Intraindividual Tumor Heterogeneity of Mismatch Repair Status in Metastatic Colorectal Cancer

Abstract

Heterogeneous mismatch repair (MMR) status in metastatic colorectal cancer (mCRC) may associate with refractoriness to immunotherapy. We aimed here to study the concordance in MMR status between primary and paired metastasis in mCRC. Our study included 84 patients diagnosed with mCRC with primary and matched metastatic cancers. Immunohistochemistry was used to determine the MMR status of primary lesions and matched metastases. Pooled analysis of 913 cases was used to evaluate the prevalence and organ specificity of MMR status heterogeneity. The correlations between MMR pattern heterogeneity and clinical outcomes were analyzed. MMR status heterogeneity between primary and corresponding metastatic sites was exhibited by 10 (11.9%) patients. The prevalence of the heterogeneous MMR phenotype was significantly higher in primary tumors with deficient MMR (dMMR) than with proficient MMR (pMMR), which was verified in the pooled analysis ( P <0.001). Among patients with a dMMR primary tumor, the discrepancy was detected in liver, lung, ovary, peritoneum, and distant lymph node metastases. However, the discrepancy was confined to liver (26/440) or peritoneum (7/112) ( P =0.02) in patients with a pMMR primary tumor. Patients with or without MMR status heterogeneity experienced comparable overall survival ( P =0.452). Heterogeneous MMR patterns generally existed in a subset of patients with mCRC, particularly those with dMMR primary tumors. Testing the metastatic site may be valuable because the discordance of MMR status may potentially affect immune surveillance and immunotherapy.

Molecular subtyping in colorectal cancer: A bridge to personalized therapy (Review)

“…After assessing the MMR status of mCRC, fewer patients with mCRC showed heterogeneity of MMR status between the primary and corresponding metastatic sites (11.9 and 18.7%, respectively), among which patients with peritoneal metastasis tended to exhibit this feature. Furthermore, the prevalence of heterogeneous MMR phenotypes in primary tumors with dMMR was significantly higher than that with pMMR (P<0.001) (74,75). However, it is noteworthy that various factors, such as the expertise of the pathologists, the quality of the tumor tissue sampling and staining can contribute to these discrepancies.…”