and therefore sensitive to estrogen-deprivation therapies. The time-to-progression (TTP) curve from the trial that compared letrozole (Femara®; Novartis Pharmaceuticals Corporation; East Hanover, NJ) with tamoxifen can be used to illustrate the different phases or types of endocrine therapy resistance (Fig. 1
) [1]. Arrow 1 indicates the subgroup of patients who experienced rapid disease progression within 3 months. This early pattern of disease progression is indicative of pan-endocrine resistance. Between 3 and 6 months, the two curves separate, indicating the presence of a population of tumors that displays intrinsic tamoxifen resistance but sensitivity to letrozole (arrow 2). After 6 months, patients continue to experience disease progression but at a slower pace. Interestingly, the curves remain separate by about the same degree even after prolonged follow-up, suggesting that the rates of acquisition of secondary resistance are similar for tamoxifen and letrozole (arrow 3).
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Figure 1. Time to disease progression in patients with panendocrine resistance (arrow 1), agent-selective resistance (arrow 2), and secondary resistance (arrow 3). Data from phase III study of letrozole versus tamoxifen as first-line therapy for postmenopausal women with advanced breast cancer. Adapted from Mouridsen et al. [1], with permission.
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ERBB-1 AND ERBB-2 AND RESISTANCE
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Approaches to the problem of resistance include in vitro studies focusing on the biochemical bases for pharmacologic actions of endocrine agents, animal models of endocrine resistance, clinical studies in which patient outcome is linked to tumor biomarker status, and controlled clinical trials that address resistance mechanisms through experimental drug intervention. These four complementary approaches can be illustrated by a discussion of the role of the ErbB family in endocrine therapy resistance. ErbB-2 is a member of a family of four plasma membrane tyrosine kinase (TK) receptors (EGFR/ErbB-1/HER-1, ErbB-2/HER-2, ErbB-3/HER-3, and ErbB-4/HER-4) that are intimately involved in development and in reproductive physiology [8]. Twenty percent to 30% of human breast cancers overexpress ErbB-2, usually as a result of gene amplification [9]. ErbB-2 expression is more common in ER– and PgR– breast cancers, and these cancers naturally exhibit endocrine therapy resistance because of the absence of the relevant target [10]. Indeed, ErbB-2-activated mitogen-activated protein kinase (MAPK) signaling may be directly responsible for ER downregulation [11]. However, approximately half of ErbB-2+ tumors entered into clinical trials of trastuzumab are ER+ and/or PgR+ [12]. The clinical behavior of ErbB-2+ ER+ tumors is, therefore, of great interest.
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PRECLINICAL DATA ON ER AND ERBB-2 CROSSTALK
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In vitro growth studies demonstrate that hormone-responsive breast cancer cells with upregulated ErbB-2 exhibit resistance to tamoxifen. Reports vary, however, on the effect of ErbB-2 on estrogen dependence. Benz et al. reported that ErbB-2-overexpressing MCF-7 cells remained estrogen dependent but became tamoxifen resistant [13]. Others have concluded, from similar experiments, that ErbB-2 overexpression reduces dependence on estrogen [14, 15]. In vivo work generally supports the notion that ER+, ErbB-2+ breast cancer cells are sensitive to estrogen deprivation, and resistant to tamoxifen, but over time tumor xenografts develop an estrogen-independent growth pattern. Taken together, these data suggest a role for ErbB-2 in the survival and eventual proliferation of ER+ breast cancers under low estrogen conditions. A role for EGFR (also designated ErbB-1 or HER-1) in endocrine therapy resistance has also been established in preclinical and clinical studies [16, 17]. Multiple preclinical experiments have demonstrated that inhibition of ErbB-1 and/or ErbB-2 with either trastuzumab (Herceptin®; Genentech, Inc.; South San Francisco, CA) or a selective TK inhibitor can reverse tamoxifen resistance [18–21]. The same effect can be achieved through inhibition of the downstream signaling enzymes Akt [22] and MAPK [23]. Importantly, in some cell culture models, long-term exposure to either tamoxifen or estrogen deprivation induces ErbB-2 upregulation to produce ErbB-2-dependent acquired resistance [24]. Preliminary data support the view that such a phenomenon may occur during the progression of human breast cancer [25], suggesting that the use of ErbB-2-targeting agents to modulate resistance should not necessarily be predicated on the expression of ErbB TK family members in a baseline tumor sample. Overall, the impression from this large body of work is that ErbB-2 may be involved in all three major patterns of endocrine resistance—pan, acquired, and tamoxifen selective.
