DPYD genotyping to prevent chemotoxicity - precision medicine in action

What is Precision Medicine?

Precision medicine (sometimes called “personalised medicine”) is the branch of genetics concerned with optimising treatment based on an individual’s genetic attributes. In contrast to historical practices in which a one-size-fits-all approach was pursued, precision medicine “considers variability in genes, environment, and lifestyle to direct disease treatment and prevention, more accurately predicting which treatment and prevention strategies will work best for a particular patient.” - NHS Transformation Directorate, Aug 2020. Pharmacogenomics (PGx) is pivotal to precision medicine, concerned with “optimising therapeutic efficacy whilst reducing the likelihood of severe adverse toxicity events (SATEs).” - FDA, August 2023.

DPYD is a real-life example of pharmacogenetic testing where a negative response to therapy can be predicted, and a safe directive towards reduced dosage or alternate therapy made. An estimated 3-8% of the global population has a DPYD mutation which places them in an "at risk" category for a SATE to a widely prescribed class of chemotherapy agents called fluropyrimidines (e.g. 5-fluoracil/5-FU, capecitabine, tegafur).

In this series, we shine a light on DPYD screening, and the ways that Yourgene DPYD could improve health outcomes for hundreds of thousands of cancer patients every year.

Why is DPYD important in the context of oncology?

The metabolism of a class of drugs called fluropyrimidines (e.g., 5-fluoracil/5-FU, capecitabine, tegafur) is performed by the dihydropyrimidine dehydrogenase (DPD) enzyme, encoded by the DPYD gene.

An estimated two million 5-FU prescriptions are written globally each year for a variety of cancers, including colorectal, head and neck, breast, pancreatic and stomach cancer.

Whilst treatment with 5-FU is generally well tolerated, variants in the DPYD gene cause reduced efficiency in the breakdown of 5-FU. When 5-FU levels are sufficiently high, cytotoxic symptoms begin to arise including diarrhoea, stomatitis, neutropenia, hyperbilirubinemia, and hand-foot syndrome.

Identifying patients with DPD deficiency prior to commencing chemotherapy treatment with 5-FU therapy is critical to avoid adverse reactions, as patients with these variants are at an increased risk of severe or fatal 5-FU toxicity.

DPYD Genotyping test results can guide personalised medicine regimes for individual patients, based on therapy dose adjustments - enabling safe treatment choices for all patients

Clinical Justification for DPYD genotyping

An estimated 3–8% of the global population has a DPYD mutation which places them in an "at risk" category for a severe adverse toxicity event (SATE). Effects of 5-FU toxicity are so severe as to be fatal in approximately 1% of patients treated with 5-FU. This means that an estimated 60,000–160,000 individuals every year are at risk of being killed by their treatment, rather than their disease.

In December 2013 the Clinical Pharmacogenetics Implementation Consortium (CPIC) published their “Guideline for Fluoropyrimidines and DPYD”. The guidelines identify six clinically actionable DPYD variants as well as outlining a dose-reduction framework, to direct safe treatment for patients with these variants.

Implementation of DPD deficiency screening by genotyping allows a more accurate prediction of toxicity and chemotherapeutic response.

Various international medical authorities have built on CPIC’s recommendations since they were published. On 30th April 2020, the European Medicines Agency recommended patients should be tested for the lack of DPD before starting cancer treatment with 5-FU medicines. Leading scientific groups, such the Dutch Pharmacogenetics Working Group, also provided updated gene and drug clinical practice guidelines accordingly.

These recommendations, as well as the availability of DPYD assays, have permitted genotyping to be adopted into clinical practice in many countries.

The clincial impact of DPYD testing is saving patients’ lives.

Be part of the personalised medicine movement and introduce DPYD screening for your patients.

Financial Motivation for DPYD genotyping

Thanks to recommendations made by organisations including CPIC, the FDA and European Medical Agency, as well as the availability of affordable commercial DPYD genotyping assays, severe adverse toxicity events and deaths due to 5-FU therapy are entirely preventable.

In May 2022, Oregon Health & Science University promised to change an aspect of its cancer treatment and pay out $1 million to settle a lawsuit claiming the university’s negligence killed a cancer patient, David McIntyre.

The university did not disclose the risk of the genetic condition to Mr. McIntyre that led to his severe adverse reaction to his chemotherapy, nor that it can be tested for.

Although testing for the genetic condition isn’t standard practice in the USA, OHSU will now include education [on DPD Deficiency] in its Oncology Fellowship program.

As part of the settlement, the university’s oncologists will now be required to tell patients about [DPD Deficiency] before initiating the chemotherapy drug capecitabine.

Read the OHSU article here: https://hubs.la/Q025rLnX0

Furthermore, “Zero severe toxicity events [have been] reported since the programme was rolled out. A night in ICU can cost £6,000 and patients with severe toxicity can spend up to six weeks in ICU; therefore, DPYD testing will have a massive impact on the NHS’ budget.” Cara Thomas, Pre-registration Clinical Scientist, AWMGS

Health Economics impact of adopting DPYD genotyping into your patient pathway

The cost of DPYD genotyping is minimal compared with the financial and health cost burden of prescribing a treatment that will have a chemotoxic reaction, as a result of not performing the simple screening test prior to 5-FU chemotherapy.

