Zsofia K. Stadler, MD
Screening for microsatellite instability (MSI) in patients with colorectal cancer (CRC) tumors is a significant step in determining which patients will benefit from immunotherapy, specifically pembrolizumab (Keytruda).
In November 2015, pembrolizumab was granted a breakthrough therapy designation by the FDA as a potential therapy for patients with MSI-high metastatic CRC.
The decision was based on results from an ongoing phase II study,1,2
in which pembrolizumab demonstrated high response rates in heavily pretreated patients with CRC who had mismatch repair (MMR) deficiency, a condition that causes MSI.
Results showed that the objective response rate was 62% with pembrolizumab in MMR-deficient CRC tumors compared with 0% in MMR-proficient tumors. Additionally, the median progression-free survival and overall survival were not reached, with many patients responding to treatment for longer than 12 months in the MMR-deficient arm.
Defects in MMR commonly lead to MSI, which can be found in most cancers, including a majority of patients with hereditary nonpolyposis CRC—otherwise known as Lynch syndrome. Without this repair mechanism, the mutational burden is generally higher, suggesting a higher likelihood of developing cancer. In total, more than 80% of patients in the MMR-deficient arm were positive for Lynch syndrome.
To provide extensive insight on MSI in CRC, OncLive
spoke with Zsofia K. Stadler, MD, a medical oncologist at Memorial Sloan Kettering Cancer Center. Stadler shared insight on the biology of and screening for MSI tumors, as well as the potential impact immunotherapy could have on the treatment paradigm for CRC.
OncLive: What are MSI tumors and how can they be screened for?
: We know that the vast majority of CRCs develop along a chromosomal instability pathway where the tumors gain large genomic alterations. Approximately 15% to 17% of all CRCs develop along a different pathway called the microsatellite instability pathway. This pathway is driven by a defective MMR mechanism; their DNA is mismatched but it is not fixed.
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.
There are different ways of testing for MSI or defective MMR. For MSI testing, we usually use a pathologic complete response (pCR)¬–based assay that looks for 5 different markers of microsatellite. If 2 or more microsatellites are unstable, the tumor is designated as MSI. If it is less than that, then it is designated as a microsatellite stable tumor.
Another way of screening for MSI is more of a direct approach, where you actually test for MMR deficiency. That is done through IHC staining for mismatch repair proteins.
If the presence for all of these proteins is seen within the tumor, then a patient has an intact mismatch repair process. If there is absence of MLH1, MSH2, MSH6, or PMS2, then the tumor is actually defective—it’s in mismatch repair. What is important is to recognize that both pCR-based screening and IHC screening are ways of screening for the same thing. However, IHC testing for the proteins’ presence and MSI staining is actually looking at the DNA itself.
The good thing about these 2 ways of screening is it has very high concordance. The concordance between these 2 tests is about 92% to 97%.
How do you determine which patients need screening?
Traditionally, the main reason to screen for defective mismatch repair was to look for Lynch syndrome, which is an autosomal dominant inherited cancer—a predisposition syndrome that accounts for about 3% of all CRCs. Though that seems like a small number, we know that patients with Lynch syndrome often have large families who could also be at risk for Lynch syndrome.
Recognizing Lynch syndrome is important, not just for the patient with CRC, but also for family members—so they can undergo genetic testing, counseling, and subsequently receive the screening information they may need.
Traditionally, we used to screen only for MMR deficiency in patients who met clinical criteria. Initially, we used the Amsterdam criteria, then the revised Bethesda criteria. However, we have come to recognize that those ways of assessing clinical criteria is not particularly efficient.
Therefore, what has been proposed is a more universal and expansive testing for the defective MMR in order to diagnose a larger number of Lynch syndrome patients who may need additional cancer surveillance and whose families may need to undergo genetic testing.