Genomics: How Next Generation Sequencing Might Play Out and the Implications for Precision Medicine

Precision medicine holds the promise of providing patients with therapies that target the biological mechanism contributing to a particular individual’s disease. Historically, the approach to developing novel medicines has lacked the ability to optimize therapy based on specific factors resulting in an individual patient’s disease state.

Although many drugs have been approved on the basis of clinical trials run in all patients with a disease, some patients enrolled in those trials have had a strong treatment effect while others had minimal to no effect due to biological diversity. With the advent of next generation sequencing (NGS), we now have the ability to understand the diversity of pathways and patient subsets that make up the broader diseased population. This affords the ability to develop therapies for a given patient that targets their specific genetic alteration.

Cancer has been a leading beneficiary of these advances. From a research perspective, biologists can now use next generation sequencing to identify mutations present in patient tumors. Many of these new insights have allowed researchers to further our understanding of cancer biology, although this is only the beginning to the development of targeted therapeutics. In addition to the identification of a novel mutation, researchers and clinicians must advance the science into clinical practice by validating the target through clinical trials in the relevant subset of patients.

This path to clinical validation runs counter to traditional drug development which typically require large trials to prove a drug is effective. With many patient subsets (or mutations) that might exist within a given cancer, it is typically not feasible to run large clinical trials. Yet, despite these challenges, a fundamental understanding of the biology and administration of appropriately targeted therapies has proven adequate by regulators to approve novel drugs. This has resulted in a rapid time to approval, bringing novel therapies to market in record time.

While NGS continues to hold tremendous promise toward the goal of precision medicine, there are a number of practical and technological challenges that currently limit broad applicability. Given the size of the human genome, there is a tremendous amount of data generated per sample of tissue. With existing sequencing technologies, performing whole genome sequencing can take 2-3 weeks due to the processing and interpretation of data. This is a challenge in the clinical setting since patients presenting with cancer may not tolerate a significant delay between diagnosis and therapy.

Additionally, while the cost of whole genome sequencing has come down over time, it can exceed thousands of dollars per sample making it prohibitive to adopt for all patients due to sheer cost. We anticipate that competition and improvement in technology will improve both the speed of a test result and cost thereby making it more accessible to the masses.

NGS also has technical limitations that limit broad clinical applicability. Genomic data derived from NGS technologies are descriptive and static representing a snapshot of the genetic mutations in a small sample of tissue. With cancer being a constantly mutating disease, it is important to keep up with the evolving genetic composition to optimize therapy over time. Additionally, a mutation in one tissue sample may not reflect the broad array of mutations present throughout the entire tumor.

A number of emerging technologies appear to have the potential to address these limitations. Liquid biopsy technologies can identify circulating genetic information, are non-invasive, and can provide a near real-time result, thereby holding the promise of a valuable monitoring and treatment optimization tool. There are also a host of functional genetic and cellular technologies that provide more detailed information as to which mutations are most importantly related to the process contributing to a given patient’s cancer. With the improvements of existing NGS technologies and introduction of novel technologies that can supplement our understanding of cancer biology, we are moving closer to the promise of precision medicine for all patients. Continued investment in the space holds the promise of making these technologies ubiquitous, low cost, and increasingly informative. Moreover, the speed at which novel biological insights can be tested and validated in the clinical setting are likely to increase rapidly as our knowledge of the underlying biology increases.