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

Abstract

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

Keywords: CDX2; caudal type homeobox transcription factor; colorectal cancer; metastatic disease; population based; prognosis; stage 4 colorectal cancer.

Figure 1

Flow chart describing collection of tumor blocks, tissue microarray (TMA), and availability of CDX2 status in a population-based Scandinavian cohort of metastatic colorectal cancer.

Figure 2

Immunohistochemical staining images of caudal-type homeobox 2 (CDX2) on tumor tissue microarray in a population-based Scandinavian cohort of metastatic colorectal cancer patients. (A) Strong staining in all cells. (B) Completely negative staining.

Figure 3

Distribution of different molecular markers in a population-based Scandinavian cohort of metastatic colorectal cancer. (A) Frequency (%) of BRAF, microsatellite instability (MSI), KRAS, and caudal-type homeobox 2 (CDX2) status and their interrelations. (B) Frequency (%) of BRAF, MSI-H, and KRAS mutations in tumors with CDX2 loss and CDX2 expression. (C) BRAF/MSI subgroups in tumors with CDX2 loss and CDX2 expression. KRASmut, KRAS mutation; BRAFmut, BRAF mutation; MSI-H, microsatellite instable high; MSS, microsatellite stable; double wild type, wild-type KRAS and BRAF; CDX2–, CDX2 loss; CDX2+, CDX2 expression.

Figure 4

Median overall survival (OS) and progression-free survival (PFS) in a population-based Scandinavian cohort of metastatic colorectal cancer according to tumor molecular alterations. Kaplan–Meier curves were calculated with log-rank test for p value and univariate Cox regression for HR and 95% CI. (A) Median OS for all patients according to CDX2 status. (B) Median OS according to CDX2 status for patients given first-line combination chemotherapy. (C) Median PFS according to CDX2 status for patients given first-line combination chemotherapy. (D) Median OS according to tumor molecular alterations in patients given first-line combination chemotherapy: double wild type 26 months (n = 88, e = 80), KRASmut/CDX2 expressed 21 months (n = 82, e = 77), BRAFmut/CDX2 expressed 21 months (n = 21, e = 20), KRASmut/CDX2 loss 11 months (n = 4, e = 4), BRAFmut/CDX2 loss 8 months (n = 18, e = 18). (E) Median PFS according to tumor molecular alterations in patients given first-line combination chemotherapy: double wild type 10 months (n = 88, e = 85), KRASmut/CDX2 expressed 8 months (n = 83, e = 78), BRAFmut/CDX2 expressed 9 months (n = 21, e = 20), KRASmut/CDX2 loss 2 months (n = 4, e = 4), BRAFmut/CDX2 loss 4 months (n = 18, e = 18). n, number; e, events; double wild type: KRAS and BRAF wild type; BRAFmut, BRAF mutation; KRASmut, KRAS mutation; HR, hazard ratio; CI, confidence interval; CDX2–, CDX2 loss; CDX2+, CDX2 expression.

Figure 5

Median overall survival (OS), progression-free survival (PFS), and response rate if given first-line mono- or combination chemotherapy according to tumor CDX2 status in a population-based Scandinavian cohort of metastatic colorectal cancer. Kaplan–Meier curves were calculated with log-rank test for p-value and univariate Cox regression for HR and 95% CI. (A) Median OS in patients with CDX2 loss. (B) Median OS in patients with CDX2 expressed. (C) Median PFS in patients with CDX2 loss. (D) Median PFS in patients with CDX2 expressed. (E) Response rate (%) after first-line combination chemotherapy according to CDX2 status. n, number; e, events; HR, hazard ratio; CI, confidence interval; CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease.