INTERVIEW For reprint orders, please contact: [email protected]
A journey through breast cancer research Fernando Schmitt speaks to Hannah Branch, Commissioning Editor Professor Fernando Schmitt obtained his medical degree at the University of Santa Maria (Brazil) and spent his pathology residency at the Medical Faculty of Botucatu (Sao Paolo, Brazil). In addition, he completed a Clinical Cytology fellowship at Karolinska Medical Hospital (Stockholm, Sweden). In 1993, Professor Schmitt relocated to Portugal and established a breast pathology research group in addition to a fine-needle aspiration service at the Institute of Pathology and Immunology of University of Porto (Portugal). He was previously Professor of Pathology at the University of Porto, in addition to the Medical Director of the Unit of Pathology at the Institute of Pathology and Immunology of University of Porto. He has recently moved to the University of Toronto (Canada) to act as Full Professor of Pathology. He is a member of 12 national and international societies and has been an author of over 370 manuscripts published in peer-reviewed journals. Professor Schmitt kindly serves as an Editorial Board member for several journals, including Women’s Health.
>>When & why did you first become interested in studying breast cancer?
My interest in studying breast cancer started when I was resident of pathology. I saw many cases of breast lesions in that time and the pre invasive lesions were a challenge for me. I wished to know if the markers that were starting to be described in breast cancer were already present in early/precursor lesions. I proposed this theme for a PhD thesis; however, at that time in my medical faculty in Brazil, only experimental theses were accepted, and the understanding of experimental was ‘studies with animals’. Since, at that time, models for early breast cancer lesions were not established in animals, I did my PhD in liver preneoplastic lesions. However, as soon as I finished the PhD I applied for a postdoctoral project to study precursor breast lesions. I was successful and in 1993 I moved to Portugal to conduct these studies. >>After moving to Portugal in 1993, you established a breast pathology research group. What were your initial goals when creating this group?
When I moved to Portugal, my new institution (Institute of Pathology and Immunology of University of Porto, Portugal) had no groups interested in breast cancer research. Therefore, during my postdoctoral project, I established a research group and one of my first students was Professor Raquel Soares, who today is Vice Dean of the Porto Medical School (Portugal). The initial goals were to understand molecular alterations in precursor lesions of the breast, namely ductal hyperplasias, atypical hyper plasias and in situ carcinoma. In that time, the idea of breast cancer progression was linear; in 10.2217/WHE.13.68 © 2014 Future Medicine Ltd
other words, invasive breast cancer comes from ductal hyperplasias, atypical hyperplasias and in situ carcinoma. We were able to demonstrate that many markers and molecular alterations present in invasive cancer were already present in these preinvasive lesions. The first 2 years were very productive and we published more than ten papers on the subject. We were also involved in a European consortium that was responsible for the discovery of BRCA1 and BRCA2, the most important genes related to hereditary breast cancer.
Fernando Schmitt Department of Pathology, Faculty of Medicine, University of Toronto & University Health Network, Toronto, ON, Canada [email protected]
>>In your opinion, why is studying the genetics of cancer so important?
Studying the genetics of cancer is extremely important as it can bring to us many answers to questions that are still puzzling in cancer research. Today we have very strong tools to study genetic alterations; for example, wholegenome sequencing. In addition to helping understand how cancer progresses and even how cancer starts, the study of genetic alterations can also offer therapeutic alternatives that may allow us to treat cancer in a more logical and efficient way. The discovery of some genetic alterations that are targets for therapy has further modified the research on cancer and helped to save the lives of many patients. HER2 amplifications in breast cancer and CKIT mutations in chronic myeloid leukemia and gastrointestinal stromal tumors are the most well-known examples, but there are many others. In fact, these two genetic alterations showed us that sometimes, even in cancers that are totally different in terms of origin and histology, the same target can be used. HER2 amplification is also a target in gastric cancer today, for example. Women's Health (2014) 10(1), 9–11
part of
ISSN 1745-5057
9
Interview – Schmitt >>What implications could understanding the genetics of breast cancer have on women’s healthcare in the future?
Prevention, early diagnosis and better treatment in local and advanced cancers. The role of BRCA1, BRCA2 and other genes related to hereditary breast cancer have increasingly helped prevent the development of invasive disease in high-risk women. In addition, understanding the genetic alterations in preinvasive lesions and the possibility to predict which in situ lesions will become invasive, and the time frame in which that will occur are some of the most important issues in the breast cancer field. The knowledge of genomic alterations that can be targetable or can be predictive of therapeutic outcomes could have important implications. Today, ER, PR and HER2 are the most important targets in breast cancer; however, I am sure that many others will arise. Moreover, genetic studies can help us to understand why some patients respond very well to certain drugs and not to others, despite the fact they have expression of the same markers. These studies are occurring at the moment. In my opinion, a fundamental point is to study the genetic alterations in metastatic lesions that certainly have differences from the primary tumors. This can be very important for patients with advanced disease. >>You established the role of EGF receptorrelated pathways in the development & progression of breast cancer. How did this discovery come about?
