Abstract
Anti-hormones (notably tamoxifen), chemotherapy and modern radiotherapeutic approaches are invaluable in the management of breast cancer, and collectively have contributed substantially to the improved survival in this disease. Moreover, there is promise that these successes will continue with the emergence of other endocrine agents (for example, aromatase inhibitors and pure anti-oestrogens). However, de novo and acquired resistance comprises a significant problem with all treatment approaches examined to date. This Workshop aimed to evaluate the contribution made by growth factor signalling pathways in the various resistant states, primarily focusing on resistance to anti-hormonal strategies and spanning experimental models and, where possible, clinical breast cancer data. The successes and limitations of therapeutic targeting of these pathways with various signal transduction inhibitors (STIs) were evaluated in model systems and from emerging clinical trials (including epidermal growth factor receptor inhibitors such as gefitinib). It was concluded that growth factor signalling is an important contributor in the development of endocrine resistance in breast cancer and that use of STIs provides a promising therapeutic strategy for this disease. However, the cancer cell is clearly able to harness alternative growth factor signalling pathways for growth and cell survival in the presence of STI monotherapy and, as a consequence, the efficacy of STIs is likely to be limited by the acquisition of resistance. A number of strategies were proposed from studies in model systems that appeared to enhance anti-tumour actions of existing STI monotherapy, notably including combination therapies targeting multiple pathways. With the increased availability of diverse STIs and improved drug delivery, there is much hope that the more complex therapeutic strategies proposed may ultimately be achievable in clinical practice.
Introduction
Anti-hormones (notably the selective oestrogen receptor modulator (SERM) tamoxifen), chemotherapy and modern radiotherapeutic approaches have collectively proved invaluable in the management of breast cancer, both as an adjuvant to surgery and in the advanced disease setting. Indeed, they have contributed substantially to the significant improvement in breast cancer survival that we have seen over recent years. Howell (Howell & Wardley 2005) described how we are furthermore on track for continued improvement, with several exciting new anti-hormones reaching the clinic. Of particular note are the aromatase inhibitors (e.g. anastrazole, letrozole and exemestane) and the pure anti-oestrogens (notably fulvestrant (Faslodex)). Both classes are valuable when tamoxifen fails in oestrogen receptor-positive (ER+) disease, while the former are emerging as superior to tamoxifen in the advanced disease and adjuvant setting. However, while there is considerable promise for the breast cancer patient, a pervading problem with all conventional therapies is development of resistance and the new anti-hormonal agents do not appear to be spared this limitation. Thus, in addition to those patients who are refractory to therapy de novo, many who initially respond ultimately relapse, having acquired resistance. Unfortunately, resistance can herald aggressive disease progression and metastasis, conferring poorer patient outlook.
The mechanisms underlying resistance in breast cancer remain relatively poorly defined, but their elucidation has potential to reveal new therapeutic targets to treat or even prevent resistance. Of particular interest are growth factor signalling pathways, in which aberrations are common in many solid human tumours. Growth factor signalling is complex and interactive, and cancer cells exhibit inherent plasticity in harnessing these pathways for growth. Nevertheless, the development of new signal transduction inhibitors (STIs) by the pharmacological industry promises future effective therapeutic strategies in cancer. This first Tenovus/ AstraZeneca Workshop provided a timely opportunity for an international panel (i) to reflect on the contribution made by growth factor signalling pathways to therapeutic resistance in experimental and clinical breast cancer, (ii) to evaluate STI experiences in therapeutic resistance and define improved STI strategies and (iii) to identify challenges for the future use of STIs in breast cancer, taking on board new agents in the industrial pipeline and state-of-the-art drug delivery. This Workshop overview document and the associated Workshop articles encompass data predominantly from the presenting groups, spanning model systems and clinical breast cancer.
