Context matters—consensus molecular subtypes of colorectal cancer as biomarkers for clinical trials

Abstract

The Colorectal Cancer Subtyping Consortium identified four gene expression consensus molecular subtypes, CMS1 (immune), CMS2 (canonical), CMS3 (metabolic), and CMS4 (mesenchymal), using multiple microarray or RNA-sequencing datasets of primary tumor samples mainly from early stage colon cancer patients. Consequently, rectal tumors and stage IV tumors (possibly reflective of more aggressive disease) were underrepresented, and no chemo- and/or radiotherapy pretreated samples or metastatic lesions were included. In view of their possible effect on gene expression and consequently subtype classification, sample source and treatments received by the patients before collection must be carefully considered when applying the classifier to new datasets. Recently, several correlative analyses of clinical trials demonstrated the applicability of this classification to the metastatic setting, confirmed the prognostic value of CMS subtypes after relapse and hinted at differential sensitivity to treatments. Here, we discuss why contexts and equivocal factors need to be taken into account when analyzing clinical trial data, including potential selection biases, type of platform, and type of algorithm used for subtype prediction. This perspective article facilitates both our clinical and research understanding of the application of this classifier to expedite subtype-based clinical trials.

Comprehensive review of targeted therapy for colorectal cancer

“…[503][504][505] Data showed that the immune desert CMS2 and CMS3 subtypes responded preferably to anti-EGFR or anti-VEGF therapy, and patients in all four CMS classifications might have different mechanisms of immune evasion, which will enable tailored targeted therapy. 504,506,507 There has been a changing trend from a clonal perspective to a clonal-stromal-immune perspective when CRC colorectal cancer, mCRC metastatic colorectal cancer, DR5 human death receptor 5, TGF transforming growth factor, IGF-1R insulin-like growth factor 1 receptor, HGF hepatocyte growth factor…”

Current challenges in the implementation of precision oncology for the management of metastatic colorectal cancer

“…CMS has emerged as a prognostic or predictive marker of targeted therapy; however, substantial work is required for more robust classification of subtypes across different platforms and diverse clinical settings. 116 Ongoing efforts to share and integrate clinical and genomic data could help in the discovery and validation of new actionable targets. 117 Combinations of target blockades and ICIs could provide potential therapeutic opportunities for mCRC cases lacking druggable targets.…”

Implications for Tumor Microenvironment and Epithelial Crosstalk in the Management of Gastrointestinal Cancers

“…Taken together, these findings demonstrate the potential for immunotherapies and specifically immune checkpoint inhibitors in the treatment of GI cancer. However, advancing the use of immunotherapies in GI cancer will require combination with chemotherapy, as well as identification of susceptible tumors using specific biomarkers (e.g., PD-1 positive/negative, MSI-H/L, and high/ low tumor mutational burdens) and from among the defined tumor subtypes that describe the origin and TME context of disease [41,42].…”