Is DPYD testing recommended before initiating Capecitabine (capecitabine) treatment in a patient with breast cancer?

DPYD Testing Before Capecitabine in Breast Cancer

Yes, DPYD testing should be performed before initiating capecitabine in this patient with residual breast cancer after neoadjuvant chemotherapy. The most recent ESMO guidelines (2021) explicitly state that patients should undergo germline variant testing for dihydropyrimidine dehydrogenase (DPD) deficiency before capecitabine treatment is initiated 1.

Guideline-Based Recommendation

The ESMO 2021 guidelines for metastatic breast cancer provide the clearest directive: "If capecitabine is used, patients should undergo germline variant testing for the lack of enzyme, dihydropyrimidine dehydrogenase (DPD), before treatment is initiated" 1. While this guideline addresses metastatic disease, the principle applies equally—if not more urgently—to the adjuvant setting where this patient will receive capecitabine based on CREATE-X trial results.

The ASCO 2018 guidelines recommend capecitabine for patients with HER2-negative breast cancer and residual disease after neoadjuvant therapy 1, but do not explicitly address DPYD testing in their breast cancer recommendations. However, the NCCN colon cancer guidelines (2024) provide detailed guidance on DPYD testing that is applicable across cancer types using fluoropyrimidines 1.

Clinical Rationale for Testing

Risk of Severe Toxicity Without Testing

• DPYD variants occur in approximately 4.1% of patients screened 1
• Treatment-related deaths occur in 2.3% of patients with known DPYD variants versus only 0.1% in those without variants (95% CI, 1.3%–3.9%) 1, 2
• Patients with DPD deficiency face significantly increased risk of severe, potentially life-threatening toxicity including bone marrow suppression, mucositis, severe diarrhea, and palmar-plantar syndrome 2

Benefits of Preemptive Testing

• Prospective studies demonstrate that DPYD genotyping is feasible in clinical practice and that dose reductions in patients with variant DPYD genes significantly diminish the risk of substantial toxicity 1
• In one prospective study, 22 patients with the DPYD*2A variant who received dose-reduced fluoropyrimidine had a significant reduction in grade ≥3 toxicity compared with historic controls (28% vs 73%; P <0.001) 1
• None of the dose-reduced patients died of drug toxicity, compared with a 10% death rate in the historical control group 1
• Implementation studies show that preemptive DPYD testing can achieve >90% testing rates using automated reminder systems 3

Specific Testing and Dosing Recommendations

Which Variants to Test

The Clinical Pharmacogenetics Implementation Consortium (CPIC) recommends testing for DPYD variants before initiating fluoropyrimidine therapy 2. At minimum, testing should include:

• DPYD*2A (most common deleterious variant) 1, 4
• I560S (DPYD*13) 5
• D949V 5
• c.1236G>A 2

Extended genotyping including additional variants (D342G, S492L, R592W, c.496A>G) improves prediction of severe toxicity and should be considered 6, 5.

Dose Modifications Based on Results

For heterozygous DPYD mutations:

• Start with 50% dose reduction of capecitabine for the first cycle 2, 7
• Monitor closely for toxicity during first two cycles 2
• The NCCN notes that dose reductions in prospective studies ranged from 17% to 91% (median 48%), with specific dosing left to physician discretion 1

For homozygous DPYD mutations:

• Avoid fluoropyrimidines completely 2, 7
• Consider alternative chemotherapy regimens that do not include fluoropyrimidines 2
• For patients with complete DPD deficiency who have high risk of recurrence, alternative treatments like raltitrexed may be considered 7

Important Caveats and Pitfalls

Timing of Testing

• Testing must be conducted before initiating treatment, not after toxicity has occurred 7
• The test should be collected at the infusion appointment as planned, but capecitabine should not be started until results are available 3
• Automated reminder systems can help ensure testing is completed before first dose 3

Limitations of Standard Testing

• Routine genetic DPYD testing for common variants may fail to explain all toxicities seen in clinical practice 8
• Approximately 23% of patients with wild-type DPYD still experience grade 3 toxicities, though these are generally manageable without hospitalization 4
• Exon sequencing in patients who test negative for common variants but experience marked toxicity can identify novel genetic variants 8

Efficacy Considerations

• For most DPYD variant carriers, progression-free survival and overall survival are not significantly affected by lower fluoropyrimidine doses 2
• However, carriers of the c.1236G>A variant showed shorter progression-free survival with reduced doses (HR, 1.43; 95% CI, 1.10–1.86; P = 0.007) 2
• Efficacy concerns may be more significant in the adjuvant setting (like this patient) than in metastatic disease 1

Regional Considerations

• In European populations, DPD testing is strongly recommended and mandatory per the European Medicines Agency 7
• In Asian populations, the incidence of DPD deficiency is significantly lower (approximately 0.6%), though the CREATE-X trial was conducted in Asian patients 7

Practical Implementation

The testing can be coordinated through the available labs as planned. An opt-out, automated reminder-based program achieves the highest testing rates (>90%) 3. Results should be available within days to allow timely treatment initiation with appropriate dose modifications if variants are identified 4, 3.

If severe toxicity develops despite negative testing for common variants, consider uridine triacetate as rescue treatment within 96 hours of fluoropyrimidine administration 2, and pursue expanded DPYD sequencing to identify rare variants 8, 5.