Cost-effectiveness of DPYD Genotyping Prior to Fluoropyrimidine-based Adjuvant Chemotherapy for Colon Cancer

Abstract

Background: Adjuvant fluoropyrimidine-based chemotherapy substantially reduces recurrence and mortality after resection of stage 3 colon cancer. While standard doses of 5-fluorouracil and capecitabine are safe for most patients, the risk of severe toxicity is increased for the approximately 6% of patients with dihydropyimidine dehydrogenase (DPD) deficiency caused by pathogenic DPYD gene variants. Pre-treatment screening for pathogenic DPYD gene variants reduces severe toxicity but has not been widely adopted in the United States.

Methods: We conducted a cost-effectiveness analysis of DPYD genotyping prior to fluoropyrimidine-based adjuvant chemotherapy for stage 3 colon cancer, covering the c.1129-5923C>G (HapB3), c.1679T>G (*13), c.1905+1G>A (*2A), and c.2846A>T gene variants. We used a Markov model with a 5-year horizon, taking a United States healthcare perspective. Simulated patients with pathogenic DPYD gene variants received reduced-dose fluoropyrimidine chemotherapy. The primary outcome was the incremental cost-effectiveness ratio (ICER) for DPYD genotyping.

Results: Compared with no screening for DPD deficiency, DPYD genotyping increased per-patient costs by $78 and improved survival by 0.0038 quality-adjusted life years (QALYs), leading to an ICER of $20,506/QALY. In 1-way sensitivity analyses, The ICER exceeded $50,000 per QALY when the cost of the DPYD genotyping assay was greater than $286. In probabilistic sensitivity analysis using a willingness-to-pay threshold of $50,000/QALY DPYD genotyping was preferred to no screening in 96.2% of iterations.

Conclusion: Among patients receiving adjuvant chemotherapy for stage 3 colon cancer, screening for DPD deficiency with DPYD genotyping is a cost-effective strategy for preventing infrequent but severe and sometimes fatal toxicities of fluoropyrimidine chemotherapy.

Keywords: 5-fluorouracil; Capecitabine; DPD deficiency; Pharmacogenetics.

Figure 1.

Structure of Markov model simulating adjuvant chemotherapy for stage 3 colon cancer ^aA subset of patients with grade 3–4 toxicity experience toxicity-related hospitalizations.

Figure 2.

Monte Carlo plot of 100,000 model iterations from probabilistic sensitivity analysis Each plotted point represents an iteration of the probabilistic sensitivity analysis. The diagonal line indicates a willingness-to-pay (WTP) threshold of $50,000 and the ellipse represents the 95% confidence interval. DPYD genotyping is preferred to the no screening strategy for green points below the WTP threshold.