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KDR genetic predictor of toxicities induced by sorafenib and regorafenib

Abstract

No biomarkers are available to predict toxicities induced by VEGFR TKIs. This study aimed to identify markers of toxicities induced by these drugs using a discovery-validation approach. The discovery set included 140 sorafenib-treated cancer patients (TARGET study) genotyped for SNPs in 56 genes. The most significant SNPs associated with grade ≥2 hypertension, diarrhea, dermatologic toxicities, and composite toxicity (any one of the toxicities) were tested for association with grade ≥2 toxicity in a validation set of 201 sorafenib-treated patients (Alliance/CALGB 80802). The validated SNP was tested for association with grade ≥2 toxicity in 107 (LCCC 1029) and 82 (Italian cohort) regorafenib-treated patients. SNP-toxicity associations were evaluated using logistic regression, and a meta-analysis between the studies was performed by inverse variance. Variant rs4864950 in KDR increased the risk of grade ≥2 composite toxicity in TARGET, Alliance/CALGB 80802, and the Italian cohort (meta-analysis p = 6.79 × 10−4, OR = 2.01, 95% CI 1.34–3.01). We identified a predictor of toxicities induced by VEGFR TKIs.

ClinicalTrials.gov Identifier:

NCT00073307 (TARGET), NCT01015833 (Alliance/CALGB 80802), and NCT01298570 (LCCC 1029).

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Fig. 1: CONSORT and quality control flowchart for the TARGET study, CALGB 80802, LCCC 1029, and the Italian cohort.
Fig. 2: Frequency of rs4864950 genotypes in patients with and without grade 2–3 composite toxicity in TARGET, CALGB 80802, and Italian cohort.

Data availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Funding

Research reported in this publication was supported by the National Cancer Institute of the National Institutes of Health under Award Numbers U10CA180821, U10CA180882, and U24CA196171 (to the Alliance for Clinical Trials in Oncology), UG1CA233373 and UG1CA233290. https://acknowledgments.alliancefound.org. Also supported in part by Bayer Healthcare/Berlex. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

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Contributions

J.C.F.Q., S.G., and F.I. wrote the manuscript; F.I. designed the research; J.C.F.Q., S.G., A.S.E., A.R., K.H., D.J.C., S.B.J., F.M., D.R., C.C., H.K.S., G.K.A.A., and F.I. performed the research; J.C.F.Q., S.G., A.S.E, A.R., S.B.J., G.K.A.A., and F.I. analyzed the data; C.E.P. contributed new reagents/analytical tools.

Corresponding authors

Correspondence to Julia C. F. Quintanilha or Federico Innocenti.

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Competing interests

FI is an AbbVie employee and receives stocks from AbbVie; this work was conceived when FI was a faculty at the University of North Carolina at Chapel Hill, and this work does not represent a potential conflict of interest.

Ethics approval

The clinical studies were conducted in accordance with recognized ethical guidelines. The studies were performed in accordance with the Declaration of Helsinki and were approved by the local IRB. All participants provided written informed consent for sample collection and pharmacogenetic analysis.

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Quintanilha, J.C.F., Geyer, S., Etheridge, A.S. et al. KDR genetic predictor of toxicities induced by sorafenib and regorafenib. Pharmacogenomics J 22, 251–257 (2022). https://doi.org/10.1038/s41397-022-00279-3

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