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

Abstract

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.

• Authors: Julie G Izzo, Usha Malhotra, Tsung-Teh Wu, Joe Ensor, Rajyalakshmi Luthra, Jeffrey H Lee, Stephen G Swisher, Zhongxing Liao, K S Clifford Chao, Walter N Hittelman, Bharat B Aggarwal, Jaffer A Ajani
• Journal: Journal of clinical oncology : official journal of the American Society of Clinical Oncology (J Clin Oncol) Vol. 24 Issue 5 Pg. 748-54 (Feb 10 2006) ISSN: 1527-7755 [Electronic] United States
• PMID: 16401681 (Publication Type: Clinical Trial, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• NF-kappa B
• Taxoids
• Docetaxel
• Irinotecan
• Fluorouracil
• Camptothecin

Topics

• Adult
• Aged
• Antineoplastic Combined Chemotherapy Protocols (therapeutic use)
• Camptothecin (administration & dosage, analogs & derivatives)
• Carcinoma (drug therapy, genetics, radiotherapy)
• Combined Modality Therapy
• Disease-Free Survival
• Docetaxel
• Esophageal Neoplasms (drug therapy, genetics, radiotherapy)
• Female
• Fluorouracil (administration & dosage)
• Gene Expression Profiling
• Humans
• Immunohistochemistry
• Infusions, Intravenous
• Injections, Intravenous
• Irinotecan
• Male
• Middle Aged
• NF-kappa B (analysis, biosynthesis)
• Neoplasm Invasiveness
• Neoplasm Staging (methods)
• Prognosis
• Taxoids (administration & dosage)
• Treatment Outcome