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Research Articles: Therapeutics, Targets, and Development

Pretherapy nuclear factor-B status, chemoradiation resistance, and metastatic progression in esophageal carcinoma

Departments of ¹ Experimental Therapeutics, ² Thoracic and Cardiovascular Surgery, ³ Pathology, ⁴ Radiation Oncology, ⁵ Pathology and Laboratory Medicine, ⁶ Biostatistics and Applied Mathematics, ⁷ Gastrointestinal Medicine and Nutrition, and ⁸ Gastrointestinal Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas

Requests for reprints: Jaffer A. Ajani, Department of Gastrointestinal Medical Oncology, Unit 426, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030-4009. Phone: 713-792-2828; Fax: 713-745-1163. E-mail: jajani{at}mdanderson.org

Abstract

Background: Transcriptional factor nuclear factor-B (NF-B) seems to be associated with aggressive clinical biology (chemoradiation resistance and metastatic progression) of esophageal cancer. We hypothesized that activated NF-B would define clinical biology irrespective of the type of chemotherapy or sequence administered. Methods: Pretherapy and/or posttherapy cancer specimens were examined for activated NF-B and correlated with pathologic response to chemoradiation, metastatic potential, overall survival, disease-free survival, and type of chemotherapy or sequence used. Findings: Eighty patients undergoing chemotherapy and concurrent radiation were studied. Activated NF-B prior to any therapy was associated with the lack of complete pathologic response (pathCR, P = 0.006). Forty-five (78%) of 58 patients achieving <pathCR had activated NF-B in pretherapy and/or posttherapy cancer specimens versus 2 (9%) of 22 patients with pathCR (P = 0.001). Twenty-four (51%) of 47 patients with activated NF-B in cancer developed metastases versus 7 (21%) of 22 patients with negative NF-B in cancer (P = 0.01). At a median follow-up of 32 months, 25 (53%) of 47 patients with activated NF-B cancer had died versus 3 (9%) of 33 patients with negative NF-B cancer. NF-B activation was the only independent predictor of disease-free survival (P = 0.01) and overall survival (P = 0.007) in a multivariate model. The class of chemotherapy or its sequence had no effect on NF-B expression or patient outcome. Conclusions: Our data are the first to show that pretreatment-activated NF-B significantly correlates with clinical biology of esophageal cancer, and most importantly, with pathCR. To therapeutically exploit NF-B-regulated genes and their pathways, further research is warranted. [Mol Cancer Ther 2006;5(11):2844–50]

Grant support: University of Texas M.D. Anderson Esophageal Multidisciplinary Research Project grant, Riverkreek Foundation, and the Dallas, Cantu, Smith, and Park Families.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received 6/19/06; revised 8/16/06; accepted 9/11/06.

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