Altered growth factor signalling commonly contributes to anti-hormone resistance in breast cancer models
Evaluation of the importance of growth factor signalling in resistance to several anti-hormonal strategies is being achieved using diverse methodologies applied to human breast cancer models. Data were presented in this Workshop showing that growth factor signalling can promote both acquired and de novo ER+ resistance to the SERM tamoxifen in breast cancer model systems. In acquired tamoxifen resistance in vitro, Nicholson presented evidence for increased epidermal growth factor receptor (EGFR)/HER2-erk1/2 MAP kinase (MAPK)/protein kinase B (AKT) signalling promoting growth of his TAMR cell line, with the insulin-like growth factor receptor (IGF-1R) facilitating this pathway (Nicholson et al. 2005). Benz described how HER2 overexpression in the ER+ MCF-7/HER2-18 model was associated with de novo tamoxifen resistance, an event appearing to involve increased activity of the transcription factor nuclear factor κB (NFκB) (Zhou et al. 2005). In this latter model, it has previously been shown that HER2-mediated growth remains dependent on ER, with cross-talk of these inputs occurring both at the non-genomic (plasma membrane) and genomic (nuclear)ERlevel. Pathway cross-talk was also noted by Nicholson in his acquired tamoxifen-resistant model, although in this case genomic interactions were predominant with EGFR/HER2-driven kinases impacting on the phosphorylation and transcriptional activity of ER to promote growth factor ligand expression and growth (Nicholson et al. 2005). Clearly, growth factor signalling can be highly interactive withERin tamoxifen resistance and indeed subsequent responses to endocrine strategies can be achieved in both these models. However, Nicholson also showed that under more extreme/ sustained conditions (apparent de novo or following acquisition of resistance to the pure anti-oestrogen fulvestrant), increased growth factor signalling can ultimately be dislocated from ER to drive growth that is completely endocrine insensitive, and may even promote ER loss (Nicholson et al. 2005). Sutherland presented data showing that c-Myc and cyclins D1 and E are major downstream mediators of both growth factor and steroid signalling pathways in breast cancer (Butt et al. 2005). Deregulation of these elements, a common event in clinical disease, may similarly circumvent a requirement for ER signalling to promote oestrogen independence and anti-oestrogen resistance.
Growth factor signalling pathways again emerged as important contributors in models of acquired resistance to oestrogen deprivation. Santen used a long-term oestrogen-deprived (LTED) in vitro model to show that increased MAPK/phosphoinositol-3-kinase (PI3K) signalling promotes oestrogen hypersensitive growth (Santen et al. 2005). A contribution of these elements was also shown by Martin in promoting oestrogen hypersensitivity of her LTED cells (Martin et al. 2005), and also in the extreme oestrogen-and growth factor-deprived, non-hypersensitive MCF-7X model described by Gee (Staka et al. 2005). IGF-1R and HER2 (and possibly EGFR) were implicated in the LTED hypersensitive models, although not in the non-hypersensitive MCF-7X model. In all these cell lines, kinase interaction with increased ER appeared important, although the nature of such interplay differed. Santen showed that cross-talk occurred in a non-genomic manner with membrane ER (Santen et al. 2005), while both Martin and Gee implicated genomic cross-talk (Martin et al. 2005; Staka et al. 2005). Further studies are required to clarify these apparent differences.
Altered growth factor signalling is emerging as a contributory factor to resistance in clinical breast cancer
The above studies were performed primarily in models derived from the MCF-7 breast cancer cell line. However, breast cancer is an heterogeneous disease, and it is therefore critical that such model system studies are underpinned by equivalent monitoring of growth factor signalling pathway elements within representative clinical breast cancer material. In this regard, it was clear from this Workshop that much remains to be learned about such signalling in the various forms of resistance to conventional therapies in patients. Nevertheless, the data profiling clinical specimens were not inconsistent with the model systems linking aberrant growth factor signalling and anti-hormone resistance.
