EGFR and AKT1 overexpression are mutually exclusive and associated with a poor survival in resected gastric adenocarcinomas

Article type: Research Article

Authors: Petrini, Iacopo^{a; *} | Lencioni, Monica^a | Vasile, Enrico^a | Fornaro, Lorenzo^a | Belluomini, Lorenzo^a | Pasquini, Giulia^a | Ginocchi, Laura^a | Caparello, Chiara^a | Musettini, Gianna^a | Vivaldi, Caterina^a | Caponi, Sara^a | Ricci, Sergio^a | Proietti, Agenese^b | Fontanini, Gabriella^b | Naccarato, Antonio Giuseppe^c | Nardini, Vincenzo^d | Santi, Stefano^e | Falcone, Alfredo^a

Affiliations: [a] Medical Oncology, University Hospital of Pisa, 56126 Pisa, Italy | [b] Surgical Pathology, Unit 3, University Hospital of Pisa, 56126 Pisa, Italy | [c] Surgical Pathology, Unit 1, University Hospital of Pisa, 56126 Pisa, Italy | [d] Surgical Pathology, Unit 2, University Hospital of Pisa, 56126 Pisa, Italy | [e] Esophageal Surgery, University Hospital of Pisa, 56126 Pisa, Italy

Correspondence: [*] Corresponding author: Iacopo Petrini, Medical Oncology, University Hospital of Pisa, Via Savi 10, 56126 Pisa, Italy. Tel.: +39 050 992070; Fax: +39 050 992467; E-mail: [email protected].

Abstract: PURPOSE: The evaluation of molecular targets in gastric cancer has demonstrated the predictive role of HER2 amplification for trastuzumab treatment in metastatic gastric cancer. Besides HER2, other molecular targets are under evaluation in metastatic gastric tumors. However, very little is known about their role in resected tumors. We evaluated the expression of HER2, EGFR, MET, AKT1 and phospho-mTOR in resected stage II–III adenocarcinomas. METHODS: Ninety-two patients with resected stomach (63%) or gastro-esophageal adenocarcinomas (27%) were evaluated. Antibodies anti-HER2, EGFR, MET, AKT1 and phospho-mTOR were used for immunostaining of formalin-fixed paraffin-embedded slides. Using FISH, HER2 amplification was evaluated in cases with an intermediate (+2) staining. RESULTS: EGFR overexpression (11%) was a poor prognostic factor for overall survival (3-year OS: 47% vs 77%; Log-Rank p= 0.033). MET overexpression (36%) was associated with a trend for a worse survival (3-year OS: 65% vs 77%; Log-Rank p= 0.084). HER2 amplification/overexpression and mTOR hyper-phosphorylation were observed in 13% and 48% of tumors, respectively. AKT1 overexpression (8%) was not a prognostic factor by itself (p= 0.234). AKT1 and EGFR overexpression was mutually exclusive and patients with EGFR or AKT1 overexpression experienced a poor prognosis (3-year OS: 52% vs. 79%, Log-Rank p= 0.005). CONCLUSIONS: EGFR is confirmed a poor prognostic factor in resected gastric cancers. We firstly describe a mutually exclusive overexpression of EGFR and AKT1 with potential prognostic implications, suggesting the relevance of this pathway for the growth of gastric cancers.

Keywords: Gastric cancer, gastro-esophageal junction cancer, EGFR, AKT1, MET

DOI: 10.3233/CBM-170865

Journal: Cancer Biomarkers, vol. 21, no. 3, pp. 731-741, 2018