TY - JOUR
T1 - Dihydropyrimidine dehydrogenase gene variants for predicting grade 4-5 fluoropyrimidine-induced toxicity
T2 - FUSAFE individual patient data meta-analysis
AU - Le Teuff, Gwénaël
AU - Cozic, Nathalie
AU - Boyer, Jean Christophe
AU - Boige, Valérie
AU - Diasio, Robert B.
AU - Taieb, Julien
AU - Meulendijks, Didier
AU - Palles, Claire
AU - Schwab, Matthias
AU - Deenen, Maarten
AU - Largiadèr, Carlo R.
AU - Marinaki, Anthony
AU - Jennings, Barbara A.
AU - Wettergren, Yvonne
AU - Di Paolo, Antonello
AU - Gross, Eva
AU - Budai, Barna
AU - Ackland, Stephen P.
AU - van Kuilenburg, André B.P.
AU - McLeod, Howard L.
AU - Milano, Gérard
AU - Thomas, Fabienne
AU - Loriot, Marie Anne
AU - Kerr, David
AU - Schellens, Jan H.M.
AU - Laurent-Puig, Pierre
AU - Shi, Qian
AU - Pignon, Jean Pierre
AU - Etienne-Grimaldi, Marie Christine
N1 - Publisher Copyright:
© 2024, The Author(s), under exclusive licence to Springer Nature Limited.
PY - 2024
Y1 - 2024
N2 - Background: Dihydropyrimidine dehydrogenase (DPD) deficiency is the main known cause of life-threatening fluoropyrimidine (FP)-induced toxicities. We conducted a meta-analysis on individual patient data to assess the contribution of deleterious DPYD variants *2A/D949V/*13/HapB3 (recommended by EMA) and clinical factors, for predicting G4-5 toxicity. Methods: Study eligibility criteria included recruitment of Caucasian patients without DPD-based FP-dose adjustment. Main endpoint was 12-week haematological or digestive G4-5 toxicity. The value of DPYD variants *2A/p.D949V/*13 merged, HapB3, and MIR27A rs895819 was evaluated using multivariable logistic models (AUC). Results: Among 25 eligible studies, complete clinical variables and primary endpoint were available in 15 studies (8733 patients). Twelve-week G4-5 toxicity prevalence was 7.3% (641 events). The clinical model included age, sex, body mass index, schedule of FP-administration, concomitant anticancer drugs. Adding *2A/p.D949V/*13 variants (at least one allele, prevalence 2.2%, OR 9.5 [95%CI 6.7–13.5]) significantly improved the model (p < 0.0001). The addition of HapB3 (prevalence 4.0%, 98.6% heterozygous), in spite of significant association with toxicity (OR 1.8 [95%CI 1.2–2.7]), did not improve the model. MIR27A rs895819 was not associated with toxicity, irrespective of DPYD variants. Conclusions: FUSAFE meta-analysis highlights the major relevance of DPYD *2A/p.D949V/*13 combined with clinical variables to identify patients at risk of very severe FP-related toxicity.
AB - Background: Dihydropyrimidine dehydrogenase (DPD) deficiency is the main known cause of life-threatening fluoropyrimidine (FP)-induced toxicities. We conducted a meta-analysis on individual patient data to assess the contribution of deleterious DPYD variants *2A/D949V/*13/HapB3 (recommended by EMA) and clinical factors, for predicting G4-5 toxicity. Methods: Study eligibility criteria included recruitment of Caucasian patients without DPD-based FP-dose adjustment. Main endpoint was 12-week haematological or digestive G4-5 toxicity. The value of DPYD variants *2A/p.D949V/*13 merged, HapB3, and MIR27A rs895819 was evaluated using multivariable logistic models (AUC). Results: Among 25 eligible studies, complete clinical variables and primary endpoint were available in 15 studies (8733 patients). Twelve-week G4-5 toxicity prevalence was 7.3% (641 events). The clinical model included age, sex, body mass index, schedule of FP-administration, concomitant anticancer drugs. Adding *2A/p.D949V/*13 variants (at least one allele, prevalence 2.2%, OR 9.5 [95%CI 6.7–13.5]) significantly improved the model (p < 0.0001). The addition of HapB3 (prevalence 4.0%, 98.6% heterozygous), in spite of significant association with toxicity (OR 1.8 [95%CI 1.2–2.7]), did not improve the model. MIR27A rs895819 was not associated with toxicity, irrespective of DPYD variants. Conclusions: FUSAFE meta-analysis highlights the major relevance of DPYD *2A/p.D949V/*13 combined with clinical variables to identify patients at risk of very severe FP-related toxicity.
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U2 - 10.1038/s41416-023-02517-2
DO - 10.1038/s41416-023-02517-2
M3 - Article
C2 - 38225422
AN - SCOPUS:85182493597
SN - 0007-0920
JO - British journal of cancer
JF - British journal of cancer
ER -