Abstract
Background:Despite high metastasis rates, adjuvant/neoadjuvant systemic therapy for localised soft tissue sarcoma (STS) is not used routinely. Progress requires tailoring therapy to features of tumour biology, which need exploration in well-documented cohorts. Hypoxia has been linked to metastasis in STS and is targetable. This study evaluated hypoxia prognostic markers in the phase III adjuvant radiotherapy VorteX trial.Methods:Formalin-fixed paraffin-embedded tumour biopsies, fresh tumour/normal tissue and blood were collected before radiotherapy. Immunohistochemistry for HIF-1α, CAIX and GLUT1 was performed on tissue microarrays and assessed by two scorers (one pathologist). Prognostic analysis of disease-free survival (DFS) used Kaplan–Meier and Cox regression.Results:Biobank and outcome data were available for 203 out of 216 randomised patients. High CAIX expression was associated with worse DFS (hazard ratio 2.28, 95% confidence interval: 1.44–3.59, P<0.001). Hypoxia-inducible factor-1α and GLUT1 were not prognostic. Carbonic anhydrase IX remained prognostic in multivariable analysis.Conclusions:The VorteX-Biobank contains tissue with linked outcome data and is an important resource for research. This study confirms hypoxia is linked to poor prognosis in STS and suggests that CAIX may be the best known marker. However, overlap between single marker positivity was poor and future work will develop an STS hypoxia gene signature to account for tumour heterogeneity.
Highlights
Despite high metastasis rates, adjuvant/neoadjuvant systemic therapy for localised soft tissue sarcoma (STS) is not used routinely
High CAIX expression was associated with worse disease-free survival (DFS)
This study confirms hypoxia is linked to poor prognosis in STS and suggests that CAIX may be the best known marker
Summary
Formalin-fixed paraffin-embedded tumour biopsies, fresh tumour/normal tissue and blood were collected before radiotherapy. Immunohistochemistry for HIF-1a, CAIX and GLUT1 was performed on tissue microarrays and assessed by two scorers (one pathologist). Prospective samples were collected for the VorteX Biobank from consenting adult patients with localised, extremity soft tissue sarcoma receiving surgery with adjuvant radiotherapy as part of the phase III randomised controlled VorteX trial. The study had appropriate ethical approval (LREC 06/MRE/ 03/3) and informed consent was obtained for sample collection and analysis. Fresh tumour, matched normal tissue, formalin-fixed, paraffin-embedded (FFPE) tissue and peripheral blood samples were collected prior to radiotherapy. Tumour areas in FFPE material were demarcated by the VorteX trial histopathologist (DH) and 1 mm diameter cores were taken in triplicate from different areas. Eleven tissue microarrays (TMAs) were prepared in total
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