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.
NCT00073307 (TARGET), NCT01015833 (Alliance/CALGB 80802), and NCT01298570 (LCCC 1029).
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The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.
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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.
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.
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