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- Title
Technical development and validation of a clinically applicable microenvironment classifier as a biomarker of tumour hypoxia for soft tissue sarcoma.
- Authors
Forker, Laura J.; Bibby, Becky; Yang, Lingjian; Lane, Brian; Irlam, Joely; Mistry, Hitesh; Khan, Mairah; Valentine, Helen; Wylie, James; Shenjere, Patrick; Leahy, Michael; Gaunt, Piers; Billingham, Lucinda; Seddon, Beatrice M.; Grimer, Rob; Robinson, Martin; Choudhury, Ananya; West, Catharine
- Abstract
Background: Soft tissue sarcomas (STS) are rare, heterogeneous tumours and biomarkers are needed to inform management. We previously derived a prognostic tumour microenvironment classifier (24-gene hypoxia signature). Here, we developed/validated an assay for clinical application. Methods: Technical performance of targeted assays (Taqman low-density array, nanoString) was compared in 28 prospectively collected formalin-fixed, paraffin-embedded (FFPE) biopsies. The nanoString assay was biologically validated by comparing to HIF-1α/CAIX immunohistochemistry (IHC) in clinical samples. The Manchester (n = 165) and VORTEX Phase III trial (n = 203) cohorts were used for clinical validation. The primary outcome was overall survival (OS). Results: Both assays demonstrated excellent reproducibility. The nanoString assay detected upregulation of the 24-gene signature under hypoxia in vitro, and 16/24 hypoxia genes were upregulated in tumours with high CAIX expression in vivo. Patients with hypoxia-high tumours had worse OS in the Manchester (HR 3.05, 95% CI 1.54–5.19, P = 0.0005) and VORTEX (HR 2.13, 95% CI 1.19–3.77, P = 0.009) cohorts. In the combined cohort, it was independently prognostic for OS (HR 2.24, 95% CI 1.42–3.53, P = 0.00096) and associated with worse local recurrence-free survival (HR 2.17, 95% CI 1.01–4.68, P = 0.04). Conclusions: This study comprehensively validates a microenvironment classifier befitting FFPE STS biopsies. Future uses include: (1) selecting high-risk patients for perioperative chemotherapy; and (2) biomarker-driven trials of hypoxia-targeted therapies.
- Publication
British Journal of Cancer, 2023, Vol 128, Issue 12, p2307
- ISSN
0007-0920
- Publication type
Article
- DOI
10.1038/s41416-023-02265-3