CK7 and consensus molecular subtypes as major prognosticators in V600EBRAF mutated metastatic colorectal cancer

Abstract

Background V600E BRAF mutated metastatic colorectal cancer (mCRC) is a subtype (10%) with overall poor prognosis, but the clinical experience suggests a great heterogeneity in survival. It is still unexplored the real distribution of traditional and innovative biomarkers among V600E BRAF mutated mCRC and which is their role in the improvement of clinical prediction of survival outcomes. Methods Data and tissue specimens from 155 V600E BRAF mutated mCRC patients treated at eight Italian Units of Oncology were collected. Specimens were analysed by means of immunohistochemistry profiling performed on tissue microarrays. Primary endpoint was overall survival (OS). Results CDX2 loss conferred worse OS (HR = 1.72, 95%CI 1.03–2.86, p = 0.036), as well as high CK7 expression (HR = 2.17, 95%CI 1.10–4.29, p = 0.026). According to Consensus Molecular Subtypes (CMS), CMS1 patients had better OS compared to CMS2-3/CMS4 (HR = 0.37, 95%CI 0.19–0.71, p = 0.003). Samples showing less TILs had worse OS (HR = 1.72, 95%CI 1.16–2.56, p = 0.007). Progression-free survival analyses led to similar results. At multivariate analysis, CK7 and CMS subgrouping retained their significant correlation with OS. Conclusion The present study provides new evidence on how several well-established biomarkers perform in a homogenous V600E BRAF mutated mCRC population, with important and independent information added to standard clinical prognosticators. These data could be useful to inform further translational research, for patients’ stratification in clinical trials and in routine clinical practice to better estimate patients’ prognosis.

CDX2: A Prognostic Marker in Metastatic Colorectal Cancer Defining a Better BRAF Mutated and a Worse KRAS Mutated Subgroup

“…Our study may, at least in part, explain this as it demonstrates that CDX2 expression defines a new prognostic subgroup in patients with BRAFmut (53%) with a much better prognosis, comparable to wild-type patients. We also verify that CDX2 loss is a poor prognostic marker in this subgroup, as demonstrated in a very recently published study (31).…”

The heterogeneous clinical and pathological landscapes of metastatic Braf-mutated colorectal cancer

“…About 45% of CMS1 group, less than 10% of CMS3/CMS4 and less than 5% of CMS2 groups harbor a BRAF mutation, in line with the well-known association between this event and MSI. Of note, our group has recently demonstrated that CMS subgrouping is significantly associated to a prognostic stratification in a large series of Italian BRAFmt mtCRCs [69].…”

BRAF Mutation in Colorectal Cancers: From Prognostic Marker to Targetable Mutation

“…Moreover, the heterogeneity of BRAF-mutated CRCs has been reported in several studies by more practical and easily available methods, such as the immunohistochemistry of clinicopathological features. Several studies have reported the differences among BRAF-mutated CRCs in the methylation phenotype (CIMP-high and CIMP-low), expression of the cytokeratin (CK7 and CK20), the transcription factors (CDX2) and immunohistochemical (IHC)-based CMS classification [198][199][200][201][202]. Furthermore, Loupakis et al suggested a more practical classification method by using data which were easily available in daily practice, such as performance status (PS) and laboratory data only.…”