- Email: [email protected]
S5 Aiming at the target: In the crosshairs or the crossfire?
S2
Session 1. News since St.Gallen 2007
been driven by a number of factors including: changes in reproductive history (earlier menarche, delayed child bearing), changes in diet and life style (e.g. body mass index), the implementation of screening (with its immediate and long term effects), and the use of exogenous agents such as hormonal agents at menopause. The influence of hormonal therapy (HT) at menopause has been widely studied both in terms of its influence of general health (in particular on cardiovascular health) and it terms of its influence on breast cancer risk. This therapy was introduced without large randomized trials to evaluate its safety and efficacy, and thus there was uncertainty as to its value. This uncertainly has been addressed by recent large epidemiologic studies, and by blinded placebo controlled randomized trials. The results of these studies have profoundly changed the use of HT by postmenopausal women. The interpretation of the epidemiologic studies has been complex because of confounding factors. A meta-analysis of these studies published now 10 years ago showed that the use of HT was associated with an increase in the risk of breast cancer.[1] The increase was greater with increased with duration, and seemed to be reversible in that the risk of elevated in current users but appeared to decrease to base line after stopping therapy. These results were confirmed by the most recent Million Women Study (a 1.3 and 2.0 fold increased risk for unopposed estrogen and regimens including a progestin respectively).[2] More influential have been the randomized studies of HT in postmenopausal women. The HERS study was designed to address whether HT had cardioprotective effects in women with a history of cardiovascular disease.[3] To the surprise of some cardioprotective effects were not seen. Even more influential studies were those of the Women’s Health Initiative. The first publication of these results occurred in July of 2002.[4] These results showed that for the average participant in the study treatment had a negative net effect. Although these estimates focusing on the “average” participant do not reflect all the nuances such as the effects of prior therapy, adherence to protocol treatment, and other effects, they are generally accepted and have result in a major decline the use of postmenopausal HT in the United States[5], and elsewhere. Because this decline in use was very large and sudden it is the basis of a large natural experiment and might be expected to then be reflected in a decrease in breast cancer increase. In fact such a decrease in breast cancer incidence has been observed in data from the SEER tumor registry in the United States.[6] Evidence consistent with this decline being predominately due to HT is that the decrease appears to start in the later half of 2002, occur only in women older that 50, and is predominiately be due to decrease in estrogen receptor positive breast cancer. The modest decrease in mammographic screening seen at that time does not rule out that a change screening might have a contributed some to the decline in breast cancer incidence. Other North American studies have strengthened the argument that the effect is largely or entirely due to the change in HT use. A study of registries in California showed there was a direct correlation between the use of HT in different counties and breast cancer incidence. In addtion when HT use decreased, incidence decreased, in a situation where there was no change in mammography rates. Other data from Australia, Canada, and Europe support the initial North American observation. Finally the WHI trial has recently reported in detail on what happened to the women on the combined therapy trial after they stopped taking HRT. In July 2002 all participants in the trial were notified of the results and stopped 96% of them reported stopping HRT. Results show that in the treatment group the increased relative risk breast cancer rapidly declined. Screening mammography rates were the same in both groups. Thus there is compelling epidemiologic and clinical trial evidence that the use of HT by postmenopausal women is associated with an increased risk of breast cancer. This increase in risk appears to be correlated with the duration of use and is reversible; important information for women deciding whether to use HT at menopause. References [1] [2] [3] [4] [5] [6] [7] [8]
Lancet 1997; 350: 1047−59. Lancet 2003; 362: 419−27. J Am Med Assoc 2002; 288: 49−57. J Am Med Assoc 2002; 288: 321−33. J Am Med Assoc 2004; 291: 47−53. N Engl J Med 2007; 356: 1670−4. Natl Cancer Inst 2007; 99: 1152−61. San Antonio Breast Cancer Symposium, December 2008. Abstract 64.
