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Department of Medicine, Royal Marsden Hospital, London SW3 6JJ, UK

(Requests for offprints should be addressed to S R D Johnston, Breast Unit, Department of Medicine, The Royal Marsden NHS Trust, 233 Fulham Road, London SW3 6JJ, UK; Email: stephen.johnston{at}rmh.nthames.nhs.uk)

This paper was presented at the 1st Tenovus/AstraZeneca Workshop, Cardiff (2005). AstraZeneca has supported the publication of these proceedings.

	Abstract

Top Abstract Introduction Preclinical efficacy of... Enhanced anticancer effects for... Clinical trials with... Presurgical biomarker studies of... Conclusion — challenges... References

 
Acquired resistance to endocrine therapy in breast cancer is associated with an increase in peptide growth factor signaling that results in cross-talk activation of the estrogen receptor (ER). Small molecule signal transduction inhibitors (STIs) can target components of these intracellular pathways, and may prove effective in anticancer therapy. However, early phase II clinical trials with various STIs as monotherapy in advanced breast cancer have shown only a modest level of efficacy for these intracellular inhibitors. Preclinical data suggest that combinations of tamoxifen with STIs may provide significantly greater growth inhibition than either therapy alone, and, furthermore, may delay the emergence of endocrine resistance. There are now several trials assessing the efficacy of combinations of small molecule tyrosine kinase inhibitors (TKIs), such as gefitinib and lapatinib, with either tamoxifen or aromatase inhibitors both in the second-line, endocrine-resistant and first-line, hormone-sensitive setting. Similar trials continue with both farnesyltransferase inhibitors (FTIs) and mTOR antagonists, where there are strong preclinical data to suggest additive or synergistic effects for either of these agents in combination with endocrine therapies. Biomarker studies in the presurgical setting are also being utilized as an alternative approach to investigate whether combined endocrine/STI therapy is an effective clinical strategy. This article reviews some of the preclinical evidence supporting this strategy, together with the current status of clinical trials in this area.

	Introduction

Top Abstract Introduction Preclinical efficacy of... Enhanced anticancer effects for... Clinical trials with... Presurgical biomarker studies of... Conclusion — challenges... References

 
Research into the mechanisms of endocrine resistance in breast cancer has revealed that various growth factor pathways and oncogenes involved in the signal transduction cascade become activated and utilized by breast cancer cells to bypass normal endocrine responsiveness (Nicholson et al. 1999). Significant clinical attention in recent years has focused on the monoclonal antibody trastuzumab (Herceptin), which targets the extracellular domain of the type 1 growth factor receptor, human epidermal growth factor receptor 2 (HER-2), an oncogene that is amplified in 20% of human breast carcinomas (Slamon et al. 2002). However, HER-2 signaling involves the activation of various downstream intracellular kinases, many of which are activated or oncogeneic in their own right and may override control by upstream membrane receptors such as HER-2. As such, these intracellular pathways represent attractive targets for pharmacologic intervention with small molecule signal transduction inhibitors (STIs) that target aberrantly or excessively expressed oncogene products. Many such drugs are in active development for breast cancer, including type 1 growth factor tyrosine kinase inhibitors, farnesyltransferase inhibitors (FTIs), MEK inhibitors and mTOR antagonists (Table 1).

	Preclinical efficacy of intracellular STIs in breast cancer

Top Abstract Introduction Preclinical efficacy of... Enhanced anticancer effects for... Clinical trials with... Presurgical biomarker studies of... Conclusion — challenges... References