To be honest, my contribution in this field was modest. We worked in a network with other laboratories from around the world and we contributed to demonstrating that EGF receptor alterations are present in some special types of breast cancer, such as metaplastic breast carcinoma. Furthermore, we helped demonstrate that gene overexpression and amplification were present and mutations are exceedingly rare, making this model different from lung cancer and potentially explaining why breast cancer is not responsive to anti-EGF receptor inhibitors, even though lung cancer is. We, as pathologists, were involved in the description of some molecules, such as CTEN, which are transcribed in response to EGF and stimulate cell motility. The laboratory of Professor Yosef Yarden (Weizmann Institute, Rehovot, Israel) demonstrated the role of this molecule in cell lines, and we contributed to the study of expression in human breast cancers. 10
www.futuremedicine.com
>>In 2009, you were president of the 35th European Congress of Cytology (Lisbon, Portugal) & more recently, the Papanicolaou Society of Cytology awarded you as ‘Educator of the Year 2011’. Why do you feel it is so important to educate individuals about cancer, especially the female population?
Education is one of the more powerful weapons against cancer. The awareness of the female population for cervical and breast cancer has helped significantly in prevention and early detection in many countries. Moreover, if the population understands how money is expended in research, it is possible that more donations would be made and there may be more acceptance regarding how money from taxes is been used. For politicians, it may be more viable to inaugurate a new road or bridge than say that they are supporting cancer research. If the people understand how important it is to also invest in cancer research, governments and politicians will pay an increasing amount of attention to it. >>What challenges do you face in your research?
Financing is a big challenge in Europe at the moment. However, it is becoming more and more common that laboratories need to work in a network and apply for joint grants. Another problem is keeping people only doing research. The career of a researcher needs to be regulated and well paid, as it is associated with an efficient system of evaluation. Surely this would attract more qualified individuals and prevent bright young people leaving this career to find another decent-paying job. >>What is your proudest achievement in your career to date?
I have a number of published research results that I am proud of. With the inestimable help of Joana Paredes, our group was fundamental in unraveling the role of P cadherin in breast cancer. The majority of the publications in this field come from our laboratory and we are still working on this molecule, which could be a therapeutic target in breast cancer in the future. The aforementioned work on the EGF receptor is also a reason to be proud. However, what I am most proud after all these years is seeing individuals that I helped to train become reputable researchers. >>If you had access to unlimited resources, what research would you conduct & why?
I would like to conduct a large, multinational clinical trial studying metastases from different future science group
A journey through breast cancer research –
types of cancer using fine-needle aspiration cytology and deep sequencing, and compare the results with the primary tumor. The reason for this is because, as I mentioned before, understanding the genetic differences and similarities between metastases and the primary tumor could help to find better treatment for patients with advanced cancer. There is a lot of evidence for discordance of mutations between primary and corresponding metastatic disease, not only in breast cancer, but also in colorectal, renal and pancreatic cancers, among others. Therefore, being able to characterize and measure clonal heterogeneity is vital to understanding metastasis biology at different sites in addition to the evolution of different clones under the selective pressure of the therapy. Moreover, fine-needle aspiration cytology is an excellent method for sampling metastatic sites with low discomfort for the patients. This simple method, established almost one century ago, is a perfect way to sample different sites of the body and may facilitate the practice of rebiopsy of metastases. >>Where do you see the breast cancer research field in 10 years?
This is a difficult question because the field has changed dramatically in the last few years. In the last decade, we have learnt that breast cancer is not a unique disease. From microarray studies, the first five different molecular subtypes were
future science group
Interview
identified and today, using genomic and transcriptomic landscapes, these were defined as ten integrative clusters of breast cancer. Each one of these clusters correlates with distinct clinical outcomes and provides fresh insights into the underlying biology and potential molecular drives. These findings have significant implications for both the individualization of therapy and a new framework for investigating the underlying biology of each novel subtype. I expect that in the coming years, we can better understand each one of these clusters and bring the potential findings to the clinic, as these could help better treat the patients and further improve the survival and quality of life. Disclaimer The opinions expressed in this interview are those of the interviewee and do not necessarily reflect the views of Future Medicine Ltd. Financial & competing interests disclosure F Schmitt has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript.
