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

Survival of metastatic colorectal cancer (mCRC) patients has improved, but mainly for trial patients. New predictive and prognostic biomarkers validated in the general mCRC population are needed. Caudal-type homeobox 2 (CDX2) is an intestine-specific transcription factor with potential prognostic and predictive effect, but the importance in mCRC has not been fully investigated. Immunohistochemistry analysis of CDX2 was performed in a Scandinavian population-based cohort of mCRC ( = 796). Frequency, clinical and tumor characteristics, response rate, progression-free survival, and overall survival (OS) were estimated. Loss of CDX2 expression was found in 87 (19%) of 452 stained cases, in 53% if mutated ( mut) and in 9% if mutated ( mut). CDX2 loss was associated with microsatellite instability, mut, and poor differentiation and inversely associated with mut. Patients with CDX2 loss received less first-line (53 vs. 64%, = 0.050) and second-line (23 vs. 39%, = 0.006) chemotherapy and secondary surgery (1 vs. 9%, = 0.019). Median progression-free survival and OS for patients given first-line combination chemotherapy was 4 and 10 months if CDX2 loss vs. 9 and 24 months if CDX2 expressed ( = 0.001, < 0.001). Immediate progression on first-line combination chemotherapy was seen in 35% of patients with CDX2 loss vs. 10% if CDX2 expressed ( = 0.003). Median OS in patients with mut or mut and CDX2 expressed in tumor (both 21 months) was comparable to wild-type patients (27 months). However, if CDX2 loss, median OS was only 8 and 11 months in mut and mut cases, respectively, and 10 months in double wild-type patients. In multivariate analysis, CDX2 loss (hazard ratio: 1.50, = 0.027) and mut (hazard ratio: 1.62, = 0.012) were independent poor prognostic markers for OS. In a population-based cohort of mCRC patients, CDX2 loss is an independent poor prognostic marker. Expression of CDX2 defines a new subgroup of mut cases with a much better prognosis. Loss of CDX2 defines a small group of mut cases with a worse prognosis. Patients with CDX2 loss receive less palliative chemotherapy with less benefit and rarely reach secondary surgery.