TY - JOUR
T1 - Tp53 mutation analysis in gastric cancer and clinical outcomes of patients with metastatic disease treated with ramucirumab/paclitaxel or standard chemotherapy
AU - Graziano, Francesco
AU - Fischer, Nicholas W.
AU - Bagaloni, Irene
AU - Di Bartolomeo, Maria
AU - Lonardi, Sara
AU - Vincenzi, Bruno
AU - Perrone, Giuseppe
AU - Fornaro, Lorenzo
AU - Ongaro, Elena
AU - Aprile, Giuseppe
AU - Bisonni, Renato
AU - Prisciandaro, Michele
AU - Malkin, David
AU - Gariépy, Jean
AU - Fassan, Matteo
AU - Loupakis, Fotios
AU - Sarti, Donatella
AU - Del Prete, Michela
AU - Catalano, Vincenzo
AU - Alessandroni, Paolo
AU - Magnani, Mauro
AU - Ruzzo, Annamaria
N1 - Funding Information:
Funding: This study has been financially supported by FanoAteneo, Italy.
Publisher Copyright:
© 2020 by the authors. Licensee MDPI, Basel, Switzerland.
Copyright:
Copyright 2020 Elsevier B.V., All rights reserved.
PY - 2020/8
Y1 - 2020/8
N2 - 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.
AB - 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.
KW - Angiogenesis
KW - Gastric cancer
KW - Paclitaxel
KW - Ramucirumab
KW - TP53
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U2 - 10.3390/cancers12082049
DO - 10.3390/cancers12082049
M3 - Article
AN - SCOPUS:85088506691
VL - 12
SP - 1
EP - 14
JO - Cancers
JF - Cancers
SN - 2072-6694
IS - 8
M1 - 2049
ER -