SNFGE SNFGE
 
Thématique :
- Cancers autres (hors CCR et CHC)
Originalité :
Très original
Solidité :
Très solide
Doit faire évoluer notre pratique :
Pas encore
 
 
Nom du veilleur :
Professeur Thomas APARICIO
Coup de coeur :
 
 
The Lancet Oncology
  2016/01  
 
  2015 Dec;16(16):1639-50  
  doi: 10.1016/S1470-2045(15)00286-7. Epub 2015 Oct 23.  
 
  Clinical relevance of DPYD variants c.1679T>G, c.1236G>A/HapB3, and c.1601G>A as predictors of severe fluoropyrimidine-associated toxicity: a systematic review and meta-analysis of individual patient data.  
 
  Meulendijks D, Henricks LM, Sonke GS, Deenen MJ, Froehlich TK, Amstutz U, Largiadèr CR, Jennings BA, Marinaki AM, Sanderson JD, Kleibl Z, Kleiblova P, Schwab M, Zanger UM, Palles C, Tomlinson I, Gross E, van Kuilenburg AB, Punt CJ, Koopman M, Beijnen JH, Cats A, Schellens JH  
  http://www.ncbi.nlm.nih.gov/pubmed/?term=Clinical+relevance+of+DPYD+variants+c.1679T%3EG%2C+c.1236G%3EA%2FHapB3%2C+and+c.1601G%3EA+as+predictors+of+severe+fluoropyrimidine-associated+toxicity%3A+a+systematic+review+and+meta-analysis+of+individual+patient+  
 
 

BACKGROUND: The best-known cause of intolerance to fluoropyrimidines is dihydropyrimidine dehydrogenase (DPD) deficiency, which can result from deleterious polymorphisms in the gene encoding DPD (DPYD), including DPYD*2A and c.2846A>T. Three other variants-DPYD c.1679T>G, c.1236G>A/HapB3, and c.1601G>A-have been associated with DPD deficiency, but no definitive evidence for the clinical validity of these variants is available. The primary objective of this systematic review and meta-analysis was to assess the clinical validity of c.1679T>G, c.1236G>A/HapB3, and c.1601G>A as predictors of severe fluoropyrimidine-associated toxicity.

METHODS: We did a systematic review of the literature published before Dec 17, 2014, to identify cohort studies investigating associations between DPYD c.1679T>G, c.1236G>A/HapB3, and c.1601G>A and severe (grade ≥3) fluoropyrimidine-associated toxicity in patients treated with fluoropyrimidines (fluorouracil, capecitabine, or tegafur-uracil as single agents, in combination with other anticancer drugs, or with radiotherapy). Individual patient data were retrieved and analysed in a multivariable analysis to obtain an adjusted relative risk (RR). Effect estimates were pooled by use of a random-effects meta-analysis. The threshold for significance was set at a p value of less than 0·0167 (Bonferroni correction).

FINDINGS: 7365 patients from eight studies were included in the meta-analysis. DPYD c.1679T>G was significantly associated with fluoropyrimidine-associated toxicity (adjusted RR 4·40, 95% CI 2·08-9·30, p<0·0001), as was c.1236G>A/HapB3 (1·59, 1·29-1·97, p<0·0001). The association between c.1601G>A and fluoropyrimidine-associated toxicity was not significant (adjusted RR 1·52, 95% CI 0·86-2·70, p=0·15). Analysis of individual types of toxicity showed consistent associations of c.1679T>G and c.1236G>A/HapB3 with gastrointestinal toxicity (adjusted RR 5·72, 95% CI 1·40-23·33, p=0·015; and 2·04, 1·49-2·78, p<0·0001, respectively) and haematological toxicity (adjusted RR 9·76, 95% CI 3·03-31·48, p=0·00014; and 2·07, 1·17-3·68, p=0·013, respectively), but not with hand-foot syndrome. DPYD*2A and c.2846A>T were also significantly associated with severe fluoropyrimidine-associated toxicity (adjusted RR 2·85, 95% CI 1·75-4·62, p<0·0001; and 3·02, 2·22-4·10, p<0·0001, respectively).

INTERPRETATION: DPYD variants c.1679T>G and c.1236G>A/HapB3 are clinically relevant predictors of fluoropyrimidine-associated toxicity. Upfront screening for these variants, in addition to the established variants DPYD*2A and c.2846A>T, is recommended to improve the safety of patients with cancer treated with fluoropyrimidines.

 

 

 

 

 

 

 

 
Question posée
 
Existe-t-il d’autres polymorphismes de la DPD associés à la toxicité du 5FU que ceux précédemment décrit ?
 
Question posée
 
Oui.
 
Commentaires

La question de la prédiction de la toxicité du 5FU par l’étude polymorphisme de la DPD est posée depuis de nombreuses années. Une enquête nationale soutenue par la FFCD visant à évaluer les pratiques concernant la détermination du polymorphisme de la DPD va bientôt débuter (enquête FUSAFE).

 
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