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CLINICAL STUDIES OF ERBB-2 AND ER INTERACTIONS IN THE ADVANCED DISEASE SETTING
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While clinical studies support a complex role for ErbB-2 in the development of endocrine therapy resistance, the interpretation of clinical biomarker studies is complicated by statistical problems associated with retrospective biomarker-based subset analysis, technical problems stemming from the different techniques used to measure ErbB-2, and major differences in the clinical contexts from which the tumor samples were collected for testing [26]. An additional problem for clinical investigators is that ErbB-2+, ER+ tumors are relatively uncommon. As a result, many studies have too few cases to make robust conclusions regarding the clinical behavior associated with this biomarker profile. Formal meta-analysis has been applied to ErbB-2 biomarker studies, but conclusions from such studies must be viewed with caution, given the heterogeneity of the clinical trial designs, the methods of ErbB-2 analyses, and the problem of publication bias (i.e., negative biomarker studies are often never reported). Nonetheless, an overview of results from studies in the advanced disease setting do suggest that patients whose tumors exhibit evidence of ErbB-2 overexpression have poorer outcomes when treated with an endocrine agent than patients whose tumors do not overexpress ErbB-2 [27]. Some of the more convincing studies concerned the outcome of patients with an elevated baseline serum biomarker for the extracellular domain of ErbB-2 (ECD). These patients do poorly when compared with patients with low levels of serum ECD regardless of whether they receive an aromatase inhibitor or tamoxifen [28].
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CLINICAL STUDIES ON ERBB-2 AND ER INTERACTIONS IN THE NEOADJUVANT AND ADJUVANT DISEASE SETTINGS
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Studies in the adjuvant and neoadjuvant settings also support a role for ErbB-2 and, to a lesser extent, ErbB-1 in tamoxifen resistance. Several studies of tamoxifen as adjuvant therapy suggest that patients with ErbB-2+ tumors receiving tamoxifen do poorly and may even do worse than patients receiving placebo [29]. In contrast, other studies show that patients with ErbB-2+, HR+ tumors can do well with endocrine treatment, particularly when estrogen deprivation is a component of the treatment strategy. For example, in a study conducted in rural Vietnam of ovarian ablation plus tamoxifen versus local therapy alone, patients with ER+, ErbB-2+ tumors apparently responded well to the combined adjuvant effects of these agents [30]. Furthermore, in a neoadjuvant study for postmenopausal women with HR+ locally advanced disease, patients with tumors typed as ER+, ErbB-1+, and/or ErbB-2+ responded well to letrozole but poorly to tamoxifen [31]. Together, these data suggest that estrogen deprivation might be a particularly important adjuvant strategy for tumors that are ErbB-2+ (or perhaps ErbB-1+) and HR+. This conclusion awaits further clarification. For example, data on ErbB-2 analysis of tissue samples collected from the anastrozole (Arimidex®; AstraZeneca Pharmaceuticals; Wilmington, DE), tamoxifen, and combination (ATAC) trial should be available soon. The use of ErbB-2 to guide decisions regarding endocrine therapy remains investigational, but could conceivably enter clinical practice as a justification for estrogen deprivation therapy versus treatment with an antiestrogen with agonist potential.
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COACTIVATORS AND COREPRESSORS AND ENDOCRINE THERAPY RESISTANCE
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A deeper understanding of the role of ErbB-2 in intrinsic tamoxifen resistance is emerging from a study of the coactivators and corepressors that complex with ERs to form either a productive interaction with RNA polymerase or hold the DNA-bound ER in an inactive conformation [32]. The amplified in breast cancer-1 (AIB-1) gene encodes an ER coactivator protein (a protein that complexes with liganded ER to promote interactions with RNA polymerase) [32]. When examined in a population of patients who did not receive adjuvant endocrine therapy, AIB-1 expression portended a relatively good prognosis. However, tamoxifen-treated patients whose tumors expressed both AIB-1 and ErbB-2 had worse prognoses than those whose tumors did not [33]. These results suggest that the combination of high levels of AIB-1 in the presence of active ErbB-2 signaling may enhance tamoxifen agonism. Another potential predictive biomarker is the transcriptional corepressor N-CoR. When N-CoR mRNA expression levels are low, patients receiving adjuvant tamoxifen experience poor outcomes because tamoxifen antagonism requires high levels of N-CoR function [34]. If these data are confirmed, measurement of coactivators and corepressors could lead to more precise application of endocrine therapies.
