Cancers (Jul 2020)

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

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

DOI
https://doi.org/10.3390/cancers12082049
Journal volume & issue
Vol. 12, no. 8
p. 2049

Abstract

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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.

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