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Linge, Annett; Löck, Steffen; Gudziol, Volker; Nowak, Alexander; Lohaus, Fabian; Neubeck, Cläre von; Jütz, Martin; Abdollahi, Amir; Debus, Jürgen; Tinhofer, Inge; Budach, Volker; Sak, Ali; Stuschke, Martin; Balermpas, Panagiotis; Rödel, Claus; Avlar, Melanie; Grosu, Anca-Ligia; Bayer, Christine; Belka, Claus; Pigorsch, Steffi; Combs, Stephanie E.; Welz, Stefan; Zips, Daniel; Buchholz, Frank; Aust, Daniela E.; Baretton, Gustavo B.; Thames, Howard D.; Dubrovska, Anna; Alsner, Jan; Overgaard, Jens; Baumann, Michael; Krause, Mechthild (2016): Low Cancer Stem Cell Marker Expression and Low Hypoxia Identify Good Prognosis Subgroups in HPV(-) HNSCC after Postoperative Radiochemotherapy: A Multicenter Study of the DKTK-ROG. In: Clinical Cancer Research, Vol. 22, No. 11: pp. 2639-2649
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Abstract

Purpose: To investigate the impact of hypoxia-induced gene expression and cancer stem cell (CSC) marker expression on outcome of postoperative cisplatin-based radiochemotherapy (PORT-C) in patients with locally advanced head and neck squamous cell carcinoma (HNSCC). Experimental Design: Expression of the CSC markers CD44, MET, and SLC3A2, and hypoxia gene signatures were analyzed in the resected primary tumors using RT-PCR and nanoString technology in a multicenter retrospective cohort of 195 patients. CD44 protein expression was further analyzed in tissue microarrays. Primary endpoint was locoregional tumor control. Results: Univariate analysis showed that hypoxia-induced gene expression was significantly associated with a high risk of locoregional recurrence using the 15-gene signature (P = 0.010) or the 26-gene signature (P = 0.002). In multivariate analyses, in patients with HPV16 DNA-negative but not with HPV16 DNA-positive tumors the effect of hypoxia-induced genes on locoregional control was apparent (15-gene signature: HR 4.54, P = 0.006;26-gene signature: HR 10.27, P = 0.024). Furthermore, MET, SLC3A2, CD44, and CD44 protein showed an association with locoregional tumor control in multivariate analyses (MET: HR 3.71, P = 0.016;SLC3A2: HR 8.54, P = 0.037;CD44: HR 3.36, P = 0.054;CD44 protein n/a because of no event in the CD44-negative group) in the HPV16 DNA-negative subgroup. Conclusions: We have shown for the first time that high hypoxia-induced gene expression and high CSC marker expression levels correlate with tumor recurrence after PORT-C in patients with HPV16 DNA-negative HNSCC. After validation in a currently ongoing prospective trial, these parameters may help to further stratify patients for individualized treatment de-escalation or intensification strategies.