Evaluation of biomarkers in the UK phase III VorteX trial confirms importance of tumour hypoxia in soft tissue sarcoma


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Laura Forker1,Piers Gaunt2,Stefano Sioletic3,Patrick Shenjere4,Joely Irlam1,Helen Valentine1,David Hughes5,Ana Hughes2,Lucinda Billingham2,Martin Robinson6,Catharine West1
1University of Manchester,2Cancer Research UK Clinical Trials Unit (CRCTU), University of Birmingham,3University Hospital of Udine,4Christie Hospital NHS Foundation Trust,5Sheffield Teaching Hospitals NHS Trust,6University of Sheffield

Abstract

Background

Research in soft tissue sarcoma (STS) is challenging due to its rarity and heterogeneity.  Progress requires tailoring therapy to individual features of tumour biology, which need identifying in well documented cohorts. VorteX assessed whether a reduced volume of tissue irradiated post-operatively improves limb function in patients with extremity STS. The VorteX-Biobank created a linked bioresource.

Method

Patients with a histologic diagnosis of localised, extremity STS requiring surgery and adjuvant radiotherapy were eligible. The trial required 210 patients to detect a difference in limb function at 2-years. Patients were randomised to two adjuvant radiotherapy volumes.  Primary outcomes were limb function and time to local recurrence; secondary outcomes were disease free (DFS) and overall survival.  The Biobank collected diagnostic formalin-fixed paraffin-embedded tumour biopsies, fresh tumour and normal tissue during surgery, and blood samples prior to radiotherapy.  Assessment of the bioresource involved immunohistochemistry for HIF-1α, CA-IX and GLUT-1 on tissue microarrays. Survival estimates were performed using Kaplan–Meier and Cox regression analysis.

Results

319 patients were enrolled and 216 randomised. Median follow up was 4.8 years.  FFPE tissue was collected from 301 (94%) enrolled and 206 (98%) randomised patients. Matched tumour and normal tissue was collected for 88% of patients. Univariate analyses indicate patients with high tumour CA-IX (HR 2.28, 95% CI 1.44-3.63, p<0.001) or HIF-1α (HR 1.76, 95% CI 1.01-3.08, p=0.047) expression had worse DFS.  GLUT-1 was not prognostic.

Conclusion

The first study from the VorteX-Biobank validates previous findings that hypoxia is associated with a poor prognosis in STS in a modern phase III trial cohort.  The successful establishment of a linked Biobank from patients entered into the largest multicentre randomised trial of radiotherapy in STS is an important resource for translational research.