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

Abstract

Colorectal cancer (CRC) biopsies underpin accurate diagnosis, but are also relevant for patient stratification in molecularly‐guided clinical trials. The consensus molecular subtypes (CMSs) and colorectal cancer intrinsic subtypes (CRISs) transcriptional signatures have potential clinical utility for improving prognostic/predictive patient assignment. However, their ability to provide robust classification, particularly in pretreatment 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) pretreatment 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. © 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

Immune status is prognostic for poor survival in colorectal cancer patients and is associated with tumour hypoxia

“…8,9 CRIS classifications offer a more robust measure of describing CRC molecular subtypes compared with CMS, as CRIS transcriptional profiles were developed independent of the tumour stromal content, which can be subject to sampling bias in CMS classifications. 21,22 We demonstrate for the first time that patients who are immune-cold (when defined by lowdensity CD3, CD4 and CD8 IHC expression) are most likely to associate with the poor prognosis of CRIS-B transcriptional profile, whilst no association with any particular CMS profile was identified. Patients with CRIS-B tumours are associated with aggressive disease and TGF-β signalling.…”

Colorectal Cancer: Genetic Abnormalities, Tumor Progression, Tumor Heterogeneity, Clonal Evolution and Tumor-Initiating Cells

“…This issue was systematically analyzed, exploring the impact of the analysis of various regions of the tumor (central tumor, invasive from of the tumor, lymph node metastasis) on the gene expression analysis using the CSM and CRIS classification systems. The classification following the CMS system was tumor-region-dependent, while the CRIS classification was patient-specific and not affected by the region of the tumor analyzed [ 262 , 479 ]. To obviate the limitations of the CMS classification system for the classification of cancer cell lines, organoids and xenografts were derived from colorectal cancers and a CMS classifier (CMS scaller) optimized for preclinical models was developed [ 265 ].…”

ColoType: a forty gene signature for consensus molecular subtyping of colorectal cancer tumors using whole-genome assay or targeted RNA-sequencing

“…Research following the derivation of the CMS subtypes suggested that classification of a tumor into a single subtype may be inappropriate due to intratumoral heterogeneity [37][38][39][40] . Rather than classifying a tumor into a single subtype, it may be more accurate to measure the concentration of a particular cell type throughout a tumor.…”