Technical development and validation of a clinically applicable microenvironment classifier as a biomarker of tumour hypoxia for soft tissue sarcoma

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

doi:10.1038/s41416-023-02265-3

Technical development and validation of a clinically applicable microenvironment classifier as a biomarker of tumour hypoxia for soft tissue sarcoma

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

Cancer Clinical Trials Unit

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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.

Original language	English
Journal	British Journal of Cancer
Early online date	21 Apr 2023
DOIs	https://doi.org/10.1038/s41416-023-02265-3
Publication status	E-pub ahead of print - 21 Apr 2023

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10.1038/s41416-023-02265-3Licence: Creative Commons: Attribution (CC BY)

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Forker, L. J., Bibby, B., Yang, L., Lane, B., Irlam, J., Mistry, H., Khan, M., Valentine, H., Wylie, J., Shenjere, P., Leahy, M., Gaunt, P., Billingham, L., Seddon, B. M., Grimer, R., Robinson, M., Choudhury, A., & West, C. (2023). Technical development and validation of a clinically applicable microenvironment classifier as a biomarker of tumour hypoxia for soft tissue sarcoma. British Journal of Cancer. Advance online publication. https://doi.org/10.1038/s41416-023-02265-3

@article{2d812b3d8ac148369051e95942f6bb2b,

title = "Technical development and validation of a clinically applicable microenvironment classifier as a biomarker of tumour hypoxia for soft tissue sarcoma",

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.",

author = "Forker, {Laura J.} and Becky Bibby and Lingjian Yang and Brian Lane and Joely Irlam and Hitesh Mistry and Mairah Khan and Helen Valentine and James Wylie and Patrick Shenjere and Michael Leahy and Piers Gaunt and Lucinda Billingham and Seddon, {Beatrice M} and Rob Grimer and Martin Robinson and Ananya Choudhury and Catharine West",

note = "{\textcopyright} 2023. The Author(s).",

year = "2023",

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day = "21",

doi = "10.1038/s41416-023-02265-3",

language = "English",

journal = "British Journal of Cancer",

issn = "0007-0920",

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Forker, LJ, Bibby, B, Yang, L, Lane, B, Irlam, J, Mistry, H, Khan, M, Valentine, H, Wylie, J, Shenjere, P, Leahy, M, Gaunt, P , Billingham, L, Seddon, BM, Grimer, R, Robinson, M, Choudhury, A & West, C 2023, 'Technical development and validation of a clinically applicable microenvironment classifier as a biomarker of tumour hypoxia for soft tissue sarcoma', British Journal of Cancer. https://doi.org/10.1038/s41416-023-02265-3

TY - JOUR

T1 - Technical development and validation of a clinically applicable microenvironment classifier as a biomarker of tumour hypoxia for soft tissue sarcoma

AU - Forker, Laura J.

AU - Bibby, Becky

AU - Yang, Lingjian

AU - Lane, Brian

AU - Irlam, Joely

AU - Mistry, Hitesh

AU - Khan, Mairah

AU - Valentine, Helen

AU - Wylie, James

AU - Shenjere, Patrick

AU - Leahy, Michael

AU - Gaunt, Piers

AU - Billingham, Lucinda

AU - Seddon, Beatrice M

AU - Grimer, Rob

AU - Robinson, Martin

AU - Choudhury, Ananya

AU - West, Catharine

PY - 2023/4/21

Y1 - 2023/4/21

N2 - 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.

AB - 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.

U2 - 10.1038/s41416-023-02265-3

DO - 10.1038/s41416-023-02265-3

M3 - Article

C2 - 37085598

SN - 0007-0920

JO - British Journal of Cancer

JF - British Journal of Cancer

ER -

Technical development and validation of a clinically applicable microenvironment classifier as a biomarker of tumour hypoxia for soft tissue sarcoma

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