With regard to tamoxifen treatment, Gee demonstrated increased EGFR/HER2/MAPK signalling both in acquired and de novo tamoxifen-resistant human breast cancer samples versus the responsive phase of this disease, with signalling most marked in ER–patients (Gee et al. 2005). There were also significant levels of IGF-1R signalling in all tamoxifen-resistant patient groups. Benz showed that higher NFκB DNA-binding activity associated with earlier relapse of ER+patients despite adjuvant therapy with tamoxifen (Zhou et al. 2005). Dowsett and Miller again reported some association between increased EGFR/HER2 and de novo tamoxifen resistance, where overexpression of these receptors associated with diminished impact of this anti-oestrogen on proliferation (Ki67) in preoperative studies (Dowsett et al. 2005; Miller et al. 2005). Some increases in HER2 and signalling through the alternative MAPK p38 were also noted by Dowsett following tamoxifen relapse. As in the model system studies, there was evidence for a retained role for ER in some acquired and de novo tamoxifen-resistant patients. Gee detected ER expression and phosphorylation in many of these patients, with some evidence of EGFR regulation of receptor activity (Gee et al. 2005). Responses to further anti-hormonal strategies are common following tamoxifen relapse, and both Dowsett and Miller showed that aromatase inhibitors can inhibit ER+ de novo tamoxifen-resistant disease in the neoadjuvant setting (Dowsett et al. 2005; Miller et al. 2005). Sutherland presented preliminary data showing that overexpression of cyclin D1 was associated with decreased duration of response to tamoxifen (Butt et al. 2005).
Clinically, there were few data presented regarding growth factor signalling pathway elements in resistance to oestrogen deprivation, although there is clearly a need to profile MAPK and PI3K activity given the in vitro observations. It is possible that erbB receptors do not play a dominant role in promoting ER+ de novo resistance to aromatase inhibitors, since such agents remain valuable in the EGFR+/HER2+ ER+ de novo tamoxifen-resistant cohort. The role of these receptors in acquired resistance to oestrogen deprivation also remains largely unknown, although Miller reported that increased HER2 associated with higher Ki67 levels prior to and during letrozole treatment (Miller et al. 2005). Finally, while few data were available for discussion, Barrett-Lee stated that there was emerging (but not conclusive data) data to relate growth factor signalling to chemotherapeutic and radiotherapeutic response/failure (where further important parameters may include topoisomerase II alpha (TOPOII) and p53) (Barrett-Lee 2005).
Evaluation of STIs in resistant model systems and breast cancer patients in order to define improved STI strategies
Based on the preclinical data presented and results emerging from clinical profiling, STIs could prove valuable in treating several forms of anti-hormone-resistant breast cancer. Excitingly, STIs targeting aspects of EGFR/HER2-MAPK/AKT signalling (notably the anti-EGFR agent gefitinib) and its inter-play with IGF-1R proved to be growth inhibitory in the acquired tamoxifen-resistant model of Nicholson (Nicholson et al. 2005). EGFR inhibition was also valuable in his extreme growth factor signalling ER independent and ER− acquired fulvestrant-resistant models. Benz showed that subversion of NFκB activity was able to improve anti-tumour response in ER+/ HER2+ de novo tamoxifen-resistant models (Zhou et al. 2005). In the LTED and MCF-7X cell models with acquired resistance to oestrogen deprivation, inhibitors of MAPK and also PI3K signalling were shown to be valuable. In LTED cells, Santen showed anti-tumour effects of farnesylthiosalicyclic acid, a Ras signalling pathway inhibitor that is able to reduce activation of MAPK and also of mammalian target of rapamycin (mTOR) (Santen et al. 2005). Targeting of IGF-1R and HER2 was also indicated from the oestrogen-hypersensitive LTED models. In this regard, Martin showed that HER2-targeting using 5 μM gefitinib was inhibitory in LTED cells, although in the non-hypersensitive MCF-7X model EGFR, HER2 and IGF-1R inhibitors were ineffective (Martin et al. 2005).
