Validation of lysyl oxidase as a prognostic marker for metastasis and survival in head and neck squamous cell carcinoma: Radiation Therapy Oncology Group trial 90-03.
OBJECTIVE
To validate lysyl oxidase (LOX), a hypoxia-related protein, as a marker for metastasis in an independent head and neck cancer (HNC) patient group enrolled onto a prospective trial.


METHODS
We performed traditional immunohistochemical (IHC) staining and automated quantitative analysis (AQUA) for LOX expression in 66 HNC patients from one institution. We also performed AQUA staining for LOX in 306 of 1,113 patients treated on a phase III trial comparing four radiation fractionation schedules in locally advanced HNC (RTOG 90-03). Pretreatment characteristics and outcome were similar between patients with and without LOX assessment. We correlated AQUA LOX expression with time to metastasis (TTM), time to progression (TTP), and overall survival (OS).


RESULTS
LOX expression from both staining methods predicted for TTM in the first 66 patients. Multivariate analysis, controlling for significant parameters including nodal stage and performance status, revealed tumor LOX expression, as a continuous variable, was an independent predictor for TTM (hazard ratio [HR], 1.21; 95% CI, 1.10 to 1.33; P = .0001), TTP (HR, 1.06; 95% CI, 1.02 to 1.10; P = .0069), and OS (HR, 1.04; 95% CI, 1.00 to 1.07; P = .0311) in RTOG 90-03 patients. This translates into a 259% increase in metastatic risk for a patient at the 75th percentile of LOX compared with one at the 25th percentile.


CONCLUSIONS
AQUA LOX expression was strongly associated with increased metastasis, progression, and death in RTOG 90-03 patients. This study validates that LOX is a marker for metastasis and survival in HNC.
Le
Quynh-Thu
QT
Department of Radiation Oncology, Stanford University, Stanford, CA 94305-5847, USA. qle@stanford.edu
Harris
Jonathan
J
Magliocco
Anthony M
AM
Kong
Christina S
CS
Diaz
Roman
R
Shin
Brian
B
Cao
Hongbin
H
Trotti
Andy
A
Erler
Janine T
JT
Chung
Christine H
CH
Dicker
Adam
A
Pajak
Thomas F
TF
Giaccia
Amato J
AJ
Ang
K Kian
KK
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000378:metabolism*; D002294:Carcinoma, Squamous Cell / Q000175:diagnosis* / Q000201:enzymology / Q000401:mortality; D002423:Cause of Death; D018450:Disease Progression; D005260:Female; D006258:Head and Neck Neoplasms / Q000175:diagnosis* / Q000201:enzymology / Q000401:mortality; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods / Q000706:statistics & numerical data; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D009362:Neoplasm Metastasis; D011379:Prognosis; D016016:Proportional Hazards Models; D008249:Protein-Lysine 6-Oxidase / Q000378:metabolism*; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D013194:Staining and Labeling / Q000379:methods / Q000706:statistics & numerical data; D016019:Survival Analysis; D015996:Survival Rate
D014408:Biomarkers, Tumor; D008249:Protein-Lysine 6-Oxidase