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PRELIMINARY DATA FROM PHASE II TRIAL OF TRASTUZUMAB PLUS LETROZOLE FOR PATIENTS WITH ERBB-2+ and ER+ ADVANCED BREAST CANCER
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A multicenter phase II trial evaluated the combination of trastuzumab and letrozole in patients with advanced breast cancer that was ErbB-2+ and ER+ and/or PgR+. Since opening the trial in 2000, 26 patients (median age 56 years) have been accrued, with disease recurrence developing after a median of 35 months (range 0–281 months) from the time of initial diagnosis (three patients presented with metastatic disease). The majority of patients had both soft tissue (96%) and visceral (73%) disease. Of the enrolled patients, 17 (65%) had either 3+ ErbB-2 overexpression by immunohistochemistry (IHC) or erbB-2 gene amplification by fluorescence in situ hybridization (FISH), and the remainder were defined as 2+ to 3+ or 2+ ErbB-2 overexpression. Sixteen patients had received previous adjuvant chemotherapy, which included an anthracycline in 14 cases. The majority of patients (n = 22) had received previous tamoxifen therapy, 14 in the adjuvant and six in the metastatic settings, and two in both settings. After trastuzumab and letrozole treatment, a complete response rate of 9% (2/22) was observed, with an overall objective response rate of 27% (complete and partial responses [4/22]) and a clinical benefit rate of 64% (complete and partial responses plus stable disease [14/22]). Of note, all responders had durable remissions in excess of 1 year, with two patients having remission for more than 2 years. With a median follow-up of 70 weeks (range 12–170 weeks), the median time to disease progression was 31 weeks (range 15–47 weeks), and 43% of patients were free from progression at 1 year [35]. These outcomes, like those from all phase II trials of combination therapy, have to be judged in the context of historical controls using single-agent therapy. As discussed earlier, the effectiveness of aromatase inhibitors for patients with ErbB-2+, ER+ advanced disease is inferior to that for patients with ErbB-2–, ER+ disease. For example, in a study of 719 patients enrolled in trials of second-line endocrine therapy for metastatic breast cancer, 30% had elevated serum levels of ErbB-2 ECD [36]. Among the latter patient subset, response rate to second-line endocrine therapy (fadrozole, letrozole, megestrol acetate) was only 7% [36]. Similarly a trial of first-line letrozole versus tamoxifen indicated that an overall response rate of 15% to letrozole could be expected for patients with elevated ECD levels [28]. Thus, the 27% objective response rate for combined targeting with letrozole and trastuzumab could be viewed as promising, particularly from the standpoint of response durability, but not particularly striking. The presence of a number of patients whose tumors exhibit absolutely no response to letrozole/ trastuzumab combination therapy suggests overlapping resistance mechanisms. One possibility is that defects in G1 checkpoint controls may engender pan-resistance to all antigrowth factor strategies [37].
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PHASE III CLINICAL TRIALS FOR ERBB-2-TARGETING AGENTS IN COMBINATION WITH AROMATASE INHIBITORS
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A phase III clinical trial examining the efficacy of the combination of anastrozole plus trastuzumab versus anastrozole alone has been initiated. This trial, like that assessing the letrozole/trastuzumab combination, focuses on patients with ErbB-2+, ER+ disease. Another possibility is to combine an aromatase inhibitor with an oral TK inhibitor. It has been argued that trastuzumab is an incompletely effective anti-ErbB-2 targeting strategy because the antibody is ineffective against tumors that express lower levels of ErbB-2. In addition, the effect of the antibody may be bypassed in some tumors by the presence of other members of the ErbB family, particularly ErbB-1. These concerns are addressed by the pharmacologic properties of the dual oral inhibitor of ErbB-1 and ErbB-2, lapatinib (GlaxoSmithKline; Research Triangle Park, NC). Lapatinib is being studied in combination with letrozole in a phase III clinical trial (GSK EGF 30008). Patients with tamoxifen-resistant advanced breast cancer are randomized to receive either letrozole (2.5 mg) plus placebo or letrozole (2.5 mg) plus lapatinib. Interestingly, tumor expression of ErbB-1 or ErbB-2 is not an eligibility criterion for the letrozole/lapatinib study. However, tumor and serum samples will be examined to determine the impact of ErbB-1 and ErbB-2 expression on efficacy. The Eastern Cooperative Oncology Group 4101 trial is also evaluating the combination of an oral ErbB TK inhibitor and an endocrine agent. In that randomized phase II study, patients with advanced breast cancer receive gefitinib (Iressa®; AstraZeneca Pharmaceuticals; Wilmington, DE) with either fulvestrant (Faslodex®; AstraZeneca) or anastrozole.
