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Prospective patient stratification into robust cancer-cell intrinsic subtypes from colorectal cancer biopsies

Alderdice, Matthew, Richman, Susan D, Gollins, Simon, Stewart, Peter, Hurt, Christopher, Adams, Richard, McCorry, Amy, Roddy, Aideen, Vimalachandran, Dale, Isella, Claudio, Medico, Enzo, Maughan, Tim, McArt, Darragh G, Lawler, Mark and Dunne, Philip D 2018. Prospective patient stratification into robust cancer-cell intrinsic subtypes from colorectal cancer biopsies. The Journal of Pathology 245 (1) , pp. 19-28. 10.1002/path.5051

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Abstract

Colorectal cancer (CRC) biopsies underpin accurate diagnosis, but are also relevant for patient stratification in molecularly-guided clinical trials. The consensus molecular subtypes (CMS) and colorectal cancer intrinsic subtypes (CRIS) transcriptional signatures have potential clinical utility for improving prognostic/predictive patient assignment. However, their ability to provide robust classification, particularly in pre-treatment biopsies from multiple regions or at different time points remains untested. In this study, we undertook a comprehensive assessment of the robustness of CRC transcriptional signatures, including CRIS and CMS, using a range of tumour sampling methodologies currently employed in clinical and translational research. These include analyses using (i) laser-capture microdissected CRC tissue, (ii) eight publically available rectal cancer biopsy data sets (n=543), (iii) serial biopsies (from AXEBeam trial, NCT00828672; n=10), (iv) multi-regional biopsies from colon tumours (n=29 biopsies, n=7 tumours) and (v) pre-treatment biopsies from the phase II rectal cancer trial COPERNCIUS (NCT01263171; n=44). Compared to previous results obtained using CRC resection material, we demonstrate that CMS classification in biopsy tissue is significantly less capable of reliably classifying patient subtype (43% unknown in biopsy versus 13% unknown in resections, p=0.0001). In contrast, there was no significant difference in classification rate between biopsies and resections when using the CRIS classifier. Additionally, we demonstrated that CRIS provides significantly better spatially- and temporally- robust classification of molecular subtypes in CRC primary tumour tissue compared to CMS (p= 0.003 and p=0.02, respectively). These findings have potential to inform ongoing biopsy-based patient stratification in CRC, enabling robust and stable assignment of patients into clinically-informative arms of prospective multi-arm, multi-stage clinical trials.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Publisher: Wiley
ISSN: 0022-3417
Funders: CRUK
Date of First Compliant Deposit: 12 February 2018
Date of Acceptance: 1 February 2018
Last Modified: 01 Jul 2019 10:00
URI: http://orca.cf.ac.uk/id/eprint/109024

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