Dihydropyrimidine dehydrogenase (DPD) enzyme deficiency

Definition

Dihydropyrimidine dehydrogenase (DPD) enzyme deficiency is an uncommon condition, but if present significantly increases the risk of severe toxicity of fluoropyrimidines.^r DPD deficiency occurs in patients who carry genetic variations in the dihydropyrimidine dehydrogenase (DPYD) gene.

Fluoropyrimidine toxicity

About 10-40% of patients treated with fluoropyrimidines (5-fluorouracil and capecitabine) develop severe adverse events that are Grade 3 or more in severity. These adverse events include myelosuppression, severe diarrhoea, stomatitis and skin toxicity, including hand-foot syndrome.^rr Fluoropyrimidines occasionally cause, life-threatening toxicities with treatment-related mortality rates of 0.2-1.0%.^r

The toxicity profile of fluoropyrimidines varies according to the administration regimen. With continuous infusion of 5-fluorouracil (5FU), diarrhoea and mucositis are the major dose limiting side effects. Intravenous bolus of 5FU results in more myelosuppression.^r Capecitabine is an orally administered fluoropyrimidine, with the most common dose limiting toxicities being hand-foot syndrome and diarrhoea.^r Other common side effects include fatigue, stomatitis, skin hyperpigmentation and photosensitivity. Coronary vasospasm that can cause myocardial damage is an uncommon but serious toxicity. Similarly, neurological toxicities such as neuropathy, cerebellar ataxia or cognitive impairment are rare, occurring in less than 1% of patients.^rr 

Pathophysiology

Of the 5-fluorouracil (5 FU) dose administered, only 1-3% is processed to cytotoxic metabolites which is required to produce the anti-cancer effect.^r DPD is an enzyme that is coded by the DPYD gene, and this promotes the first step of the 5 FU degradation pathway.^r This pathway helps to convert 80% of fluorouracil to its inactive metabolite. The remaining 5FU is excreted in urine.^r DPD deficiency leads to increased risk of severe 5FU related toxicity.^r

Incidence/prevalence

A partial DPD deficiency occurs in about 3-8% of Caucasian population, due to variations in the DPYD gene, that leads to the inability to fully metabolise fluorouracil.^r Complete DPD deficiency occurs in about 0.3% of Caucasian population and this results in extreme toxicity of fluorouracil.^r

Symptoms and signs

Patients with partial or complete DPD deficiency who are treated with a standard dose of fluoropyrimidine will have increased level of active 5FU metabolites. Patients with DPD deficiency after being treated with 5FU or capecitabine are at significant risk of developing toxicity earlier and higher risk of serious, grade 3 or 4 toxicities with neutropenia, mucositis and diarrhoea, which can be fatal.^r Read more about Fluoropyrimidine overdose or overexposure. 

Investigations and diagnosis

Expert consensus recommends testing for 4 genetic variants of DPYD, ie. DPYD*2A (rs3918290 c.1905+ IG>A), DPYD*13 rs55886062, c.1679T>G), DPYD c.2846A>T (rs67376798, D949V) and DPYD c.1236G>A/HapB3 (rs56038477, E412E).^r Testing for all these 4 variants is estimated to predict 20-30% of early onset life threatening 5-fluorouracil toxicities.^r It is also estimated to predict severe (grade ≥ 3) fluoropyrimidine related toxicities.^rr

The quickest and most economic method of DPYD testing is by real time polymerase chain reaction (RT-PCR). SNP panels with thousands of SNPs in multiple genes, gene panels and exome sequencing can also be used.^r

Both RT-PCR and SNP panels are available in Australia, however, they are currently not reimbursed by the Government and the cost and turnaround times may be limiting factors in testing upfront.

DPYD genotype test is available through some commercial providers, with costs and turnaround times varying (e.g. $95 - 160 with 5-10 business day turnaround from receipt of sample). There may be delays in rural and regional areas.

DPD phenotype testing can be performed by measuring the actual DPD enzyme activity. There are different possible methods for phenotype testing; one is to measure the DPD enzyme activity in peripheral blood mononuclear cells and the other is to measure the uracil concentrations in plasma or urine. The 2-13C uracil breath test and quantification of dihydrouracil/uracil ratio in plasma are other methods of phenotype testing.^r

Dihydrouracil/uracil ratios are available through NSW Health Pathology. The current cost is $250 with a maximum turnaround time of 2 weeks from receipt of sample.