Wednesday, 11 March 2009
S4
Did we learn more about adjuvant chemotherapy? The dark side of data from clinical trials
C. Oakman1 , A. Di Leo1 . 1 “Sandro Pitigliani” Medical Oncology Unit, Istituto Toscano Tumori, Hospital of Prato, Prato, Italy The role of adjuvant chemotherapy is to treat micrometastatic disease and prevent the onset of incurable metastatic disease. We know that adjuvant chemotherapy leads to improved relapse free and overall survival in the general breast cancer population. We now understand that breast cancer is a heterogenous disease, with subgroups reflecting diverse pathophysiologies. As our understanding of tumour biology evolves, so must our undertaking of ‘targeted’ therapies. In the absence of measurable micrometastatic disease being directly linked with relapse, we depend on characteristics of the primary tumour to assess risk. Traditionally these features have included tumour size, grade and lymph node involvement, and host age and menopausal status. More recently, we are seeing multigene signatures and specific biomarkers. The critical issue in adjuvant chemotherapy is identification of patients who have chemosensitive tumours and micro-metastatic disease. Risk of relapse, unfortunately, does not always correlate with chemosensitivity, and cytotoxic therapy in patients with chemorefractory disease may be ineffective and associated only with toxicity. Large adjuvant trials, over many years, have randomised thousands of women with early breast cancer to different regimens. However in clinical practice with an individual patient, we still have the difficulty of targeting her individual therapy, as results relating to the average trial population are often not transferable to the individual. Assessment of specific biomarkers as predictive tools may individualise care. Already with trastuzumab, we have a subgroup predicted by Her2 gene amplification. Anthracyclines and taxanes, whilst widely used, do not yet have prospectively proven biomarkers to predict response. Potential biomarkers for anthracyclines include topoisomerase II alpha and markers of DNA repair dysfunction, whilst for taxanes microtubule-associated proteins may play a role. Rather than general sensitivity to cytotoxics, we need predictive biomarkers to guide which specific therapy will be effective in a particular patient. The heterogeneity of tumours should be reflected in heterogeneity of intervention.
S5
Aiming at the target: In the crosshairs or the crossfire?
M. Piccart-Gebhart1 , P.L. Bedard2 , P. Dinh2 . 1 Medicine Department, Jules Bordet Institute, 2 Jules Bordet Institute − BIG, Brussels, Belgium The guiding principle of targeted oncology is that targeted therapies are only effective in patients with characteristic molecular alterations. Early studies with trastuzumab in metastatic breast cancer were in line with this way of thinking; only patients with HER-2 positive disease, marked by FISH-detected HER-2 gene amplification and/or IHC 3+ protein overexpression, benefited from the addition of a monoclonal antibody directed against the HER-2 receptor. Likewise, prior Oxford overviews have clearly established that endocrine therapy is only effective in patients with ERpositive disease. Patients with receptor positive disease were then further stratified into “highly endocrine-responsive” and “incompletely endocrineresponsive” based upon the absolute value of endocrine receptor expression present and other features such as the proliferation index. Recently, data from the adjuvant trastuzumab trials challenge this paradigm that responsiveness to a targeted therapy is proportional to the quantity of the target present. Central FISH-testing in the HERA trial did not demonstrate a clear relationship between the magnitude of HER-2 gene amplification and the degree of benefit from adjuvant trastuzumab. Similarly, central review of N9831 failed to show that numerical chromosome 17 abnormalities were predictive of trastuzumab response. Provocative data from the NSABP B31 trial indicate that patients with centrally confirmed HER-2 negative disease may derive similar benefits from adjuvant trastuzumab as centrallyconfirmed HER-2 positive patients, implying that the mechanism of action of trastuzumab may be different in early versus advanced disease. These results, however, are based on a very small number of events and should be interpreted with great caution. An intriguing observation made by our Greek colleagues is that trastuzumab is able to clear from the blood HER2-positive circulating cancer cells which can be detected in up to one third of women with HER2-negative primary tumours who have completed adjuvant chemotherapy. A randomized clinical trial aimed at validating this
Wednesday, 11 March 2009
Session 2. Biology of breast cancer I: Clinical relevance of biological findings
observation − as well as its potential impact on clinical outcome − is under preparation. Rapid advances in technology will undoubtedly reveal many other exciting therapeutic targets in the near future. High-throughput DNA sequencing platforms will dramatically accelerate translational research, by enabling whole genome analysis to identify mutated genes that can be modulated by a new generation of targeted therapies. The early experience with whole genome sequencing of a limited number of tumours demonstrates that distinguishing between “driver mutations” − that promote oncogenic transformation − and “passenger mutations” − that reflect underlying genomic instability − is inherently difficult. Sorting through the vast quantities of data generated by these high-throughput sequencing technologies to discern druggable targets in different subtypes of breast cancer will be an important challenge. Moreover, there is a growing recognition that tumours within individual patients demonstrate marked molecular heterogeneity, highlighted by the discovery of stem-like cancer cells and their relationship to the epithelial mesenchymal transition (EMT) that drives metastatic progression. Testing rationale therapeutic strategies to account for intratumoural heterogeneity will add an additional layer of complexity. As the evolving story of trastuzumab illustrates, we still have much to learn about identification and modulation of the HER-2 target more than 25 years after its initial discovery. Further progress in the field of targeted therapy will require innovation in the design and conduct of clinical trials, integrating emerging technologies and discoveries in basic science research with novel approaches to patient selection, response evaluation, and statistical analysis. The Breast International Group (BIG) is building a platform of expertise for the efficient conduct of such innovative trials that hope to delineate − early on − whether a new targeted drug has clinical potential in a molecularly defined subpopulation of patients.
