Originally published as JCO Early Release 10.1200/JCO.2005.03.8810 on January 9 2006

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Association of Activated Transcription Factor Nuclear Factor B With Chemoradiation Resistance and Poor Outcome in Esophageal Carcinoma

From the Department of Experimental Therapeutics; Department of Pathology; Department of Biostatistics and Applied Mathematics; Department of Pathology and Laboratory Medicine; Department of Gastrointestinal Medicine and Nutrition; Department of Thoracic and Cardiovascular Surgery; Department of Radiation Oncology; Department of Gastrointestinal Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX

Address reprint requests to Jaffer A. Ajani, MD, Department of Gastrointestinal Medical Oncology, Unit 426, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030-4009; e-mail: jajani{at}mdanderson.org

PURPOSE: The lack of effective treatment for localized esosphageal cancer leads to poor patient outcome. Nuclear factor B (NF-B), 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-B 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-B positive cancer, but only one (7%) of 14 patients achieving pathCR had NF-B positive cancer (P = < .001). Activated NF-B was significantly associated with aggressive pathologic features such as perineural, lymphatic, and/or vascular invasion (P = .0004). Eight (38%) of 21 NF-B positive patients developed metastases compared to none of 22 NF-B negative patients (P = .001). At a median follow-up of 23 months, 10 (48%) of 21 NF-B positive patients had died compared to only one (5%) of 22 NF-B 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-B expression) NF-B activation was the only independent predictor of DFS (P = .010) and OS (P = .015).

CONCLUSION: Our data suggest that esophageal cancers with activated NF-B have aggressive clinical biology and poor treatment outcome. Additional understanding of NF-B regulated pathways may uncover potential therapeutic targets.

Supported by The University of Texas M.D. Anderson Esophageal Multidisciplinary Research Project Grant, the Rivercreek Foundation, and the Dallas, Cantu, Smith, and Park Families (J.A.A.). Also supported in part by National Institutes of Health (Bethesda, MD) Grant No. CA89189 (K.S.C.C.).

Presented in part at the 41st Annual Meeting of the American Society for Clinical Oncology, Orlando, FL, May 13-17, 2005.

Terms in blue are defined in the glossary, found at the end of this article and online at www.jco.org.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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