Other intracellular signaling and cell survival pathways are also activated in hormone-resistant breast cancer, particularly the phosphatidylinositol 3-kinase (PI3K)/Akt pathway. Akt (or PKB) is a serine/threonine kinase that promotes cell survival and is activated in response to many different growth factors, including insulin, insulin-like growth factor 1 (IGF-1), basic fibroblast growth factor (bFGF), EGF, heregulin and vascular endothelial growth factor (VEGF). Once activated, Akt exerts antiapoptotic effects through phosphorylation of substrates that directly regulate the apoptotic machinery (i.e., Bad, caspase 9). In addition, the mammalian target of rapamycin (mTOR) is a down-stream effector of the PI3K/Akt signaling pathway that activates p70S6 kinase and 4E-binding protein-1, which, in turn, regulate transition through the G1/S phase of the cell cycle. Approaches to targeting these cell survival pathways have included either specific PI3K inhibitors, such as LY294002, or rapamycin analogues, such as temsirolimus (CCI-779) or everolimus (RAD-001), that target mTOR. Breast cancer cell lines with activated Akt (as by loss of the regulatory PTEN tumor suppressor gene) are especially sensitive to mTOR antagonism (Yu et al. 2001).

	Enhanced anticancer effects for STIs in combination with endocrine therapy

Top Abstract Introduction Preclinical efficacy of... Enhanced anticancer effects for... Clinical trials with... Presurgical biomarker studies of... Conclusion — challenges... References

 
Several preclinical reports have implied that, in hormone-sensitive, ER-positive breast cancer, STIs as monotherapy may have only a minimal effect on tumor growth, especially if cells lack the activation and dependence of the various signal transduction pathways described above. Emerging evidence suggests that adaptive changes occur during prolonged endocrine therapy, particularly upregulation of growth factor signaling. Thus, strategies to combine endocrine with STI therapies have been used as a means to prevent development of resistance and improve therapeutic efficacy. In vitro, combined tamoxifen and gefitinib provided nearly complete inhibition of phosphorylated ERK1/2 MAPK and Akt, together with greater G0/G1 cell-cyle arrest and suppression of the cell-survival protein bcl-2 than that observed with just tamoxifen (Gee et al. 2003). In particular, combined therapy prevented the acquired expression of EGFR/MAPK signaling and the subsequent resistance that occurred after 5 weeks in tamoxifen-alone-treated cells.

For established hormone-resistant, HER-2-positive breast cancer, the strategy of combined STIs and endocrine therapy may also be more effective than using STIs alone (Kurokawa et al. 2000). In vivo, gefitinib and tamoxifen provided maximal growth inhibition and significantly delayed the growth of HER-2-positive MCF-7 xenografts compared with gefitinib alone (Shou et al. 2004). Moreover, similar effects were seen with gefitinib combined with estrogen deprivation, which provided greater inhibition of growth and substantially delayed acquired resistance compared with estrogen deprivation alone (Massaraweh et al. 2002). A synergistic effect has also been reported for trastuzumab combined with tamoxifen in ER-positive, HER-2-positive BT-474 breast cancer cells, with enhanced accumulation of cells in G0/G1 and reduction in S phase of the cell cycle compared with either therapy alone (Argiris et al. 2004). Of interest, there was no evidence for any induction of apoptosis. Recently, the dual EGFR/HER-2 inhibitor lapatinib has been shown to cooperate with tamoxifen to provide more rapid and profound cell-cycle arrest than either therapy alone in hormone-resistant cells (Chu et al. 2005). The two drugs together caused a greater reduction in cyclin D1, together with a greater increase in the kinase inhibitor p27 and cyclin E-cdk2 inhibition, in various tamoxifen-resistant breast cancer cell lines. Lapatinib was able to restore tamoxifen sensitivity in EGFR- or HER-2-expressing cells, while, in vivo, combined laptaninib and tamoxifen caused maximal regression of HER-2-overexpressing, tamoxifen-resistant MCF-7 xenografts (Chu et al. 2005).