Wednesday, 11 March 2009
17.30–18.45
Session 2. Biology of breast cancer I: Clinical relevance of biological findings S6
Mining the steroid receptor cistrome for novel targets, biomarkers and risk alleles
M. Brown1 . 1 Medical Oncology, Dana-Farber Cancer Institute, Boston, USA Sequencing of the human genome has allowed the near complete identification of the expressed regions of protein-coding genes, however, little is known on a genomic scale concerning the organization of the cisregulatory elements. Steroid hormone receptors such as the estrogen (ER), progesterone (PR), and androgen (AR) receptors act as ligandregulated transcription factors that play critical roles in normal physiology and pathologic functions in breast cancer. An understanding of the regulatory networks controlled by these receptors is fundamental to the understanding of steroid hormone biology. We have taken an unbiased approach combining chromatin immunoprecipitation with oligonucleotide microarrays (ChIP-chip) or more recently high throughput sequencing (ChIP-seq) to identify the complete set of steroid receptor regulatory sites. We coined the term CISTROME to define the set of cis-regulatory targets of trans-acting factors across the entire genome. The analyses of steroid receptor cistromes combined with gene expression profiling data have revealed new insights into the organization of hormone-responsive genes and the existence of a transcription factor and epigenomic code that dictates cellular responses to steroid hormones. Mining of the steroid receptor cistromes in breast cancer has led to the discovery of factors involved in the development of endocrine resistance. These factors are being tested as both predictive biomarkers and as therapeutic targets. Finally genomewide association studies in breast cancer have implicated causal variants that are frequently outside of the protein coding regions of genes. We are currently testing whether these breast cancer risk alleles reside within regulatory regions defined by the cistromes of steroid receptors or other transcription factors that play important roles in hormone-dependent breast cancer.
S7
S3
EGFR and HER2: Systemic approaches to oncogenic networks and to pharmaceutical perturbations
Y. Yarden1 . 1 Department of Biological Regulation, The Weizmann Institute of Science, Rehovot, Israel Growth factors and their transmembrane receptors contribute to all steps of tumor progression, from the initial phase of clonal expansion, through angiogenesis to metastasis. An important example comprises the epidermal growth factor (EGF) and the respective receptor tyrosine kinase, namely ErbB-1/EGFR, which belongs to a prototype signaling module that drives carcinoma development. The extended module includes two autonomous receptors, EGFR and ErbB-4, and two non-autonomous receptors, namely: a ligand-less oncogenic receptor, HER2/ErbB-2, and a kinase-dead receptor (ErbB-3). This signaling module is richly involved in human cancer and already serves as a target for several cancer drugs. From an evolutionary point of view, the four receptors and dozen ligands evolved from a single ligand–receptor pair, which throws light on network evolution and features conferring robust operation. Due to inherent complexity and a large amount of experimental data, we propose a systemic approach to understanding ErbB signaling in mammals. EGF-to-ErbB signaling is envisioned as a bow-tie configured network, sharing modularity, redundancy and control circuits with robust biological and engineered systems. Our work concentrates on system controls, a plethora of positive and negative feedback loops, which include rapidly synthesized ligands of ErbBs (e.g., transforming growth factor alpha), E3 ubiquitin ligases (e.g., Cbl and Nedd4), receptor endocytosis and newly transcribed genes. Because network fragility is an inevitable tradeoff of robustness, systems level understanding is expected to identify therapeutic opportunities for targeting aberrant activation of the network in human pathologies. Specific examples include anti-receptor monoclonal antibodies, such as Trastuzumab, as well as dual-specificity kinase inhibitors, such as Lapatinib, drugs targeting essential network hubs. Combinations of targeted therapies and chemo- or radiotherapy are relatively effective in clinical settings, but the underlying molecular mechanisms remain incompletely understood. Another fragile aspect of oncogenic networks, especially those incorporating protein kinases, comprises reliance on chaperones. Accordingly, chaperone inhibitors, such as blockers of the nucleotide binding site of heat shock protein 90, may develop into effective drugs. Upon inhibition of HSP90 or the binding site at the kinase domain of HER2, the oncogenic kinase is directed to degradation in proteasomes. Mechanisms underlying response to approved, as well as experimental drugs, and evolvement of secondary patient resistance will be discussed.
