Prognostic, predictive, and pharmacogenomic assessments of CDX 2 refine stratification of colorectal cancer

We aimed to refine the value of CDX 2 as an independent prognostic and predictive biomarker in colorectal cancer ( CRC ) according to disease stage and chemotherapy sensitivity in preclinical models. CDX 2 expression was evaluated in 1045 stage I– IV primary CRC s by gene expression ( n  =   403) or immunohistochemistry ( n  =   642) and in relation to 5‐year relapse‐free survival ( RFS ), overall survival ( OS ), and chemotherapy. Pharmacogenomic associations between CDX 2 expression and 69 chemotherapeutics were assessed by drug screening of 35 CRC cell lines. CDX 2 expression was lost in 11.6% of cases and showed independent poor prognostic value in multivariable models. For individual stages, CDX 2 was prognostic only in stage IV , independent of chemotherapy. Among stage I– III patients not treated in an adjuvant setting, CDX 2 loss was associated with a particularly poor survival in the BRAF ‐mutated subgroup, but prognostic value was independent of microsatellite instability status and the consensus molecular subtypes. In stage III , the 5‐year RFS rate was higher among patients with loss of CDX 2 who received adjuvant chemotherapy than among patients who did not. The CDX 2‐negative cell lines were significantly more sensitive to chemotherapeutics than CDX 2‐positive cells, and the multidrug resistance genes MDR 1 and CFTR were significantly downregulated both in CDX 2‐negative cells and in patient tumors. Loss of CDX 2 in CRC is an adverse prognostic biomarker only in stage IV disease and appears to be associated with benefit from adjuvant chemotherapy in stage III . Early‐stage patients not qualifying for chemotherapy might be reconsidered for such treatment if their tumor has loss of CDX 2 and mutated BRAF .