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VEGF Signaling Pathway Germline Polymorphisms as Prognostic Pharmacogenetic Biomarkers in Localized High-Grade Osteosarcoma Patients from the GEIS-33 Protocol

Juliana Salazar,María J. Arranz,J. Martín-Broto,Massimo Serra,E. Palmerini,J. Martínez-García,A. Juan-Ribelles,M. Andión,J. Martínez-Trufero,G. Gutiérrez,A. Echebarria-Barona,M. A. Vaz-Salgado,A. Regueiro,Rosa Álvarez,C. Valverde,Pablo Luna,Pilar Blay,Ana Sebio

Published 2025 in Pharmaceuticals

ABSTRACT

Background/Objective: The vascular endothelial growth factor (VEGF) signaling pathway induces angiogenesis, which impacts tumor progression and clinical outcomes in patients with localized osteosarcoma. This study evaluates whether genetic polymorphisms in the VEGF signaling pathway are associated with survival outcomes in these patients. Methods: Sixty-nine patients with localized high-grade osteosarcoma enrolled in the GEIS-33 protocol and treated with MAP (methotrexate, doxorubicin, cisplatin) chemotherapy, surgery, and subsequent adjuvant treatment were included. Nine variants of interest in the VEGFA (rs1570360, rs2010963 and rs699947), FLT1 (VEGFR1; rs7993418, rs9513070 and rs9582036), and KDR (VEGFR2; rs1551641 and rs1870377 and rs2071559) genes were genotyped from peripheral blood samples using TaqMan Assay technology. Genetic data were correlated with relapse-free survival (RFS) and overall survival (OS) considering clinical variables as covariates. Results: The analyses showed nominally significant associations between the FLT1 variants rs7993418 and rs9582036 and survival. Patients carrying the rs7993418(C) allele had worse RFS (p = 0.01) and OS (p = 0.01). Carriers of the minor rs9582036(C) allele also had worse RFS (p = 0.02) and OS (p = 0.03). Additionally, patients harboring the TT genotype of the KDR rs1551641 variant had significantly worse RFS (p = 0.002). These polymorphisms remained statistically significant in the multivariate Cox regression analyses that included surgical margins and pathological response as covariates. Conclusions: Pharmacogenetics may contribute to precision medicine in oncology. Germline polymorphisms in the VEGF pathway may be useful as predictors of survival in high-grade localized osteosarcoma patients treated with chemotherapy, following validation in a large cohort of patients. Current treatment strategies aimed at improving outcomes for osteosarcoma patients may benefit from the identification of new biomarkers, such as these FLT1 rs7993418 and rs9582036 variants.

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