Association of CDX2 expression with clinical, pathologic, and molecular features in MSI-H colorectal cancer.
Authors: Gonzalez Cyndi , Neyaz Azfar , Layding Caroline Jane , Ferrell Morgan , Giza Richard , Cheng Svea , Syed Masood Pasha , Magge Tara , Saeed Anwaar , Tatsuoka Curtis , Singhi Aatur D. , Sahin Ibrahim Halil Halil 
Published: June 2024

e15583

Background: Microsatellite unstable (MSI) colorectal cancers (CRCs) are due to DNA mismatch repair (MMR) deficiency and are seen in 15% of early stage and 5% of metastatic disease. CRC with the MMR-D/MSI-H phenotype carries unique characteristics that are associated with increase mutational burden. Specifically, loss of CDX2 expression is associated with aggressive carcinomas and correlates with worse disease-free survival in the general population. However, the impact of loss of CDX2 expression in MMR-D/MSI-H phenotype is not well known. In this study, we investigated the association of loss of CDX2 expression with clinical and pathological outcomes. Methods: We retrospectively reviewed 543 patients who were diagnosed with colorectal cancer with pathological findings for the presence of MMR-D/MSI-H phenotype, and who had been seen at UPMC Hillman Cancer Center from 2013-2020. CDX2 expression was evaluated across all patients for the association with various molecular, pathological features and survival. In our investigations of association with loss of CDX2, coded as a binary variable in an H score, we used Mann-Whitney or two-sample (Welch’s) t-test for continuous variables, and Chi-square or Fisher’s exact tests for categorical variables. For RFS and OS, we compared H score groups with log-rank tests at two-sided alpha = 0.05 and plotted respective Kaplan-Meier curves. Results: A total of 99 patients were identified with adequate tissue sample to assess for CDX2 expression and with consistent clinical follow-up from date of diagnosis to present. When examining loss of CDX2 expression and association with pathological factors, we observed a significant association with a higher T4 stage (43% vs 14%; p = 0.008), and high grade tumor (86% vs 22%; p = 1.086 x 10-8 ) as well as presence of PNI (peri-neural invasion) (36% vs 17%; p = 0.030). There was no association observed between CDX2 expression and N stage or location of tumor. When examining loss of CDX2 expression and association with molecular factors, we observed that patients with Lynch syndrome were more likely to preserve CDX2 expression (0% vs 27%; p = 0.001) while patients with BRAF mutation were more likely to present with loss of CDX2 expression. Finally, patients with loss of CDX2 expression had numerically lower median survival (8.2 years vs. 9.3 years) though this did not reach statistical significance (p = 0.120). Conclusions: Overall, loss of CDX2 expression correlates with worse pathological features as it was significantly seen in patients with a diagnosis of CRC at a higher T stage, grade, presence of PNI and presence of BRAF mutation. Although no significant association was observed in terms of survival outcomes due to likely insufficient power, a notable separation of survival curves was noted, which indicates overall lower survival.