학술논문
Pathogenic DPYD Variants and Treatment-Related Mortality in Patients Receiving Fluoropyrimidine Chemotherapy: A Systematic Review and Meta-Analysis
Cancer Diagnostics and Molecular Pathology
Cancer Diagnostics and Molecular Pathology
Document Type
Report
Author
Source
The Oncologist. December 2021, Vol. 26 Issue 12, p1008, 9 p.
Subject
Language
English
ISSN
1083-7159
Abstract
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 [...]
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. The Oncologist 2021;26:1008-1016 Key Words. 5-fluorouracil * Capecitabine * DPYD * Dihydropyrimidine dehydrogenase deficiency * Pharmacogenomics
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. The Oncologist 2021;26:1008-1016 Key Words. 5-fluorouracil * Capecitabine * DPYD * Dihydropyrimidine dehydrogenase deficiency * Pharmacogenomics