Preliminary data of VEGF-A and VEGFR-2 polymorphisms as predictive factors of radiological response and clinical outcome in iodine-refractory differentiated thyroid cancer treated with sorafenib

Excerpt

Tyrosine-kinase inhibitors (TKIs) have revolutioned the management of iodine-refractory differentiated thyroid cancer (DTC), previously considered as an orphan disease [1, 2]. Basing on results from the international phase III trial DECISION, which reported significant improvement of median progression-free survival (PFS) in the treatment group, as compared with placebo (10.8 vs. 5.8 months; HR 0.58, 95% CI 0.45–0.75, p < 0.0001) [3], sorafenib was the first TKI to be approved by the regulatory agencies. To date, sorafenib should still be considered as the first-line therapeutic option for progressive iodine-refractory DTC, as lenvatinib, another TKI showing higher efficacy in terms of both objective response and PFS in a recent phase III trial [4], proved to be active independently from previous TKIs administration. Considering that the DECISION cohort only included naive patients and therefore activity of sorafenib in TKIs pre-treated subjects is theoretically unmet, the best evidence-based approach is to preserve lenvatinib as salvage option after sorafenib failure. Importantly, a post-hoc analysis of the DECISION trial showed that the actual disease control rate obtained through sorafenib administration, with inclusion of partial response (PR) and stable disease (SD) lasting at least 6 months, was only 54.1%, meaning that nearly half of patients do not experience significant benefit from the treatment. This has been also confirmed by some studies reporting data from “real-life” clinical practice [5, 6]. Therefore, the identification of predictive factors of response is mandatory in order to avoid useless drug administration leading to toxicities and expensive costs for public health. Although use of sorafenib in iodine-refractory DTC was initially emphasized due to its inhibitory activity on both wild type and mutant BRAF [7], which represents the most frequent DTC-related molecular alteration [8], the exploratory biomarker analysis reported by the DECISION trial failed to demonstrate any predictive role for the BRAF mutation [3]. Nevertheless, it is important to consider that sorafenib anti-cancer effect relies not only on the inhibition of tumor cells proliferation through the RAF kinases blockage, but also on the inhibition of tumor vascularization through the blockage of angiogenesis controlling tyrosine-kinase receptors (VEGFR-2, VEGFR-3, PDGFR-β, and Ftl-3). This anti-angiogenic effect was even stronger, as compared with the anti-proliferative activity [9]. Angiogenesis, including that related to cancer, is mainly determined by genetic background, rather than environmental exposure [10]. Particularly, a set of single nucleotide polymorphisms (SNPs) of the VEGF-A and VEGFR-2 genes, representing the most important angiogenic regulators [11], have demonstrated functional implications through the modulation of gene expression/post-trascriptional regulation and ligand affinity, respectively [12, 13], and could theoretically represent predictors of response to anti-angiogenic therapies, such as TKIs. We present a preliminary single center study about the possible role of germline VEGF-A and VEGFR-2 SNPs in predicting objective response and clinical outcome in iodine-refractory DTC patients treated with sorafenib. …