TP53 Mutation Analysis in Gastric Cancer and Clinical Outcomes of Patients with Metastatic Disease Treated with Ramucirumab/Paclitaxel or Standard Chemotherapy.

Loss of p53 promotes vascular endothelial growth factor (VEGF)-A up-regulation and the angiogenic potential of cancer cells. We investigated TP53 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 ( TP53 ) mutant-specific residual transcriptional activity scores ( TP53 _RTAS ) and used to stratify patients into two groups: transcriptionally TP53 _Active and TP53 _Inactive . 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 TP53 _RTAS . In the Ramucirumab/Paclitaxel group, 29/48 (60.4%) patients had TP53 mutations. Ten patients with TP53 _Inactive mutations showed better OS than carriers of other TP53 mutations. This effect was retained in the multivariate model analysis (Hazard Ratio = 0.29, 95% confidence interval = 0.17-0.85, p = 0.02). In the chemotherapy group, 41/62 (66%) patients had TP53 mutations, and the 11 carriers of TP53 _Inactive mutations showed the worst OS (Hazard Ratio = 2.64, 95% confidence interval = 1.17-5.95, p = 0.02). VEGF-A mRNA expression levels were significantly increased in TP53 _Inactive cases. Further studies are warranted to explore the effect of TP53 _Inactive mutations in different anti-cancer regimens. This information would lead to new tailored therapy strategies for this lethal disease.