Trusted Bodies for PGx

Pharmacogenomics (PGx) is a rapidly growing field of medicine that explores how a person's DNA, or their genetic makeup, affects how their body processes or metabolizes medication.

As with any technique in its growth phase, it will only become trusted once the methods and results are comparable between different centers. And that’s why guidelines, agreed by the most trusted bodies in the field, are so valuable in informing lab processes.

The Association for Molecular Pathology (AMP) has been instrumental in facilitating the standardization of PGx methodology. Here, Vicky Pratt, Co-Chair of the AMP Clinical Practice Committee’s PGx Working Group, tells us about the group’s progress in this area.

What is the history of PGx?
 

PGx has been around for quite a while. One of the earliest described versions of it came about from research into Fauvism – an hereditary disorder that causes an allergic reaction to fava beans. Scientists wanted to establish why the allergy was selective. The cause was eventually linked to a deficiency of the enzyme glucose-6-phosphate dehydrogenase (G6PD). People with that G6PD deficiency are at risk of developing acute hemolytic anemia when they eat fava beans. And the deficiency was found to result from a genetic disorder.

This opened up a whole field of genetic research to explain why human bodies react to chemicals in different ways.

What work still needs to be done to bring pharmacogenomics into mainstream pathology practice?
 

Until recently, there's been little effort to standardize the content or specific variants or alleles that should be included in clinical PGx testing. One of the issues is that PGx spans a number of medical specialties, each of which prefers to use its own recognized guidelines. Outside of pathology, there is little recognition of all the work done by the Clinical Pharmacogenomics Implementation Consortium (CPIC) or the Dutch Pharmacogenetics Working Group (DPWG), for example. For PGx to enter mainstream practice, standardization of testing will need to be adopted across those different specialties.

How will the work of the AMP PGx Working Group help with that standardization?
 

The PGx Working Group brings together leading subject matter experts and representatives from the clinical PGx testing community in the US as well as Europe. It includes organizational representation from AMP, American College of Medical Genetics and Genomics, CPIC, College of American Pathologists, DPWG, European Society for Pharmacogenomics and Personalized Therapy, Pharmacogenomics Knowledgebase, and Pharmacogene Variation Consortium..

CPIC and DPWG have been developing PGx guidelines for a while, but don’t recommend specific alleles to include in testing. AMP established the PGx Working Group to help standardize clinical testing across laboratories such that assays investigate the most clinically relevant variants or alleles, and enable health care professionals to provide high quality patient care. The aim of the group is to define a minimum set of variants – what I call a must test list – that should be included in common clinical genotyping assays.

The working group has invested a lot of time and effort in this work, resulting in seven PGx guidelines being published so far – most recently the DPYD Genotyping Recommendations. Testing for variants in the DPYD gene can help identify cancer patients who may be at increased risk of toxicity from fluoropyrimidine-based chemotherapy.

This new report is intended to improve clinical practice and facilitate standardization across clinical laboratories and ensure that the appropriate variants are included in clinical PGx DPYD assays. It builds on our earlier clinical genotyping recommendations for CYP3A4/CYP3A5, TPMT/NUDT15, CYP2D6, genes important for warfarin testing, CYP2C9, and CYP2C19. We will continue to update the recommendations as new data and reference materials become available.

It is important that the recommendations are implemented along with other relevant clinical guidelines, such as those issued by CPIC and DPWG, which focus on interpreting PGx test results, and give therapeutic recommendations for specific drug–gene pairs.

With all those learned bodies involved, how difficult is it to reach consensus on the guidelines?
 

So far, we’ve all managed to agree. What’s interesting is the degree of health equity that’s introduced by having an international panel. The DPWG’s original label for the drug 5FU recommended PGx testing for four genetic variants. However, those variants are very specific to people with white European ancestry. Collectively, the AMP PGx Working Group’s recommendation for 5FU takes a more pan-ethnic approach, including variants that are common throughout the world

How have the guidelines been received by the laboratories delivering these services?
 

We have received some favorable feedback, particularly on the DPYD guidelines. That gene has been regularly mentioned in the news as there have been some lawsuits related to the tragic deaths of patients with DPYD variants from adverse drug reactions. So the DPYD Genotyping Recommendations have been regarded as very timely.

Are you able to share any case studies of pharmacogenomics success stories?

One famous case involved Miss America 2020, Camille Schrier. She was struggling with depression and anxiety that were not responding to medication. PGx testing was able to match Shrier with medication that would be metabolized more efficiently, according to her genetic profile. After switching medications, her symptoms improved and she was able to move on with her life.

There was also a patient treated at Mayo Clinic – Karen Daggett – who took ill due to adverse reactions to her regular medications. PGx testing revealed a hereditary variant in her CYP2D6 gene, which controlled metabolization of her medications. Daggett urged her family members to undergo testing, of whom 19 tested positive for the same CYP2D6 variant. Some of her close relatives also went on to receive life-changing medication switches due to the PGx test results.

Stanford Medicine also has a PGx program, called the Humanwide Project. One of their patients, Debbie Spaizman, experienced dizziness and disorientation when she used pain medication. Her Humanwide PGx evaluation found this was due to a CYP2D6 variant, and she then received advice on more suitable medication to use after an important operation.

We hope that our PGx guidelines will result in many more patients receiving improved treatment outcomes.