Stephen C. Peiper M.D. Peter A. Herbut Professor & Chair Thomas Jefferson University
Zi-Xuan Wang Ph.D. Scientific Director, Genomic Pathology and Assistant Professor Thomas Jefferson University
Issues Have Been Raised As Precision Medicine Becomes Increasingly More Precise
A vast “technocopia” of powerful tools is available to be employed in the clinical arena following the evolution from forme fruste to research tools. This armamentarium promises to revolutionize the diagnosis and treatment of patients with catastrophic diseases. The emergence of next-generation sequencing (NGS) as a diagnostic technology has opened the door to examining malignant, infectious, and inherited diseases with the highest power of resolution, at the level of individual genetics.
“Since we have no choice but to be swept along by [this] vast technological surge, we might as well learn to surf.” —Michael Soule
Consequently, the application of personalized/precision medicine enabled by NGS to develop genomic classifications in oncology has been fueled with the zeal of the newly converted. One of the primary considerations in the creation of NGS panels has been the number of genes to be interrogated. With an ever-enlarging pipeline of targeted agents, panels have grown to include over 400 genes, although many of the genes sequenced are not actionable molecular targets.
Solid rationale for this level of interrogation includes the identification of genes that modify the action of driver genes, the emergence of resistance genes, and the characterization of heterogeneity within the tumor. The Food and Drug Administration has opened a dialog with stakeholders to discuss regulatory standards for NGS testing in oncology in order to promote and ensure the highest level of quality inpatient care. While many of the issues that are under discussion by stakeholders in industry and academia are beyond the scope of this forum, a number of important issues have been raised.
The role of “good genomic practice” in guiding precision medicine forward is analogous to good laboratory practice and good manufacturing practice in ensuring a high level of quality in laboratory tests and therapeutic agents, respectively. Key considerations include pre-analytical handling, ethical, and legal issues, reporting, and interpretation of data (Barker et al. Nature Medicine 2013;19:530).
The handling of tissue samples represents a critical first step in NGS analysis and the quality and quantity of DNA (or, more frequently, nucleic acids including RNA) are central to successful analysis. Challenges include the trend for small, noninvasive biopsies and the need to identify appropriate areas of tumor for the preparation of target nucleic acids, avoiding the dilutional effects of DNA from normal cells as well as necrosis.
A recent report describing guidelines for diagnostic NGS has been communicated for the European Society of Human Genetics and EuroGentest (Matthijs et al. European Journal of Human Genetics 2016;24:2-5). Although the primary focus is testing for rare and monogenic diseases, the guidelines are highly applicable to oncology testing and recognize the challenges of performing adequate validation and maintaining a high level of quality when using a technology that is rapidly changing. The considerations covered include diagnostic/clinical utility, informed consent, and information to the patient and the clinician, validation, reporting, and distinction between research and diagnostics.
One of the ethical and legal issues considered in depth is the communication of unsolicited or secondary findings to the patient. At this time there is no strong consensus regarding providing incidental genomic findings to patients, but the practices of the clinical genomic laboratory must be consistent with those of the institutional ethical committee (or IRB). The American College of Medical Genetics and Genomics (ACMG) currently recommends that patients be informed of unsolicited findings obtained in clinical exome and genome sequencing from a formulary list of medically relevant genes (Green et al. Genet Med 2013;15:565-574), both in the case of constitutional studies and testing paired normal DNA in oncology. The laboratory should establish a clear policy for the handling of incidental genetic findings and this should be communicated to the patient.
The attitudes of a large population of health professionals and lay public from over 75 countries toward the communication of incidental findings has recently been reported by Middleton and co-workers (European Journal of Human Genetics 2016;24:21-29). Interest by the lay public (n=4961) in receiving information regarding unexpected genetic findings regarding a serious, preventable condition obtained during research genomic analysis was approximately 60% if the risk were 1%, 80% if the risk were 10%, and over 90% if the risk were 50%. While there was agreement among the public and genetic health professionals regarding the communication of pertinent genomic findings to patients, the latter group was more conservative regarding the communication of incidental findings of undetermined significance, life-threatening conditions that cannot be prevented, and ancestry.
This underscores the importance of developing a clear diagnostic strategy for panel and more extensive genomic sequencing, formulating a policy for the disclosure of findings that do not have direct relevance to the diagnostic focus that is sensitive to the wishes of patients and in keeping with institutional policies, and the distinction between diagnostic findings that are directed toward answering a clinical question that will have an impact on the patients care and a research finding that may answer a hypothesis, but have minimal impact on the patient’s medical condition.
Both the FDA-sponsored workshop and the European Society of Human Genetics/EuroGentest policies emphasize the importance of validating the bioinformatics system used to analyze NGS data and formulate diagnoses, the use of structured databases for interpreting and cataloging the findings. The FDA approach emphasizes the importance of pooling mutation findings in order to understand their clinical significance. To date, funding for these types of activities has been limited.
The National Institutes of Health recently announced that it will designate funding to support the enhancement of molecular cancer diagnostics that have generated interest in pilot studies, but require enhancement before they could be used in clinical trials supported by the National Cancer Institute. Funding will be provided in the form of supplements to ongoing U10 awards, in the amount up to $150,000 in annual direct costs. The candidate biomarkers may provide pharmacodynamics, mechanistic, or predictive insights into cancer biology or be relevant to cancer risk or prevention.
These approaches will help to refine the application of next-generation sequencing for the precision diagnosis of oncologic disorders, as well as infectious and inherited diseases, at the highest level of quality. This will clearly apply this powerful technology at the highest level of quality to promote the health of our population.
Stephen C. Peiper, M.D., is Peter A. Herbut Professor & Chair, Department of Pathology, Anatomy & Cell Biology, Thomas Jefferson University. (firstname.lastname@example.org)
Zi-Xuan Wang, Ph.d., is Scientific Director, Genomic Pathology Laboratory, Assistant Professor, Departments of Surgery and Pathology, Anatomy & Cell Biology, Thomas Jefferson University.