Journal of Surgical Oncology 2015;111:1–2
EDITORIAL The Genomic Medicine Paradigm Shift MIRA MILAS, MD* Department of Surgery, Division of Surgical Oncology, Oregon Health and Science University (OHSU), Portland, Oregon
Genomic medicine is here to stay. The timeline it took to get here is quite impressive, when viewed in broad milestones of accomplishments, from discovery of the DNA double helix in the 1950s, recognition of hereditary cancer syndromes in the 1960s, basic molecular biology techniques to study DNA and RNA in the 1970s and 1980s, the Human Genome Project that spanned 1990–2003, and, in the last decade, to genomic profiling of cancer [1,2]. The extraordinary research of this last decade was translated into effective new clinical therapies more rapidly than ever before, especially in the field of oncology. In 2014, the paradigm shift thus refers to the adaptation that will be required of clinical medicine to usher in the future, when thinking about and taking care of a patient becomes inseparable from genetic information. We are at that threshold now, and cancer is a great case in point. Both in scientific and lay venues, phrases that try to capture the new language of the paradigm shift abound: “cancer is a disease of the genome” [3], “personalized cancer care,” “individual cancer profile,” “actionable molecular cytology” [4], “precision cancer treatment” [5], and the “advent of precision medicine” [6]. In many ways, “personalized care” in its fundamental meaning takes place at every physician–patient encounter. It is a person, not his or her disease or genome, sitting on the examining table, whether the clinic is family medicine, ophthalmology, or urology. It takes time and acquisition of skill for physicians to deliver this most basic form of personalized care—pattern recognition that leads to correct assessment about each unique patient and matches an appropriate therapy, reassuring the patient about known outcomes. Cancer is complex. Pattern recognition here is challenged by the fact that cancer patterns are multiple, changing and diverse. At Oregon Health and Science University in late 1990s, Druker et al. [7] pioneered the development of imatinib as a specific therapy for chronic myeloid leukemia (CML). Imatinib targeted the BCR‐ABL translocation, an oncogene, itself the first such genetic abnormality to be associated with cancer [8]. In many ways, this contribution, curative for CML, ushered in the era of personalized cancer care. It also overcame the first hurdle demonstrating that a “genomic” way of thinking is possible. In a recent review, Tursz and Bernards [9] describe anticipated future hurdles on the road to personalized medicine, including standardization of molecular tests and optimal preservation of nucleic acids from tumor samples, escalating intricacy of molecular tests, need for re‐biopsy of cancer recurrences due to expected genetic changes, evolution of drug development, and structure/speed of clinical trials. Other investigators provide comments related to the optimal implementation of genomic data into medical care [10–12]. This special issue of the Journal of Surgical Oncology is dedicated to the theme of genomic medicine as it affects surgeons and their care of cancer patients. Authored by experts in the field who have led this paradigm shift, the chapters provide both practical insights for current
ß 2014 Wiley Periodicals, Inc.