Other STIs that have only a minimal effect on hormone-sensitive breast cancer may also be more effective when combined with endocrine therapy. The FTI tipifarnib inhibits the growth of a number of human breast cancer cells lines in vitro, most of which contain normal wild-type ras genes (End et al. 2001). However, in vivo, tipifarnib produced only a modest cytostatic effect on hormone-sensitive MCF-7 xenograft growth, with evidence of induction of apoptosis and enhanced expression of the cell-cycle inhibitory protein p21 (Kelland et al. 2001). In contrast, when tipifarnib was combined with tamoxifen or estrogen deprivation therapy, combined treatment induced significantly greater tumor regression than either endocrine therapy alone (Johnston et al. 2002). Three other groups have since reported a similar interaction for FTIs with tamoxifen or aromatase inhibitors, and have suggested either a synergistic (Ellis et al. 2003) or an additive antitumor effect (Long et al. 2004). One recent study implied an additive effect on G0/G1 cell-cycle arrest, and that the FTI-277, when combined with tamoxifen, maintained higher levels of the cdk inhibitor p21^waf/cip1, resulting in an additive effect on inactivation of cyclin E/Cdk2 complexes and decreased phosphorylation of pRb (Doisneau-Sixou et al. 2003).

More recently, a similar rationale has emerged to support the combination of mTOR antagonists with either tamoxifen or an aromatase inhibitor in preclinical models of ER-positive, hormone-sensitive and resistant breast cancer (DeGraffenried et al. 2004, Rudolf et al. 2004). The estrogen-dependent growth of both wild-type MCF7 and aromatase-expressing (MCF7/Aro) breast cancer cells was inhibited in a dose-dependent manner by the mTOR antagonist everolimus (RAD-001), suggesting that mTOR signaling is required for the estrogen-dependent proliferation of these cells. In subsequent experiments with the MCF7/Aro cells, the combination of letrozole and everolimus produced maximal growth inhibition with clear evidence for additive/synergistic effects (Rudolf et al. 2004). Evidence has emerged that activation of Akt/PKB and the downstream mTOR pathway can cause resistance to tamoxifen (Clark et al. 2002, Pancholi et al. 2004). MCF-7 cells expressing a constitutively active Akt were able to proliferate under reduced estrogen conditions and were resistant to the growth inhibitory effects of tamoxifen, both in vitro and in vivo, in xenograft models (DeGraffenried et al. 2004). However, cotreatment with the mTOR inhibitor temsirolimus (CCI-779) inhibited mTOR activity and restored sensitivity to tamoxifen, primarily through induction of apoptosis, thus suggesting that Akt-induced tamoxifen resistance may in part be mediated by signaling through the mTOR pathway.

	Clinical trials with intracellular STIs in breast cancer

Top Abstract Introduction Preclinical efficacy of... Enhanced anticancer effects for... Clinical trials with... Presurgical biomarker studies of... Conclusion — challenges... References

 
Taken together, these experimental data indicate that various intracellular signaling pathways may be activated or overexpressed in breast cancer, especially in endocrine-resistant cells, and suggest that targeting such pathways may be an effective therapy. Proof of principle for therapies that target growth factor pathways in breast cancer has already been provided with trastuzumab (Herceptin), the monoclonal antibody to the external domain of HER-2. Clinical use of trastuzumab has been exclusively in HER-2-positive breast cancer, and significant activity has been seen as first-line monotherapy, with up to a 48% clinical benefit rate in HER-2-positive tumors, including a 34% objective response rate in tumors reported positive by fluorescence in situ hybridization (FISH) (Vogel et al. 2002). Thus, it was hoped that various small molecule STIs may also prove effective anticancer strategies in this setting. Early phase II clinical studies were initiated with EGFR/HER-2 tyrosine kinase inhibitors, FTIs and more recently mTOR antagonists, each as monotherapy, in patients with advanced (often heavily pretreated) disease. At the same time, the encouraging preclinical data suggesting that a more effective strategy may be to combine STIs with endocrine therapy has led to several randomized clinical trials designed to test this hypothesis in the clinic.

