TY - JOUR
T1 - KDR genetic predictor of toxicities induced by sorafenib and regorafenib
AU - Quintanilha, Julia C.F.
AU - Geyer, Susan
AU - Etheridge, Amy S.
AU - Racioppi, Alessandro
AU - Hammond, Kelli
AU - Crona, Daniel J.
AU - Peña, Carol E.
AU - Jacobson, Sawyer B.
AU - Marmorino, Federica
AU - Rossini, Daniele
AU - Cremolini, Chiara
AU - Sanoff, Hanna K.
AU - Abou-Alfa, Ghassan K.
AU - Innocenti, Federico
N1 - Publisher Copyright:
© 2022, The Author(s), under exclusive licence to Springer Nature Limited.
PY - 2022/12
Y1 - 2022/12
N2 - 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).
AB - 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).
UR - http://www.scopus.com/inward/record.url?scp=85129111041&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85129111041&partnerID=8YFLogxK
U2 - 10.1038/s41397-022-00279-3
DO - 10.1038/s41397-022-00279-3
M3 - Article
C2 - 35484400
AN - SCOPUS:85129111041
SN - 1470-269X
VL - 22
SP - 251
EP - 257
JO - Pharmacogenomics Journal
JF - Pharmacogenomics Journal
IS - 5-6
ER -