S8
Integrating molecular profiling, histologic type and other variables: Defining the fingerprint of responsiveness to treatment
G. Viale1 . 1 Department of Pathology, University of Milan, European Institute of Oncology, Milan, Italy One of the most important aims of the multidisciplinary approach to patients with breast carcinoma is tailoring systemic treatments. To achieve this goal several questions remain to be addressed, including who are the patients that could be spared chemotherapy, who are those getting the greatest benefit from aromatase inhibitors, and who is benefitting most from the different anti-HER2 interventions? Much has been done in the past to select the candidate patients to different treatments, but it is now necessary to identify, among the candidate patients, those who actually are responsive to a given treatment. Undoubtedly, responsiveness to different treatments is determined by multifactorial processes, and it is very unlikely that it will ever be possible to predict tumor response to a given treatment by the analysis of a single (or a few) parameters. On the other side, it is also unrealistic − at least for the time being − to conclude that gene expression profiling (by whole genome screening or by targeting a finite number of genes) is the only viable and reliable approach to predict tumor responsiveness. A more feasible and cost-effective way of addressing this issue is to adopt a hierarchical approach, starting from the traditional morphological examination of the tumor samples, then performing a complete and accurate immunohistochemical assay for the relevant predictive parameters, and eventually adding the more sophisticated molecular assays to address additional questions or to refine the predictive model.
Session 1. News since St.Gallen 2007
been driven by a number of factors including: changes in reproductive history (earlier menarche, delayed child bearing), changes in diet and life style (e.g. body mass index), the implementation of screening (with its immediate and long term effects), and the use of exogenous agents such as hormonal agents at menopause. The influence of hormonal therapy (HT) at menopause has been widely studied both in terms of its influence of general health (in particular on cardiovascular health) and it terms of its influence on breast cancer risk. This therapy was introduced without large randomized trials to evaluate its safety and efficacy, and thus there was uncertainty as to its value. This uncertainly has been addressed by recent large epidemiologic studies, and by blinded placebo controlled randomized trials. The results of these studies have profoundly changed the use of HT by postmenopausal women. The interpretation of the epidemiologic studies has been complex because of confounding factors. A meta-analysis of these studies published now 10 years ago showed that the use of HT was associated with an increase in the risk of breast cancer.[1] The increase was greater with increased with duration, and seemed to be reversible in that the risk of elevated in current users but appeared to decrease to base line after stopping therapy. These results were confirmed by the most recent Million Women Study (a 1.3 and 2.0 fold increased risk for unopposed estrogen and regimens including a progestin respectively).[2] More influential have been the randomized studies of HT in postmenopausal women. The HERS study was designed to address whether HT had cardioprotective effects in women with a history of cardiovascular disease.[3] To the surprise of some cardioprotective effects were not seen. Even more influential studies were those of the Women’s Health Initiative. The first publication of these results occurred in July of 2002.[4] These results showed that for the average participant in the study treatment had a negative net effect. Although these estimates focusing on the “average” participant do not reflect all the nuances such as the effects of prior therapy, adherence to protocol treatment, and other effects, they are generally accepted and have result in a major decline the use of postmenopausal HT in the United States[5], and elsewhere. Because this decline in use was very large and sudden it is the basis of a large natural experiment and might be expected to then be reflected in a decrease in breast cancer increase. In fact such a decrease in breast cancer incidence has been observed in data from the SEER tumor registry in the United States.