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

Background: Transcriptional factor nuclear factor-κB (NF-κB) seems to be associated with aggressive clinical biology (chemoradiation resistance and metastatic progression) of esophageal cancer. We hypothesized that activated NF-κB 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-κB 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-κB 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-κB 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-κB in cancer developed metastases versus 7 (21%) of 22 patients with negative NF-κB in cancer (P = 0.01). At a median follow-up of 32 months, 25 (53%) of 47 patients with activated NF-κB cancer had died versus 3 (9%) of 33 patients with negative NF-κB cancer. NF-κB 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-κB expression or patient outcome. Conclusions: Our data are the first to show that pretreatment-activated NF-κB significantly correlates with clinical biology of esophageal cancer, and most importantly, with pathCR. To therapeutically exploit NF-κB-regulated genes and their pathways, further research is warranted.