TY - JOUR
T1 - Clinical relevance of DPYD variants c.1679T>G, c.1236G>A/HapB3, and c.1601G>A as predictors of severe fluoropyrimidine-associated toxicity
T2 - A systematic review and meta-analysis of individual patient data
AU - Meulendijks, Didier
AU - Henricks, Linda M.
AU - Sonke, Gabe S.
AU - Deenen, Maarten J.
AU - Froehlich, Tanja K.
AU - Amstutz, Ursula
AU - Largiadèr, Carlo R.
AU - Jennings, Barbara A.
AU - Marinaki, Anthony M.
AU - Sanderson, Jeremy D.
AU - Kleibl, Zdenek
AU - Kleiblova, Petra
AU - Schwab, Matthias
AU - Zanger, Ulrich M.
AU - Palles, Claire
AU - Tomlinson, Ian
AU - Gross, Eva
AU - van Kuilenburg, André B P
AU - Punt, Cornelis J A
AU - Koopman, Miriam
AU - Beijnen, Jos H.
AU - Cats, Annemieke
AU - Schellens, Jan H M
PY - 2015/12
Y1 - 2015/12
N2 - 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, pA/HapB3 (1·59, 1·29-1·97, pA 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, pT were also significantly associated with severe fluoropyrimidine-associated toxicity (adjusted RR 2·85, 95% CI 1·75-4·62, pG 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. Funding: None.
AB - 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, pA/HapB3 (1·59, 1·29-1·97, pA 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, pT were also significantly associated with severe fluoropyrimidine-associated toxicity (adjusted RR 2·85, 95% CI 1·75-4·62, pG 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. Funding: None.
UR - http://www.scopus.com/inward/record.url?scp=84951335101&partnerID=8YFLogxK
U2 - 10.1016/S1470-2045(15)00286-7
DO - 10.1016/S1470-2045(15)00286-7
M3 - Article
AN - SCOPUS:84951335101
SN - 1470-2045
VL - 16
SP - 1639
EP - 1650
JO - Lancet Oncology
JF - Lancet Oncology
IS - 16
ER -