A sarcoma hypoxia signature (nanoString (R) assay) validates in the phase III VorteX radiotherapy trial
Forker, Laura-Jane Bibby, Becky A Yang, Lingjian Irlam, Joely J Valentine, Helen R Shenjere, Patrick Wylie, James P Leahy, Michael G Gaunt, P. Billingham, L.
Forker, Laura-Jane
Bibby, Becky A
Yang, Lingjian
Irlam, Joely J
Valentine, Helen R
Shenjere, Patrick
Wylie, James P
Leahy, Michael G
Gaunt, P.
Billingham, L.
Citations
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Abstract
Purpose or Objective
Soft tissue sarcomas (STS) are a rare group of tumours
encompassing ~50 malignant, heterogeneous subtypes.
Localised disease is managed with surgery ± radiotherapy.
Neoadjuvant radiotherapy response is varied and despite
high metastatic recurrence rates, there is no definite
overall survival benefit from the addition of systemic
chemotherapy.
Each subtype is very rare; therefore, biomarkers of
adverse biological features present across subtypes might
be more successful in selecting high-risk patients for
clinical trials. Tumour hypoxia is associated with poor
radiotherapy response and metastasis. We previously
derived a 24-gene STS hypoxia signature that was
prognostic in two independent cohorts.
The study aims were (1) signature validation in a new
whole transcriptome cohort (2) assay development for pretreatment
biopsies (3) assay validation.
Material and Methods
Three cohorts were used (1) VorteX n=203 (2) single centre
retrospective n=165 (3) MCRC Biobank n=28. VorteX was a
randomised phase III trial comparing radiotherapy volumes
in adults with localised extremity STS. Validation cohorts
included mainly high-risk patients (85% high-grade).
Whole transcriptome RNA-sequencing data (Illumina
HiSeq4000) were generated from fresh frozen tumour
samples for VorteX. Two targeted assays (Taqman® array
cards and nanoString®) were compared in formalin-fixed,
paraffin-embedded (FFPE) biopsies. Prognostic validation
of the nanoString® assay was performed in FFPE samples
from the retrospective and VorteX cohorts. Intra-tumour
heterogeneity was assessed in patients (n=10) with
multiple biopsies and compared with CAIX expression.
Results
In the RNA-sequencing VorteX cohort, data were generated
for 125/140 patients with available tissue. There was a
trend towards poor disease-free survival (DFS) in patients
with hypoxic tumours (HR 1.68 95% CI 0.95-2.98 p=0.061).
Taqman® array cards and nanoString® demonstrated
excellent pass rates and reproducibility. The nanoString®
was more sensitive, required lower input and can measure
more genes simultaneously. The gene signature showed
considerably less intra-tumour heterogeneity than a single
marker (figure 1).
The nanoString® assay produced a result for 126/127
(99.2%) and 154/159 (96.9%) of patients with sufficient
RNA yield and classified 41.3% and 44.8% of samples as
hypoxic from the retrospective and VorteX cohorts,
respectively. In a univariate analysis patients with hypoxic
tumours had worse disease free survival in both cohorts
(retrospective HR 2.302 95% CI 1.182-4.486 p=0.0083,
VorteX HR 1.687 95% CI 1.013-2.81 p=0.0377) Conclusion
A hypoxia signature nanoString® assay with excellent
technical performance is prognostic in two independent
cohorts of patients with high-grade tumours, including the
phase III VorteX radiotherapy trial. The assay could
identify high-risk patients for adjuvant chemotherapy
trials.
Description
Date
2020
Publisher
Collections
Keywords
Type
Meetings and Proceedings
Citation
Forker L, Bibby B, Yang L, Irlam J, Valentine H, Shenjere P, et al. OC-0086: A sarcoma hypoxia signature (nanoString® assay) validates in the phase III VorteX radiotherapy trial. Radiotherapy and Oncology . 2020 Nov;152:S39–40.