Gene expression classifier predicts for hypoxic modification of radiotherapy with nimorazole in squamous cell carcinomas of the head and neck

TY - JOUR

T1 - Gene expression classifier predicts for hypoxic modification of radiotherapy with nimorazole in squamous cell carcinomas of the head and neck

AU - Toustrup, Kasper

AU - Sørensen, Brita Singers

AU - Lassen, Pernille

AU - Wiuf, Carsten

AU - Alsner, Jan

AU - Overgaard, Jens

N1 - Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

PY - 2012/1

Y1 - 2012/1

N2 - Purpose: To validate the predictive impact of a hypoxia gene expression classifier in identifying patients with head and neck squamous cell carcinoma (HNSCC) having benefit from hypoxic modification of radiotherapy. Patients and methods: Gene expressions were quantified from formalin-fixed, paraffin-embedded tumour biopsies of 323 HNSCC patients randomized for placebo or nimorazole in conjunction with radiotherapy in the DAHANCA 5 study. Tumours were classified as either "more" or "less" hypoxic with a classifier constituting of 15 hypoxia responsive genes. The predictive impact was evaluated by analysing the response to nimorazole vs. placebo in terms of loco-regional tumour control (LRC) and disease-specific survival (DSS) in the two classified groups. Results: Hundred and fourteen patients (35%) were classified as having "more" hypoxic tumours. These patients had a significant benefit of hypoxic modification with nimorazole compared with placebo in terms of LRC (5-year actuarial values 49% vs. 18%; p = 0.001) and DSS (48% vs. 30%; p = 0.04). "Less" hypoxic tumours had no significant effect of hypoxic modification (LRC: 50% vs. 44%; p = 0.39, DSS: 57% vs. 51%; p = 0.49) and generally an outcome, which was similar to "more" hypoxic tumours treated with nimorazole. In contrast to HPV-negative tumours, HPV-positive tumours had a substantially better outcome in response to radiotherapy, which was irrespective of hypoxic modification. Conclusions: A predictive 15-gene hypoxia classifier could identify patients associated with improved outcome after combining radiotherapy with hypoxic modification and underlines the relevance of such therapy. The impact of the classifier was limited to HPV-negative tumours.

AB - Purpose: To validate the predictive impact of a hypoxia gene expression classifier in identifying patients with head and neck squamous cell carcinoma (HNSCC) having benefit from hypoxic modification of radiotherapy. Patients and methods: Gene expressions were quantified from formalin-fixed, paraffin-embedded tumour biopsies of 323 HNSCC patients randomized for placebo or nimorazole in conjunction with radiotherapy in the DAHANCA 5 study. Tumours were classified as either "more" or "less" hypoxic with a classifier constituting of 15 hypoxia responsive genes. The predictive impact was evaluated by analysing the response to nimorazole vs. placebo in terms of loco-regional tumour control (LRC) and disease-specific survival (DSS) in the two classified groups. Results: Hundred and fourteen patients (35%) were classified as having "more" hypoxic tumours. These patients had a significant benefit of hypoxic modification with nimorazole compared with placebo in terms of LRC (5-year actuarial values 49% vs. 18%; p = 0.001) and DSS (48% vs. 30%; p = 0.04). "Less" hypoxic tumours had no significant effect of hypoxic modification (LRC: 50% vs. 44%; p = 0.39, DSS: 57% vs. 51%; p = 0.49) and generally an outcome, which was similar to "more" hypoxic tumours treated with nimorazole. In contrast to HPV-negative tumours, HPV-positive tumours had a substantially better outcome in response to radiotherapy, which was irrespective of hypoxic modification. Conclusions: A predictive 15-gene hypoxia classifier could identify patients associated with improved outcome after combining radiotherapy with hypoxic modification and underlines the relevance of such therapy. The impact of the classifier was limited to HPV-negative tumours.

KW - Adult

KW - Aged

KW - Aged, 80 and over

KW - Biopsy

KW - Carcinoma, Squamous Cell

KW - Cell Hypoxia

KW - Chi-Square Distribution

KW - Female

KW - Gene Expression Regulation, Neoplastic

KW - Head and Neck Neoplasms

KW - Humans

KW - Male

KW - Middle Aged

KW - Nimorazole

KW - Predictive Value of Tests

KW - Proportional Hazards Models

KW - Radiation-Sensitizing Agents

KW - Survival Rate

KW - Tumor Markers, Biological

U2 - 10.1016/j.radonc.2011.09.010

DO - 10.1016/j.radonc.2011.09.010

M3 - Journal article

C2 - 21996521

SN - 0167-8140

VL - 102

SP - 122

EP - 129

JO - Radiotherapy & Oncology

JF - Radiotherapy & Oncology

IS - 1

ER -