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OTHER APPROACHES TO ENDOCRINE THERAPY RESISTANCE—FARNESYLTRANSFERASE INHIBITORS
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Since HER-1 and HER-2 can only partially explain endocrine therapy resistance, broader-based signal transduction inhibitors that target key signaling enzymes common to several TK pathways also have potential as endocrine therapy resistance modulators. farnesyltransferase inhibitors (FTIs) are an example of this approach. Farnesylation is a posttranslation lipid modification that is vital for the function of several proteins critical to cell signaling and proliferation [38]. It was originally proposed that FTIs would operate by inactivating the Ras-dependent growth factor receptor pathway because a farnesyl moiety had been shown to be critical for anchoring Ras and Ras-like G proteins to the inner aspect of the plasma membrane [39]. After the development and clinical testing of FTIs, it now appears that these drugs may operate though a more complex mechanism involving functional modulation of multiple classes of proteins [40, 41]. Treatment of nude mice bearing MCF-7 xenografts with the combination of an FTI, tipifarnib, and estrogen deprivation, or alternatively with tipifarnib and tamoxifen, was recently found to be more effective than estrogen deprivation or tamoxifen alone in preventing tumor progression [42]. FTI treatment may also reverse tamoxifen resistance [43]. Several ongoing clinical trials are comparing aromatase inhibitor therapy alone with an aromatase inhibitor in combination with an FTI. The Cancer and Leukemia Group B (CALGB) is planning a randomized trial (CALGB 40301) in postmenopausal women with HR+ advanced breast cancer that is either endocrine therapy naïve or tamoxifen resistant. Treatment will consist of continuous letrozole (2.5 mg) plus placebo or continuous letrozole (2.5 mg) plus the FTI, tipifarnib, 300 mg twice daily administered for 14 days in a 21-day cycle. The primary end point is time to disease progression.
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OTHER APPROACHES TO ENDOCRINE THERAPY RESISTANCE—RAPAMYCIN ANALOGUES
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Another signaling pathway that becomes overactive in breast cancer cells involves the enzyme phosphatidylinositol-3-kinase (PI3K). Overactivity can result from ErbB TK signaling, insulin-like growth factor signaling, or loss of the tumor suppressor and phosphatase, PTEN, all of which may conspire to engender endocrine resistance [44]. While direct inhibition of PI3K is currently not clinically feasible because of toxicity problems, a key target protein for this enzyme—molecular target of rapamycin (mTOR)—can be inhibited using rapamycin analogues, for example CCI 779 [45]. In preclinical studies, CCI 779 was quite active against ER+ cell lines [46], and ongoing clinical trials are examining activity of the combination of an aromatase inhibitor with CCI 779 [47]. A second mTOR inhibitor, RAD 001, is also in clinical development in combination with letrozole [48]. The cell cycle inhibitor p27 is also regulated by PI3K via the enzyme PKB/Akt. p27 is an inhibitor of the cyclin E-Cdk2 complex that promotes cell cycle transition from the G1 to S phase. Tissue culture experiments indicate that loss of p27 in ER+ breast cancer cells leads to resistance to both estrogen deprivation and antiestrogens, because without this protein cells cannot undergo G1-to-S phase arrest [37]. In biomarker studies, low levels of p27 are associated with poor prognoses and resistance to adjuvant endocrine therapy in premenopausal women [49]. Cytoplasmic rather than nuclear localization (driven by PKB/Akt) is also associated with poor clinical outcome in breast cancer [50]. An evolving view in this field is that careful examination of the key proteins responsible for G1-to-S phase arrest, including cyclin E, PKB/Akt, and p27, may well lead to clinically useful endocrine therapy resistance biomarkers [51].
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CONCLUSION
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Endocrine therapy resistance modulators are a diverse group of agents with the common property of targeting an aspect of the complex network of signal transduction proteins that modulate ER function. As more clinical data emerge, we are likely to be faced with the dilemma that several of these approaches are modestly active. The key to the correct application of these agents will be the ability to subtype ER+ breast cancer so that the correct combination of agents can be applied to improve outcomes. It is, therefore, of interest that gene expression profiling experiments have clearly defined two distinct classes of ER+ breast cancer, the clinically indolent luminal type A and the more aggressive luminal type B. The luminal type B appears to be a diverse group of tumors that has enhanced expression of proliferation genes and also is enriched for ErbB-2 expression and p53 mutation [52]. An appropriate first step will be to subtype tumor samples from endocrine therapy resistance modulation trials to determine whether treatment benefits are subtype specific.
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ACKNOWLEDGMENT
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Grants and research support were from Novartis, Genentech, and the National Cancer Institute.
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Received March 26, 2004;
accepted for publication April 15, 2004.
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