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

Didier Meulendijks; Linda M Henricks; Gabe S Sonke; Maarten J Deenen; Tanja K Froehlich; Ursula Amstutz; Carlo R Largiadèr; Barbara A Jennings; Anthony M Marinaki; Jeremy D Sanderson; Zdenek Kleibl; Petra Kleiblova; Matthias Schwab; Ulrich M Zanger; Claire Palles; Ian Tomlinson; Eva Gross; André B P van Kuilenburg; Cornelis J A Punt; Miriam Koopman; Jos H Beijnen; Annemieke Cats; Jan H M Schellens

doi:10.1016/S1470-2045(15)00286-7

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

Didier Meulendijks, Linda M Henricks, Gabe S Sonke, Maarten J Deenen, Tanja K Froehlich, Ursula Amstutz, Carlo R Largiadèr, Barbara A Jennings, Anthony M Marinaki, Jeremy D Sanderson, Zdenek Kleibl, Petra Kleiblova, Matthias Schwab, Ulrich M Zanger, Claire Palles, Ian Tomlinson, Eva Gross, André B P van Kuilenburg, Cornelis J A Punt, Miriam KoopmanJos H Beijnen, Annemieke Cats, Jan H M Schellens

Cancer and Genomic Sciences

Research output: Contribution to journal › Review article › peer-review

172 Citations (Scopus)

Abstract

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.

FUNDING: None.

Original language	English
Pages (from-to)	1639-1650
Number of pages	12
Journal	The Lancet Oncology
Volume	16
Issue number	16
Early online date	23 Oct 2015
DOIs	https://doi.org/10.1016/S1470-2045(15)00286-7
Publication status	Published - Dec 2015

Keywords

Antimetabolites, Antineoplastic
Capecitabine
Dihydrouracil Dehydrogenase (NADP)
Fluorouracil
Gastrointestinal Diseases
Genetic Predisposition to Disease
Hematologic Diseases
Humans
Multivariate Analysis
Neoplasms
Odds Ratio
Pharmacogenetics
Phenotype
Polymorphism, Genetic
Risk Assessment
Risk Factors
Severity of Illness Index
Tegafur
Journal Article
Meta-Analysis
Review

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Meulendijks, D., Henricks, L. M., Sonke, G. S., Deenen, M. J., Froehlich, T. K., Amstutz, U., Largiadèr, C. R., Jennings, B. A., Marinaki, A. M., Sanderson, J. D., Kleibl, Z., Kleiblova, P., Schwab, M., Zanger, U. M., Palles, C., Tomlinson, I., Gross, E., van Kuilenburg, A. B. P., Punt, C. J. A., ... Schellens, J. H. M. (2015). 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. The Lancet Oncology, 16(16), 1639-1650. https://doi.org/10.1016/S1470-2045(15)00286-7

@article{e44b249ae6924773b84e28f866d9a004,

title = "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",

abstract = "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.FUNDING: None.",

keywords = "Antimetabolites, Antineoplastic, Capecitabine, Dihydrouracil Dehydrogenase (NADP), Fluorouracil, Gastrointestinal Diseases, Genetic Predisposition to Disease, Hematologic Diseases, Humans, Multivariate Analysis, Neoplasms, Odds Ratio, Pharmacogenetics, Phenotype, Polymorphism, Genetic, Risk Assessment, Risk Factors, Severity of Illness Index, Tegafur, Journal Article, Meta-Analysis, Review",

author = "Didier Meulendijks and Henricks, {Linda M} and Sonke, {Gabe S} and Deenen, {Maarten J} and Froehlich, {Tanja K} and Ursula Amstutz and Largiad{\`e}r, {Carlo R} and Jennings, {Barbara A} and Marinaki, {Anthony M} and Sanderson, {Jeremy D} and Zdenek Kleibl and Petra Kleiblova and Matthias Schwab and Zanger, {Ulrich M} and Claire Palles and Ian Tomlinson and Eva Gross and {van Kuilenburg}, {Andr{\'e} B P} and Punt, {Cornelis J A} and Miriam Koopman and Beijnen, {Jos H} and Annemieke Cats and Schellens, {Jan H M}",

year = "2015",

month = dec,

doi = "10.1016/S1470-2045(15)00286-7",

language = "English",

volume = "16",

pages = "1639--1650",

journal = "The Lancet Oncology",

issn = "1470-2045",

publisher = "Elsevier",

number = "16",

}

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, ABP, Punt, CJA, Koopman, M, Beijnen, JH, Cats, A & Schellens, JHM 2015, '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', The Lancet Oncology, vol. 16, no. 16, pp. 1639-1650. https://doi.org/10.1016/S1470-2045(15)00286-7

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, Didier; Henricks, Linda M; Sonke, Gabe S et al.
In: The Lancet Oncology, Vol. 16, No. 16, 12.2015, p. 1639-1650.

Research output: Contribution to journal › Review article › peer-review

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, 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.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, 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.FUNDING: None.

KW - Antimetabolites, Antineoplastic

KW - Capecitabine

KW - Dihydrouracil Dehydrogenase (NADP)

KW - Fluorouracil

KW - Gastrointestinal Diseases

KW - Genetic Predisposition to Disease

KW - Hematologic Diseases

KW - Humans

KW - Multivariate Analysis

KW - Neoplasms

KW - Odds Ratio

KW - Pharmacogenetics

KW - Phenotype

KW - Polymorphism, Genetic

KW - Risk Assessment

KW - Risk Factors

KW - Severity of Illness Index

KW - Tegafur

KW - Journal Article

KW - Meta-Analysis

KW - Review

U2 - 10.1016/S1470-2045(15)00286-7

DO - 10.1016/S1470-2045(15)00286-7

M3 - Review article

C2 - 26603945

SN - 1470-2045

VL - 16

SP - 1639

EP - 1650

JO - The Lancet Oncology

JF - The Lancet Oncology

IS - 16

ER -

Meulendijks D, Henricks LM, Sonke GS, Deenen MJ, Froehlich TK, Amstutz U et al. 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. The Lancet Oncology. 2015 Dec;16(16):1639-1650. Epub 2015 Oct 23. doi: 10.1016/S1470-2045(15)00286-7