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 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 TP53 mutant-specific residual transcriptional activity scores (TP53RTAS) and used to stratify patients into two groups: transcriptionally TP53Active and TP53Inactive. The primary endpoint was overall survival (OS). An additional analysis was addressed to measure VEGF/VEGFR2 expression levels in relation to the TP53RTAS. In the Ramucirumab/Paclitaxel group, 29/48 (60.4%) patients had TP53 mutations. Ten patients with TP53Inactive 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 TP53Inactive 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 TP53Inactive cases. Further studies are warranted to explore the effect of TP53Inactive mutations in different anti-cancer regimens. This information would lead to new tailored therapy strategies for this lethal disease.