management and perspectives for future therapies. The content was intended to be comprehensive, relevant, and innovative. Thus, for example, the first section addresses the infrastructure needed to build a personalized medicine program in cancer care, the communication that can facilitate a cancer patient’s understanding and acceptance of what is and what is not possible with genomic medicine, and ethical principles that help surgical oncologists navigate decisions based on genetic data. None of these topics receive enough attention either in published literature or as part of professional society meetings. All are meaningful if personalized, genomic‐based medical practice is truly to thrive in the next phase of healthcare evolution nationally and worldwide. In oncology, it is also clear that genomic medicine stands to impact practice in three specific ways: facilitating more precise diagnosis; refining cancer prognosis and expected outcomes; and targeting therapeutics to be most effective at the level of an individual patient, instead of an individual malignancy. This issue of the Journal summarizes our current state of knowledge in these three areas and then elaborates on how personalized medical care has played out in some of the most commonly encountered fields of surgical oncology, such as endocrine surgery (thyroid cancer), breast oncology, colorectal cancer surgery, and gynecologic oncology. Finally, the topic of Cowden Syndrome, belonging to the PTEN Hamartoma Tumor Syndrome (PHTS), is presented to illustrate the timeline of progress and achievements in genomic medicine for a specific, multiorgan cancer syndrome. PHTS exemplifies the shift in understanding certain human illnesses from being a collection of clinical features, many of which were given eponyms (e.g., Cowden’s named in honor of the first patient in the 1960s [13] and Bannayan–Riley– Ruvalcaba syndrome) to being a consequence a shared germline mutation (PTEN). No longer thought to be as rare, PHTS is now appreciated to be relevant to many disciplines of surgical oncology because of the cancer risks. Its management spans all the themes of this issue, including diagnosis, communication and involvement of genetic counselors, therapy tailored to an individual patient’s clinical profile, prognosis and predicted future cancer risks, and an infrastructure to support the coordinated efforts of multidisciplinary specialists in delivering preventative cancer care. We hope that this issue offers practical guidance to surgeons who have undoubtedly witnessed the relevance of molecular and genomic *Correspondence to: Mira Milas, MD, Department of Surgery, Division of Surgical Oncology, Oregon Health and Science University (OHSU), Portland, OR. Fax: þ1‐503‐494‐7573. E‐mail: [email protected] Received 22 September 2014; Accepted 22 September 2014 DOI 10.1002/jso.23818 Published online 24 October 2014 in Wiley Online Library (wileyonlinelibrary.com).
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Milas
data in the care of their cancer patients. Genetic information is, after all, complementary to our current tradition of anatomical medicine. However, genomic medicine stands to have a much greater role in the personalized cancer care model. While giving a contemporary snapshot of cancer genomic medicine, we also hope that this issue cultivates a preparation for the paradigm shift that awaits.
7. 8. 9.
REFERENCES 1. Lander ES: Initial impact of the sequencing of the human genome. Nature 2011;470:187–197. 2. Stratton MR, Campbell PJ, Futreal PA: The cancer genome. Nature 2009;458:719–724. 3. http://www.nature.com/nature/focus/cancergenomics/#cur. Accessed 9.21. 2014. Special on Cancer Genomics. 4. Beaudenon‐Huibregtse S, Alexander E, Guttler RB, et al.: Centralized molecular testing of oncogenic gene mutations complements the local cytopathologic diagnosis of thyroid nodules. Thyroid 2014;24:1479–1487.doi: 10.1089/thy.2013.0640 5. http://www.cancercenter.com/treatments/genomic‐tumor‐assessment/ Cancer Treatment Centers of America website (accessed 9.21.2014). 6. Bottomly D, Ryabinin PA, Tyner JW: Comparison of methods to identify aberrant expression patterns in individual patients:
Journal of Surgical Oncology
10.
11.
12. 13.
Augmenting our toolkit for precision medicine. Genome Med 2013;5:103. http://genomemedicine.com/cintent/5/11/103 Druker BJ, Talpaz M, Resta D, et al.: Efficacy and safety of a specific inhibitor of the Bcr‐Abl tyrosine kinase in chronic myeloid leukemia. N Engl J Med 2001;344:1031–1037. Druker BJ: Translation of the Philadelphia chromosome into therapy for CML. Blood 112:4808–4817. Tursz T, Bernards R: Hurdles on the road to personalized medicine. Mol Oncol 2014;1–5. http://dx.doi.org/10.1016/j.molonc.2014.08. 009. Epub ahead of print. Prince AER, Berg JS, Evans JO, et al.: Genomic screening of the general adult population: Key concepts for assessing net benefit with systematic evidence reviews. Genet Med 2014;doi: 10.1038/ gim2014.129. Epub ahead of print. Dander A, Baldauf M, Sperk M: Personalized Oncology Suite: Integrating next generation sequencing data and whole‐slide bioimages. BMC Bioinformatics 2014;15:306.doi: 10.1186/1471‐ 2105‐15‐306 (18 September 2014). Crawford JM, Bry L, Pfeifer J: The business of genomic testing: A survey of early adopters. Genet Med 2014;1–8. doi: 10.1038/gim/ 2014.60. Epub ahead of print. Lloyd KM, Dennis M: Cowden’s disease. A possible new symptom complex with multiple system involvement. Ann Intern Med 1963;58:136–142.
