**4.1 Clinical and prognostic associations of the consensus molecular subtypes**

Associations between CMS subgroups and clinical features and prognosis were also investigated and showed that CMS1 tumours were more common in females, more likely to be right-sided and of higher histopathological grade. Conversely, CMS2 tumours were more likely to be left-sided and present at more advanced stages. CMS4 tumours show the worst OS and RFS even after adjustment for BRAF and KRAS mutations and MSI status. CMS1 tumours display good survival but very poor SAR in keeping with known data of MSI tumours associated with BRAFV600E mutations. CMS2 and CMS3 subgroups display intermediate survival, but a superior survival following relapse was noted in the CMS2 subgroup.

Further prognostic associations of the CMS subtypes have been explored via retrospective analysis of large clinical trial datasets, as have their association with biological therapies. 392 KRAS wild-type samples from the CALGB 80405 dataset were analysed via a NanoString platform to determine their CMS subtype classification, and this was correlated with survival [25]. It was found that CMS1 tumours treated with bevacizumab had significantly longer OS compared to those treated with cetuximab. CMS2 tumours treated with bevacizumab had a trend towards shorter OS than those treated with cetuximab. A meta-analysis of six randomised trials, including the CRYSTAL and FIRE-3 datasets, also confirmed the improvement in PFS and OS of left-sided tumours (CMS2) treated with anti-EGFR antibodies compared to no significant benefit for right-sided tumours (CMS1) [26]. No survival differences were found for left- or right-sided tumours treated with bevacizumab. This suggests sidedness of the primary tumour that determines efficacy of biological therapies, and this can possibly be explained by the biological differences of tumours from different sides of the bowel: left-sided tumours overexpress the EGFR ligands amphiregulin (AREG) and epiregulin (EREG) and also display amplifications of markers of cetuximab sensitivity, whereas right-sided tumours show reduced expression of EGFR ligands [27].

#### **4.2 Clinical utility of the consensus molecular subtypes**

Much hope was placed upon the CMS classification system allowing stratification of patients for clinical trials to validate the prognostic and predictive value of the subgroups and enable translation into clinical care. Although CMS classification

**13**

*Advances in Molecular Subclassification of Colorectal Cancer*

prognostic factor over and above CMS subtype [28].

phenotypes and the clinical implications of this.

**5. Conclusions**

**Acknowledgements**

**Conflict of interest**

AA has no conflicts of interest.

has enabled refinement of the large 'non-MSI' group of CRC patients and provided a tool for systemic interrogation, there is some data which suggests that critical clinical information which predicts for outcome is still not distinguishable under this classification system. For example, a separate analysis of the CALGB 80405 dataset identified that sidedness of the primary tumour was still an independent

The association with treatment outcomes of the CMS subtypes, especially in the metastatic setting, still requires further exploration and validation. Kim et al. found that colorectal cancer assigner (CRCA) is subtyping more clearly defined oxaliplatin benefit group than CMS subtyping did prior to their analysis of the NSABP-C07 trial [29]. It is also important to consider the 13% of samples which could not be classified into CMS subtypes and the need to better characterise samples of mixed

The challenge of reproducibility of this classification system which requires complex transcriptomic, proteomic and genomic analyses is also an issue, and its implementation is not feasible in many centres in its current form. There has been some work already undertaken to develop a robust and practical classifier based on immunohistochemistry (IHC) which appears promising but requires prospective validation [30]. All in all, the clinical utility and widespread reproducibility of this classification system in CRC is still to be determined, and it is likely that, with further characterisation, we may see additional subtyping of the four described subtypes in the future.

Much progress has been made in our understanding of the complex underlying biology of CRC which leads to heterogeneous drug responses and outcomes. Comprehensive integrative molecular analysis has led to the identification of molecularly distinct subgroups within this disease, and the consensus molecular subtypes have enabled some refinement of these subgroups. However, widespread reproducibility and confirmation of the clinical utility of CMS classification still need to be addressed. There are vast amounts of data being generated from molecular classification systems, and this needs to be prospectively integrated into clinical trial design in order to confirm biomarkers of resistance and response as well as to allow rational combinations of therapies to be explored. The ultimate goal is to streamline biomarker and drug codevelopment and recruit patients to innovative clinical trials of targeted agents to which they are more likely to respond based on the underlying molecular makeup of their tumours.

The authors would like to acknowledge the National Health Service funding to the National Institute for Health Research Biomedical Research Centre at the Royal

IC sits on the advisory board for Eli Lilly and Company, Bristol-Myers Squibb, MSD, Bayer, Roche, Merck Serono and Five Prime Therapeutics, Inc. He has received research funding from Eli Lilly and Company, Janssen-Cilag, Sanofi Oncology and Merck Serono and has received an honorarium from Eli Lilly and Company.

Marsden NHS Foundation Trust and the Institute of Cancer Research.

*DOI: http://dx.doi.org/10.5772/intechopen.80679*

*Advances in Molecular Subclassification of Colorectal Cancer DOI: http://dx.doi.org/10.5772/intechopen.80679*

has enabled refinement of the large 'non-MSI' group of CRC patients and provided a tool for systemic interrogation, there is some data which suggests that critical clinical information which predicts for outcome is still not distinguishable under this classification system. For example, a separate analysis of the CALGB 80405 dataset identified that sidedness of the primary tumour was still an independent prognostic factor over and above CMS subtype [28].

The association with treatment outcomes of the CMS subtypes, especially in the metastatic setting, still requires further exploration and validation. Kim et al. found that colorectal cancer assigner (CRCA) is subtyping more clearly defined oxaliplatin benefit group than CMS subtyping did prior to their analysis of the NSABP-C07 trial [29]. It is also important to consider the 13% of samples which could not be classified into CMS subtypes and the need to better characterise samples of mixed phenotypes and the clinical implications of this.

The challenge of reproducibility of this classification system which requires complex transcriptomic, proteomic and genomic analyses is also an issue, and its implementation is not feasible in many centres in its current form. There has been some work already undertaken to develop a robust and practical classifier based on immunohistochemistry (IHC) which appears promising but requires prospective validation [30].

All in all, the clinical utility and widespread reproducibility of this classification system in CRC is still to be determined, and it is likely that, with further characterisation, we may see additional subtyping of the four described subtypes in the future.