Trials with EGFR tyrosine kinase inhibitors (TKIs)

The most extensively studied TKI in breast cancer is the EGFR TKI gefitinib (Iressa), an orally active, low-molecular- weight, synthetic anilinoquinazoline and a potent selective inhibitor of EGFR-TK. In various breast cancer cell lines that express EGFR and/or HER-2, gefitinib given as a single agent induced a dose-dependent antiproliferative effect which delayed growth (Moulder et al. 2001). Experiments have demonstrated that gefitinib may inhibit the growth of acquired endocrine-resistant MCF-7 breast cancer cells in vitro (Hutcheson et al. 2003, Knowlden et al. 2003, Martin et al. 2003) and in vivo (Shou et al. 2004). There have been three phase II monotherapy studies of gefitinib in patients with advanced breast cancer (Albain et al. 2002, Baselga et al. 2003, Robertson et al. 2003). Overall, the data are relatively disappointing with low clinical response rates and short times to disease progression (Table 2). The only trial to report a significant number of responses included patients with ER-positive, tamoxifen-resistant breast cancer (Robertson et al. 2003), the setting in which preclinical models had shown the best evidence of activity for gefitinib. Pharmacodynamic studies have been performed in one of these trials, confirming that EGFR tyrosine kinase signaling is inhibited in both skin and tumor biopsies by doses of gefitinib delivered orally (Baselga et al. 2003). However, there was discordance in the effect of gefitinib on downstream intracellular signaling in treated tumor biopsies, with lack of inhibition of Ki-67 (a marker of cell proliferation) in tumor, but not in matched skin biopsies. This suggested that activation of other intracellular pathways downstream of EGFR (especially in breast cancer as opposed to normal skin cells) may determine the clinical response to gefitinib. More research is required to establish tumor phenotypes in responding versus nonresponding patients (Dancey et al. 2003). Fewer clinical data exist regarding the other EGFR TKI in breast cancer, although a phase II monotherapy trial of the selective EGFR TKI erlotinib (OSI-774) in breast cancer was relatively disappointing (Winer et al. 2002).

View larger version (26K): [in this window] [in a new window]   Figure 1 Design of a randomized, placebo-controlled trial of endocrine therapy with or without tyrosine kinase inhibitors in ER-positive, advanced metastatic breast cancer. ORR, overall response rate.

Cooperative activation of different type I growth factor receptors (EGFR, HER-2, HER-3 or HER-4) may limit the efficacy of targeting just one single receptor. Lapatinib (GW572016) is a potent dual inhibitor of both EGFR and HER-2 and inhibits autophosphorylation of the receptors (Rusnack et al. 2001). In the phase I study, diarrhea and skin rash were the main toxicities (Xia et al. 2002), and clinical activity was reported in trastuzumab-resistant breast cancer patients (Spector et al. 2003). Several biologic and pharmacologic reasons may account for the efficacy of a small molecule inhibitor of HER-2 in patients resistant to monoclonal therapy with trastuzumab. A phase II trial of lapatinib has been completed in heavily pretreated patients with advanced breast cancer that progressed on prior trastuzumab-containing regimens. A recent interim analysis in the first 41 patients confirmed clinical activity for lapatinib in breast cancer, with partial responses in 7% of patients and/or stable disease in 24% of patients after 16 weeks of therapy (Blackwell et al. 2004).

One of the pivotal trials for lapatinib will be the large, randomized, phase III trial of letrozole with or without lapatinib in ER-positive advanced metasatic breast cancer (Table 3; Fig. 2). This study in over 760 patients is powered to detect a 30% improvement in median time to disease progression from 10 to 13 months (hazard ratio of 0.769). Recruitment has started, and exporatory biologic studies will accompany the main clinical protocol to try to identifiy who benefits most from the combination. Again, the recently published preclinical data showing the ability of lapatinib to reverse hormone resistance and to cooperate with tamoxifen in providing maximal growth arrest strongly underpin the design of this study (Chu et al. 2005). Secondary endpoints will include objective response rate and clinical benefit rate, a feature which should allow the impact of the combination on delaying disease progression to be detected.

View larger version (30K): [in this window] [in a new window]   Figure 2 Design of a randomized, placebo-controlled trial of endocrine therapy with or without tyrosine kinase inhibitors in ER-positive, advanced metastatic breast cancer.

