Antonia Sepulveda, MD, PhD
The FDA’s recent approval of 2 immunotherapies for the treatment of certain patients with tumors that exhibit microsatellite instability (MSI) has propelled the emerging biomarker into clinical practice, prompting calls for broader genetic testing. The body of research into the optimal use of MSI testing is growing, and clinicians will no doubt encounter evolving data about its clinical utility.
In May, the FDA granted accelerated approval for pembrolizumab (Keytruda) for the treatment of adult and pediatric patients with unresectable or metastatic MSI-H or deficient mismatch repair (dMMR) refractory solid tumors for whom there are no alternative treatment options, and for patients with MSI-H or dMMR colorectal cancer (CRC) who are resistant to fluoropyrimidine, oxaliplatin, and irinotecan. In August, nivolumab (Opdivo) gained an accelerated approval for adult and pediatric patients with MSI-H or dMMR metastatic CRC (mCRC) that has progressed after standard chemotherapy.
Microsatellites, or tandem repeats of short DNA sequences, are abundant throughout the genome.1
Tumors can develop along the MSI pathway, which is driven by a defective MMR mechanism, explained Zsofia K. Stadler, MD, a medical oncologist at Memorial Sloan Kettering Cancer Center (MSK) in New York City. “Their DNA is mismatched but it is not fixed,” she said in an interview with OncologyLive®
. “Therefore, throughout the entire tumor genome, you get the introduction of small point mutations within the tumors; these are called microsatellites. These essentially become unstable in these tumors, which is MSI.”
Although MSI testing has become an established part of the workup for patients with CRC, researchers are increasingly finding that MSI plays a role in other tumor types. “MSI may occur in a broad spectrum of tumors,” said Antonia R. Sepulveda, MD, PhD, a professor of pathology and cell biology and vice chair for translational research at Columbia University in New York City, in an interview. She noted that, in patients with Lynch syndrome, MSI may be a factor in endometrial, ovarian, skin, brain, and upper gastrointestinal tumors.
“Then there are sporadic types of MSI tumors. In every tumor type, they’re going to be of much lower frequency,” she said. “For example, we’ll find MSI tumors in prostate cancers and bladder cancers, but very infrequently in other cancers, like sarcomas. Nonetheless, especially for patients who might have had other risk factors, like previous therapies and/or enhanced exposure to carcinogens, we’re still not clear about what [the MSI rate] might be. Occasionally in lower frequencies, we might find MSI across the board in most tumors.”
In sporadic cases, MSI is caused by inactivation of MMR genes (eg, MLH1, MSH2, MSH3, MSH6,
) through somatic mutations, with increased cancer risk in individuals with inherited germline mutations (ie, Lynch syndrome).2
Hypermethylation of the MLH1
promoter, epigenetic inactivation of MSH2
, or downregulation of MMR genes by microRNAs can also cause MSI.3-5
When MSI occurs within coding regions, the reading frame can be altered, resulting in functionally impaired proteins.6
Typical tumors may have approximately 100 mutations in the exome; however, MSI-positive CRCs, for example, characteristically have thousands of mutations in the coding regions of tumor cells.7
MSI-positive tumors also have higher numbers of tumor infiltrating lymphocytes (TILs), such as cytotoxic T cells, which is thought to be a result of increased neoantigen production induced by the high mutational load. These neoantigens are recognized as foreign, driving an inflammatory response.8
As a compensatory response to this inflammation, MSI-positive tumors upregulate molecules such as the immune checkpoint protein PD-L1, which allows cells to evade the immune system. A phase I study in treatment-refractory MSI-positive tumors reported responses to a PD-1 blockade with pembrolizumab, demonstrating that reversing this inhibitory pathway leads to durable immune-mediated tumor control by reactivating TILs.9
Measurement and Classification of MSI
MSI can be classified as MSI-high (MSI-H), MSI-low (MSI-L), or microsatellite stable (MSS). Using MSI testing, tumors are identified as MSI-H when 30% or more of the repeats are unstable, as MSI-L if fewer than 30% of the repeats are unstable, and as MSS if no repeats are unstable.10