Sep 11, 2015
Article reprinted courtesy of China Medical Tribune © 2015.
Where are we on the way to precision medicine?
The “storm” of precision medicine has been blowing through all areas this year, however, what is its real meaning in oncologists’ eyes? What should and could scientists do now? These questions still need reflection and discussion. China Medical Tribune, the editorial group of CSCO Daily News, invited Peter Paul Yu, MD, FACP, FASCO, the Immediate Past President of ASCO, who is giving presentations on the topic of precision medicine at the 2015 CSCO Annual Meeting this September, to share his perspective.
The following is the letter from Dr. Yu in response to CSCO Daily News interview questions.
China Medical Tribune: What is your own understanding of the concept of “precision medicine”?
Dr. Yu: Precision medicine is the term favored by Francis Collins, MD, PhD, Director of the United States National Institutes of Health, to describe the application of molecular data to human health. It was selected to distinguish molecular-based medicine from the older term “personalized medicine,” which includes non-molecular aspects such as patient preferences, lifestyles, and the existence of other unrelated health problems that may influence the treatment decisions and outcomes of patients. Precision medicine includes all aspects of molecular medicine including the germ line and somatic genome (genomics), RNA expression (transcriptome), proteins (proteomics), and metabolites (metabolome). Collectively these are referred to as panomics. The actual molecules that are measured are often referred to as biomarkers. Personalized medicine is sometimes referred to as "individualized medicine." President Obama highlighted the growing awareness that precision medicine has tremendous potential to impact all human diseases and at all stages of health care delivery, from prevention to detection to treatment.
China Medical Tribune: What kinds of specific areas can precision medicine be applied in for the treatment of cancer? What advantages and gaps exist?
Dr. Yu: For germ-line mutations, precision medicine helps us identify special populations that are at heightened risk for developing cancer, such as those carrying BRCA mutations. Patients with cancer harbor acquired mutations that are drivers of cancer growth or provide escape from apoptosis and immune surveillance. Understanding these mechanisms of cancer biology will identify targets of treatment and guide new small molecules and antibody development. Protein expression and the metabolome will help us understand the functional molecules and provide additional targets for therapy.
Among the challenges to precision medicine is coning down on the drivers of cancer and other diseases and distinguishing those from the background noise of coexisting molecules that are aberrant, but not related to the disease itself. One example is variants of uncertain significance (VUS). These are mutations found within genes associated with cancer, but the clinical significance of which has not yet been characterized. It may be that the mutation does not alter the function of the corresponding protein, in which case the genetic aberrancy is benign and classified as a polymorphism.
Another challenge for precision medicine is the many methodologies for identifying biomarkers, each of which has its own strength and limitations. Does one measure the genetic mutation, the gene copy number for amplification, the gene expression levels, or the protein? Should one measure more than one, as we do with HER2 when protein expression is equivocal? With next-generation sequencing, laboratories differ in primers, depth of analysis, and which genes are included for testing. The lack of standards will limit the ability of research to compare results and clinicians to make consistent treatment decisions.
China Medical Tribune: What are the short- and long-term goals of precision medicine in cancer treatment, and what is the key way to achieve them?
Dr. Yu: The short-term goals of precision medicine should be to show early proof-of-concept by delivering tangible benefits for human health. Targeted therapies, of course, are already well beyond the proof-of-concept stage of linkage of biomarkers with the development and selection of drugs, the use of monoclonal antibodies as therapeutic agents and checkpoint inhibitors. However, the unaffordable and unsustainable cost of these new therapies has created an unmanageable financial burden on both society and individuals that threatens to abort the early successes. If patients cannot gain access to the benefits of precision medicine because drugs do not appear on national formularies or are not covered by insurance policies, precision medicine will fail.
Long-term challenges include the emergence of drug resistance due to downstream activation of signal transduction pathways or the activation of accessory pathways. We are already seeing that drug resistance can emerge and emerge predictably within a few months of starting a targeted agent. It is likely that such resistance development mechanisms are predictable and combinations of agents might be rationally designed. Another long-term challenge is understanding why not all patients respond to therapy equally and what the role of epigenetic alterations may be.
China Medical Tribune: In the United States, the application of big data for scientific research is a mature idea. What then are the requirements of big data for precision medicine? How will patients’ personal data be protected?
Dr. Yu: The requirements to apply big data design to precision medicine are numerous. First, we still lack data standards for the digital documentation of biomarkers. These are lengthy and complicated reports that are not readily searchable. This means that test results cannot be identified by computers (machine readable) and require human data entry and curation. If the search, extraction, and interoperability of molecular data cannot be automated, then big data does not exist. Second, the interpretation of molecular data is haphazard due to the absence of standards as to what level of evidence is necessary to support claims that “actionable” alterations are present. Often the laboratories performing the test are acting as arbiters of what the medical literature means. Because there is a vested interest in a laboratory claiming that it posses a unique knowledge base, we need trusted and open knowledge bases.
The protection of patient privacy and the associated security of patient data are critical because much of the success of big data relies on the implicit or explicit agreement that data will be used for purposes that benefit individual and population health. Traditionally, this has relied upon protecting patient information that could be used to identify patients, either directly (such as names and addresses) or by statistical analysis. However, since each patient’s molecular profile is in theory unique to that individual, if enough biomarkers are measured, patients and their relatives could in theory be identified through precision medicine data. As data breaches become an increasing reality, data security and privacy will remain a matter of high concern.
China Medical Tribune: Is precision medicine the ultimate goal for human beings? What disadvantages could it bring to us?
Dr. Yu: The ultimate goal of medicine is that every patient achieves the highest level of health possible for their situation, whether that is through precision medicine, behavioral modification, vaccination, or any other of our health intervention strategies. The danger is that we devalue or fail to support public health and other population health needs because we are so busy looking at molecules that we forget the individual patient.
Acknowledgement: The answers were written by Peter Paul Yu, MD, FACP, FASCO, and we appreciate Dr. Yu’s ongoing support.
Interview by Chunshi Jia, Mai Wang from China Medical Tribune.