VEGF and VTE Risk in Cancer Patients—Letter
Authors: Patrizia Ferroni, Silvia Riondino, Fiorella Guadagni, Mario Roselli
Journal: Clinical Cancer Research (2016)

We read with great interest the article by Posch and colleagues discussing the association between elevated soluble plasma VEGF levels and an increased risk of venous thromboembolism in cancer patients (1). Among the study findings, what particularly drew our attention was the substantial rate of undetectable levels of sVEGF (roughly 30%) that associated with a reduced incidence of venous thromboembolism. More interestingly, leukocyte and/or platelet activation (both major determinants of physiologic sVEGF levels) explained only a limited amount of variation in sVEGF, which slightly increased when endothelial cell activation and tumor cell decay markers were considered jointly in a multivariable regression analysis (1).These results are in agreement with the current concept that sVEGF levels are regulated by complex genetic, epigenetic, and posttranslational mechanisms (2). Accordingly, it has been suggested that the heritability of sVEGF production ranges between 60% and 80% (3, 4), whereas environmental factors might account for 20% to 30% of the variation (3). In this context, the results reported by Posch and colleagues (1) fit well with our recent finding that VEGFA may represent a candidate gene contributing to venous thromboembolism development in chemotherapy-treated cancer patients (5). In particular, we demonstrated that the 1154G/A VEGFA gene promoter polymorphism (to a lesser extent 634G/C) was associated to venous thromboembolism, with the low-producing A allele conferring to carriers an approximately 5-fold reduced risk of venous thromboembolism, independently of other cancer- or patient-associated risk factors (5). In particular, no venous thromboembolism episodes were recorded in patients homozygous for –1154A allele, suggesting that genetic predisposition may play a role in venous thromboembolism development, particularly under pharmacologic triggers (5).Interestingly, besides being protective against venous thromboembolism, the –1154A allele conferred a reduced risk of early progression in cancer patients, possibly by providing a less proangiogenic environment capable of reducing the risk of disease progression. Likewise, we might hypothesize that the VEGFA-sustained prothrombotic state responsible for venous thromboembolism might also contribute to a more aggressive tumor phenotype and adverse outcome, as evidenced both in the study by Posch and colleagues (1) and in ours (5).Currently, the issue of an association between functional polymorphisms and sVEGF levels is yet unsolved, and the possibility that lower systemic VEGF levels in carriers of the –1154A allele may confer an advantage against venous thromboembolism in chemotherapy-treated patients, although attractive, remains speculative. Nonetheless, we hope that these findings may prompt new multicenter prospective studies, which could specifically answer our doubts and acquire improved knowledge on the pathophysiology of cancer-associated venous thromboembolism.No potential conflicts of interest were disclosed.