Genetic polymorphisms in ABCG2 and CYP1A2 are associated with imatinib dose reduction in patients treated for gastrointestinal stromal tumors

Michiel C. Verboom; Jacqueline S.L. Kloth; Jesse J. Swen; Stefan Sleijfer; Anna K.L. Reyners; Neeltje Steeghs; Ron H.J. Mathijssen; Hans Gelderblom; Henk Jan Guchelaar

doi:10.1038/s41397-019-0079-z

Genetic polymorphisms in ABCG2 and CYP1A2 are associated with imatinib dose reduction in patients treated for gastrointestinal stromal tumors

Michiel C. Verboom^*, Jacqueline S.L. Kloth, Jesse J. Swen, Stefan Sleijfer, Anna K.L. Reyners, Neeltje Steeghs, Ron H.J. Mathijssen, Hans Gelderblom, Henk Jan Guchelaar

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

Abstract

Imatinib has a mild toxicity profile, although severe adverse events may develop. In this pharmacogenetic pathway analysis the need for dose reduction and cessation of therapy was tested for an association with single nucleotide polymorphisms (SNPs) in genes related to imatinib pharmacology. Retrospective data from 315 patients with a gastrointestinal stromal tumor who received imatinib 400 mg o.d. was associated with 36 SNPs. SNPs that showed a trend in univariate testing were tested in a multivariate model with clinical factors and correction for multiple testing was performed. Dose reduction was associated with carriership of the A-allele in rs2231137 in ABCG2 (OR 7.35, p = 0.0002) and two C-alleles in rs762551 in CYP1A2 (OR 7.12, p = 0.001). Results remained significant after correction for multiple testing. Therapy cessation did not show an association with any of the tested SNPs. These results may help identifying patients at increased risk for toxicity who could benefit from intensified follow-up.

Original language	English
Pages (from-to)	473-479
Number of pages	7
Journal	Pharmacogenomics Journal
Volume	19
Issue number	5
DOIs	https://doi.org/10.1038/s41397-019-0079-z
Publication status	Published - 1 Oct 2019
Externally published	Yes

Access to Document

10.1038/s41397-019-0079-z

Cite this

Verboom, M. C., Kloth, J. S. L., Swen, J. J., Sleijfer, S., Reyners, A. K. L., Steeghs, N., Mathijssen, R. H. J., Gelderblom, H., & Guchelaar, H. J. (2019). Genetic polymorphisms in ABCG2 and CYP1A2 are associated with imatinib dose reduction in patients treated for gastrointestinal stromal tumors. Pharmacogenomics Journal, 19(5), 473-479. https://doi.org/10.1038/s41397-019-0079-z

@article{b285f88c06c247bdad9e820db81f0b5c,

title = "Genetic polymorphisms in ABCG2 and CYP1A2 are associated with imatinib dose reduction in patients treated for gastrointestinal stromal tumors",

abstract = "Imatinib has a mild toxicity profile, although severe adverse events may develop. In this pharmacogenetic pathway analysis the need for dose reduction and cessation of therapy was tested for an association with single nucleotide polymorphisms (SNPs) in genes related to imatinib pharmacology. Retrospective data from 315 patients with a gastrointestinal stromal tumor who received imatinib 400 mg o.d. was associated with 36 SNPs. SNPs that showed a trend in univariate testing were tested in a multivariate model with clinical factors and correction for multiple testing was performed. Dose reduction was associated with carriership of the A-allele in rs2231137 in ABCG2 (OR 7.35, p = 0.0002) and two C-alleles in rs762551 in CYP1A2 (OR 7.12, p = 0.001). Results remained significant after correction for multiple testing. Therapy cessation did not show an association with any of the tested SNPs. These results may help identifying patients at increased risk for toxicity who could benefit from intensified follow-up.",

author = "Verboom, {Michiel C.} and Kloth, {Jacqueline S.L.} and Swen, {Jesse J.} and Stefan Sleijfer and Reyners, {Anna K.L.} and Neeltje Steeghs and Mathijssen, {Ron H.J.} and Hans Gelderblom and Guchelaar, {Henk Jan}",

note = "Publisher Copyright: {\textcopyright} 2019, Springer Nature Limited.",

year = "2019",

month = oct,

day = "1",

doi = "10.1038/s41397-019-0079-z",

language = "English",

volume = "19",

pages = "473--479",

journal = "Pharmacogenomics Journal",

issn = "1470-269X",

publisher = "Springer Nature",

number = "5",

}

TY - JOUR

T1 - Genetic polymorphisms in ABCG2 and CYP1A2 are associated with imatinib dose reduction in patients treated for gastrointestinal stromal tumors

AU - Verboom, Michiel C.

AU - Kloth, Jacqueline S.L.

AU - Swen, Jesse J.

AU - Sleijfer, Stefan

AU - Reyners, Anna K.L.

AU - Steeghs, Neeltje

AU - Mathijssen, Ron H.J.

AU - Gelderblom, Hans

AU - Guchelaar, Henk Jan

PY - 2019/10/1

Y1 - 2019/10/1

N2 - Imatinib has a mild toxicity profile, although severe adverse events may develop. In this pharmacogenetic pathway analysis the need for dose reduction and cessation of therapy was tested for an association with single nucleotide polymorphisms (SNPs) in genes related to imatinib pharmacology. Retrospective data from 315 patients with a gastrointestinal stromal tumor who received imatinib 400 mg o.d. was associated with 36 SNPs. SNPs that showed a trend in univariate testing were tested in a multivariate model with clinical factors and correction for multiple testing was performed. Dose reduction was associated with carriership of the A-allele in rs2231137 in ABCG2 (OR 7.35, p = 0.0002) and two C-alleles in rs762551 in CYP1A2 (OR 7.12, p = 0.001). Results remained significant after correction for multiple testing. Therapy cessation did not show an association with any of the tested SNPs. These results may help identifying patients at increased risk for toxicity who could benefit from intensified follow-up.

AB - Imatinib has a mild toxicity profile, although severe adverse events may develop. In this pharmacogenetic pathway analysis the need for dose reduction and cessation of therapy was tested for an association with single nucleotide polymorphisms (SNPs) in genes related to imatinib pharmacology. Retrospective data from 315 patients with a gastrointestinal stromal tumor who received imatinib 400 mg o.d. was associated with 36 SNPs. SNPs that showed a trend in univariate testing were tested in a multivariate model with clinical factors and correction for multiple testing was performed. Dose reduction was associated with carriership of the A-allele in rs2231137 in ABCG2 (OR 7.35, p = 0.0002) and two C-alleles in rs762551 in CYP1A2 (OR 7.12, p = 0.001). Results remained significant after correction for multiple testing. Therapy cessation did not show an association with any of the tested SNPs. These results may help identifying patients at increased risk for toxicity who could benefit from intensified follow-up.

UR - http://www.scopus.com/inward/record.url?scp=85061023772&partnerID=8YFLogxK

U2 - 10.1038/s41397-019-0079-z

DO - 10.1038/s41397-019-0079-z

M3 - Article

C2 - 30713339

AN - SCOPUS:85061023772

SN - 1470-269X

VL - 19

SP - 473

EP - 479

JO - Pharmacogenomics Journal

JF - Pharmacogenomics Journal

IS - 5

ER -

Genetic polymorphisms in ABCG2 and CYP1A2 are associated with imatinib dose reduction in patients treated for gastrointestinal stromal tumors

Abstract

Access to Document

Other files and links

Fingerprint

Cite this