Perineural invasion after preoperative chemotherapy predicts poor survival in patients with locally advanced gastric cancer: Gene expression analysis with pathologic validation

BACKGROUND: We examined gene expression profiles and clinicopathologic features (tumor location, stage, graded pathologic response, perineural invasion (PNI), Lauren's classification, and survival) of patients with gastric cancer who received preoperative chemotherapy to identify prognostic markers. METHODS: Thirty-eight patients with locally advanced gastric cancer received preoperative chemotherapy on a phase II trial. Twelve fresh-frozen tumor samples were available for RNA expression analysis. Differential gene expression between tumors with and without PNI was identified and correlated with clinicopathologic features. RESULTS: Preliminary hierarchical clustering suggested a separation between long- and short-term survivors. The close association between PNI and overall survival was identified and validated immunohistochemically in 31 completely resected gastric tumors. Five-year survival for patients with PNI and without PNI was 5% and 65%, respectively (P < 0.01). PNI added significant prognostic value to posttreatment pathologic stage, (P < 0.01). Differential gene expression profile for PNI and non-PNI tumors identified 111 potentially relevant genes. CONCLUSIONS: Our results demonstrate that the presence of PNI after preoperative chemotherapy is associated with poor survival. These results need to be validated in prospective studies, to help establish whether patients with evidence of PNI would be candidates for more aggressive therapy or enrollment into clinical trials. The presence of PNI provides additional prognostic importance to posttreatment pathologic stage and may indicate treatment resistance. Understanding the molecular events associated with PNI, may provide insight into new therapeutic agents for this subset of patients with resistant tumors.