Answers about clinical activity.

<p>Answers about clinical activity.</p

Data about residents.

<p>Data about residents.</p

Answers about teaching (first part).

<p>Answers about teaching (first part).</p

Answers about research activity.

<p>Answers about research activity.</p

Answers about teaching (third part).

<p>Answers about teaching (third part).</p

Answers about teaching (second part).

<p>Answers about teaching (second part).</p

Prospective Validation of Candidate SNPs of <i>VEGF/VEGFR</i> Pathway in Metastatic Colorectal Cancer Patients Treated with First-Line FOLFIRI Plus Bevacizumab

<div><p>Purpose</p><p>The potential impact of different SNPs of <i>VEGF/VEGFR</i> pathway on the clinical outcome of mCRC patients receiving bev-containing regimens has been investigated in retrospective experiences with contrasting results. We previously reported the association of <i>VEGFA</i> rs833061 C/T variants with PFS in metastatic colorectal cancer patients treated with first-line FOLFIRI plus bevacizumab. The primary objective of this work was to prospectively validate that retrospective finding. A confirmatory analysis of other SNPs of <i>VEGF/VEGFR</i> pathway genes was included.</p><p>Experimental design</p><p>To detect a HR for PFS of 1.7 for <i>VEGFA</i> rs833061 T/T compared to C- variants in metastatic colorectal cancer patients treated with first-line FOLFIRI plus bevacizumab, setting two-sided α = 0.05 and β = 0.20, 199 events were required. <i>VEGFA</i> rs699946 A/G, rs699947 A/C, <i>VEGFR1</i> rs9582036 A/C and rs7993418 A/G, <i>VEGFR2</i> rs11133360 C/T, rs12505758 C/T and rs2305948 C/T and <i>EPAS1</i> rs4145836 A/G were also tested. Germ-line DNA was extracted from peripheral blood. SNPs were analyzed by PCR and sequencing.</p><p>Results</p><p>Four-hundred-twenty-four pts were included. At the univariate analysis, no differences according to <i>VEGFA</i> rs833061 C/T variants were observed in PFS (p = 0.38) or OS (p = 0.95). Among analyzed SNPs, only <i>VEGFR2</i> rs12505758 C- variants, compared to T/T, were associated to shorter PFS (HR: 1.36 [1.05–1.75], p = 0.015, dominant genetic model) and OS, with a trend toward significance (HR: 1.34 [0.95–1.88], p = 0.088). In the multivariate model, this association retained significance (HR: 1.405 [1.082–1.825], p = 0.012) in PFS, that was lost by applying multiple testing correction (p = 0.14).</p><p>Conclusion</p><p>This prospective experience failed to validate the hypothesized predictive impact of <i>VEGFA</i> rs833061 variants. Retrospective findings on different candidate SNPs were not confirmed. Only <i>VEGFR2</i> rs12505758 variants, whose prognostic and not predictive impact was previously reported, correlated with PFS. Given the complexity of angiogenesis, it is rather unlike that a single germ-line SNP might be a good predictor of benefit from bevacizumab.</p></div

Genes differentially expressed in short survival versus long survival patients, considered according to cancer type and cancer class.

Volcano plots showing significantly downregulated (the thresholds are FDR -0.5) genes in green and red, respectively. Here short survival patients are compared with long survival patients, so in all three panels genes found to be upregulated are genes that are upregulated in short survival patients, and genes found downregulated are genes that are downregulated in short survival patients. Grey indicates genes that are not significantly downregulated or upregulated. Log of fold change (LogFC) is on the x-axis and significance level (-log10P) is on the y-axis. Panel A shows differentially expressed genes when all of the patients are considered (n = 515). Panel B shows differentially expressed genes when only patients with solid cancers are considered (n = 293), and panel C shows differentially expressed genes when only patients with blood cancers are considered (n = 222). In all panels, the significantly downregulated and upregulated genes are labelled with their Hugo Gene Nomenclature Committee (HGNC) gene symbols. The three genes (SSX1, MAGEC2 and ULBP2) that are found to be significantly differentially expressed in all three analyses are shown in bold.</p

<i>VEGFA 833061</i> C/T allelic variants and PFS.

<p><i>VEGFA 833061</i> C/T allelic variants and PFS.</p

<i>VEGFA 833061</i> SNP allelic variants and survival.

*<p><i>P</i> value was based on Cochran-Mantel-Haenszel test for response and log-rank test for PFS and OS.</p