Transcription factor NFkB a potential molecular marker for predicting and improving treatment efficacy in esophageal cancer

J G Izzo, T Wu, U Malhotra, J Ensor, R Luthra, C K Chao, S G Swisher, Z Liao, B B Aggarwal, W N Hittelman, J A Ajani

Research output: Contribution to journalArticle

Abstract

10065 Background: Esophageal/gastroesophageal junction adenocarcinoma (E/GEJAC) remains one of the most aggressive malignancies. Chemoradiotherapy (CTXRT) followed by surgery has been used for localized E/GEJAC. Patients (pts) achieving pathologic complete response (pathCR) have an improved survival, but ≈70% of pts exhibit at surgery resistant residual, highly aggressive tumors despite CTXRT. There is a need to identify this high-risk population and target molecular pathways associated with cancer resistance. We have shown that nuclear NFκB was associated with poor clinical outcome of E/GEJAC pts undergoing 5FU, Docetaxel and Cisplatinum therapy. To validate our findings, we examined the impact of nuclear NFκB on clinical outcome of pts undergoing diverse CTXRT regimens.

METHODS: Pre- treatment tumor biopsies and post-treatment resected residual tumors were analyzed from pts receiving neo-adjuvant CT or CTXRT. NFκB protein expression was assessed by immunochemistry and correlated to pathCR and clinical outcome. Tumors were considered NFκB positive (pos) when ≥5% of cells expressed nuclear NFκB.

RESULTS: 80 pts, clinically staged II, III and IVA, were studied. All pts received antifolates, and 80%, 65% & 31% received taxanes, topo-1 inhibitors and/or platinum analogues, respectively. Radiation therapy was 50.4 Gy at 1.8 Gy once a day to all pts. 75/80 pts had available pre-treatment biopsies, all 58 pts with <pathCR had available residual tumors. Pre-treatment NFκB was predictive for lack of response to CTXRT [NFκB pos: 2/22 pathCR vs 27/53 <pathCR; P=.006]. In multivariate analysis, including clinical stage, tumor histology, pathCR and lymph nodes metastasis, pre-treatment NFκB was an independent prognostic factor of progression-free (P=.0029, HR=2.90, 95%CI:1.44-5.86) and overall (P=.0073,HR=2.70, 95%CI:1.30-5.60) survivals. NFκB was associated with recurrent disease [pre-treatment NFκB pos 14/29 (48%) vs NFκB negative11/46 (24%), P=.04; pre- or post- NFκB pos 22/47 (47%) vs NFκB neg 4/33 (12%), P=.003].

CONCLUSIONS: our data suggest that NFκB defines cancer biology and patterns to therapy response irrespective of the type of chemoradiation used. NFκB may serve as potential molecular target to improve treatment efficacy. No significant financial relationships to disclose.

Original languageEnglish (US)
Pages (from-to)10065
JournalJournal of Clinical Oncology
Volume24
Issue number18_suppl
StatePublished - Jun 20 2006

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