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

Clin Cancer Res. 2016 Jun 1;22(11):2639-49. doi: 10.1158/1078-0432.CCR-15-1990. Epub 2016 Jan 11.

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. Clin Cancer Res; 22(11); 2639-49. ©2016 AACR.

Publication types

  • Multicenter Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / therapeutic use
  • Biomarkers, Tumor / metabolism
  • Carcinoma, Squamous Cell / metabolism*
  • Carcinoma, Squamous Cell / mortality
  • Carcinoma, Squamous Cell / pathology
  • Carcinoma, Squamous Cell / therapy
  • Cell Hypoxia
  • Chemoradiotherapy
  • Cisplatin / therapeutic use
  • Fusion Regulatory Protein 1, Heavy Chain / metabolism
  • Human papillomavirus 16 / genetics
  • Humans
  • Hyaluronan Receptors / metabolism
  • Kaplan-Meier Estimate
  • Mouth Neoplasms / metabolism*
  • Mouth Neoplasms / mortality
  • Mouth Neoplasms / pathology
  • Mouth Neoplasms / therapy
  • Multivariate Analysis
  • Neoplastic Stem Cells / metabolism*
  • Papillomavirus Infections / diagnosis
  • Prognosis
  • Prospective Studies
  • Transcriptome
  • Treatment Outcome

Substances

  • Antineoplastic Agents
  • Biomarkers, Tumor
  • CD44 protein, human
  • Fusion Regulatory Protein 1, Heavy Chain
  • Hyaluronan Receptors
  • SLC3A2 protein, human
  • Cisplatin