Hypoxic gene expression is a prognostic factor for disease free survival in a cohort of locally advanced squamous cell cancer of the uterine cervix

Abstract

Introduction

Tumour hypoxia in locally advanced squamous cervical cancer (LACC) has been shown to be of substantial prognostic importance. The aims of the present study were therefore to investigate if hypoxia could be identified by a newly validated hypoxic gene expression classifier and used as a prognostic factor for disease free survival (DFS).

Material and methods

Paraffin embedded biopsies were obtained from 190 patients with LACC with squamous cell carcinoma treated 2005–2016 with chemo-radiation and image guided adaptive brachytherapy. Analysis of hypoxia was successful in 183 patients (96%). Hypoxic classification of tumours into ‘more’ or ‘less’ hypoxic was based on 15 genes using the same method as in a prospective head and neck cancer trial (NCT02661152). HPV was genotyped using INNO-LiPA. Local tumour invasion was evaluated by the T-score. Primary endpoint was DFS analysed by Kaplan-Meier and Cox regression. Events were death of any cause, persistent disease, or recurrence.

Results

The FIGO₂₀₀₉ stage distribution was IB–IIA 9%, IIB 64%, and III–IVA 27%, and mean T-score was 7.2. Pathological nodes were present in 53%. Median observation time was 5.2 years. Local control rate at 5 years was 96%, and pelvic (loco-regional) control 91%. Overall, 36% of the tumours were classified as ‘more’ hypoxic. The frequency of ‘more’ hypoxic tumours increased with local tumour intrusion (30% for T-score 0–9 vs. 55% for T-score ≥10, p = 0.004). Hypoxia was associated with decreased DFS in univariate, HR 1.71 (1.04–2.82), and multivariate analysis, HR 1.75 (1.04–2.92), and the effect was particularly observed among tumours with a T-score ≥10. HPV 16/18 was not associated with improved DFS in neither in univariate nor in multivariate analysis.

Conclusion

Hypoxic gene expression is a prominent prognostic factor for DFS in LACC with SCC histology and should be considered for treatment stratification in clinical trials.

Keywords:

• Locally advanced SCC cervical cancer
• hypoxia
• gene expression
• prognostic factor

Disclosure statement

Jan Alsner and Jens Overgaard are registered as co-inventors on a patent on a method (gene expression profile) for determining clinically relevant hypoxia in cancer (WO2012146259 A1) that is owned by Aarhus University, Aarhus, Denmark.

Data availability statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.

Additional information

Funding

This work was supported by the Danish Cancer Society under grant numbers R90-A5903, R146-A9519, and R231-A14155, and the Health Research Foundation of Central Denmark Region [A2943].