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.

TP53 mutation analysis in gastric cancer and clinical outcomes of patients with metastatic disease treated with Ramucirumab-Paclitaxel or standard chemotherapy

Irene Bagaloni;Mauro Magnani;Annamaria Ruzzo
2020-01-01

Abstract

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.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11576/2678318
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