Immunotherapy for Colorectal Cancer with High Microsatellite Instability: The Ongoing Search for Biomarkers

SIMPLE SUMMARY: Immunotherapy has reshaped the prognosis of several tumor types. In metastatic colorectal cancer, only tumors with microsatellite instability or mismatch repair deficiency achieve profound benefits under immune checkpoint inhibitors. As a result, immunotherapy has moved to the early stage, showing promising results in neoadjuvant settings. However, not all patients respond, and some responses are shortlived, thus highlighting the need for accurate and reliable biomarkers to identify patients who are more likely to achieve clinical benefit, as well as those patients with refractory tumors who will require a different therapeutic approach. Surprisingly, classical biomarkers such as PD-L1 expression or TMB seem to be poorly informative in MSI colorectal cancer. Therefore, the development of novel biomarkers in this population remains an unmet medical need. ABSTRACT: Microsatellite instability (MSI) is a biological condition associated with inflamed tumors, high tumor mutational burden (TMB), and responses to immune checkpoint inhibitors. In colorectal cancer (CRC), MSI tumors are found in 5% of patients in the metastatic setting and 15% in early-stage disease. Following the impressive clinical activity of immune checkpoint inhibitors in the metastatic setting, associated with deep and long-lasting responses, the development of immune checkpoint inhibitors has expanded to early-stage disease. Several phase II trials have demonstrated a high rate of pathological complete responses, with some patients even spared from surgery. However, in both settings, not all patients respond and some responses are short, emphasizing the importance of the ongoing search for accurate biomarkers. While various biomarkers of response have been evaluated in the context of MSI CRC, including B2M and JAK1/2 mutations, TMB, WNT pathway mutations, and Lynch syndrome, with mixed results, liver metastases have been associated with a lack of activity in such strategies. To improve patient selection and treatment outcomes, further research is required to identify additional biomarkers and refine existing ones. This will allow for the development of personalized treatment approaches and the integration of novel therapeutic strategies for MSI CRC patients with liver metastases.