Clinical OMICS

MAY-JUN 2019

Healthcare magazine for research scientists, labs, pathologists, hospitals, cancer centers, physicians and biopharma companies providing news articles, expert interviews and videos about molecular diagnostics in precision medicine

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www.clinicalomics.com May/June 2019 Clinical OMICs 17 www.clinicalomics.com May/June 2019 Clinical OMICs 17 need to incorporate the new tiers and levels and develop a new visual method for displaying the results. A laboratory that does its own interpretation would also need to backfill tiers and levels of evidence for all variants that have already been curated. Working with a vendor that has adopted the guidelines, such as N-of-One, reduces the need for additional research, interpretation, and backfill, but would still require software changes and report redesign. However, as more laboratories adopt the tier-based approach, it is likely that competitive pressure will push others to adapt to the standards. Guidelines, With a Twist Although the AMP guidelines are a welcome sense of structure, the first version, as is often the case, is likely to be enhanced based on feedback from the field. In its initial implementation of the guidelines, N-of-One adhered as closely as possible to the descriptions in the publication, but took the opportunity to make a few adjustments. The four tiers established by the AMP guidelines include: • Tier 1: variants of strong clinical significance • Tier II: variants of potential clinical significance • Tier III: variants of unknown clinical significance • Tier IV: benign or likely benign variants Within the top two tiers (I and II), each potential therapy for a variant is annotated with a level of evidence A through D, and variants with prognostic or diagnostic significance are annotated with levels of evidence A through C. Tier I includes variants with levels of evidence A or B, and Tier II comprises variants with levels of evidence C or D. As N-of-One evaluated the guidelines, the scientists struggled with a class of variants that seemed to fall between tier II and tier III: variants with biological significance but no clear clinical significance. N-of-One created an intermediate tier for these variants, known internally as "tier 2.5." Tier 2.5 serves to distinguish variants that have a clear effect on the gene or protein, but for which there are no associated therapies and for which any prognostic or diagnostic information does not reach a level of clinical significance that satisfies the criteria for the levels of evidence described in the AMP guidelines. "A designation of tier 2.5, or even expanding to five tiers, would be helpful," says Timothy L. Cannon, MD, Clinical Director, Molecular Tumor Board & Medical Director, Gastrointestinal Cancers, Inova Medical Group. "Trying to distinguish between alterations that are biologically significant only versus those that are truly clinically significant is very important," he stressed. "It is useful to have this additional tier," says Dr. Elkin. She explains that the cancer genomics field is rapidly advancing, and more and more genes are identified that play a role in the development of cancer. However, many genes that are clearly associated with cancer are not targetable with a drug. Other genes may have prognostic or diagnostic significance in one specific disease, but not in other cancer types. Even for variants with known biological significance in these genes, they lack clinical significance. For example, RB1 is a tumor suppressor, and inactivating mutations in RB1 play a well- known role in the development of certain cancers. However, there are no drugs to target RB1 mutations, and in most cancer types, RB1 mutations do not have sufficient evidence of prognostic or diagnostic relevance. Therefore, a known inactivating RB1 mutation would fall into tier 2.5. "Having this tier is useful because rather than label a variant as having unknown significance and effectively ruling it out, a clinician can see that the variant does have biological significance and could be a driver of the cancer. The variant can be monitored to see if evidence emerges as to its clinical significance," she says. The overall incorporation of the AMP guidelines, as well as the creation of tier 2.5, into N-of-One's variant curation has been well received. "Feedback from N-of-One clients has been largely positive," says Dr. Elkin. "The clients appreciate the visual separation of variants that are clinically or biologically significant from those that are not known to be clinically or biologically significant. Clients also appreciate the continued transparency of the evidence that has been used to make the determination." Sponsored by

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