Is DPYD testing recommended before initiating Capecitabine (capecitabine) therapy in a patient with breast cancer to assess for potential variants in the DPYD gene that could affect drug metabolism?

DPYD Testing Before Capecitabine in Breast Cancer with Residual Disease

Patients with breast cancer and residual disease after neoadjuvant chemotherapy who are planned for capecitabine therapy should undergo DPYD genotyping before treatment initiation to identify those at substantially elevated risk of severe, potentially fatal toxicity. 1, 2, 3

Guideline Framework

The European Society for Medical Oncology (ESMO) explicitly recommends germline DPYD variant testing before capecitabine treatment is initiated 2. While the NCCN does not currently support universal pretreatment DPYD genotyping, they acknowledge that patients with DPYD variants could receive dose reductions or be offered non-fluoropyrimidine regimens 4, 1. The ASCO guidelines recommend capecitabine for HER2-negative breast cancer patients with residual disease after neoadjuvant therapy based on the CREATE-X trial, but do not explicitly address DPYD testing 4, 2.

Critical Risk Data Supporting Testing

The mortality risk is dramatically elevated in DPYD variant carriers:

• Treatment-related deaths occur in 2.3% of patients with known DPYD variants versus only 0.1% in those without variants, representing a 25.6-fold increased risk of treatment-related death 1, 2, 3
• DPYD variants occur in approximately 4.1% of patients screened for fluoropyrimidine therapy 1, 5, 3
• In a prospective study of 2,038 patients, 22 patients (1.1%) with the DPYD*2A variant who received dose-reduced fluoropyrimidine had grade ≥3 toxicity of 28% versus 73% in historic controls (P <0.001) 4, 1, 2
• Zero treatment-related deaths occurred in the dose-reduced group compared to 10% mortality in the historical control group 4, 1, 2

Specific Testing and Dosing Algorithm

Test for at minimum the 4 most common DPYD variants: DPYD*2A (c.1905+1G>A), *13 (c.1679T>G), D949V (c.2846A>T), and HapB3 (c.1129-5923C>G) 1, 2

Based on test results:

• For intermediate metabolizers (heterozygous for DPYD decreased/no function variants): Reduce starting dose by 25-50% depending on the specific variant 1, 2
• For poor metabolizers (homozygous variants): Avoid fluoropyrimidines entirely and use alternative chemotherapy regimens 4, 1, 2
• For wild-type DPYD: Proceed with standard dosing (1,250 mg/m² twice daily on days 1-14 of a 21-day cycle for 6-8 cycles as used in CREATE-X) 4

Efficacy Considerations with Dose Reduction

A critical concern is whether dose reduction compromises efficacy, particularly in the adjuvant setting where cure is the goal:

• For most DPYD variant carriers, progression-free survival and overall survival are not significantly affected by lower fluoropyrimidine doses 1, 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) 4
• Efficacy concerns may be more significant in the adjuvant setting than in metastatic disease 4, 1, 2

This patient has residual disease after neoadjuvant therapy, placing her in an adjuvant treatment context where the goal is cure, making the efficacy question particularly relevant 4.

Clinical Implementation for This Patient

For this specific patient scenario:

1. Coordinate DPYD testing through the designated laboratory as required by the State HMO plan's genetic testing policy 1
2. Collect sample at the infusion appointment as planned 1
3. Wait for DPYD results before initiating capecitabine 2, 6
4. If DPYD variants are identified, reduce dose by 25-50% for heterozygous variants or avoid capecitabine entirely for homozygous variants 1, 2
5. If wild-type, proceed with standard CREATE-X dosing: capecitabine 1,250 mg/m² twice daily on days 1-14 of a 21-day cycle for 6-8 cycles 4

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 1
• Be aware that the CPIC dosing recommendations do not distinguish between intravenous bolus, infusional 5-FU, or oral capecitabine, despite different pharmacokinetics 4, 1
• Note that the capecitabine dosage used in CREATE-X (1,250 mg/m² twice daily) is associated with higher toxicity in patients ≥65 years old 4
• If testing is not performed, monitor extremely closely for early signs of severe toxicity including bone marrow suppression, mucositis, palmar-plantar syndrome, and diarrhea 1
• Uridine triacetate should be available as rescue treatment within 96 hours of fluoropyrimidine administration if severe toxicity develops 4, 2

Additional Considerations

Routine genetic DPYD testing can be successfully implemented in clinical practice, with one institution achieving >90% testing rates using an opt-out, reminder-based program 5. In a clinical implementation study at a large cancer center, 8.4% of metastatic breast cancer patients were found to carry DPYD genetic polymorphisms, and prospective testing reduced the risk of severe fluoropyrimidine toxicities 6.