Investigating the concordance in molecular subtypes of primary colorectal tumors and their matched synchronous liver metastasis

To date, no systematic analyses are available assessing concordance of molecular classifications between primary tumors (PT) and matched liver metastases (LM) of metastatic colorectal cancer (mCRC). We investigated concordance between PT and LM for four clinically relevant CRC gene signatures. Twenty‐seven fresh and 55 formalin‐fixed paraffin‐embedded pairs of PT and synchronous LM of untreated mCRC patients were retrospectively collected and classified according to the MSI‐like, BRAF‐like, TGFB activated‐like and the Consensus Molecular Subtypes (CMS) classification. We investigated classification concordance between PT and LM and association of TGFBa‐like and CMS classification with overall survival. Fifty‐one successfully profiled matched pairs were used for analyses. PT and matched LM were highly concordant in terms of BRAF‐like and MSI‐like signatures, (90.2% and 98% concordance, respectively). In contrast, 40% to 70% of PT that were classified as mesenchymal‐like, based on the CMS and the TGFBa‐like signature, respectively, lost this phenotype in their matched LM (60.8% and 76.5% concordance, respectively). This molecular switch was independent of the microenvironment composition. In addition, the significant change in subtypes was observed also by using methods developed to detect cancer cell‐intrinsic subtypes. More importantly, the molecular switch did not influence the survival. PT classified as mesenchymal had worse survival as compared to nonmesenchymal PT (CMS4 vs CMS2, hazard ratio [HR] = 5.2, 95% CI = 1.5‐18.5, P = .0048; TGFBa‐like vs TGFBi‐like, HR = 2.5, 95% CI = 1.1‐5.6, P = .028). The same was not true for LM. Our study highlights that the origin of the tissue may have major consequences for precision medicine in mCRC. What's new? No systematic analyses have assessed concordance of molecular classifications between primary tumors and matched liver metastases in metastatic colorectal cancer (mCRC). Here, the authors show that 40% to 70% of primary colon tumors cease to exhibit an epithelial‐to‐mesenchymal transition phenotype (EMT) at the transcription level in their matched liver metastasis (LM). While EMT‐positive PT show worse outcome compared to EMT‐negative PT, this is not true for LM. The data argue in favor of using the primary tumor for molecular analysis rather than distant metastases. Overall, this study highlights that tissue origin may have major consequences for precision medicine in mCRC.