AUTHOR=Aasebø Kristine , Dragomir Anca , Sundström Magnus , Mezheyeuski Artur , Edqvist Per-Henrik , Eide Geir Egil , Ponten Fredrik , Pfeiffer Per , Glimelius Bengt , Sorbye Halfdan 

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

JOURNAL=Frontiers in Oncology

VOLUME=10

YEAR=2020

URL=https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2020.00008

DOI=10.3389/fonc.2020.00008

ISSN=2234-943X

ABSTRACT=<p><bold>Background:</bold> 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.</p><p><bold>Methods:</bold> Immunohistochemistry analysis of CDX2 was performed in a Scandinavian population-based cohort of mCRC (<italic>n</italic> = 796). Frequency, clinical and tumor characteristics, response rate, progression-free survival, and overall survival (OS) were estimated.</p><p><bold>Results:</bold> Loss of CDX2 expression was found in 87 (19%) of 452 stained cases, in 53% if <italic>BRAF</italic> mutated (<italic>BRAF</italic>mut) and in 9% if <italic>KRAS</italic> mutated (<italic>KRAS</italic>mut). CDX2 loss was associated with microsatellite instability, <italic>BRAF</italic>mut, and poor differentiation and inversely associated with <italic>KRAS</italic>mut. Patients with CDX2 loss received less first-line (53 vs. 64%, <italic>p</italic> = 0.050) and second-line (23 vs. 39%, <italic>p</italic> = 0.006) chemotherapy and secondary surgery (1 vs. 9%, <italic>p</italic> = 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 (<italic>p</italic> = 0.001, <italic>p</italic> &lt; 0.001). Immediate progression on first-line combination chemotherapy was seen in 35% of patients with CDX2 loss vs. 10% if CDX2 expressed (<italic>p</italic> = 0.003). Median OS in patients with <italic>BRAF</italic>mut or <italic>KRAS</italic>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 <italic>BRAF</italic>mut and <italic>KRAS</italic>mut cases, respectively, and 10 months in double wild-type patients. In multivariate analysis, CDX2 loss (hazard ratio: 1.50, <italic>p</italic> = 0.027) and <italic>BRAF</italic>mut (hazard ratio: 1.62, <italic>p</italic> = 0.012) were independent poor prognostic markers for OS.</p><p><bold>Conclusion:</bold> In a population-based cohort of mCRC patients, CDX2 loss is an independent poor prognostic marker. Expression of CDX2 defines a new subgroup of <italic>BRAF</italic>mut cases with a much better prognosis. Loss of CDX2 defines a small group of <italic>KRAS</italic>mut cases with a worse prognosis. Patients with CDX2 loss receive less palliative chemotherapy with less benefit and rarely reach secondary surgery.</p>