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.