The era of personalized medicine, also known as precision medicine, has been burgeoning for decades – ever since the advent of the Human Genome Project in 1990, which culminated with the completion of the first human DNA sequence in 2000. With the rapid adoption of next-generation sequencing technology since the turn of the century, an individual’s entire genome can be sequenced in under 2 weeks, at a cost of under $1,000 dollars. This latter detail is crucial to understanding why – after such a protracted period of anticipation – genomics is finally rising to the forefront in scientific publications and the public discourse. The promises of personalized medicine were highlighted prominently in President Barack Obama’s State of the Union Address on January 20th, 2015.
In essence, the precision medicine initiative seeks to expand and accelerate biomedical research that tailors disease prevention and treatment approaches to an individual’s genomic profile, environment, and lifestyle factors. The two prongs of the personalized medicine approach include an upfront investment in cancer research and a longer-term initiative to establish a national cohort of at least 1 million research volunteers.
The focus on cancer is pertinent since the field of oncology has been an early adopter of genomic sequencing to understand the origins, behavior, and treatment vulnerabilities of tumors. In a simplistic model, tumors are just collections of cells that divide uncontrollably due to an accumulation of genetic changes. Already, large-scale collaborative initiatives such as The Cancer Genome Atlas have worked to catalogue the spectrum of genetic alterations found in various cancers, uncovering thousands of mutations, some of which may be essential for tumor survival and thus serve as the basis for targeted therapies. For diseases such as non-small cell lung cancer and colorectal cancer, genetic testing is highly useful for predicting whether a patient’s tumor will respond to these targeted therapies, especially small molecule inhibitors that interfere with survival signaling pathways. Consequently, enhancing our understanding of tumors’ molecular signatures will continue to guide clinical decision-making and optimize outcomes for cancer patients.
The second objective will provide scientists with a richly detailed database to study a multitude of common illnesses, such as obesity and heart disease, and examine the impact of individual-level variation in genetics, medications, and other variables on long-term health outcomes. Another dogma of personalized medicine is to deliver “the right drug, at the right dose, to the right patient.” This area of science, known as pharmacogenomics, will also be greatly abetted by establishing a database that links information from the electronic medical record to a patient’s genetic sequence.
The importance of a cohort of 1 million plus subjects cannot be understated. In order to interpret the meaning of any of the approximately 4 million DNA sequence variants present in one person, it is essential to compare variation among many thousands of individuals. In the fall of 2014, when the Broad Institute of MIT and Harvard released data from over 60,000 subjects’ protein-coding DNA variants, this generated a flurry of excitement in the genetics community, since a publically accessible resource of this scope was absolutely unprecedented. The prospect of data from 1 million subjects appears poised to transform our approach to unraveling the mysteries of the human genome.
Yet, substantial challenges remain to realizing this vision. Currently, the evidence base in support of sequencing every patient that seeks medical care in this country is slim-to-none. Even within oncology, substantial challenges to personalizing every patient’s chemotherapy regimen include the vast genetic heterogeneity exhibited within many tumor types, let alone the discrepancies between subpopulations of tumor cells in one patient. Targeting specific mutations is often only effective on a temporary basis, since tumors may mutate and escape annihilation. In other disciplines, such as cardiology, genetic testing may indicate that some patients are at an increased risk for sudden death due to inherited disorders in ion channels or disordered heart muscle fibers, but these can also be suspected on the basis of commonly obtained tests and procedures like an EKG and echocardiogram.
Physicians are also wary of the information overload that can occur when prying into an individual’s entire genome, which will typically result in the return of incidental findings that may have therapeutic importance for the patient but are unrelated to the original indication for sequencing. Although there are guidelines available for reporting such incidental findings, the time and resources essential for appropriate follow-up care for unrelated findings may serve as a strong deterrent to ordering genetic testing. Even more challenging are so-called “variants of unknown significance” that may be found in genes known to confer an increased risk of disease, such as in the BRCA1/2 genes implicated in breast and ovarian cancer, but these variants may not have been formally designated as pathogenic mutations, which leaves patients and providers in a limbo of uncertainty and anxiety.
The aspiration of medical geneticists is to make genetic testing available as a point-of-care option, so that relevant results will be available with the same ease and turnaround time as a patient’s chemistry panel during a routine doctor’s appointment. If the enthusiasm (and funding) for the precision medicine initiative continues unabated for years to come, we may finally arrive at an era where variants of unknown significance cease to exist, doctors welcome the opportunity to receive all of the genetic information that can improve patients’ lives, and every patient receives every drug at the right dose.
References:
Collins FS, Varmus H. A new initiative on precision medicine. N Engl J Med. 2015 Feb 26;372(9):793-5. doi: 10.1056/NEJMp1500523. Epub 2015 Jan 30. PubMed PMID: 25635347.
Holst, Lindsay. “The Precision Medicine Initiative: Data-Driven Treatments as Unique as Your Own Body.” http://www.whitehouse.gov/blog/2015/01/30/precision-medicine-initiative-data-driven-treatments-unique-your-own-body. Accessed March 8 2015.
Marian AJ. Challenges in medical applications of whole exome/genome sequencing discoveries. Trends Cardiovasc Med. 2012 Nov;22(8):219-23. doi: 10.1016/j.tcm.2012.08.001. Epub 2012 Aug 24. Review. PubMed PMID: 22921985; PubMed Central PMCID: PMC3496831.
