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

Izzo JG, Malhotra U, Wu TT, Ensor J, Luthra R, Lee JH, Swisher SG, Liao Z, Chao KS, Hittelman WN, Aggarwal BB, Ajani JA

Department of Experimental Therapeutics, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030-4009, USA.

PURPOSE: The lack of effective treatment for localized esosphageal cancer leads to poor patient outcome. Nuclear factor kappaB (NF-kappaB), 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-kappaB 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-kappaB positive cancer, but only one (7%) of 14 patients achieving pathCR had NF-kappaB positive cancer (P = < .001). Activated NF-kappaB was significantly associated with aggressive pathologic features such as perineural, lymphatic, and/or vascular invasion (P = .0004). Eight (38%) of 21 NF-kappaB positive patients developed metastases compared to none of 22 NF-kappaB negative patients (P = .001). At a median follow-up of 23 months, 10 (48%) of 21 NF-kappaB positive patients had died compared to only one (5%) of 22 NF-kappaB 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-kappaB expression) NF-kappaB activation was the only independent predictor of DFS (P = .010) and OS (P = .015). CONCLUSION: Our data suggest that esophageal cancers with activated NF-kappaB have aggressive clinical biology and poor treatment outcome. Additional understanding of NF-kappaB regulated pathways may uncover potential therapeutic targets.

Published 10 February 2006 in J Clin Oncol, 24(5): 748-54.
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