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.
Highlights
Recent studies have defined the molecular taxonomy of colorectal cancer (CRC) by transcriptional, methylation and mutational profiling [1,2,3,4,5], culminating in publication of four consensus molecular subtypes (CMSs) [6], two of which reflect pathological well-defined entities within the tumour microenvironment(TME): CMS1(high immunecell infiltration; better prognosis), CMS4 [7]
We demonstrated an increase in relative classification score for CMS1 and 4 subtypes in invasive front (IF) samples compared to patientmatched central tumour (CT) samples in this laser capture microdissected (LCM) cohort
Using a cohort of patientmatched LCM invasive front and central tumour regions from Colorectal cancer (CRC) resections, we demonstrated that the epithelial-enrichment achieved by LCM is not sufficient to overcome the confounding effect of stromal intratumour heterogeneity
Summary
Recent studies have defined the molecular taxonomy of colorectal cancer (CRC) by transcriptional, methylation and mutational profiling [1,2,3,4,5], culminating in publication of four consensus molecular subtypes (CMSs) [6], two of which reflect pathological well-defined entities within the tumour microenvironment(TME): CMS1(high immunecell infiltration; better prognosis), CMS4 (high relative density of stroma, fibroblasts; poorer prognosis) [7]. The potential clinical utility of both CMS and CRIS molecular subtyping has been extensively validated in CRC resection specimens, and while molecular profiling of surgical resection material is possible in large retrospective studies [1], the suitability of CRC biopsy material for prospective molecular stratification has not been comprehensively assessed. This is increasingly important, given the number of molecularly-guided CRC trials that require profiling of pre-treatment biopsies for patient stratification [12]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
