1. Università Politecnica delle Marche AOU Ospedali Riuniti “Umberto I – GM Lancisi – G Salesi” Ancona - Italy
The role of tumour Vascular Endothelial Growth Factor (VEGF) and Vascular Endothelial Growth Factor Receptors (VEGFR) polymorphisms in the prediction of clinical outcome for advanced hepatocellular carcinoma receiving sorafenib.
Luca Faloppi1, Mario Scartozzi1, Gianluca Svegliati Baroni2, Cristian Loretelli1, Samuele De Minicis2, Alessandra Mandolesi3,
Simona Biagetti3, Maristella Bianconi1, Stefano Gemini2, Italo Bearzi3, Antonio Benedetti2, Stefano Cascinu1.
1) Clinica di Oncologia Medica; 2) Clinica di Gastroenterologia; 4) Anatomia Patologica.
Background: Hepatocellular carcinoma (HCC) still represents a medical challenge in cancer therapy. In recent years the introduction of new targeted therapies has radically changed the approach to the disease and patients outcome. Currently the therapeutic stronghold is a TKIs directed against the VEGF family sorafenib. Polymorphisms of VEGF and its receptor genes are involved in regulating angiogenesis and lymphangiogenesis and thus in growth tumor control. The aim of our study is to evaluate the potential predictive and prognostic role of VEGF and VEGFR polymorphisms in determining the clinical outcome of HCC patients receiving sorafenib.
Methods: 17 histologic samples (biopsies and surgical specimens) of HCC patients receiving sorafenib were tested for VEGF-A, VEGF-C and VEGFR-1,2,3 single nucleotide polymorphisms (SNPs). Patients time to progression (TTP) and overall survival (OS) were analysed.
Results: VEGF-AI rs25648 C>T polymorphism was statistically significant in OS (15.0 months for C vs 9.4 months for T; p=0.025). VEGF-AII rs10434 G>A was statistically significant for TTP (4.1 months for G vs 1.2 months for A; p=0.0076) and OS (14.2 months for G vs 1.7 for A; p<0.0001). VEGF-CII rs C>T was significant in TTP (13.4 months for C vs 2.0 for T; p=0.0125) and OS (14.7 months for C vs 5.6 for T; p=0.0007). VEGR2-I rs A>T was significant in TTP (19.9 months for A vs 3.0 for T; p=0.0271) and OS (29.6 months for A vs 11.9 for T; p=0.0096).
Conclusions: In our analysis patients with G polymorphism at rs10434, C polymorphism at rs and A polymorphism at rs have a better response (PFS and OS) during treatment with sorafenib. Patients with C polymorphism of rs and A polymorphism of rs show a favourable impact in this setting. Notably, VEGFR polymorphism result closely related to the treatment response and the specific signalling of sorafenib. Thus analysis of VEGF and its receptor genes polymorphisms represents a clinical tool to identify patients with favourable response to sorafenib presumably related to a more efficient control of tumor growth.
Figure 1: Overall Survival
VEGF A – RS25648 (CC > TT+CT)
Figure 2: Progression Free Survival
VEGF A – RS10431 (AA < GG+AG)
Figure 3: Overall Survival
VEGF A – RS10431 (AA < GG+AG)
Figure 4: Progression Free Survival
VEGF-CII RS (CC > TT+TC)
Sample ID
NCBI SNP Reference
Reporter
1 Dye
Reporter 1 Sequence
Reporter 1 Frequence
2 Dye
Reporter 2 Sequence
Reporter 2 Frequence
Design Strand
Gene Symbol
SNP Type
VEGFA I
rs25648
VIC C
0,836
FAM T
0,164
Reverse
VEGFA
SILENT MUTATION
VEGFA II
rs10434 A
0,371 G
0,629
Forward
UTR 3
VEGFA III rs
0,205
0,795
INTERGENIC/UNKNOWN
VEGFA IV
rs833061
0,422
0,578
VEGFA V
rs699947
0,408
0,592
VEGFA VI rs
0,431
0,569
UTR 5
VEGFA VII rs
0,886
0,114
VEGF-C I rs
0,678
0,322
VEGFC
INTRON
VEGF-C II rs
0,792
0,208
VEGF-C III rs
0,94
0,06
VEGFR-1 I
rs664393
0,858
0,142
FLT1
VEGFR-1 II rs
0,75
0,25
VEGFR-1 III rs
0,492
0,508
MIS-SENSE MUTATION
VEGFR-2 I rs
0,275
0,725
KDR
VEGFR-2 II rs
0,483
0,517
VEGFR-2 III rs
0,933
0,067
VEGFR-2 IV rs
0,5
VEGFR-3 I
rs307822
0,914
0,086
FLT4
VEGFR-3 II
rs307805
0,108
0,892
VEGFR-3 III rs
0,942
0,058
Figure 5: Overall Survival
VEGF-CII RS (CC > TT+TC)
Figure 6: Progression Free Survival
VEGR2-I RS (TT< AA+AT)
Correspondence to: Dr. Luca Faloppi
Clinica di Oncologia Medica AOU “Ospedali Riuniti” Via Conca 71, Ancona Italy
Scuola Specializzazione Oncologia Medica Università Politecnica delle Marche Via Tronto 10, Ancona Italy
Figure 7: Overall Survival
VEGR2-I RS (TT< AA+AT)