Monotherapy activity has been reported for the FTI tipifarnib (Zarnestra) in advanced breast cancer. A total of 76 patients were treated with tipifarnib, either as a continuous dose of 300 or 400mg b.i.d. (n=41) or an intermittent dose of 300mg b.i.d. for 21 days followed by 7 days off therapy (n=35) (Johnston et al. 2003). In the continuous treatment arm, there were four partial responses (10%) lasting 4–12 months and six patients with stable disease (15%) for at least 6 months. In the intermittent treatment arm, there were five partial responses (14%) and three patients with stable disease (9%). Objective responses were seen in both soft-tissue and viscereal sites of disease (Fig. 3). The main toxicities were neutropenia, thrombocytopenia, neurotoxicity and fatigue. These results were independent of ras status, estrogen/progesterone receptor or HER-2/EGFR receptor status, and 40% of patients had received only prior adjuvant and/or metastatic endocrine therapy at entry into the trial. Thus, while FTIs may have modest antitumor activity as a single-agent therapy, stabilization of disease in those resistant to endocrine therapy may represent a meaningful response.

View larger version (138K): [in this window] [in a new window]   Figure 3 Clinical response in a postmenopausal patient with endocrine-resistant, ER-positive metastatic breast cancer to single-agent tipifarnib. Top CT scan shows three liver mestastases which, after 3 months of treatment with tipifarnib, shrunk significantly as shown in the lower CT scan.

Single-agent activity has been reported for the mTOR antagonist temsirolimus (CCI-779) given by weekly intravenous administration to 109 patients with heavily pretreated, locally advanced or metastatic breast cancer whose disease relapsed or was refractory to previous anthracyclines and/or taxanes (Chan et al. 2003). Based on 94 evaluable patients, partial responses were seen in 11% patients with stable disease in an additional 33% of patients. The main toxicities included alteration in transaminases, mucositis, rash and mild nausea.

Again based on encouraging preclinical data for possible synergistic effects when mTOR antagonists were combined with endocrine therapy (DeGraffenried et al. 2004, Rudolf et al. 2004), clinical trials looking at combined therapy have been initiated – these are not as far advanced as those described above for TKIs and FTIs. In these phase II studies, clinical response is the primary endpoint, with stable disease for at least 6 months being an additional endpoint in some studies. Preliminary data from a small, three-arm randomized study has compared two different schedules of oral temsirolimus (10mg continuous or 30 mg for 5/14 days) combined with letrozole. Initial higher doses of temsirolimus were used but were poorly tolerated (grade 2/3 stomatitis) when combined with long-term endocrine therapy (Baselga et al. 2004). Efficacy results have suggested similar response rates for the combination compared with letrozole alone. However, clinical endpoints using objective tumor response rates in small, nonrandomized phase II studies must be viewed cautiously, and the primary role of such studies should be to provide safety and supportive biologic data for the combination in advance of definitive randomized trials. A large-scale phase III clinical trial with an orally active formulation of temsirolimus (30mg for 5 out of 14 days) in combination with letrozole has started, and aims to recruit over 1200 postmenopausal patients with ER-positive, locally advanced/metasatic breast cancer that are suitable for first-line hormonal therapy with an aromatase inhibitor. The primary endpoint of this study will be progression-free survival. A similar, randomized phase III study assessing letrozole with or without everolimus is also underway.

	Presurgical biomarker studies of endocrine/STI therapy

Top Abstract Introduction Preclinical efficacy of... Enhanced anticancer effects for... Clinical trials with... Presurgical biomarker studies of... Conclusion — challenges... References

