Whether it is called individualized medicine, personalized medicine, or precision medicine, the Human Genome Project helped to make it possible. Mapping the human genome gave hope for the day when the genetic origin of diseases would be fully understood and would lead to targeted medical therapy or preventive therapy for people who had a genetic mutation for certain diseases, according to an article in the May 2, 2010, New England Journal of Medicine.
“What precision medicine really means is taking advantage of all of the tools of modern biomedical science and all of the kinds of information that can be gathered with those tools,” said Richard Weinshilboum, MD, Mary Lou and John H. Dasburg Professor of Cancer Genomics at the Mayo Clinic Center for Individualized Medicine in Rochester, Minn. “With genomics leading the way, we can try to go beyond the individualization that we've all done when we take a family history or when we ask about environmental factors. These new tools will not change everything, but they will complement and extend what we have been doing all along.”
The Precision Medicine Initiative launched by President Obama in January is envisioned as the next step forward in bringing more precision to medical decision making, according to a statement from the White House. The president's initiative calls for a $215 million investment in the project as part of the 2016 budget, which must be approved by Congress. Of that $215 million, $130 million would go to the National Institutes of Health (NIH) for development of a national research cohort of at least 1 million volunteers, and $70 million would be allocated to the National Cancer Institute to further its efforts in identifying the molecular underpinning of different cancer types and in applying that information to develop new therapies.
Francis S. Collins, MD, PhD, director of the NIH, said at an NIH workshop about the initiative in February that the concept of precision medicine is not new but that a broader concept is now emerging. “The time is right to say that this initiative can come together,” he said.
Several developments over the past decade have made the timing of this initiative promising. The cost of sequencing the human genome is much lower, and it can be done much more quickly. The understanding of cancer because of the genome “has come a long way but is now poised for a big leap,” Dr. Collins said.
Cohort of 1 million
Development of a large cohort study is a key part of the precision medicine initiative, according to the White House. The study would share the genomic information and biological specimens provided by voluntary participants. Clinical information from the electronic medical records (EMRs) of these volunteers would be part of the cohort study and would include test results, lifestyle data, and history of environmental exposure.
“A lot of the leaders in genomics have seen the need for a very large, well-characterized cohort of individuals in which you could make robust correlations between genetic variations and characteristics,” but there have not been enough resources to assemble the cohort or to get the sequence information, said W. Gregory Feero, MD, PhD, a family practitioner in Fairfield, Maine, and a faculty member at Maine-Dartmouth Family Medicine Program in Augusta.
Those conditions have now changed, he said. Whole-genome sequencing is much more affordable, and several cohorts are available across the country that can be combined into 1 large cohort. The NIH has identified 50 large-scale research cohorts, including 42 federally funded studies, 6 hospital-based cohort studies, and 9 hospitals and health care systems with research-oriented databases of their patients. All of these combined include about 12.3 million individuals, according to a white paper prepared for the NIH by Rebecca Baker, PhD, and colleagues on the NIH website. According to the white paper, assembly of the large 1-million-person cohort from existing ones is possible, but additional recruitment is envisioned.
Long-term benefits of such a large cohort will be “a demonstrably large leap forward in our understanding of the impacts of genetic variation on both health and disease states,” Dr. Feero said. “Figuring out the consequences of rare [genetic] variations requires having enough people with a variation to determine whether it means anything.”
That could potentially lead to better diagnostic approaches, better ideas of how diseases work, and better targeted treatment, said Dr. Feero, a former senior advisor to the director of the National Human Genome Research Institute.
Building a large cohort means tackling some privacy and ethical issues, such as obtaining patient permission, educating patients and the physicians of those patients about the purpose of the cohort, and securing and protecting patient privacy, Dr. Weinshilboum said, but those are not insurmountable. Mayo, which has a “group of medical ethicists,” has been able to form a biobank with DNA samples from 50,000 patients who have consented to have their genetic information available to join with their medical records.
Focus first on cancer
The emphasis on cancer research and treatment is an obvious first choice of this initiative because cancer is a class of disease that is inherently genetic, research has come a long way in identifying the genomic fingerprints of many types of cancers, and targeted therapies are already being used, experts said.
An article by Dr. Collins and Harold Varmus, MD, in the Feb. 26 New England Journal of Medicine said that the initiative should lead to discoveries about some of the obstacles in precision oncology, such as unexplained drug resistance, genomic heterogeneity of tumors, and limited knowledge about drug combinations.
“At this point we really are beginning to get a handle on the molecular underpinning for a variety of different cancer types, and this push will move that forward at a much more rapid pace ... yielding tangible benefits in the not-too-distant future in terms of less toxic and more effective therapies,” Dr. Feero said.
At Mayo, the field of pharmacogenomics is having a significant effect on cancer treatment, Dr. Weinshilboum said. Preemptive genotyping is being used to identify patients with a certain genetic variation that places them at risk of myelotoxicity if a certain anticancer drug is prescribed. That type of information is now being used at Mayo with about a dozen so-called drug/gene pairs, he said.
Other research efforts are underway that use sequencing information to understand why a specific therapy is ineffective in patients with a genetic variation. Mayo is biopsying and sequencing tumors that have failed on multiple drugs, and researchers there are also looking at the genetic basis for “diagnostic odysseys, serious illnesses that have not yet been given a name,” Dr. Weinshilboum continued.
Moving beyond cancer is a long-term goal of precision medicine, with the intention of establishing the scientific foundation that can lead to better understanding of other complex diseases, such as diabetes and heart disease.
“Even with genome-wide association studies where we have a number of studies about the risk of disease, we still can't explain much of the genetic risk of someone getting diabetes,” Dr. Feero said. If full sequence data are gathered on a very large number of people with type 2 diabetes, that would eventually provide more information about the role of rare types of variations in risk of the disease, he said. Instead of treating type 2 diabetes as a single disease, eventual therapies would focus on specific molecular and environmental causes.
The genetic basis of some cardiomyopathies and conduction disorders is known, but the genetic basis of much “garden-variety heart disease” is not well understood, he added. Researchers still don't understand why 1 person with high cholesterol has 3 heart attacks before age 50 and yet another person with the same numbers will live until age 90 and have no heart attacks, he said.
Over the longer term, internists and others physicians may face needed changes in EMR systems that are compatible with a new era in precision medicine. “We are really far away from seamless transfer of genomic sequence information that can be readily queried and updated in most community hospital settings,” Dr. Feero said.
Currently, it is impractical to believe that genomic information will move with the patient or even be electronically transferred into a patient's medical record when the patient moves to another health care system, he explained. Eventually, he said, EMR systems will have to make genomic information a centerpiece of a patient's health record depository.
The impact of the large national cohort could be substantial for internists who have patients enrolled, particularly as reports emerge about the genomes of these patients and the benefits or harms of certain therapies for certain patients. Physicians will need a basic understanding of genomics to explain to patients why a targeted therapy may work for them, Dr. Feero said.
Genomics and all the other “omics,” such as proteomics and metabolomics, “are now getting out of the laboratory and moving to the bedside,” Dr. Weinshilboum said. “We are dealing with real people with real problems. This is not the answer to everything, but it will significantly change medicine if we do things right.”