| Summary: | Loss of p53 promotes vascular endothelial growth factor (VEGF)-A up-regulation and the angiogenic potential of cancer cells. We investigated <i>TP53</i> somatic mutations in 110 primary gastric adenocarcinomas of two retrospective metastatic series including 48 patients treated with second-line Ramucirumab/Paclitaxel and 62 patients who received first-line chemotherapy with Cisplatin or Oxaliplatin plus 5-Fluorouracil. Missense mutations were classified by tumor protein p53 (<i>TP53</i>) mutant-specific residual transcriptional activity scores (<i>TP53</i><sub>RTAS</sub>) and used to stratify patients into two groups: transcriptionally <i>TP53</i><sub>Active</sub> and <i>TP53</i><sub>Inactive</sub>. The primary endpoint was overall survival (OS). An additional analysis was addressed to measure VEGF/VEGF receptor 2 (VEGFR2) expression levels in relation to the <i>TP53</i><sub>RTAS</sub>. In the Ramucirumab/Paclitaxel group, 29/48 (60.4%) patients had <i>TP53</i> mutations. Ten patients with <i>TP53</i><sub>Inactive</sub> mutations showed better OS than carriers of other <i>TP53</i> mutations. This effect was retained in the multivariate model analysis (Hazard Ratio = 0.29, 95% confidence interval = 0.17–0.85, <i>p</i> = 0.02). In the chemotherapy group, 41/62 (66%) patients had <i>TP53</i> mutations, and the 11 carriers of <i>TP53</i><sub>Inactive</sub> mutations showed the worst OS (Hazard Ratio = 2.64, 95% confidence interval = 1.17–5.95, <i>p</i> = 0.02). VEGF-A mRNA expression levels were significantly increased in <i>TP53</i><sub>Inactive</sub> cases. Further studies are warranted to explore the effect of <i>TP53</i><sub>Inactive</sub> mutations in different anti-cancer regimens. This information would lead to new tailored therapy strategies for this lethal disease.
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