Based on generally promising preclinical data with STIs, Johnston described how clinical trials using such agents are in progress in breast cancer (Johnston 2005). For example, gefitinib is currently undergoing phase II monotherapy studies in advanced/ metastatic, ER− and recurrent tamoxifen-resistant disease. Robertson described his study that includes ER+ acquired tamoxifen-resistant patients with locally advanced/metastatic disease (Agrawal et al. 2005). All ER+ acquired tamoxifen-resistant tumours examined had detectable (but generally not over-expressed) EGFR. In this patient group, a 66% clinical benefit rate was achieved with gefitinib with an increased time to progression. Sequential biopsies are being collected for this study, taken prior to gefitinib therapy, at 8 weeks and 6 months of treatment, and on disease progression. Encouragingly, in the treated biopsies available for signalling studies, clinical benefit with gefitinib was associated with decreases in proliferation and some parallel inhibition of EGFR signal transduction. These clinical observations appear to be in agreement with the acquired tamoxifen-resistant model described by Nicholson (Nicholson et al. 2005). Furthermore, a 30% response rate is reported with Herceptin in HER2+ patients.
However, it emerged from model data presented at the Workshop that STI monotherapy is unlikely to be sufficient for full anti-tumour activity and that resistance can be acquired or apparent de novo with such agents. There is also evidence that resistance to such agents occurs relatively frequently in the clinic. Thus, response rates to anti-erbB strategies have to date been generally low (albeit largely evaluated in heavily pretreated patients) as described by Johnston (2005), while many HER2+ patients are refractory to Herceptin. Robertson observed, in his acquired tamoxifen-resistance study, that initial response to gefitinib comprised predominantly disease stabilisation, with therapeutic resistance emerging thereafter (Agrawal et al. 2005). Surprisingly, he also noted limited efficacy within the ER−/EGFR+ patient cohort. Clearly, resistance to erbB inhibitors does not simply equate with lack of the target receptor.
The signalling mechanisms of de novo and acquired resistance to STIs such as gefitinib remain largely unexplored in the patient and this will require a concerted future effort to obtain appropriate clinical trial samples to address this deficiency. However, data were available regarding the signalling pathways that limit STI monotherapy effects within several model systems in this Workshop. Based on knowledge of these monotherapy resistance mechanisms, new STI strategies were rationally designed to improve the antitumour effect and these were subsequently tested within the models. These included combination treatments, STIs targeting multiple receptors, and limited data on STIs used in sequence. A key feature associated with improved anti-tumour effect appeared to be promotion of substantial cell loss, an event achieved with several of the combination treatment strategies examined experimentally.
Combined STI treatment with anti-hormones
Incomplete inhibition of ER activation was demonstrated by Nicholson and Gee to provide a ready compensatory mechanism that limited tumour response to STI monotherapy in cells resistant to tamoxifen or oestrogen deprivation (Nicholson et al. 2005; Staka et al. 2005). Nicholson showed that some kinase activity and resultant ER phosphorylation remained in acquired tamoxifen-resistant cells during growth inhibition with gefitinib (Nicholson et al. 2005). However, this signalling was eliminated by a combination of gefitinib plus fulvestrant, resulting in substantial cell loss and prevention of the emergence of STI resistance. Similarly, Gee showed incomplete inhibition of ER phosphorylation and transcriptional activity in the presence of a MAPK inhibitor or a PI3K inhibitor, but that triple treatment of both STIs together with fulvestrant to maximally deplete ER activity again resulted in extreme cell loss (Staka et al. 2005). Benz and Johnston both described improved anti-tumour activity of tamoxifen when combined with STIs such as gefitinib in the HER2+ tamoxifen-resistant MCF-7/ HER2-18 model (Zhou et al. 2005; Johnston 2005).
Rationally combining STIs with anti-hormonal strategies (e.g. oestrogen deprivation, tamoxifen or fulvestrant) also exerted improved anti-tumour activity during the anti-hormone responsive phase in models. Nicholson described that compensatory cell survival signalling induced by anti-hormonal challenge (notably including EGFR signalling) allows emergence of anti-hormone resistance but that this can be blocked by combining treatment with gefitinib (Nicholson et al. 2005). This results in substantially decreased proliferation, marked increases in apoptosis, improved growth inhibition and delay/prevention of emergence of anti-hormone resistance. Johnston described how STIs targeting intracellular signalling, including farnesyltransferase inhibitors and mTOR inhibitors, may be valuable when combined with anti-hormones (Johnston 2005). Martin showed that anti-tumour responses to tamoxifen or letrozole can be enhanced in various aromatase-transfected ER+ models (HER2 negative and particularly HER2 positive) by combined treatment with AEE788, an inhibitor of EGFR/ HER2 and vascular endothelial growth factor receptor (VEGFR) (Martin et al. 2005).
