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

Francesco Graziano,Michele Prisciandaro,Irene Bagaloni,Elena Ongaro,Maria Di Bartolomeo,Sara Lonardi,Mauro Magnani,Annamaria Ruzzo,Giuseppe Aprile,Bruno Vincenzi,David Malkin,Michela Del Prete,Matteo Fassan,Renato Bisonni,Nicholas W Fischer,Donatella Sarti,Vincenzo Catalano,Paolo Alessandroni,Jean Gariépy,Giuseppe Perrone,Lorenzo Fornaro,Fotios Loupakis

doi:10.3390/cancers12082049

Abstract

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 (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/VEGF receptor 2 (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.

Highlights

Tumor protein p53 (TP53) is a multifunctional tumor suppressor gene that is intimately involved in the control of target genes that regulate “healthy” biological processes, including cell-cycle arrest, apoptosis, senescence, energy metabolism, and antioxidant defense to prevent tumorigenesis [1]
The overall study population consisted of 110 gastric cancer patients whose primary tumors were analyzed for tumor protein p53 (TP53) mutations
The limitation of this study is the relative sample size, so our findings warrant further investigations to confirm the association between transcriptionally inactive TP53 missense mutations and improved clinical outcomes of patients with metastatic gastric adenocarcinoma who received anti-VEGF receptor 2 (VEGFR2) plus

Summary

Introduction

Tumor protein p53 (TP53) is a multifunctional tumor suppressor gene that is intimately involved in the control of target genes that regulate “healthy” biological processes, including cell-cycle arrest, apoptosis, senescence, energy metabolism, and antioxidant defense to prevent tumorigenesis [1]. Several experimental and clinical studies have indicated a role for TP53 in the control of tumor angiogenesis [2] This effect seems to be linked to cross-talk mechanisms between TP53, vascular endothelial growth factor (VEGF), and VEGF receptors. Mutant TP53 can up-regulate the transcription of VEGF receptor 2 (VEGFR2) by promoter remodeling [7] These molecular mechanisms may explain analyses of human cancer tissues that have reported significant increases in VEGF expression levels in the presence of TP53 mutations [8,9,10]. In a large pan-cancer study [9], the association between VEGF up-regulation and TP53 mutants remained independent of HIF-1 and MDM2 overexpression This translational background explains recent clinical findings in advanced cancer patients who had improved responses and survival outcomes after VEGF/VEGF receptor (VEGFR)

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Results

Conclusion