Beyond MSI: Expanding the Reach of Immunotherapy in Colorectal Cancer

Approximately 15 percent of all colorectal cancers (CRCs) are genetically defined as microsatellite instability (MSI) high.¹ This means that the DNA repair mechanisms in the tumor cells are faulty, and as a result, they can acquire a significant number of mutations that can make them easily recognizable by the immune system, potentially making these tumors good candidates for immunotherapy. Indeed, the data we've seen so far show that using MSI as a biomarker could help identify people more likely to respond to checkpoint inhibitor immunotherapy, but questions remain regarding the other 85 percent of CRC patients with microsatellite stable disease. Recently published data suggest that MSI-high is only one hallmark among many in hyper mutant tumors. So how do we find these remaining potential responders? In CRC, another biomarker offers a more comprehensive solution.

Tumor mutational burden (TMB) is a quantitative genomic biomarker that has been shown to help predict response to immunotherapy across a number of different cancer types, and could complement the clinical sensitivity of MSI for determining likely responders. With our collaborators, we recently published a new study evaluating the largest number of CRC tumor samples with a validated TMB assay published to date, and found that TMB can be used to identify nearly all MSI-high cases, while also identifying an additional subset of microsatellite stable CRC patients that might benefit from cancer immunotherapy.

Results from over 6,000 CRC patients showed that a TMB score of 12 mut/Mb could effectively identify nearly all MSI-high cases, while also including an additional 3 percent of the much larger microsatellite stable population. These data suggest that the number of total CRC cases that could benefit from immunotherapy could potentially be significantly expanded if TMB was used to make immunotherapy treatment related decisions, rather than MSI status alone.

Read our paper to learn more: bit.ly/2MHtuiW