Blocking multiple growth factor signalling pathways using combined STI treatment, inhibitors of multiple receptors or sequential STIs
Gullick detailed the multiple erbB receptors and their diverse ligand stimulation, heterodimerisation patterns, receptor mutations and recruited second messengers, and it was clear that this complexity has considerable potential to influence responsiveness and provide resistance mechanisms for selective inhibitors of individual erbB receptors such as gefitinib (Bazley & Gullick 2005). The potential for alternative growth factor signalling pathways to subvert the response to gefitinib was also highlighted by the studies from Jones and Ciardiello (Jones et al. 2005; Bianco et al. 2005). They both demonstrated the considerable potential for increased activation of alternative growth factor signalling, apparent prior to or gained during treatment with anti-EGFR/anti-HER2 agents (e.g. IGF- 1R/insulin receptor (InsR) signalling; VEGFR signalling), to provide a proliferation/cell survival input that can promote acquired or de novo resistance to such agents. Further elements implicated in this regard included phosphatase and tensin homologue deleted on chromosome 10 (PTEN) mutation/constitutive AKT activity, where interestingly Robertson reported that increased AKT activity was also a feature of de novo gefitinib resistance in his patient series with acquired tamoxifen resistance (Agrawal et al. 2005).
These observations allowed the design and testing of a number of new STI strategies in model systems. Jones demonstrated that anti-IGF-1R agents could be valuable in treating gefitinib resistance in vitro, although a more powerful anti-tumour approach appeared to be combination anti-IGF-1R treatment plus gefitinib employed during the gefitinib-responsive phase (Jones et al. 2005). This latter combination brought about cell loss and was able to delay or even prevent the emergence of STI resistance. Improved anti-tumour effects were also reported by Ciardiello combining anti-EGFR treatments with AKT blockade (Bianco et al. 2005). Furthermore, use of ZD6474 (an agent targeting both VEGFR and EGFR) was inhibitory in cells resistant to anti-EGFR agents. However, a markedly superior anti-tumour effect was observed when ZD6474 was used sequentially after anti-EGFR monotherapy in GEO human colon cancer xenografts during the anti-EGFR responsive phase.
Summary and challenges for the future use of STIs in breast cancer
The preclinical data presented at this Workshop demonstrated that growth factor signalling pathways are important in several forms of anti-hormone-resistant breast cancer. The limited data available from the clinical setting were generally compatible with this concept. Moreover, various STIs were able to bring about growth inhibitory effects across the model systems. As such, we are supportive of further clinical evaluation of STIs in breast cancer, and eagerly anticipate the results of ongoing trials with such agents. However, the cancer cells have an inherent ability to harness diverse growth factor signalling pathways for growth advantage and cell survival, processes which may even be facilitated by the use of therapeutic agents including STIs. Because of these escape mechanisms, STI monotherapy is unlikely to prove fully effective and de novo/acquired resistance will again comprise a significant problem; experimental and clinical experience with anti-EGFR or anti-HER2 strategies in cancer to date demonstrate that resistance does occur. A number of more successful strategies with STIs were proposed during the course of this Workshop based on model system studies, notably including various combination therapies where improved anti-tumour activity and the delay/prevention of resistance can be achieved.
