Genetic Markers Can Help Predict CRC Outcomes

The identification of microsatellite status, tumor mutational burden and protein expression in colorectal cancer (CRC) tumors may lead to better outcomes in a subgroup of patients, according to a study recently presented at the 2018 Gastrointestinal Cancers Symposium.

“Comprehensive molecular profiling of CRC can inform treatment decisions by identifying patient subgroups at varying risks of death,” the authors wrote.

For example, patients with microsatellite instability (MSI) tumors are likely to respond to immunotherapy treatment, while high tumor mutational burden (TMB) points toward genomic instability and is currently used as a prognostic factor in melanoma. Also, the p16 protein is prognostic in many tumor types.

The researchers used mass spectrometry-based proteomics and genomic profiling to gather 145 clinical samples of colorectal cancer to determine which measures from comprehensive molecular profiling could be associated with survival. Patients were grouped by microsatellite status (MSI vs. microsatellite stable), TMB (high vs. low) and p16 protein expression level.

Thirty-nine samples (27 percent) had high TMB, meaning that their cancer tumor cells had a high number of genetic mutations.

Twentiy-nine samples (20 percent) had MSI status. MSI occurs when mismatch repair (MMR) fails to fix an error or errors in protein creation during DNA replication. The mistake then continues to be reproduced, MSI-high (MSI-H).

While MSI and MSI-H can make a person more prone to getting colorectal cancer in the first place, the good news is that the mutation may expand their treatment options and chances of having better responses.

In fact, two immunotherapy agents — Opdivo (nivolumab) and Keytruda (pembrolizumab) – are specifically approved by the Food and Drug Administration (FDA) to treat patients with MSI-H or MMR deficiency who progressed on fluropyrimidine, oxaliplatin and irinotecan.

The study findings reported that patients with MSI tumors had longer overall survival (OS) than those with microsatellite stable tumors. Similarly, patients with high TMB had longer OS than those with low TMB. The prognoses were poorer for those that had high p16 expression.

However, among patients with microsatellite stable tumors or low TMB, those with low p16 levels had longer survival outcomes than those with high p16 expression.

The researchers also noted there was a combination between microsatellite stable tumors, low TMB and low p16 levels that showed different outcomes between long- and short-term survival intervals. “A combination of microsatellite stability, low TMB and low p16 expression characterized a subset of patients with longer survival,” they wrote.

Overall, these results point toward a potential benefit this subgroup of patients can find when treated with personalized therapy.

“This is important because patients with microsatellite stable tumors have limited treatment options but may respond to CDK4/6 inhibitors due to low p16 expression,” the authors wrote. “Molecular profiling of CRC may identify patient subgroups with a relatively poor prognosis who could benefit from personalized therapy.”