Treatment Considerations for Patients with DPD Mutations Requiring Chemotherapy

Understanding DPD Deficiency and Risk

DPD deficiency affects approximately 3-5% of the population (partial deficiency) and 0.5% have complete deficiency 1, 2
Patients with DPD mutations have significantly increased risk of severe, potentially life-threatening toxicity 2
Treatment-related deaths were reported in 0.1% of patients without identified DPYD variants versus 2.3% of those with known DPYD variants 2

For heterozygous DPD mutations, start with 50% dose reduction of fluoropyrimidines for the first cycle, as recommended by the National Comprehensive Cancer Network 1, 2
For homozygous DPD mutations, avoid fluoropyrimidines completely, as recommended by the National Comprehensive Cancer Network 1, 2
Monitor closely for toxicity during first two cycles, and consider alternative chemotherapy regimens that do not include fluoropyrimidines for homozygous mutations 2

Watch for early signs of severe toxicity, including bone marrow suppression, mucositis, palmar/plantar syndrome, diarrhea, and hair loss 1, 3
For patients who develop severe toxicity despite precautions, consider uridine triacetate as rescue treatment within 96 hours of fluoropyrimidine administration, as recommended by the National Comprehensive Cancer Network 2

The Clinical Pharmacogenetics Implementation Consortium (CPIC) Guidelines recommend testing for DPYD variants before initiating fluoropyrimidine therapy 2
While the NCCN does not currently recommend universal pretreatment DPYD genotyping, they acknowledge the value of testing in reducing toxicity 2

A prospective study found that for most DPYD variant carriers, progression-free survival and overall survival were 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 than in metastatic disease, according to the National Comprehensive Cancer Network 2

The European Society for Medical Oncology (ESMO) recommends that patients should undergo germline variant testing for dihydropyrimidine dehydrogenase (DPD) deficiency before capecitabine treatment is initiated, as stated in the ESMO 2021 guidelines for metastatic breast cancer 4
The American Society of Clinical Oncology (ASCO) recommends capecitabine for patients with HER2-negative breast cancer and residual disease after neoadjuvant therapy, although they do not explicitly address DPYD testing in their breast cancer recommendations 5, 6, 7, 8
The National Comprehensive Cancer Network (NCCN) provides detailed guidance on DPYD testing that is applicable across cancer types using fluoropyrimidines, as stated in the NCCN colon cancer guidelines (2024) 9

DPYD variants occur in approximately 4.1% of patients screened, according to the NCCN colon cancer guidelines (2024) 9
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%), as reported in the NCCN colon cancer guidelines (2024) 9
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, as stated in the NCCN colon cancer guidelines (2024) 9
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), as reported in the NCCN colon cancer guidelines (2024) 9
None of the dose-reduced patients died of drug toxicity, compared with a 10% death rate in the historical control group, according to the NCCN colon cancer guidelines (2024) 9

For most DPYD variant carriers, progression-free survival and overall survival are not significantly affected by lower fluoropyrimidine doses, although efficacy concerns may be more significant in the adjuvant setting, as stated in the NCCN colon cancer guidelines (2024) 9