The proposed strategies were rationally designed around a knowledge of monotherapy escape mechanisms in model systems (for example: residual ER activity in several forms of anti-hormone resistance limiting response to various STIs; EGFR induction limiting response to anti-oestrogens; IGF-1R/InsR, AKT and VEGFR signalling limiting response to anti- EGFR or anti-HER2 agents). These various resistance mechanisms need to be confirmed in appropriate patient material to support the proposed strategies. A further gain from such mechanistic studies would be the identification of biological markers predictive of monotherapy response/resistance in patients. There is therefore an urgent priority that responsive, de novo resistant and acquired resistance tumour samples be collected from ongoing and proposed STI clinical trials for the monitoring of signal transduction elements. Improved patient recruitment is vital in this regard. In addition, development of reproducible, sensitive assays should continue so that we can measure growth factor signalling pathway activation with increased accuracy in clinical material. Previous experience with neoadjuvant studies described by Miller and Dowsett indicate that this approach has considerable potential to study mechanisms of STI response and de novo resistance in patients, and indeed these types of studies are already ongoing, monitoring cell biological and molecular endpoints during treatment with agents such as gefitinib (Miller et al. 2005; Dowsett et al. 2005). Such neoadjuvant trials may also begin to reveal mechanisms associated with the very early stages of acquired resistance. However, access to patient samples treated for more extended durations will be essential in order to fully study the compensatory growth factor pathways triggered to promote acquired resistance. Access to sequential tumour samples from locally advanced/ metastatic disease patients taken prior to, during treatment and following relapse with STIs will be valuable in this regard (as demonstrated in studies from Robertson) (Agrawal et al. 2005).
Notwithstanding the requirement for access to appropriate clinical material, however, we believe that the data presented here from model systems provide a powerful proof-of-principle that should expedite clinical exploitation of the various proposed therapeutic scenarios with STIs in order to maximise their benefit. Combination strategies, either with endocrine agents or other STIs, appear to be particularly high priority. It was therefore exciting to hear from Wakeling, Johnston and Robertson that clinical trials of combination treatments with anti-oestrogens or aromatase inhibitors and STIs have already commenced in anti-hormone- responsive/resistant breast cancer, while other trials using combinations of erbB inhibitors/ inhibitors of multiple erbB receptors are also emerging (Wakeling 2005; Johnston 2003; Agrawal et al. 2005). Many of these trials are in the neoadjuvant setting and so will allow us to explore mechanisms of response at the cellular end-point and signal transduction level. Such knowledge will be important to determine well tolerated, inhibitory doses and to select breast cancer patient cohorts with the appropriate molecular targets for combination treatment. Measurement of proliferation changes should comprise one of the end-points to assess cellular effect of combination therapy; robust evaluation of apoptotic index would also be valuable since there is overt cell loss with such approaches preclinically. While studies will focus on advanced disease in the first instance, it is our belief that such strategies should also be considered in the adjuvant setting to evaluate potential long-term side-effects. Indeed, in early disease, tumour cells may be inherently less flexible in their ability to recruit alternative pathways for growth and so may be more vulnerable to effective STI challenge.
Wakeling described how many new agents inhibiting aspects of growth factor receptor pathways are now in the pharmaceutical pipeline, including those targeting EGFR, EGFR/VEGFR, Src, prenyl transferases, MEK1/2 and cell cycle kinases (Wakeling 2005). This increased access to diverse STIs will certainly expand our capacity for rational mono- and combined therapies in cancer. It was also encouraging to hear from Duncan that state-of-the-art drug delivery may allow more efficient and specific therapeutic targeting of the cancer cell, potentially allowing the complex therapeutic targeting strategies proposed in this Workshop to become a reality (Duncan et al. 2005).
The Organising Committee would like to thank all participants for their contribution towards the success of this Workshop.
Funding
This workshop was generously supported by the Tenovus organisation and AstraZeneca. The authors declare the following potential conflicts of interest regarding this research: R I Nicholson, H E Jones, J M W Gee and F Ciardiello are in receipt of research grants from AstraZeneca; R I Nicholson and J F Robertson have been Advisory Board members for AstraZeneca; A Howell has received Speaker’s honoraria and is an Advisory Board member for AstraZeneca, Novartis, Pfizer, Wyeth and Roche. Details of funding for the research contributions to this workshop are provided in each associated article.
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