Prognostic Features and Potential for Immune Therapy in Metastatic Mismatch Repair-Deficient Colorectal Cancer: A Retrospective Analysis of a Large Consecutive Population-Based Patient Series

BACKGROUND: Immune checkpoint inhibition therapies have provided remarkable results in numerous metastatic cancers, including mismatch repair-deficient (dMMR) colorectal cancer (CRC). To evaluate the potential for PD-1 blockade therapy in a large population-based cohort, we analyzed the tumor microenvironment and reviewed the clinical data and actualized treatment of all dMMR CRCs in Central Finland province between 2000 and 2015.

MATERIAL AND METHODS: Of 1343 CRC patients, 171 dMMR tumors were identified through immunohistochemical screening. Histological tumor parameters were evaluated from hematoxylin- and eosin-stained whole-slide samples. CD3 and CD8 immunohistochemistry were analyzed to calculate T-cell densities in the tumor center and invasive margin, and G-cross function values to estimate cancer cell-T-cell co-localization. Multiplex immunohistochemistry was used to identify CD68+PD-L1+ and CD3+PD-1+ immune cells and PD-L1 expression on tumor cells.

RESULTS: A total of 35 (20%) patients with dMMR tumors were diagnosed as having a metastatic disease. Twelve patients (34%) were fit enough to be offered oncological treatments at the onset of non-curable metastatic disease. High proportions of necrosis and stroma were common in metastatic tumors and were associated with worse survival. Crohn's-like reaction, T-cell proximity score, and CD68+/PD-L1+ on the tumor center and invasive margin were independent prognostic immune factors.

CONCLUSION: As dMMR CRC patients are generally older, with often significant comorbidities, only a limited portion of patients with metastatic dMMR tumors ended up in oncological treatments. Many of the metastatic tumors presented features that may impair response to PD-1 blockade therapy.