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Local inflammatory biomarkers and their association with systemic inflammation as well as overall survival in primary metastatic gastroesophageal cancer patients
Background
Immunotherapy has recently led to a major breakthrough in the treatment of metastatic gastroesophageal cancer patients. Yet, further analyses of large trials investigating checkpoint inhibitor monotherapy or combination with standard chemotherapy suggest, that only a subgroup of patients might benefit from addition of immunotherapy to chemotherapy. Despite these advances, prognosis remains poor, especially in patients with Caucasian ethnicity. Thus, novel prognostic as well as predictive biomarkers are desperately needed to improve patient management. Further knowledge on the complex local inflammatory mechanisms might help to improve our understanding on the efficacy of immunotherapy. Thus, the aim of this study was to further characterize local inflammatory processes in patients with advanced gastroesophageal cancer and investigate their association with systemic inflammation as well as the overall survival (OS).
Methods
We analyzed local inflammatory biomarkers for T-cells (CD3, CD8), macrophages (CD68) and immune checkpoint inhibition (Lymphocyte-activation gene 3 (LAG3)) in previously untreated, primary tumor tissue samples of advanced gastroesophageal cancer patients treated at the Medical University of Vienna between 2003 and 2016. FFPE tissue was stained using an automated immunohistochemistry slide staining system (Roche Ventana Medical Systems Inc., Tucson, AZ, USA). Analyses of the immunohistochemical staining was performed by Definiens Tissue Studio 4.0 software. Systemic serum inflammatory parameters including leucocyte levels (WBC), C-reactive protein levels (CRP) and albumin (Alb) as well as the OS was evaluated retrospectively by hospital chart review. Local inflammatory parameters were then associated with systemic parameters and the OS using log-rank test and Kruskal-Wallis-test.
Results
Primary tumor tissue samples (localization: 29% esopheageal, 25% gastroesophageal junction, 46% stomach; histological subtype: 77% adenocarcinoma, 23% squamous cell carcinoma) of 48 patients (65% male) were analyzed. CD3 was positive in 5.6%, CD8 in 1.8%, CD68 in 2.4% and LAG3 in 0.24% of analyzed cells. Slides were then divided by the median expression into samples with more positive and less positive cells. The median OS of the cohort was 7.6 months (95%CI 5.3-9.9). Local inflammatory biomarker could not be statistically significantly associated with the OS (CD3: p=0.317; CD8: p=0.905, CD68: p=0.369; LAG3: p=0.428). In addition, no clinically significant association with systemic inflammatory parameters could be identified (CD3: CRP p=0.168, WBC p=0.706, Alb p=0.849; CD8: CRP p=0.214, WBC p=0.275, Alb p=0.340; CD68: CRP p=0.499, WBC p=0.992, Alb p=0.181; LAG3: CRP p=0.766, WBC p=0.384), only Alb was associated with LAG3 expression (p=0.048).
Conclusions
Local inflammation might play an important role as a prognostic and predictive tool. However, the understanding of local inflammation in gastroesophageal cancer is still scarce and, thus, further research is warranted to identify promising novel biomarkers. Additional staining for further local inflammatory markers as well as expansion of sample size are underway to further characterize the local inflammatory microenvironment in advanced gastroesophageal cancer patients.
Legal entity responsible for the study
The authors.
Funding
Has not received any funding.
Disclosures
All authors have declared no conflicts of interest.
