Therapy-induced expression of NF-kappa;B portends poor prognosis in patients with localized esophageal cancer undergoing preoperative chemoradiation

Activated nuclear factor-kappa B (NF-κB) in the pretreatment cancer tissue of patients with localized esophageal adenocarcinoma (LEA) undergoing preoperative chemoradiation is associated with poor prognosis. It is known that constitutively activated NF-κB prior to any therapy portends poor prognosis, and it is also known that activated NF-κB in the treated specimen is associated with poor prognosis. However, the prognosis of patients who have treatment-induced activation of NF-κB (meaning their cancers activate NF-κB during or after therapy) is not been reported. We hypothesized that the treatment-induced activation of NF-κB would impart poor prognosis similar to that imparted by constitutively activated NF-κB cancer. Patients with LEA who had undergone preoperative chemoradiation plus surgery and had pre- and post-therapy cancer tissue available were selected. Pre- and post-therapy cancer tissues were stained by immunohistochemistry for nuclear staining of NF-κB. The overall survival (OS) and disease-free survival were assessed and compared for patients who had intrinsic constitutively activated NF-κB cancer with those who had induced activation of NF-κB only post-therapy. A total of 41 patients with LEA were investigated. Twenty-five patients had NF-κB positive cancer at baseline, and 16 had NF-κB negative cancer at baseline but became positive post-therapy. There was no difference in the location, histology grade, clinical stage, or the curative resection (RO) resection rate in the two populations. OS (P = 0.71), disease-free survival (P = 0.86), and median survivals (Converters: 24 months [95% confidence intervals: 7.78 to 40.22] vs. Nonconverters: 34.13 months [95% confidence intervals: 3.54 to 64.27]) were not different between the two groups. Our data suggest that activation of NF-κB in response to stress/injury of therapy leads to poor OS. These results need to be confirmed in a larger number of patients. It may be that only pre-therapy evaluation of NF-κB is insufficient to assess prognosis of patients with LEA. Additional implications include that when effective anti-NF-κB therapies become available, they may have to be considered in patients whose cancers do not have constitutively activated NF-κB or cancer may have to be monitored during therapy with biomarker assessments.