Molecular Testing Is Key in Understanding MSI-H Colorectal Cancer

In recent years, next-generation sequencing has allowed physicians and researchers alike to gather more genetic data for patients with gastrointestinal cancers. And while this kind of profiling continues to advance, so do treatment options for this patient population.

According to John L. Marshall, M.D., chief of the Division of Hematology/Oncology at MedStar Georgetown University Hospital, there are two genetic factors for patients with advanced colorectal cancer (CRC) and their physicians to look out for — if the tumor is microsatellite instability-high (MSI-H) and/or PD-L1 positive.

“When you are making a decision for patients with metastatic CRC, depending on the location of the tumor, you may have to know the molecular testing results,” said Marshall, who is also a professor of Medicine and Oncology at Lombardi Comprehensive Cancer Center and director of the Otto J. Reusch Center for the Cure of Gastrointestinal cancer. “Now, the minority are going to be MSI-high, but you want to know because it could change your thinking about everything.

There are currently two PD-1 inhibitors — Keytruda (pembrolizumab) and Opdivo (nivolumab) – that are FDA-approved for patients with MSI-H or mismatch repair deficient CRC whose disease has progressed on a fluropyrimidine, oxaliplatin and irinotecan regimen.

With potential misconceptions of what “immune therapy” means, Marshall explained what checkpoint inhibition is, and how it works.

“The breakthrough has been this thing called checkpoint inhibition and, in that situation, the immune system is all ready, charged and ready to go, but the tumor is preventing it from being attacked,” he said. “All these drugs do is take that force field out so that the immune system can go in and do its thing.”

However, this strategy will not work for every single patient. If that immune system “force field” is not existent, then these agents will not work. In fact, recent research found that giving PD-1 inhibitors to the wrong patient could actually speed up the growth of the tumors.

This loops back to the importance of knowing a patient’s PD-L1 or MSI-H status, according to Marshall.

“I would argue that for all our patients with metastatic disease, we need to know the MSI status. For some of our patients, such as those with gastric cancer, we need to know PD-L1, too. And, you need to be doing these tests in almost everyone,” he said. “If a patient is positive for any of these things, immune therapies have profound positive effects and we are all chasing this.”

As molecular sequencing becomes more common in CRC, it is crucial to establish a better understanding of how the results can impact treatment decisions.

“I will challenge that most oncologists, including me, don’t really understand all the molecular testing that is going on to pick which [patient] needs the treatment and which one doesn’t. I would argue that for all our patients with metastatic disease, we need to know the MSI status,” Marshall said.