Acute Hypoxia Profile is a Stronger Prognostic Factor than Chronic Hypoxia in Advanced Stage Head and Neck Cancer Patients.

Martijn Van Der Heijden,C René Leemans,Sebastian Sanduleanu,Michiel W M Van Den Brekel,Conchita Vens,Caroline V M Verhagen,Reinout H De Roest,Ruud H Brakenhoff,Monique C De Jong,Frank Hoebers,Marcel Verheij

doi:10.3390/cancers11040583

Abstract

Hypoxic head and neck tumors respond poorly to radiotherapy and can be identified using gene expression profiles. However, it is unknown whether treatment outcome is driven by acute or chronic hypoxia. Gene expression data of 398 head and neck cancers was collected. Four clinical hypoxia profiles were compared to in vitro acute and chronic hypoxia profiles. Chronic and acute hypoxia profiles were tested for their association to outcome using Cox proportional hazard analyses. In an initial set of 224 patients, scores of the four clinical hypoxia profiles correlated with each other and with chronic hypoxia. However, the acute hypoxia profile showed a stronger association with local recurrence after chemoradiotherapy (p = 0.02; HR = 3.1) than the four clinical (chronic hypoxia) profiles (p = 0.2; HR = 0.9). An independent set of 174 patients confirmed that acute hypoxia is a stronger prognostic factor than chronic hypoxia for overall survival, progression-free survival, local and locoregional control. Multivariable analyses accounting for known prognostic factors substantiate this finding (p = 0.045; p = 0.042; p = 0.018 and p = 0.003, respectively). In conclusion, the four clinical hypoxia profiles are related to chronic hypoxia and not acute hypoxia. The acute hypoxia profile shows a stronger association with patient outcome and should be incorporated into existing prediction models.

Highlights

The average overall survival for advanced stage head and neck cancer patients is around 50% [1], but this varies greatly among different groups of patients
The poor association of the acute hypoxia profile with patient outcome was validated in an independent validation cohort (n = 174) and multivariable analysis showed that acute hypoxia is a significant prognostic factor independent of clinical factors, tumor volume and chronic hypoxia
We selected four gene expression profiles for hypoxia that are clinically validated for head and neck cancer, namely, Winter et al, Buffa et al, Toustrup et al and Eustace et al Gene expression profiles generated by Seigneuric et al were used for in vitro acute and chronic hypoxia

Summary

Introduction

The average overall survival for advanced stage head and neck cancer patients is around 50% [1], but this varies greatly among different groups of patients. Clinical (TNM) staging explains survival variation only partially for these patients [2,3,4]. Human papillomavirus (HPV) positive oropharyngeal tumors represent a distinct subgroup of head and neck squamous cell carcinoma (HNSCC) that is associated with a good prognosis [5]. We have previously shown that the addition of HPV status and a prognostic gene expression profile can improve outcome prediction, suggesting that a substantial part of the survival variation is explained by tumor biology [5]. Hypoxia is one of the most studied biological factors affecting prognosis in HNSCC [6]. Tumor cells can become hypoxic by chronic (diffusion limited) and acute (perfusion limited) mechanisms [7]

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Conclusion