[6] Evidence consistent with this decline being predominately due to HT is that the decrease appears to start in the later half of 2002, occur only in women older that 50, and is predominiately be due to decrease in estrogen receptor positive breast cancer. The modest decrease in mammographic screening seen at that time does not rule out that a change screening might have a contributed some to the decline in breast cancer incidence. Other North American studies have strengthened the argument that the effect is largely or entirely due to the change in HT use. A study of registries in California showed there was a direct correlation between the use of HT in different counties and breast cancer incidence. In addtion when HT use decreased, incidence decreased, in a situation where there was no change in mammography rates. Other data from Australia, Canada, and Europe support the initial North American observation. Finally the WHI trial has recently reported in detail on what happened to the women on the combined therapy trial after they stopped taking HRT. In July 2002 all participants in the trial were notified of the results and stopped 96% of them reported stopping HRT. Results show that in the treatment group the increased relative risk breast cancer rapidly declined. Screening mammography rates were the same in both groups. Thus there is compelling epidemiologic and clinical trial evidence that the use of HT by postmenopausal women is associated with an increased risk of breast cancer. This increase in risk appears to be correlated with the duration of use and is reversible; important information for women deciding whether to use HT at menopause. References [1] [2] [3] [4] [5] [6] [7] [8]
Lancet 1997; 350: 1047−59. Lancet 2003; 362: 419−27. J Am Med Assoc 2002; 288: 49−57. J Am Med Assoc 2002; 288: 321−33. J Am Med Assoc 2004; 291: 47−53. N Engl J Med 2007; 356: 1670−4. Natl Cancer Inst 2007; 99: 1152−61. San Antonio Breast Cancer Symposium, December 2008. Abstract 64.
Wednesday, 11 March 2009
S4
Did we learn more about adjuvant chemotherapy? The dark side of data from clinical trials
C. Oakman1 , A. Di Leo1 . 1 “Sandro Pitigliani” Medical Oncology Unit, Istituto Toscano Tumori, Hospital of Prato, Prato, Italy The role of adjuvant chemotherapy is to treat micrometastatic disease and prevent the onset of incurable metastatic disease. We know that adjuvant chemotherapy leads to improved relapse free and overall survival in the general breast cancer population. We now understand that breast cancer is a heterogenous disease, with subgroups reflecting diverse pathophysiologies. As our understanding of tumour biology evolves, so must our undertaking of ‘targeted’ therapies. In the absence of measurable micrometastatic disease being directly linked with relapse, we depend on characteristics of the primary tumour to assess risk. Traditionally these features have included tumour size, grade and lymph node involvement, and host age and menopausal status. More recently, we are seeing multigene signatures and specific biomarkers. The critical issue in adjuvant chemotherapy is identification of patients who have chemosensitive tumours and micro-metastatic disease. Risk of relapse, unfortunately, does not always correlate with chemosensitivity, and cytotoxic therapy in patients with chemorefractory disease may be ineffective and associated only with toxicity. Large adjuvant trials, over many years, have randomised thousands of women with early breast cancer to different regimens. However in clinical practice with an individual patient, we still have the difficulty of targeting her individual therapy, as results relating to the average trial population are often not transferable to the individual. Assessment of specific biomarkers as predictive tools may individualise care. Already with trastuzumab, we have a subgroup predicted by Her2 gene amplification. Anthracyclines and taxanes, whilst widely used, do not yet have prospectively proven biomarkers to predict response. Potential biomarkers for anthracyclines include topoisomerase II alpha and markers of DNA repair dysfunction, whilst for taxanes microtubule-associated proteins may play a role. Rather than general sensitivity to cytotoxics, we need predictive biomarkers to guide which specific therapy will be effective in a particular patient. The heterogeneity of tumours should be reflected in heterogeneity of intervention.
S5
Aiming at the target: In the crosshairs or the crossfire?