 
Randomized clinical trials of endocrine/STI therapy in metastatic breast cancer, as outlined above, are large and expensive, and always run the risk of a very heterogeneous patient population, making results potentially difficult to interpret. If any benefit for the combined therapy exists, its use in the adjuvant setting needs ultimately to be tested to see whether survival from breast cancer can be enhanced further beyond the improvement already seen with aromatase inhibitors by such an approach (ATAC Trialists 2002). However, large, randomized, adjuvant clinical trials to establish whether any benefit exists for combined endocrine/STI therapy versus endocrine therapy alone will involve many thousands of patients with follow-up extending over many years before first results emerge. Reliable intermediate endpoints that allow a more rapid evaluation of the potential benefit of combined endocrine/STI therapy in early breast cancer would be of enormous value. The neoadjuvant (preoperative) setting in which medical therapies are given and evaluated prior to surgery is being increasingly exploited with these issues in mind (Ayers et al. 2004). Clinical response to neoadjuvant chemotherapy has been found to predict disease-free survival and overall survival (Fisher et al. 1998), but there are no direct data to confirm this for endocrine therapy.

Changes in the biologic determinants of tumor regression or progression, namely, proliferation and apoptosis, might be able to provide an earlier – and possibly more reliable — prediction of long-term outcome. Data from relatively small studies supported the possibility that biomarkers may predict tumor response to chemotherapy (Chang et al. 2000). In a neoadjuvant endocrine therapy trial, the aromatase inhibitor vorozole was compared with tamoxifen, and after 2 weeks it showed a greater fall in Ki-67 (58% vs 43%, respectively) that was weakly associated with clinical response at 12 weeks (Harper-Wynne et al. 2002). In the recently reported IMPACT trial, the neoadjuvant use of tamoxifen versus the third-generation aromatase inhibitor anastrozole versus the combination was compared in 330 postmenopausal patients with primary ER-positive breast cancer (Dowsett et al. 2005). Suppression of the proliferation marker Ki-67 after 2 and 12 weeks was significantly greater with anastrozole than with tamoxifen (P=0.004 and P<0.001), but similar between tamoxifen and the combination. There was no significant correlation overall between a fall in Ki-67 and clinical tumor response. However, the 2-week change in Ki-67 in the neoadjuvant IMPACT trial closely paralleled the improved recurrence-free survival seen after 5 years in the adjuvant ATAC trial that compared these same agents in the adjuvant setting (ATAC Trialists 2002). For the first time, therefore, change in an intermediate biomarker in an endocrine therapy trial may predict for the subsequent long-term outcome, and provide a quicker and more reliable outcome measure than clinical response criteria alone.

This approach is now being tested for combined endocrine/STI therapy in presurgical neoadjuvant studies. Figure 4 shows the design of a multicenter, double-blind, randomized, controlled trial that will assess whether the addition of the TKI gefitinib to anastrozole will improve its efficacy. A novel aspect is that the primary endpoint will be change in cell proliferation as assessed by Ki-67. In addition, the design will look at whether the change in Ki-67 after just 2 weeks of therapy can predict long-term benefit of therapy for the combination (arm A) versus endocrine therapy alone (arm C), and in arm B whether the addition of gefitinib after an initial 2 weeks of therapy with anastrozole can further lower Ki-67 in those tumors that do not response to initial aromatase inhibitor therapy. Secondary endpoints will include clinical response, tolerability and pharmacokinetics, as well as proteomics and gene expression profiles that may predict response to therapy. Recruitment to the trial is well underway. A similar design is being considered for the combination of the mTOR antagonist everolimus and letrozole in the neoadjuvant setting.

View larger version (43K): [in this window] [in a new window]   Figure 4 Design of a presurgical, randomized, placebo-controlled trial of anastrozole with or without gefitinib in postmenopausal women with operable ER-positive, primary breast cancer. MAPK, mitogen activated protein kinase.

	Conclusion — challenges for development of STIs in breast cancer

Top Abstract Introduction Preclinical efficacy of... Enhanced anticancer effects for... Clinical trials with... Presurgical biomarker studies of... Conclusion — challenges... References

	Acknowledgements

 
The author declares that there is no conflict of interest that would prejudice the impartiality of this scientific work.

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Top Abstract Introduction Preclinical efficacy of... Enhanced anticancer effects for... Clinical trials with... Presurgical biomarker studies of... Conclusion — challenges... References

 
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