A novel pretherapeutic gene expression based risk score for treatment guidance in gastric cancer

Background

Perioperative chemotherapy is an established treatment for advanced gastric cancer patients. Treatment selection is based on clinical staging (cT). We aimed to establish and validate a prognostic score including clinical and molecular factors, to optimize treatment decisions for these patients.

Patients and methods

We analyzed 626 carcinomas of the stomach and of the gastro-oesophageal junction from two academic centers including primarily resected and pre-/perioperatively treated patients. Patients were divided into a training (N = 269) and validation (N = 357) set. Expression of11 target genes was measured by quantitative PCR in resected tumors. A risk score to predict overall survival (OS) was generated and validated. Intra-tumoral heterogeneity was assessed by analysing 50 tumor areas from 10 patients.

Results

A risk score including the expression of CCL5, CTNNB1, EXOSC3 and LZTR1 and the clinical parameters cT, tumor localization and histopathological type suggested two groups with a significant difference in OS (hazard ratio [HR], 0.30; 95% confidence interval [CI], 0.17-0.52). The risk score was successfully validated in an independent cohort (HR, 0.32; 95% CI, 0.21-0.51; P < 0.001) as well as in subgroups of primarily resected (HR, 0.30; 95% CI, 0.17-0.54; P < 0.001) and pre-/perioperatively treated patients (HR, 0.37; 95% CI, 0.17-0.81; P = 0.009). A significant difference in OS of high and low risk patients was also found in primarily resected patients with intestinal (HR: 0.45; 95% CI, 0.23-0.90;P = 0.020) and non-intestinal type carcinomas (HR: 0.1; 95% CI 0.02-0.42; P < 0.001). Intra-tumor heterogeneity analysis indicated a classification reliability of 95% for a supposed analysis of three biopsies.

Conclusion

The identified risk score could substantially contribute to an improved management of gastric cancer patients in the context of perioperative chemotherapy.