M. Piccart-Gebhart1 , P.L. Bedard2 , P. Dinh2 . 1 Medicine Department, Jules Bordet Institute, 2 Jules Bordet Institute − BIG, Brussels, Belgium The guiding principle of targeted oncology is that targeted therapies are only effective in patients with characteristic molecular alterations. Early studies with trastuzumab in metastatic breast cancer were in line with this way of thinking; only patients with HER-2 positive disease, marked by FISH-detected HER-2 gene amplification and/or IHC 3+ protein overexpression, benefited from the addition of a monoclonal antibody directed against the HER-2 receptor. Likewise, prior Oxford overviews have clearly established that endocrine therapy is only effective in patients with ERpositive disease. Patients with receptor positive disease were then further stratified into “highly endocrine-responsive” and “incompletely endocrineresponsive” based upon the absolute value of endocrine receptor expression present and other features such as the proliferation index. Recently, data from the adjuvant trastuzumab trials challenge this paradigm that responsiveness to a targeted therapy is proportional to the quantity of the target present. Central FISH-testing in the HERA trial did not demonstrate a clear relationship between the magnitude of HER-2 gene amplification and the degree of benefit from adjuvant trastuzumab. Similarly, central review of N9831 failed to show that numerical chromosome 17 abnormalities were predictive of trastuzumab response. Provocative data from the NSABP B31 trial indicate that patients with centrally confirmed HER-2 negative disease may derive similar benefits from adjuvant trastuzumab as centrallyconfirmed HER-2 positive patients, implying that the mechanism of action of trastuzumab may be different in early versus advanced disease. These results, however, are based on a very small number of events and should be interpreted with great caution. An intriguing observation made by our Greek colleagues is that trastuzumab is able to clear from the blood HER2-positive circulating cancer cells which can be detected in up to one third of women with HER2-negative primary tumours who have completed adjuvant chemotherapy. A randomized clinical trial aimed at validating this
Wednesday, 11 March 2009
Session 2. Biology of breast cancer I: Clinical relevance of biological findings
observation − as well as its potential impact on clinical outcome − is under preparation. Rapid advances in technology will undoubtedly reveal many other exciting therapeutic targets in the near future. High-throughput DNA sequencing platforms will dramatically accelerate translational research, by enabling whole genome analysis to identify mutated genes that can be modulated by a new generation of targeted therapies. The early experience with whole genome sequencing of a limited number of tumours demonstrates that distinguishing between “driver mutations” − that promote oncogenic transformation − and “passenger mutations” − that reflect underlying genomic instability − is inherently difficult. Sorting through the vast quantities of data generated by these high-throughput sequencing technologies to discern druggable targets in different subtypes of breast cancer will be an important challenge. Moreover, there is a growing recognition that tumours within individual patients demonstrate marked molecular heterogeneity, highlighted by the discovery of stem-like cancer cells and their relationship to the epithelial mesenchymal transition (EMT) that drives metastatic progression. Testing rationale therapeutic strategies to account for intratumoural heterogeneity will add an additional layer of complexity. As the evolving story of trastuzumab illustrates, we still have much to learn about identification and modulation of the HER-2 target more than 25 years after its initial discovery. Further progress in the field of targeted therapy will require innovation in the design and conduct of clinical trials, integrating emerging technologies and discoveries in basic science research with novel approaches to patient selection, response evaluation, and statistical analysis. The Breast International Group (BIG) is building a platform of expertise for the efficient conduct of such innovative trials that hope to delineate − early on − whether a new targeted drug has clinical potential in a molecularly defined subpopulation of patients.
Wednesday, 11 March 2009
17.30–18.45
Session 2. Biology of breast cancer I: Clinical relevance of biological findings S6
Mining the steroid receptor cistrome for novel targets, biomarkers and risk alleles
M. Brown1 . 1 Medical Oncology, Dana-Farber Cancer Institute, Boston, USA Sequencing of the human genome has allowed the near complete identification of the expressed regions of protein-coding genes, however, little is known on a genomic scale concerning the organization of the cisregulatory elements. Steroid hormone receptors such as the estrogen (ER), progesterone (PR), and androgen (AR) receptors act as ligandregulated transcription factors that play critical roles in normal physiology and pathologic functions in breast cancer. An understanding of the regulatory networks controlled by these receptors is fundamental to the understanding of steroid hormone biology. We have taken an unbiased approach combining chromatin immunoprecipitation with oligonucleotide microarrays (ChIP-chip) or more recently high throughput sequencing (ChIP-seq) to identify the complete set of steroid receptor regulatory sites. We coined the term CISTROME to define the set of cis-regulatory targets of trans-acting factors across the entire genome. The analyses of steroid receptor cistromes combined with gene expression profiling data have revealed new insights into the organization of hormone-responsive genes and the existence of a transcription factor and epigenomic code that dictates cellular responses to steroid hormones. Mining of the steroid receptor cistromes in breast cancer has led to the discovery of factors involved in the development of endocrine resistance. These factors are being tested as both predictive biomarkers and as therapeutic targets. Finally genomewide association studies in breast cancer have implicated causal variants that are frequently outside of the protein coding regions of genes. We are currently testing whether these breast cancer risk alleles reside within regulatory regions defined by the cistromes of steroid receptors or other transcription factors that play important roles in hormone-dependent breast cancer.