EDITORIAL The Genomic Medicine Paradigm Shift MIRA MILAS, MD* Department of Surgery, Division of Surgical Oncology, Oregon Health and Science University (OHSU), Portland, Oregon
Genomic medicine is here to stay. The timeline it took to get here is quite impressive, when viewed in broad milestones of accomplishments, from discovery of the DNA double helix in the 1950s, recognition of hereditary cancer syndromes in the 1960s, basic molecular biology techniques to study DNA and RNA in the 1970s and 1980s, the Human Genome Project that spanned 1990–2003, and, in the last decade, to genomic profiling of cancer [1,2]. The extraordinary research of this last decade was translated into effective new clinical therapies more rapidly than ever before, especially in the field of oncology. In 2014, the paradigm shift thus refers to the adaptation that will be required of clinical medicine to usher in the future, when thinking about and taking care of a patient becomes inseparable from genetic information. We are at that threshold now, and cancer is a great case in point. Both in scientific and lay venues, phrases that try to capture the new language of the paradigm shift abound: “cancer is a disease of the genome” [3], “personalized cancer care,” “individual cancer profile,” “actionable molecular cytology” [4], “precision cancer treatment” [5], and the “advent of precision medicine” [6]. In many ways, “personalized care” in its fundamental meaning takes place at every physician–patient encounter. It is a person, not his or her disease or genome, sitting on the examining table, whether the clinic is family medicine, ophthalmology, or urology. It takes time and acquisition of skill for physicians to deliver this most basic form of personalized care—pattern recognition that leads to correct assessment about each unique patient and matches an appropriate therapy, reassuring the patient about known outcomes. Cancer is complex. Pattern recognition here is challenged by the fact that cancer patterns are multiple, changing and diverse. At Oregon Health and Science University in late 1990s, Druker et al. [7] pioneered the development of imatinib as a specific therapy for chronic myeloid leukemia (CML). Imatinib targeted the BCR‐ABL translocation, an oncogene, itself the first such genetic abnormality to be associated with cancer [8]. In many ways, this contribution, curative for CML, ushered in the era of personalized cancer care. It also overcame the first hurdle demonstrating that a “genomic” way of thinking is possible. In a recent review, Tursz and Bernards [9] describe anticipated future hurdles on the road to personalized medicine, including standardization of molecular tests and optimal preservation of nucleic acids from tumor samples, escalating intricacy of molecular tests, need for re‐biopsy of cancer recurrences due to expected genetic changes, evolution of drug development, and structure/speed of clinical trials. Other investigators provide comments related to the optimal implementation of genomic data into medical care [10–12]. This special issue of the Journal of Surgical Oncology is dedicated to the theme of genomic medicine as it affects surgeons and their care of cancer patients. Authored by experts in the field who have led this paradigm shift, the chapters provide both practical insights for current
ß 2014 Wiley Periodicals, Inc.
