Pretherapy nuclear factor-kappaB status, chemoradiation resistance, and metastatic progression in esophageal carcinoma.
BACKGROUND
Transcriptional factor nuclear factor-kappaB (NF-kappaB) seems to be associated with aggressive clinical biology (chemoradiation resistance and metastatic progression) of esophageal cancer. We hypothesized that activated NF-kappaB 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-kappaB and correlated with pathologic response to chemoradiation, metastatic potential, overall survival, disease-free survival, and type of chemotherapy or sequence used.


RESULTS
Eighty patients undergoing chemotherapy and concurrent radiation were studied. Activated NF-kappaB 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-kappaB 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-kappaB in cancer developed metastases versus 7 (21%) of 22 patients with negative NF-kappaB in cancer (P = 0.01). At a median follow-up of 32 months, 25 (53%) of 47 patients with activated NF-kappaB cancer had died versus 3 (9%) of 33 patients with negative NF-kappaB cancer. NF-kappaB 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-kappaB expression or patient outcome.


CONCLUSIONS
Our data are the first to show that pretreatment-activated NF-kappaB significantly correlates with clinical biology of esophageal cancer, and most importantly, with pathCR. To therapeutically exploit NF-kappaB-regulated genes and their pathways, further research is warranted.
Izzo
Julie G
JG
Department of Gastrointestinal Medical Oncology, Unit 426, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030-4009, USA. jajani@mdanderson.org
Correa
Arlene M
AM
Wu
Tsung-Teh
TT
Malhotra
Usha
U
Chao
Clifford K S
CK
Luthra
Rajyalakshmi
R
Ensor
Joe
J
Dekovich
Alexander
A
Liao
Zhongxing
Z
Hittelman
Walter N
WN
Aggarwal
Bharat B
BB
Ajani
Jaffer A
JA
D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000032:analysis*; D002277:Carcinoma / Q000188:drug therapy / Q000532:radiotherapy / Q000628:therapy*; D017024:Chemotherapy, Adjuvant; D018450:Disease Progression; D019008:Drug Resistance, Neoplasm; D004938:Esophageal Neoplasms / Q000188:drug therapy / Q000532:radiotherapy / Q000628:therapy*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D016328:NF-kappa B / Q000032:analysis*; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D016896:Treatment Outcome
D014408:Biomarkers, Tumor; D016328:NF-kappa B