What is the role of DPYD (Dihydropyrimidine Dehydrogenase) gene testing in patients receiving capecitabine (Xeloda)?

DPYD Gene Testing for Capecitabine

Capecitabine is contraindicated in patients with known dihydropyrimidine dehydrogenase (DPD) deficiency, and while universal pretreatment DPYD genotyping is not currently mandated by NCCN, the evidence strongly supports testing to prevent life-threatening toxicity and treatment-related deaths. 1

FDA Contraindication and Risk Profile

• Capecitabine is absolutely contraindicated in patients with known DPD deficiency, as stated in the FDA drug label 1
• DPYD variants occur in approximately 4.1% of patients screened for fluoropyrimidine therapy 2
• Treatment-related mortality is 2.3% in patients with known DPYD variants versus only 0.1% in those without variants (95% CI, 1.3%-3.9%), representing a 25.6-fold increased risk of treatment-related death 2, 3

Current Guideline Recommendations

NCCN Position (2024)

• The NCCN does not currently support universal pretreatment DPYD genotyping, acknowledging that fluoropyrimidines are a pillar of therapy and it remains uncertain whether all DPYD variant carriers are necessarily at increased risk 2
• However, NCCN recognizes that patients with DPYD variants could receive dose reductions or be offered non-fluoropyrimidine regimens 2
• NCCN acknowledges that prospective studies have demonstrated DPYD genotyping is feasible in clinical practice and that dose reductions diminish substantial toxicity risk 2

CPIC Guidelines

• The Clinical Pharmacogenetics Implementation Consortium provides standardized dosing recommendations based on DPYD genotype 2
• For intermediate metabolizers (heterozygous for DPYD decreased/no function variants): reduce starting dose by 25-50% depending on the specific variant 2
• For poor metabolizers (homozygous variants): avoid fluoropyrimidines entirely 2, 4
• Doses can be increased in subsequent cycles for patients with minimal or no toxicity in the first 2 cycles 2

European Guidelines

• The European Society for Medical Oncology (ESMO) recommends germline variant testing for DPD deficiency before capecitabine treatment is initiated 4

Evidence Supporting DPYD Testing

Toxicity Reduction

• In a prospective study of 2,038 patients screened, 22 patients (1.1%) with the DPYD*2A variant received dose-reduced fluoropyrimidine, resulting in grade ≥3 toxicity of 28% versus 73% in historic controls (P <0.001) 2
• Zero treatment-related deaths occurred in the dose-reduced group compared to 10% mortality in the historical control group 2
• Another prospective study of 1,103 patients identified 85 patients (8%) with any of the 4 most common DPYD variants who received 25-50% dose reductions, demonstrating reduced severe toxicity compared to historical cohorts 2

Cost-Effectiveness

• Cost-effectiveness modeling concluded that pretreatment testing was cost-effective, primarily by avoiding intensive care unit hospitalizations and the cost of uridine triacetate rescue treatment (approximately $75,000 per cycle) 2

Efficacy Considerations with Dose Reduction

• For most DPYD variant carriers, progression-free survival and overall survival are not significantly affected by lower fluoropyrimidine doses 4
• 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) 4
• Efficacy concerns may be more significant in the adjuvant setting than in metastatic disease 2, 4
• A prospective multicenter study of 156 DPYD variant carriers matched to 775 wild-type controls found that dose-reduced fluoropyrimidines did not result in inferior efficacy for most variants 2

Specific Variants to Test

High-Priority Variants

• DPYD*2A (c.1905+1G>A): Most well-established pathogenic variant, associated with severe toxicity 2
• **I560S (*13) (c.1679T>G)**: Established pathogenic variant requiring dose reduction 2, 5
• D949V (c.2846A>T): Common variant associated with increased toxicity 2, 5
• c.1129-5923C>G (HapB3): More common but less deleterious variant 3

Extended Genotyping

• Additional variants including D342G, S492L, R592W, and F100L may improve sensitivity for predicting grade 3-4 toxicity (sensitivity increased to 26.7%, PPV 72.7%, RR 7.6, p<0.001) 5
• Extended genotyping also significantly predicts grade 4 toxicity (sensitivity 60%, PPV 27.3%, RR 31.4, p = 0.001) 5

Clinical Implementation Algorithm

Before Starting Capecitabine

1. Consider DPYD genotyping for at minimum the 4 most common variants (DPYD*2A, *13, D949V, HapB3), particularly in patients where severe toxicity would be catastrophic or in those receiving adjuvant therapy where efficacy is paramount 2, 4
2. If testing is not performed, monitor extremely closely for early signs of severe toxicity including bone marrow suppression, mucositis, palmar-plantar syndrome, and diarrhea 4, 1

If DPYD Variant Identified

• Heterozygous variants: Start with 50% dose reduction for first cycle per NCCN recommendations 4
• Homozygous variants: Avoid fluoropyrimidines completely and use alternative non-fluoropyrimidine regimens 2, 4
• Monitor closely during first two cycles and consider dose escalation if minimal toxicity occurs 2

If Severe Toxicity Develops

• Administer uridine triacetate as rescue treatment within 96 hours of fluoropyrimidine administration 4
• Consider retrospective DPYD testing if not performed preemptively 6

Common Pitfalls

• Do not assume all patients with DPYD variants will experience toxicity - there is heterogeneity in clinical presentation, but the risk is substantially elevated 2
• Do not use phenotyping (plasma uracil measurement) alone - combining genotyping with phenotyping does not substantially increase sensitivity while impairing positive predictive value 5
• Do not overlook that 23% of wild-type patients still experience grade 3 toxicities, primarily palmar-plantar erythrodysesthesia and gastrointestinal toxicities 6
• Be aware that the CPIC dosing recommendations do not distinguish between intravenous bolus, infusional 5-FU, or oral capecitabine, despite different pharmacokinetics 2