management and perspectives for future therapies. The content was intended to be comprehensive, relevant, and innovative. Thus, for example, the first section addresses the infrastructure needed to build a personalized medicine program in cancer care, the communication that can facilitate a cancer patient’s understanding and acceptance of what is and what is not possible with genomic medicine, and ethical principles that help surgical oncologists navigate decisions based on genetic data. None of these topics receive enough attention either in published literature or as part of professional society meetings. All are meaningful if personalized, genomic‐based medical practice is truly to thrive in the next phase of healthcare evolution nationally and worldwide. In oncology, it is also clear that genomic medicine stands to impact practice in three specific ways: facilitating more precise diagnosis; refining cancer prognosis and expected outcomes; and targeting therapeutics to be most effective at the level of an individual patient, instead of an individual malignancy. This issue of the Journal summarizes our current state of knowledge in these three areas and then elaborates on how personalized medical care has played out in some of the most commonly encountered fields of surgical oncology, such as endocrine surgery (thyroid cancer), breast oncology, colorectal cancer surgery, and gynecologic oncology. Finally, the topic of Cowden Syndrome, belonging to the PTEN Hamartoma Tumor Syndrome (PHTS), is presented to illustrate the timeline of progress and achievements in genomic medicine for a specific, multiorgan cancer syndrome. PHTS exemplifies the shift in understanding certain human illnesses from being a collection of clinical features, many of which were given eponyms (e.g., Cowden’s named in honor of the first patient in the 1960s [13] and Bannayan–Riley– Ruvalcaba syndrome) to being a consequence a shared germline mutation (PTEN). No longer thought to be as rare, PHTS is now appreciated to be relevant to many disciplines of surgical oncology because of the cancer risks. Its management spans all the themes of this issue, including diagnosis, communication and involvement of genetic counselors, therapy tailored to an individual patient’s clinical profile, prognosis and predicted future cancer risks, and an infrastructure to support the coordinated efforts of multidisciplinary specialists in delivering preventative cancer care. We hope that this issue offers practical guidance to surgeons who have undoubtedly witnessed the relevance of molecular and genomic *Correspondence to: Mira Milas, MD, Department of Surgery, Division of Surgical Oncology, Oregon Health and Science University (OHSU), Portland, OR. Fax: þ1‐503‐494‐7573. E‐mail: [email protected] Received 22 September 2014; Accepted 22 September 2014 DOI 10.1002/jso.23818 Published online 24 October 2014 in Wiley Online Library (wileyonlinelibrary.com).
2
Milas
data in the care of their cancer patients. Genetic information is, after all, complementary to our current tradition of anatomical medicine. However, genomic medicine stands to have a much greater role in the personalized cancer care model. While giving a contemporary snapshot of cancer genomic medicine, we also hope that this issue cultivates a preparation for the paradigm shift that awaits.
7. 8. 9.
REFERENCES 1. Lander ES: Initial impact of the sequencing of the human genome. Nature 2011;470:187–197. 2. Stratton MR, Campbell PJ, Futreal PA: The cancer genome. Nature 2009;458:719–724. 3. http://www.nature.com/nature/focus/cancergenomics/#cur. Accessed 9.21. 2014. Special on Cancer Genomics. 4. Beaudenon‐Huibregtse S, Alexander E, Guttler RB, et al.: Centralized molecular testing of oncogenic gene mutations complements the local cytopathologic diagnosis of thyroid nodules. Thyroid 2014;24:1479–1487.doi: 10.1089/thy.2013.0640 5. http://www.cancercenter.com/treatments/genomic‐tumor‐assessment/ Cancer Treatment Centers of America website (accessed 9.21.2014). 6. Bottomly D, Ryabinin PA, Tyner JW: Comparison of methods to identify aberrant expression patterns in individual patients:
Journal of Surgical Oncology
10.
11.
12. 13.
Augmenting our toolkit for precision medicine. Genome Med 2013;5:103. http://genomemedicine.com/cintent/5/11/103 Druker BJ, Talpaz M, Resta D, et al.: Efficacy and safety of a specific inhibitor of the Bcr‐Abl tyrosine kinase in chronic myeloid leukemia. N Engl J Med 2001;344:1031–1037. Druker BJ: Translation of the Philadelphia chromosome into therapy for CML. Blood 112:4808–4817. Tursz T, Bernards R: Hurdles on the road to personalized medicine. Mol Oncol 2014;1–5. http://dx.doi.org/10.1016/j.molonc.2014.08. 009. Epub ahead of print. Prince AER, Berg JS, Evans JO, et al.: Genomic screening of the general adult population: Key concepts for assessing net benefit with systematic evidence reviews. Genet Med 2014;doi: 10.1038/ gim2014.129. Epub ahead of print. Dander A, Baldauf M, Sperk M: Personalized Oncology Suite: Integrating next generation sequencing data and whole‐slide bioimages. BMC Bioinformatics 2014;15:306.doi: 10.1186/1471‐ 2105‐15‐306 (18 September 2014). Crawford JM, Bry L, Pfeifer J: The business of genomic testing: A survey of early adopters. Genet Med 2014;1–8. doi: 10.1038/gim/ 2014.60. Epub ahead of print. Lloyd KM, Dennis M: Cowden’s disease. A possible new symptom complex with multiple system involvement. Ann Intern Med 1963;58:136–142.
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