S7
S3
EGFR and HER2: Systemic approaches to oncogenic networks and to pharmaceutical perturbations
Y. Yarden1 . 1 Department of Biological Regulation, The Weizmann Institute of Science, Rehovot, Israel Growth factors and their transmembrane receptors contribute to all steps of tumor progression, from the initial phase of clonal expansion, through angiogenesis to metastasis. An important example comprises the epidermal growth factor (EGF) and the respective receptor tyrosine kinase, namely ErbB-1/EGFR, which belongs to a prototype signaling module that drives carcinoma development. The extended module includes two autonomous receptors, EGFR and ErbB-4, and two non-autonomous receptors, namely: a ligand-less oncogenic receptor, HER2/ErbB-2, and a kinase-dead receptor (ErbB-3). This signaling module is richly involved in human cancer and already serves as a target for several cancer drugs. From an evolutionary point of view, the four receptors and dozen ligands evolved from a single ligand–receptor pair, which throws light on network evolution and features conferring robust operation. Due to inherent complexity and a large amount of experimental data, we propose a systemic approach to understanding ErbB signaling in mammals. EGF-to-ErbB signaling is envisioned as a bow-tie configured network, sharing modularity, redundancy and control circuits with robust biological and engineered systems. Our work concentrates on system controls, a plethora of positive and negative feedback loops, which include rapidly synthesized ligands of ErbBs (e.g., transforming growth factor alpha), E3 ubiquitin ligases (e.g., Cbl and Nedd4), receptor endocytosis and newly transcribed genes. Because network fragility is an inevitable tradeoff of robustness, systems level understanding is expected to identify therapeutic opportunities for targeting aberrant activation of the network in human pathologies. Specific examples include anti-receptor monoclonal antibodies, such as Trastuzumab, as well as dual-specificity kinase inhibitors, such as Lapatinib, drugs targeting essential network hubs. Combinations of targeted therapies and chemo- or radiotherapy are relatively effective in clinical settings, but the underlying molecular mechanisms remain incompletely understood. Another fragile aspect of oncogenic networks, especially those incorporating protein kinases, comprises reliance on chaperones. Accordingly, chaperone inhibitors, such as blockers of the nucleotide binding site of heat shock protein 90, may develop into effective drugs. Upon inhibition of HSP90 or the binding site at the kinase domain of HER2, the oncogenic kinase is directed to degradation in proteasomes. Mechanisms underlying response to approved, as well as experimental drugs, and evolvement of secondary patient resistance will be discussed.
S8
Integrating molecular profiling, histologic type and other variables: Defining the fingerprint of responsiveness to treatment
G. Viale1 . 1 Department of Pathology, University of Milan, European Institute of Oncology, Milan, Italy One of the most important aims of the multidisciplinary approach to patients with breast carcinoma is tailoring systemic treatments. To achieve this goal several questions remain to be addressed, including who are the patients that could be spared chemotherapy, who are those getting the greatest benefit from aromatase inhibitors, and who is benefitting most from the different anti-HER2 interventions? Much has been done in the past to select the candidate patients to different treatments, but it is now necessary to identify, among the candidate patients, those who actually are responsive to a given treatment. Undoubtedly, responsiveness to different treatments is determined by multifactorial processes, and it is very unlikely that it will ever be possible to predict tumor response to a given treatment by the analysis of a single (or a few) parameters. On the other side, it is also unrealistic − at least for the time being − to conclude that gene expression profiling (by whole genome screening or by targeting a finite number of genes) is the only viable and reliable approach to predict tumor responsiveness. A more feasible and cost-effective way of addressing this issue is to adopt a hierarchical approach, starting from the traditional morphological examination of the tumor samples, then performing a complete and accurate immunohistochemical assay for the relevant predictive parameters, and eventually adding the more sophisticated molecular assays to address additional questions or to refine the predictive model.