Technical Development and Validation of a Clinically Applicable Microenvironment Classifier As a Biomarker of Tumour Hypoxia for Soft Tissue Sarcoma

Overview

Journal Br J Cancer

Specialty Oncology

Date 2023 Apr 21

PMID 37085598

Authors

Laura J Forker

Becky Bibby

Lingjian Yang

Brian Lane

Joely Irlam

Hitesh Mistry

Mairah Khan

Helen Valentine

James Wylie

Patrick Shenjere

Michael Leahy

Piers Gaunt

Lucinda Billingham

Beatrice M Seddon

Rob Grimer

Martin Robinson

Ananya Choudhury

Catharine West

Affiliations

Soon will be listed here.

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.

Citing Articles

A Review on Canine and Human Soft Tissue Sarcomas: New Insights on Prognosis Factors and Treatment Measures.

DellAnno F, Giugliano R, Listorti V, Razzuoli E Vet Sci. 2024; 11(8).

PMID: 39195816 PMC: 11358912. DOI: 10.3390/vetsci11080362.

Opportunities and Challenges in Soft Tissue Sarcoma Risk Stratification in the Era of Personalised Medicine.

Chowdhury A, Thway K, Pasquali S, Callegaro D, Gronchi A, Jones R Curr Treat Options Oncol. 2024; 25(8):1124-1135.

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Implementation of Oxygen Enhanced Magnetic Resonance Imaging (OE-MRI) and a Pilot Genomic Study of Hypoxia in Bladder Cancer Xenografts.

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