NEW YORK – In June, the Association for Molecular Pathology (AMP) and the College of American Pathologists (AMP) sent a letter to US Centers for Medicare and Medicaid Services contractor Palmetto GBA regarding its proposed coverage policy for next-generation sequencing lab-developed tests for myeloid malignancies and suspected myeloid malignancies.
The letter made a number of recommendations, including to make such testing more frequently available and to expand the list of biopsy specimens deemed appropriate for testing. Most prominently, the organizations suggested changes to the draft policy's list of genes and variants that covered tests would be required to include and recommended the creation of an expert working group to develop and finalize such a list.
This latter recommendation highlights the challenge within the field of harmonizing NGS-based panels and establishing which genes and variants should and should not be included in different tests.
It is an effort that is still in its infancy, suggested Marina DiStefano, a clinical molecular genetics fellow at Harvard University and a curator of the Clinical Genome Resource. She said that she didn't believe "that at this point there are really any clear guidelines as to what types of genes should be going on tests."
DiStefano said that her familiarity with the matter is largely limited to germline testing and curation of germline variants, but as the AMP and CAP letter regarding myeloid disorder panels indicates, the question is still being worked out for somatic testing, as well.
NGS has made testing relatively large panels of genes technically and economically feasible. However, the level of evidence linking different variants to a particular condition varies and can change as clinical evidence for or against a variant's involvement grows. Additionally, some variants may have higher penetrance in certain populations than others, meaning that it might not be appropriate to test for them in all patients.
"I think the biggest challenge right now is a lack of agreement," said Mary Relling, chair of the pharmaceutical department at St. Jude Children's Research Hospital and leader of the Clinical Pharmacogenetics Implementation Consortium (CPIC), which was created to help guide the development and application of pharmacogenetic test panels.
"Some people tend to be leaning towards, if a variant has been positively shown to be associated with a serious impact on function, it must be included in a clinical genetic test, no matter how rare it is," she said. "Other people don't buy that and think that for rare alleles it can be kind of discretionary."
Another challenge is the fact that data informing inclusion decisions is constantly changing, Relling said.
"There are always new functional genomic variants that are being discovered, and that makes it difficult for testing companies and guideline-setting bodies to keep up with the changing literature," she said. "Occasionally, something considered functional will later be considered not to have a clear function, and so that creates another set of controversies."
Relling added that at least in the case of PGx testing, decisions around which genes need to be tested must take into account the potential severity of the consequences of improperly dosing a patient.
She cited the example of the gene TPMT, which is involved in metabolizing drugs used to treat conditions including leukemia.
"Almost all the important actionable [TPMT] variants are rare," she said. "And so we really don't want to use the criteria of is an allele rare or not in order to decide [what to test for]. We're using a drug that is a life-saving drug, because it can cure leukemia, and it can be a life-threating drug because it can cause life-threatening toxicity if you give it to a patient who has one of these defects and you don't change the dose."
"It's a big responsibility for any organization to take on to say what are the minimum requirements for a useful genetic test," she said.
DiStefano said that she and her colleagues have done several investigations looking at which genes clinical tests assess for a given phenotype. She cited the example of hypertrophic cardiomyopathy, where the researchers looked at test panels from 14 different labs, finding that they varied widely.
"It was anywhere from maybe 17 genes to 120 genes for the same phenotype, so there's really just not consistency in the field at this point," she said.
DiStefano noted that it would be important to build flexibility into any framework for recommending minimum test requirements, suggesting that rather than specifying particular genes that should go on a panel, the community would be better served by recommending genes meeting a certain evidence level that should be tested.
"That way, if new genes are discovered and they meet that [required] evidence level, they can be added to the test without needing to update the guidelines," she said.
AMP and CAP have taken this approach in developing their guidelines around PGx testing. The organizations have issued guidelines for CYP2C9 and CYP2C19 variant alleles that should be included in clinical PGx tests.
In their guidelines, the organizations identified a set of Tier 1 alleles that they recommend testing for in all populations and a Tier 2 set of alleles for which testing may be appropriate in particular circumstances or subpopulations.
Tier 1 alleles are those that "have been well characterized and shown to significantly affect the function of the protein and/or gene leading to an alteration in a drug response phenotype … have an appreciable minor allele frequency in a population/ethnicity group, and … have publicly available reference materials."
Tier 2 alleles are those that meet "at least one but not all three" of the Tier 1 requirements, the authors wrote, noting that Tier 2 alleles may be moved into the Tier 1 category if reference materials or additional evidence supporting their linkage to drug response becomes available.
Samuel Caughron, AMP's economic affairs committee chair, suggested that the PGx efforts could serve as a template for establishing guidelines for other tests, including the myeloid disorder panels covered in the Palmetto proposed coverage policy.
"These recommendations are intended to facilitate testing by laboratories, increase concordance across laboratories, and improve patient care," he said. "This same process [used for the PGx guidelines] has been and will be applied to myeloid disorders and other conditions in the future."
"I think curation bodies should continue to publish their work," DiStefano said, discussing how the field might move forward. "And hopefully in the future these professional societies like ACMG and AMP will write some sort of guidance and maybe look to some of these curation experts and, of course, their community of members to provide feedback."
She noted that while payors are key decision makers in determining which requirements a test must meet to qualify for reimbursement, "in general, I think payors are probably looking for professional societies to give them some sort of guidance as to how they should reimburse tests and what should be on tests."
Relling likewise said she believed payors and CMS contractors like Palmetto would look to professional bodies like AMP and CAP for guidance.
In their letter commenting on the proposed coverage proposal for myeloid disorders, the CAP and AMP authors highlighted several variants listed in the proposal as "required" as being "of unclear clinical significance" and recommended they "not be required for panels to be reimbursed."
They further suggested that they create an expert working group to finalize a minimum gene/variant list, which they said could be done over the course of two to three meetings.
Caughron said it was AMP's understanding that Palmetto "is currently reviewing comment, including the minimum gene list provided by AMP and CAP members."