Bhavina B Sharma1, Karan Rai2, Heather Blunt3, Wenyan Zhao4, Tor D Tosteson4,5, Gabriel A Brooks1,5. 1. Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire, USA. 2. Geisel School of Medicine at Dartmouth, Lebanon, New Hamphsire, USA. 3. Biomedical Libraries, Dartmouth College, Hanover, New Hampshire, USA. 4. Department of Biomedical Data Science, Geisel School of Medicine, Lebanon, New Hampshire, USA. 5. The Dartmouth Institute for Health Policy and Clinical Practice, Geisel School of Medicine, Lebanon, New Hampshire, USA.
Abstract
BACKGROUND: Pathogenic variants of the DPYD gene are strongly associated with grade ≥3 toxicity during fluoropyrimidine chemotherapy. We conducted a systematic review and meta-analysis to estimate the risk of treatment-related death associated with DPYD gene variants. MATERIALS AND METHODS: We searched for reports published prior to September 17, 2020, that described patients receiving standard-dose fluoropyrimidine chemotherapy (5-fluorouracil or capecitabine) who had baseline testing for at least one of four pathogenic DPYD variants (c.1129-5923C>G [HapB3], c.1679T>G [*13], c.1905+1G>A [*2A], and c.2846A>T) and were assessed for toxicity. Two reviewers assessed studies for inclusion and extracted study-level data. The primary outcome was the relative risk of treatment-related mortality for DPYD variant carriers versus noncarriers; we performed data synthesis using a Mantel-Haenszel fixed effects model. RESULTS: Of the 2,923 references screened, 35 studies involving 13,929 patients were included. DPYD variants (heterozygous or homozygous) were identified in 566 patients (4.1%). There were 14 treatment-related deaths in 13,363 patients without identified DPYD variants (treatment-related mortality, 0.1%; 95% confidence interval [CI], 0.1-0.2) and 13 treatment-related deaths in 566 patients with any of the four DPYD variants (treatment-related mortality, 2.3%; 95% CI, 1.3%-3.9%). Carriers of pathogenic DPYD gene variants had a 25.6 times increased risk of treatment-related death (95% CI, 12.1-53.9; p < .001). After excluding carriers of the more common but less deleterious c.1129-5923C>G variant, carriers of c.1679T>G, c.1905+1G>A, and/or c.2846A>T had treatment-related mortality of 3.7%. CONCLUSION: Patients with pathogenic DPYD gene variants who receive standard-dose fluoropyrimidine chemotherapy have greatly increased risk for treatment-related death. IMPLICATIONS FOR PRACTICE: The syndrome of dihydropyrimidine dehydrogenase (DPD) deficiency is an uncommon but well-described cause of severe toxicity related to fluoropyrimidine chemotherapy agents (5-fluorouracil and capecitabine). Patients with latent DPD deficiency can be identified preemptively with genotyping of the DPYD gene, or with measurement of the plasma uracil concentration. In this systematic review and meta-analysis, the authors study the rare outcome of treatment-related death after fluoropyrimidine chemotherapy. DPYD gene variants associated with DPD deficiency were linked to a 25.6 times increased risk of fluoropyrimidine-related mortality. These findings support the clinical utility of DPYD genotyping as a screening test for DPD deficiency.
BACKGROUND: Pathogenic variants of the DPYD gene are strongly associated with grade ≥3 toxicity during fluoropyrimidine chemotherapy. We conducted a systematic review and meta-analysis to estimate the risk of treatment-related death associated with DPYD gene variants. MATERIALS AND METHODS: We searched for reports published prior to September 17, 2020, that described patients receiving standard-dose fluoropyrimidine chemotherapy (5-fluorouracil or capecitabine) who had baseline testing for at least one of four pathogenic DPYD variants (c.1129-5923C>G [HapB3], c.1679T>G [*13], c.1905+1G>A [*2A], and c.2846A>T) and were assessed for toxicity. Two reviewers assessed studies for inclusion and extracted study-level data. The primary outcome was the relative risk of treatment-related mortality for DPYD variant carriers versus noncarriers; we performed data synthesis using a Mantel-Haenszel fixed effects model. RESULTS: Of the 2,923 references screened, 35 studies involving 13,929 patients were included. DPYD variants (heterozygous or homozygous) were identified in 566 patients (4.1%). There were 14 treatment-related deaths in 13,363 patients without identified DPYD variants (treatment-related mortality, 0.1%; 95% confidence interval [CI], 0.1-0.2) and 13 treatment-related deaths in 566 patients with any of the four DPYD variants (treatment-related mortality, 2.3%; 95% CI, 1.3%-3.9%). Carriers of pathogenic DPYD gene variants had a 25.6 times increased risk of treatment-related death (95% CI, 12.1-53.9; p < .001). After excluding carriers of the more common but less deleterious c.1129-5923C>G variant, carriers of c.1679T>G, c.1905+1G>A, and/or c.2846A>T had treatment-related mortality of 3.7%. CONCLUSION: Patients with pathogenic DPYD gene variants who receive standard-dose fluoropyrimidine chemotherapy have greatly increased risk for treatment-related death. IMPLICATIONS FOR PRACTICE: The syndrome of dihydropyrimidine dehydrogenase (DPD) deficiency is an uncommon but well-described cause of severe toxicity related to fluoropyrimidine chemotherapy agents (5-fluorouracil and capecitabine). Patients with latent DPD deficiency can be identified preemptively with genotyping of the DPYD gene, or with measurement of the plasma uracil concentration. In this systematic review and meta-analysis, the authors study the rare outcome of treatment-related death after fluoropyrimidine chemotherapy. DPYD gene variants associated with DPD deficiency were linked to a 25.6 times increased risk of fluoropyrimidine-related mortality. These findings support the clinical utility of DPYD genotyping as a screening test for DPD deficiency.
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