Women's Health (2014) 10(1)
11
A journey through breast cancer research Fernando Schmitt speaks to Hannah Branch, Commissioning Editor Professor Fernando Schmitt obtained his medical degree at the University of Santa Maria (Brazil) and spent his pathology residency at the Medical Faculty of Botucatu (Sao Paolo, Brazil). In addition, he completed a Clinical Cytology fellowship at Karolinska Medical Hospital (Stockholm, Sweden). In 1993, Professor Schmitt relocated to Portugal and established a breast pathology research group in addition to a fine-needle aspiration service at the Institute of Pathology and Immunology of University of Porto (Portugal). He was previously Professor of Pathology at the University of Porto, in addition to the Medical Director of the Unit of Pathology at the Institute of Pathology and Immunology of University of Porto. He has recently moved to the University of Toronto (Canada) to act as Full Professor of Pathology. He is a member of 12 national and international societies and has been an author of over 370 manuscripts published in peer-reviewed journals. Professor Schmitt kindly serves as an Editorial Board member for several journals, including Women’s Health.
>>When & why did you first become interested in studying breast cancer?
My interest in studying breast cancer started when I was resident of pathology. I saw many cases of breast lesions in that time and the pre invasive lesions were a challenge for me. I wished to know if the markers that were starting to be described in breast cancer were already present in early/precursor lesions. I proposed this theme for a PhD thesis; however, at that time in my medical faculty in Brazil, only experimental theses were accepted, and the understanding of experimental was ‘studies with animals’. Since, at that time, models for early breast cancer lesions were not established in animals, I did my PhD in liver preneoplastic lesions. However, as soon as I finished the PhD I applied for a postdoctoral project to study precursor breast lesions. I was successful and in 1993 I moved to Portugal to conduct these studies. >>After moving to Portugal in 1993, you established a breast pathology research group. What were your initial goals when creating this group?
When I moved to Portugal, my new institution (Institute of Pathology and Immunology of University of Porto, Portugal) had no groups interested in breast cancer research. Therefore, during my postdoctoral project, I established a research group and one of my first students was Professor Raquel Soares, who today is Vice Dean of the Porto Medical School (Portugal). The initial goals were to understand molecular alterations in precursor lesions of the breast, namely ductal hyperplasias, atypical hyper plasias and in situ carcinoma. In that time, the idea of breast cancer progression was linear; in 10.2217/WHE.13.68 © 2014 Future Medicine Ltd
other words, invasive breast cancer comes from ductal hyperplasias, atypical hyperplasias and in situ carcinoma. We were able to demonstrate that many markers and molecular alterations present in invasive cancer were already present in these preinvasive lesions. The first 2 years were very productive and we published more than ten papers on the subject. We were also involved in a European consortium that was responsible for the discovery of BRCA1 and BRCA2, the most important genes related to hereditary breast cancer.
Fernando Schmitt Department of Pathology, Faculty of Medicine, University of Toronto & University Health Network, Toronto, ON, Canada [email protected]
>>In your opinion, why is studying the genetics of cancer so important?
Studying the genetics of cancer is extremely important as it can bring to us many answers to questions that are still puzzling in cancer research. Today we have very strong tools to study genetic alterations; for example, wholegenome sequencing. In addition to helping understand how cancer progresses and even how cancer starts, the study of genetic alterations can also offer therapeutic alternatives that may allow us to treat cancer in a more logical and efficient way. The discovery of some genetic alterations that are targets for therapy has further modified the research on cancer and helped to save the lives of many patients. HER2 amplifications in breast cancer and CKIT mutations in chronic myeloid leukemia and gastrointestinal stromal tumors are the most well-known examples, but there are many others. In fact, these two genetic alterations showed us that sometimes, even in cancers that are totally different in terms of origin and histology, the same target can be used. HER2 amplification is also a target in gastric cancer today, for example. Women's Health (2014) 10(1), 9–11
part of
ISSN 1745-5057
9
Interview – Schmitt >>What implications could understanding the genetics of breast cancer have on women’s healthcare in the future?
Prevention, early diagnosis and better treatment in local and advanced cancers. The role of BRCA1, BRCA2 and other genes related to hereditary breast cancer have increasingly helped prevent the development of invasive disease in high-risk women. In addition, understanding the genetic alterations in preinvasive lesions and the possibility to predict which in situ lesions will become invasive, and the time frame in which that will occur are some of the most important issues in the breast cancer field. The knowledge of genomic alterations that can be targetable or can be predictive of therapeutic outcomes could have important implications. Today, ER, PR and HER2 are the most important targets in breast cancer; however, I am sure that many others will arise. Moreover, genetic studies can help us to understand why some patients respond very well to certain drugs and not to others, despite the fact they have expression of the same markers. These studies are occurring at the moment. In my opinion, a fundamental point is to study the genetic alterations in metastatic lesions that certainly have differences from the primary tumors. This can be very important for patients with advanced disease. >>You established the role of EGF receptorrelated pathways in the development & progression of breast cancer. How did this discovery come about?