Trends in global adoption of DPYD genotyping

Research on heritable DNA variation in DPYD has provided a wide range of knowledge, from in vitro function of genetic variants to cost evaluation of genetic testing in the clinic. Widespread adoption of DPYD testing has been facilitated by the publication of guidelines, ministry recommendations and government reimbursement provisions.

Since CPIC’s first guidance in 2013, implementation of DPYD testing at the local, regional and national level has commenced in earnest.

In 2019 Yourgene Health brought the Yourgene® DPYD assay to market and have seen its uptake grow in real-time – first across the UK and Europe, and now reaching 21 countries as far as Northern America, South Africa and Australasia.

To reach an informed decision about implementation, practicing oncologists need access to concise information on the genetic variants to be tested and interpretation of the test results.

The American Journal of Clinical Oncology (AJCO) recommend that practicing oncologists familiarise themselves with the subject of DPD deficiency and its clinical implications by using their practitioner-friendly guide, before they search for more specialised information from other sources.

DPYD genotyping for 5-FU toxicity has been adopted in many countries internationally.
As a result, testing has been introduced into cancer care clinical pathways following government reimbursement.

Summary of IVDR Scope and Key Dates

The European Union In Vitro Diagnostics Regulation 2017/746 (EU IVDR) expanded upon IVD Directive 98/79/EC (IVD-D) requirements, which have been in effect since 1998. The changes come into effect immediately, without having to be implemented into the respective states’ laws.

Whilst some things, like the number of risk device classes, are remaining the same, the scope of the IVDR changes are wide reaching, with key changes as follows:

• Product scope expansion
• Reclassification of devices according to risk
• More stringent clinical evidence
• More stringent documentation
• Implementation of unique device identification
• Rigorous post-market surveillance
• Nomination of a responsible person for regulatory compliance
• Increased Notified Body involvement

The intention of the regulation is to set tighter and broader requirements for the quality, performance and safety of IVD products, with implications for both manufacturers and consumers.

Learn more about Yourgene's IVDR timeline on our Quality section of our website.

Yourgene are committed to sharing our IVDR expertise with our distribution partners and end users – we will be bringing you informative content to help guide you through your IVDR fears.

If you have any questions about IVDR, please contact dpyd@yourgenehealth.com to speak with an expert.

Who is affected by IVDR?

The reach of The European Union In Vitro Diagnostics Regulation 2017/746 (EU IVDR) extends to all EU member states, plus all European Free Trade Association States and EEA territories, with implications for both manufacturers and consumers.

Regulatory requirements will be more demanding under the IVDR for all IVD devices, but the need to prove compliance to a notified body prior to CE marking will increase the burden on the manufacturers and result in a higher cost of regulatory compliance.

The strengthened requirements are all intended to reduce risk, for both users and patients. To this end, devices continue to be certified by an appointed Notified Body (NB) according to risk class (See graphic below)

“In some cases, it may not be possible to generate adequate proof of compliance with the new requirements. These factors may result in some devices no longer being commercially viable.” - BSI Medical Device White Paper Series, Explaining IVD classification issues.

If you have any questions about IVDR, please contact dpyd@yourgenehealth.com

What does IVDR mean for me?

The EU IVDR holds manufacturers of in vitro diagnostic devices (IVDs) to a higher standard. Conformity assessment requirements of IVDR specify that manufacturers must provide, among other things, considerable evidence of scientific validity, as well as data demonstrating analytical and clinical performance of the devices.

Because of this, there are also implications for users of IVDs, and significant requirements for labs who develop and run their own “in-house devices” as part of workflows intended for clinical use.

Users of laboratory-developed tests (LDTs) who wish to continue to do so beyond the May 2028 deadline will be required to prove that their home-brew test(s) fulfil Article 5(5) requirements, which briefly state:

- Experience from clinical use regularly reviewed and corrective action taken if necessary
- Information (including justification of manufacture, modification and use) is available on request to the competent authority
- Specific needs of the target patient group cannot be met to an appropriate level of performance by a commercially available CE-IVD
- Device cannot be made on an industrial scale, or transferred outside of the health institution
- Device manufacture/use occurs under an appropriate Quality Management System
- Device meets general safety and performance requirements set out in Annex I
- Laboratory is compliant with ISO:15189 (or equivalent) standard

To summarise, if a laboratory intends to continue using their own LDT, they adopt the role of a manufacturer and must undertake the onerous task of compiling the relevant data.

If you have any IVDR questions, please contact dpyd@yourgenehealth.com to speak to an expert

Why is the IVDR timeline so long?

Under the European Union In Vitro Diagnostics Directive 98/79/EC (IVD-D), approximately 8% of IVDs required Notified Body involvement.

Under European Union In Vitro Diagnostics Regulation 2017/746 (EU IVDR), approximately 80% of IVDs require Notified Body involvement.

Given that there are 34,000 companies within the European medical device sector, and only 36 designated notified bodies for IVDR, the limited capacity of the notified bodies plus a slower than expected uptake and recognition of the regulation has contributed to the protracted timelines of the transition to this point.

If you have any questions about IVDR, please contact dpyd@yourgenehealth.com to speak to an expert

What does IVDR status mean?

A product with IVDR certification enables clinician and patient confidence in a superior high quality test - where accuracy matters

Yourgene DPYD: One of the first examples of an IVDR pharmacogenomics test that will continue to have a positive impact on cancer patients’ lives