International consensus recommendations 

Several oncology societies^rr have made recommendations for DPYD testing and tailoring fluoropyrimidine administration based on the results. Some of these recommendations include:

• Prior to the start of fluoropyrimidine treatment. Patients should be tested for the 4 most common genetic DPYD variants
• Based on the test results, FU containing drugs are dose adjusted or restricted
• Therapeutic drug monitoring may be required

To individualise treatment based on DPYD genotyping, European Medicines Agency (EMA) recommend classifying individuals as normal metabolisers (activity score of 2), intermediate metabolisers (activity score of 1- 1.5) or poor metabolisers (activity score of 0-0.5). The normal metabolisers do not need dose modifications, but for the intermediate group it is suggested that the dose of fluoropyrimidine is reduced by 50%. The dose may be escalated for subsequent cycles if no toxicity is observed. Fluoropyrimidines are contraindicated in poor metabolisers and other therapeutic options should be considered.^r

The Advisory Committee on Medicines (ACM) of the Therapeutic Goods Administration (TGA) advised that DPD testing can be a reasonable clinical choice but need not be mandated. The treating team would consider the value of testing for the individual patient, taking into account test availability and cost and the potential for testing to delay treatment.^r

Clinical Studies

A Dutch study,^r prospectively genotyped patients before the start of fluoropyrimidine therapy for four DPYD variants viz, DPYD*2A, c.2846A>T, c.1679T>G(DPYD*13) and haplotype B3. Heterozygous DPYD variant allele carriers were given either 25% dose reduction (for c.2846A>T and haplotype B3) or 50% dose reduction (for DPYD*2A and *13). They found that dose reduction of 50% was safe to reduce risk of severe toxicity for DPYD*2A and *13 carriers. However dose reductions of 25% in heterozygous c.2846A and haplotype B3 were insufficient to reduce the risk of fluoropyrimidine toxicity when compared to the observed risk in wild-type patients. Hence, they also recommended initial dose reduction of fluropyrimidines by 50% in c.2846A>T and haplotype B3 carriers. Henricks et al (2018) also suggest phenotyping to allow DPD functional assessment by measuring uracil levels in the blood. If the levels are >16 ng/ml, the dose of fluoropyrimidines could be reduced by 50% and if the levels are >150 ng/ml, fluoropyrimidines are contraindicated.^r

Recommendations for DPD testing 

Based on this data, clinicians should discuss DPYD gene testing with all patients who are going to start fluoropyrimidines, with the decision to conduct testing made between the clinician and the patient.

There are a number of barriers to carrying out routine testing on all patients prior to receiving fluoropyrimidine treatment including:

• Testing is not yet widely available; specimens may need to be sent interstate
• Neither genotyping nor phenotype testing is currently reimbursed by Medicare so patient payment could be substantial
• Turnaround time for testing may delay timely initiation of therapy
• Treatment options for those that are found to have DPD deficiency are less clear unless a functional DPYD variant is identified.

All patients receiving fluoropyrimidines should be closely monitored for toxicity, regardless of the results of DPYD genotyping, as the absence of the four DPYD variants does not eliminate a patient’s risk of developing life-threatening toxicity.

For those who are found to have partial DPD deficiency, or who are heterozygous carriers of one of the four genetic variations of the DPYD gene, clinicians could consider an initial dose reduction of 50%. This should be followed by clinical assessment and possible further dose reduction, continuation of current dose or even up titration of dose depending on clinical tolerance. For those who have a near complete or complete DPD deficiency, or who are homozygous carriers of one variant, or compound heterozygote carriers of two different variants, avoiding fluoropyrimidines is suggested as the safest management.^r See tables below for specific recommendations.

Dose recommendation for specific DPYD variants

Recommendations in the tables below are based on the CPIC (2018)^r and DPWG (2020)^r guidelines, and in line with recommendations endorsed by the UK chemotherapy board (2020).^r

Allele  (Heterozygous genotype)	Predicted % DPD enzyme activity  In the presence of one DPYD variant	Starting dose recommendation	Dose titration** The dose increment (%) is a proportion of the target treatment dose (100%).
c.1905+1G>A  (IVS14+1G>A or rs3918290, also known as DPYD*2A)	50%	50% of target dose or  consider alternative treatment*.	If tolerant after cycle 1, consider a dose increment of 12.5%. Dose increments to a dose intensity of 75% of the target dose, over subsequent cycles may be possible.
c.1679T>G  (p.I560S or rs55886062,  also known as DPYD*13)	50%	50% of target dose or  consider alternative treatment*.	If tolerant after cycle 1, consider a dose increment of 12.5%. Dose increments to a dose intensity of 75% of the target dose, over subsequent cycles, may be possible.
c.2846A>T  (p.D949V or rs67376798)	50 – 75%	50% of target dose or  consider alternative treatment*.	If tolerant after cycle 1, consider a dose increment of 12.5%. Dose increments to a dose intensity of 75% of the target dose, over subsequent cycles may be possible. If no toxicity is observed at a dose of 75%, a further increment to a maximum 85% may be possible, but caution is advised.
c.1236G>A/ HapB3 (rs56038477) synonymous variant to  c.1129-5923C>G rs75017182	50 – 75%	50% of target dose or  consider alternative treatment*.	If tolerant after cycle 1, consider a dose increment of 12.5%.  Dose increments to a dose intensity of 75% of the target dose, over subsequent cycles may be possible. If no toxicity is observed at a dose of 75%, a further increment to a maximum 85% may be possible, but caution is advised.
Treatment optimisation:	To maintain efficacy, consider increasing the dose after cycle 1 to a dose intensity of 62.5%, in patients who experience no or clinically tolerable toxicity. Where treatment cycles are defined as Monday to Friday (over 5 days), it may be recommended to increase doses at a later stage.   Consider conservative dose increments in patients who tested positive for c.1905+1G>A and c.1679T>G, as these two variants have the most deleterious effect on DPD enzyme activity.   To minimise toxicity-related complications, decrease the dose or withhold treatment promptly in patients who experience clinically intolerable toxicity.

