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Published on: January 7, 2019
KDR genetic predictor of toxicities induced by sorafenib and regorafenib
Julia C F Quintanilha1, Susan Geyer2, Amy S Etheridge3
1UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. juquint@email.unc.edu.
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).
Insights
A genetic marker, rs4864950 in KDR, predicts toxicities from vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR TKIs). This discovery identifies a potential biomarker for managing side effects in cancer patients.
Area of Science:
- Oncology
- Pharmacogenomics
- Clinical Trial Research
Background:
- Vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR TKIs) are crucial cancer therapies.
- Predictive biomarkers for VEGFR TKI-induced toxicities are currently unavailable, limiting personalized treatment strategies.
- Understanding genetic predispositions to drug toxicity is essential for improving patient outcomes.
Conclusions:
- The KDR rs4864950 variant is a validated predictor of toxicities induced by VEGFR TKIs.
- This finding offers a potential biomarker for personalized medicine, enabling proactive management of side effects.
- Further research can explore the clinical utility of rs4864950 for optimizing VEGFR TKI treatment regimens.
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