Association of activated transcription factor nuclear factor κB with chemoradiation resistance and poor outcome in esophageal carcinoma

Purpose: The lack of effective treatment for localized esosphageal cancer leads to poor patient outcome. Nuclear factor κB (NF-κB), a transcriptional factor, is constitutively activated or treatment induced in esophageal cancer and may influence treatment outcomes. Patients and Methods: Pre- and post-treatment cancer specimens from patients enrolled onto a clinical trial were studied for the expression of activated NF-κB protein and it was correlated with histologic features, pathologic response, metastatic potential, overall survival (OS), and disease-free survival (DFS). Results: Forty-three patients undergoing the same therapy on a protocol were studied. Twenty-one (72%) of 29 patients achieving less than complete pathologic response (pathCR) had NF-κB positive cancer, but only one (7%) of 14 patients achieving pathCR had NF-κB positive cancer (P = < .001). Activated NF-κB was significantly associated with aggressive pathologic features such as perineural, lymphatic, and/or vascular invasion (P = .0004). Eight (38%) of 21 NF-κB positive patients developed metastases compared to none of 22 NF-κB negative patients (P = .001). At a median follow-up of 23 months, 10 (48%) of 21 NF-κB positive patients had died compared to only one (5%) of 22 NF-κB negative patients (P = .0013). Observations were similar for DFS (P = .0006). In a multivariate model (using baseline stage, pathCR or less than pathCR, age, presence of metastatic lymph nodes in the surgical specimen, and NF-κB expression) NF-κB activation was the only independent predictor of DFS (P = .010) and OS (P = .015). Conclusion: Our data suggest that esophageal cancers with activated NF-κB have aggressive clinical biology and poor treatment outcome. Additional understanding of NF-κB regulated pathways may uncover potential therapeutic targets.