* When alternative therapy is recommended the therapy is to be determined by the treating oncologist, and informed by the tumour type, clinical indication and predicted severity of enzyme deficiency based on DPYD genotype. It is beyond the scope of this guideline to state the appropriate decision making for each indication.  

** In rare cases, patients may tolerate a dose intensity of near 100% of the target treatment dose.

Dose recommendation for more than one DPYD variants 

Genotypes Homozygous (two of the same variants) Or Compound heterozygous (two different variants)	Predicted % DPD enzyme activity In the presence of two DPYD variants	Starting dose recommendation	Dose titration
c.1905+1G>A and c.1905+1G>A homozygous or c.1679T>G and c.1679T>G homozygous or c.1905+1G>A and c.1679T>G compound heterozygous	0% Complete DPD deficiency	DO NOT administer fluoropyrimidine therapy in patients with these genotypes.	Not applicable
c.1905+1G>A and c.1236G>A/HapB3 compound heterozygous or c.1905+1G>A and c.2846A>T compound heterozygous or c.1679T>G and c.1236G>A/HapB3 compound heterozygous or c.1679T>G and c.2846A>T compound heterozygous	10 – 25%	Consider alternative treatment*. Where alternative therapy is not considered suitable, 5-FU (IV) may be considered in centres with expertise and therapeutic drug monitoring (TDM) services. Consider a strongly reduced dose at 10% of the target dose.	If tolerant after cycle 1, titrate dose against toxicity over subsequent cycles to a maximum of 25% of the target dose.
c.1236G>A/HapB3 and c.1236G>A/HapB3 homozygous or c.2846A>T and c.2846A>T homozygous or c.1236G>A/HapB3 and c.2846A>T compound heterozygous	10 – 50%	Consider alternative treatment*. Where alternative therapy is not suitable, 5-FU (IV) may be considered in centres with expertise and therapeutic drug monitoring (TDM) services. Consider a strongly reduced dose at 10% of the target dose.	If tolerant after cycle 1, titrate dose against toxicity over subsequent cycles to a maximum of 50% of the target dose.
Treatment optimisation:	In patients who experience severe toxicity, promptly decrease the dose or withhold treatment until toxicity has resolved. Centres with TDM services, are recommended to utilise TDM to determine plasma 5-FU concentrations at the earliest timepoint of steady state, and to cease treatment if concentrations are too high.

* When alternative therapy is recommended the therapy is to be determined by the treating oncologist, and informed by the tumour type, clinical indication and predicted severity of enzyme deficiency based on DPYD genotype. It is beyond the scope of this guideline to state the appropriate decision making for each indication.  

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Version 6

Date	Summary of changes
24/02/2023	Document reviewed by Medical Oncology Reference Committee at a standalone meeting held on 24 February 2023. All sections reviewed and updated.
24/05/2023	Document approved by Medical Oncology Reference Committee. Version number increased to Version 6. Next review 4 years.
08/12/2023	Dose recommendation for specific DPYD variants table updated to clarify dose increments.

Version 5

Date	Summary of changes
28/09/2020	Document reviewed electronically by Medical Oncology Reference Committee. All sections updated. ESMO guidelines, EMA recommendations, link to CPIC added and testing information updated. Testing time frames and costs confirmed with providers. Version number changed to Version 5. Next review 2 years.
21/06/2022	DPYD genotype and dihydrouracil/uracil ratio testing time frames and costs updated.
14/12/2022	Addition of flag linking to TGA Medicine safety update (14 Sept 2022), and removal of reference to TGA under Investigations and diagnosis section.

Version 4

Date	Summary of changes
16/02/2018	Document reviewed at Medical Oncology Upper Gastrointestinal Reference Committee and substantial changes made. Changed to a Clinical Resource and version number changed to Version 4.

Version 3

Date	Summary of changes
31/05/2017	Reformatted as Side Effect document ID: 1744. Transferred to new eviQ website. Version 3.

Version 2

Date	Summary of changes
30/06/2015	Reviewed and reformatted. Version 2.

Version 1

Date	Summary of changes
01/05/2012	First approved on eviQ as an Additional Clinical Information (ACI) ID: 4. Version 1.