To be honest, my contribution in this field was modest. We worked in a network with other laboratories from around the world and we contributed to demonstrating that EGF receptor alterations are present in some special types of breast cancer, such as metaplastic breast carcinoma. Furthermore, we helped demonstrate that gene overexpression and amplification were present and mutations are exceedingly rare, making this model different from lung cancer and potentially explaining why breast cancer is not responsive to anti-EGF receptor inhibitors, even though lung cancer is. We, as pathologists, were involved in the description of some molecules, such as CTEN, which are transcribed in response to EGF and stimulate cell motility. The laboratory of Professor Yosef Yarden (Weizmann Institute, Rehovot, Israel) demonstrated the role of this molecule in cell lines, and we contributed to the study of expression in human breast cancers. 10
www.futuremedicine.com
>>In 2009, you were president of the 35th European Congress of Cytology (Lisbon, Portugal) & more recently, the Papanicolaou Society of Cytology awarded you as ‘Educator of the Year 2011’. Why do you feel it is so important to educate individuals about cancer, especially the female population?
Education is one of the more powerful weapons against cancer. The awareness of the female population for cervical and breast cancer has helped significantly in prevention and early detection in many countries. Moreover, if the population understands how money is expended in research, it is possible that more donations would be made and there may be more acceptance regarding how money from taxes is been used. For politicians, it may be more viable to inaugurate a new road or bridge than say that they are supporting cancer research. If the people understand how important it is to also invest in cancer research, governments and politicians will pay an increasing amount of attention to it. >>What challenges do you face in your research?
Financing is a big challenge in Europe at the moment. However, it is becoming more and more common that laboratories need to work in a network and apply for joint grants. Another problem is keeping people only doing research. The career of a researcher needs to be regulated and well paid, as it is associated with an efficient system of evaluation. Surely this would attract more qualified individuals and prevent bright young people leaving this career to find another decent-paying job. >>What is your proudest achievement in your career to date?
I have a number of published research results that I am proud of. With the inestimable help of Joana Paredes, our group was fundamental in unraveling the role of P cadherin in breast cancer. The majority of the publications in this field come from our laboratory and we are still working on this molecule, which could be a therapeutic target in breast cancer in the future. The aforementioned work on the EGF receptor is also a reason to be proud. However, what I am most proud after all these years is seeing individuals that I helped to train become reputable researchers. >>If you had access to unlimited resources, what research would you conduct & why?
I would like to conduct a large, multinational clinical trial studying metastases from different future science group
A journey through breast cancer research –
types of cancer using fine-needle aspiration cytology and deep sequencing, and compare the results with the primary tumor. The reason for this is because, as I mentioned before, understanding the genetic differences and similarities between metastases and the primary tumor could help to find better treatment for patients with advanced cancer. There is a lot of evidence for discordance of mutations between primary and corresponding metastatic disease, not only in breast cancer, but also in colorectal, renal and pancreatic cancers, among others. Therefore, being able to characterize and measure clonal heterogeneity is vital to understanding metastasis biology at different sites in addition to the evolution of different clones under the selective pressure of the therapy. Moreover, fine-needle aspiration cytology is an excellent method for sampling metastatic sites with low discomfort for the patients. This simple method, established almost one century ago, is a perfect way to sample different sites of the body and may facilitate the practice of rebiopsy of metastases. >>Where do you see the breast cancer research field in 10 years?
This is a difficult question because the field has changed dramatically in the last few years. In the last decade, we have learnt that breast cancer is not a unique disease. From microarray studies, the first five different molecular subtypes were
future science group
Interview
identified and today, using genomic and transcriptomic landscapes, these were defined as ten integrative clusters of breast cancer. Each one of these clusters correlates with distinct clinical outcomes and provides fresh insights into the underlying biology and potential molecular drives. These findings have significant implications for both the individualization of therapy and a new framework for investigating the underlying biology of each novel subtype. I expect that in the coming years, we can better understand each one of these clusters and bring the potential findings to the clinic, as these could help better treat the patients and further improve the survival and quality of life. Disclaimer The opinions expressed in this interview are those of the interviewee and do not necessarily reflect the views of Future Medicine Ltd. Financial & competing interests disclosure F Schmitt has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript.
Women's Health (2014) 10(1)
11
