Abstract 3488: External validation of lysyl oxidase-like 2 (LOXL2) as a novel prognostic marker for gastro-entero-pancreatic neuroendocrine tumors (GEP-NET)
Authors: Barriuso Jorge , Benavent Marta , Lamarca Angela , Bernal Elsa , Pastrian Laura Guerra , Heredia Victoria , Miguel Maria , Garcia-Calderon Clara Beatriz , Alvarez-Escola Cristina , Castell Jose , Custodio Ana , Burgos Emilio , Feliu Jaime , Garcia-Carbonero Rocio , Mendiola Marta 
Published: July 2016

Abstract
Aims: LOXL2 is a protein with a key role in epithelial-to-mesenchymal transition (EMT). EMT was established as an early event in GEP-NET. LOXL2 emerged as a new prognostic marker in the analysis of a 115 GEP-NET cases (training cohort (TC); Barriuso et al, ASCO 2014). Our main objective was to validate LOXL2 expression by immunohistochemistry (IHC) in an independent cohort.
Methods: Formalin-fixed paraffin-embedded samples (FFPEs) of consecutive GEP-NET patients from 1999 to 2010 who underwent surgery and their clinical data were collected from a different Spanish institution (validation cohort (VC)). Tissue microarrays were constructed from two non-necrotic areas of tumour foci. LOXL2 expression was studied by IHC and classified as presence (P) vs absence (A). Log rank test and cox regression were used to study Disease Free Survival (DFS) and Overall Survival (OS) in the VC and the combined series (TC+VC; n = 206). Univariate (UVA) and multivariable analysis (MVA) were performed.
Results: A total of 91 FFPE samples were included in the VC. Median follow up was 77 months. Tumor grade was differently distributed between the TC and the VC (p&lt;0.001) while stage was not (p = 0.195). LOXL2 P was associated with better OS (p = 0.023) and showed a trend for better DFS (p = 0.066) in the VC. DFS at 3 years was 85% in LOXL2-P group vs 45% in LOXL2-A group. OS at 5 years was 82% vs 51% respectively. LOXL2 P was associated with better DFS and OS (p&lt;0.001) when the combined series was analysed. LOXL2 remained as an independent prognostic factor for OS adjusted for grade and stage in the MVA in both settings.
Conclusion: Our results validated LOXL2 as a novel prognostic biomarker candidate for GEP-NETs in an independent cohort. Further testing in prospective studies to depict its potential value in the clinic is warranted. LOXL2 could also represent an actionable target in this scenario. UVA for DFSMVA for DFSUVA for OSMVA for OSTraining cohort (TC) (n = 115)0.3 (0.1-0.7) P = 0.012*0.5 (0.1-1.8) P = 0.280.2 (0.1-0.5) P = 0.001*0.2 (0.04-0.8) P = 0.024*Validation cohort (VC) (n = 91)0.5 (0.2-1.1) P = 0.0790.3 (0.1-0.7) P = 0.011*0.4 (0.1-0.9) P = 0.029*0.2 (0.1-0.6) P = 0.01*Combined series (n = 206)0.3 (0.2-0.6) P&lt;0.001*0.3 (0.1-0.6) P = 0.002*0.2 (0.1-0.4) P&lt;0.001*0.2 (0.1-0.5) P&lt;0.001*Cox regression for LOXL2. MVA adjusted for grade and stage. Hazard ratios, 95% confidence intervals and p values. *statistically significant differences.
Citation Format: Jorge Barriuso, Marta Benavent, Angela Lamarca, Elsa Bernal, Laura Guerra Pastrian, Victoria Heredia, Maria Miguel, Clara Beatriz Garcia-Calderon, Cristina Alvarez-Escola, Jose Castell, Ana Custodio, Emilio Burgos, Jaime Feliu, Rocio Garcia-Carbonero, Marta Mendiola. External validation of lysyl oxidase-like 2 (LOXL2) as a novel prognostic marker for gastro-entero-pancreatic neuroendocrine tumors (GEP-NET). [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3488.