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Exploratory Analysis of FIRE-3 According CRC Consensus Molecular Subgroups

Molecular classification provides deeper insights into biology of colorectal cancer, but at present time with no impact on clinical decision-making
21 Nov 2019
Gastrointestinal cancers;  Translational research

Consensus molecular subgroups (CMS) classification is prognostic for metastatic colorectal cancer (mCRC). Prolonged overall survival (OS) induced by FOLFIRI plus cetuximab vs FOLFIRI plus bevacizumab in the FIRE-3 study appears to be driven by CMS3 and CMS4. The CMS classification provides deeper insights into biology of CRC, but at present time it has no direct impact on clinical decision-making concluded Prof. Sebastian Stintzing of the Charité Universitaetsmedizin Berlin, Berlin, Germany and colleagues on the basis of retrospective, exploratory analysis of data published on 14 November 2019 in the Annals of Oncology.

  • CMS based on gene-expression analysis have gained attention since being published by Guinney and colleagues1. By using gene-expression data from 6 different cohorts, 4 different types of CRC have been defined:
  • CMS1 defined by an upregulation of immune genes is highly associated with microsatellite instability (MSI-h).
  • CMS2 reflects the canonical pathway of carcinogenesis as defined by the adenoma-carcinoma sequence. Genetically chromosomal instable tumours are associated with mutations in APC, p53, and RAS. Overall, CMS2 represents an overactivated epithelial growth factor (EGF) pathway with higher expression of the EGFR and the EGFR-ligands amphiregulin and epiregulin as far as HER2 overexpression.
  • CMS3 is defined by metabolic dysregulation with higher activity in glutaminolysis and lipidogenesis.
  • CMS4 is defined by an activated TGF-ß pathway and by epithelial-mesenchymal transition making it in general more chemo-resistant.

The study team explained that previously the data have been derived most from the stage II and III samples which showed a strong prognostic effect of the 4 CMS subgroups for both, disease-free survival and OS. The prognostic relevance of CMS in stage IV disease has remained uncertain, as well as its possible predictive effect for the use of EGFR-antibodies or VEGF-A antibodies.

The aims of the retrospective, exploratory analyses of data from the FIRE-3 study were:

i) Can the prognostic value of the CMS classification be validated in mCRC?

ii) Is there a predictive value for the use of the CMS classification for either bevacizumab or cetuximab in the treatment of mCRC?

iii) Do RAS mutated tumours show a different pattern of CMS distribution when compared to RAS wild-type tumours?

iv) Are there differences in right- versus left-sided tumours with regard to data on CMS classification?

FIRE-3 compared first-line therapy with FOLFIRI plus either cetuximab or bevacizumab in 592 KRAS exon 2 wild-type mCRC patients. CMS classification could be determined in 438 out of 514 specimens available from the intent-to-treat population (n = 592). Frequencies for the remaining 438 samples were: CMS1 (14%), CMS2 (37%), CMS3 (15%), CMS4 (34%).

For the 315 RAS wild-type tumours, frequencies were: CMS1 (12%), CMS2 (41%), CMS3 (11%), CMS4 (34%). CMS distribution in right- versus (vs) left-sided primary tumours was: CMS1 (27% vs 11%), CMS2 (28% vs 45%), CMS3 (10% vs 12%), CMS4 (35% vs 32%).

Independent of the treatment, CMS was a strong prognostic factor for overall response rate (ORR) (p = 0.051), progression-free survival (PFS, p < 0.001) and OS (p < 0.001). Within the RAS wild-type population, OS observed in CMS4 significantly favoured FOLFIRI cetuximab over FOLFIRI bevacizumab. In CMS3, OS showed a trend in favour of the cetuximab arm, while OS was comparable in CMS1 and CMS2, independent of targeted therapy.

The authors concluded that CMS classification within the FIRE-3 study could be confirmed as of significant prognostic value. It was also predictive for outcome in CMS4, favouring FOLFIRI plus cetuximab in RAS wild-type tumours. Although a significantly higher ORR was seen in CMS2 for FOLFIRI plus cetuximab, it did not translate into a difference in PFS or OS when compared to the bevacizumab arm. However, from a clinical standpoint, CMS appear not to be of superior value regarding selection of patients optimally treated with either anti-EGFR or anti-VEGF agents. Taken together, the authors concluded that CMS classification at present time has no impact on clinical decision-making.

Funding for the clinical study came from Merck KGaA, Darmstadt, Germany and Pfizer GmbH, Germany. Funding for the transcriptome-based microarray for gene-expression using Xcel® Array came from ALMAC Ltd, Belfast, UK. Funding for FoundationOne® based sequencing analysis (MSI) was obtained from Roche Pharma AG, Grenzach, Germany.


1Guinney J, et al. Nat Med 2015; 21: 1350-1356.


Stintzing S, Wirapati P, Lenz H-J, et al. Consensus molecular subgroups (CMS) of colorectal cancer (CRC) and 1st-line efficacy of FOLFIRI plus cetuximab or bevacizumab in the FIRE3 (AIO KRK-0306) trial. Annals of Oncology; Published online 14 November 2014. DOI: https://doi.org/10.1093/annonc/mdz387

Last update: 21 Nov 2019

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