Microsatellite instability (MSI) has evolved as a marker of potential hereditary cancer risk and is now a tissue agnostic immune biomarker. Advances in immunotherapy and liquid biopsies have ushered in a new era of cancer treatment. In the expanding immunotherapy era of treating cancer, certain cancers can achieve remarkably durable cancer response and control. MSI-high is the first tissue agnostic predictive immune biomarker achieving FDA approval with immune checkpoint blockade therapy extended across multiple cancers irrespective of the anatomical tissue of origin and solely based upon a confirmed MSI-high status tumor biology. 

Advances in technology have now extended the capability of MSI testing to liquid biopsies. Liquid biopsy testing will be able to extend MSI testing and potential durable immunotherapy survival benefits in the future to patients that otherwise have tissue acquisition limitations. Liquid biopsy MSI can overcome the known heterogeneity of metastatic sites and allow treatment to specifically target the more aggressive metastatic clones. The potential utility of MSI-high based immunotherapy is now extending to earlier stages of cancers.

In our experience, liquid biopsy MSI has a higher incidence than tissue MSI in lung cancers and is associated with high tumor mutational burden (TMB) than microsatellite stable (MSS) cancers. Ongoing research of the potential dynamic changes and integration of liquid MSI with TMB, co-mutations, angiogenesis, and other components of an immune hot versus cold tumor microenvironment (TME) is needed to further extend the potential of cancer curability with immunotherapy.