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

Abstract

Purpose 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. Patients and 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. Conclusion 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.

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“…Our data further show that high nuclear expression of LOX was positively correlated with poor survival in rectal cancer patients in multivariable analysis. Recently, LOX has been clinically validated as a prognostic biomarker for metastatic head and neck cancer [10]. This work complements our findings and, furthermore, LOX has also been proposed to offer similar prognostic value in oral and oropharyngeal squamous carcinoma, whereby high expression is correlated with poor diseasefree and overall survival [11].…”

“…In contrast, recent publications have demonstrated the overexpression of LOX in many types of solid cancer, including brain [9], head and neck [10], oral and oropharyngeal squamous cell [11], breast [12] and ovarian cancer [13]. LOX has been shown to promote cancer cell proliferation, metastasis and angiogenesis [14,15], supporting a role for LOX as a tumour and metastasis promoter.…”

Lysyl Oxidase: From Basic Science to Future Cancer Treatment

“…Inhibiting copperdependent LOX activity, TM treatment decreased tumor cell motility and invasiveness in vitro. They hypothesized Le et al, 2009. 11.…”

Development of a Hypoxia Gene Expression Classifier with Predictive Impact for Hypoxic Modification of Radiotherapy in Head and Neck Cancer

“…Thus, the experimental plan involved identifying specific hypoxiainduced genes responding with a significant increase in expression correlating to a radiobiological relevant oxygen level (20) that could additionally identify patients having benefit from hypoxic modification of radiotherapy. Such "hypoxia-regulated genes" have previously been suggested in the literature (21)(22)(23), but to our knowledge none of the developed hypoxia gene expression signatures (24)(25)(26)) have yet shown to be predictive for beneficial treatment strategies and consequently implemented in the clinic.…”