Originally published as JCO Early Release 10.1200/JCO.2008.20.6003 on August 10 2009

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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

From Stanford University, Stanford, CA; Department of Statistics, American College of Radiology; Thomas Jefferson University, Philadelphia, PA; University of Calgary, Calgary, Alberta, Canada; Moffitt Cancer Center, Tampa, FL; Institute of Cancer Research, Chester Beatty Laboratories, London, United Kingdom; Division of Hematology/Oncology, Vanderbilt University School of Medicine, Nashville, TN; and the M. D. Anderson Cancer Center, Houston, TX.

Corresponding author: Quynh-Thu Le, MD, Department of Radiation Oncology, 875 Blake Wilbur Dr, MC 5847, Stanford, CA 94305-5847; e-mail: qle{at}stanford.edu.

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.

Supported by an RTOG Translational grant (T.M., R.D., B.S.), National Cancer Institute RTOG Grant No. U10 CA21661 (J.H., T.F.P., K.K.A.), CCOP Grant No. U10 CA3742 (J.H., T.F.P.), Pennsylvania Department of Health Grant No. 4100026182 (J.H.), and Grants No. 1 R01 CA118582-01 (Q.T.L., C.S.K.), P01- CA67166 (Q.T.L., J.T.E., A.J.G.), and P01-CA06294 (K.K.A.).

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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