Microsatellite Instability Potential Biomarker for Pembrolizumab Benefit in CRC

Zsofia K. Stadler, MD

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,Targeted Oncologyspoke 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.

TARGETED ONCOLOGY:What are MSI tumors and how can they be screened for?

Stadler: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%.

TARGETED ONCOLOGY:How do you determine which patients need screening?

Stadler: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.

The current NCCN guidelines say to either test all new patients with CRC for MMR deficiency, or test all patients under the age of 70 with CRC for MMR deficiency plus patients over the age of 70 who have a family history of Lynch syndrome—associated cancers. The latter is what we are doing at our current institution.

Usually the testing is done through IHC and you identify patients who have MMR deficiency and certain patterns, including MSH2 and MSH6 protein loss. The expansion of the MMR-deficiency testing for Lynch syndrome came at the same time that we began to recognize that MMR deficiency is also important as a prognostic and predictive marker in early stage CRC. In fact, MMR deficiency testing is recommended for all patients with stage II CRC.

TARGETED ONCOLOGY:What is the role of MSI in CRC?

Stadler:The role of MSI in CRC is recognition of Lynch syndrome and for cancer prevention. Once MMR deficiency is detected, we test for other markers such as BRAF V600E mutation or MLH1-high permethylation. The presence of these markers would suggest that the tumor is a sporadic MMR-deficient tumor.

However, in other cases, the BRAF V600E mutation is not there. Or, if there is a lack of MLH1-high permethylation, we would think about it being a germline or an inherited defective MMR tumor. In those patients, we refer them to genetic counseling. This algorithm needs to be in place to try and identify which patients are actually at risk for Lynch syndrome.

In addition, it appears that stage II patients with MMR deficiency have a much better prognosis than patients with MMR-intact tumors. This has been replicated in many different large studies and meta-analyses. Moreover, not only do they have a better prognosis, but they also appear to have less benefit from 5-FU—based chemotherapy. The chemotherapy is just not as effective in the MMR-deficient population.

This becomes very important. Because they have an excellent prognosis and chemotherapy is not as effective in that tumor, we do not recommend adjuvant chemotherapy for stage II MMR-deficient tumors. In the stage III setting, there also seems to be a signal for a better prognosis in the MMR-deficient versus MMR-proficient tumors; however, the improvement in prognosis seems to be much less or attenuated compared to stage II patients.

To date, there is no evidence that suggests that treatment of MMR-deficient stage III patients should be different from the MMR-intact population. In stage III patients, the general recommendation is to treat it as you would for MMR-intact patients with a FOLFOX or CAPOX regimen.

In addition, data by Dr Dung Le, suggest that MMR-deficient CRC tumors are also ones that respond to immunotherapy. Her work demonstrates that it is only the defective MMR tumors, whether that is in the colon or perhaps another primary source, that responds to PD-1 immunotherapy.

TARGETED ONCOLOGY:What are the screening recommendations for Lynch syndrome patients?

Stadler:For patients who are diagnosed with Lynch syndrome, it is important to recognize that they are at higher risk of a second CRC—as much as 16% to 30% risk within 10 to 15 years after diagnosis. Therefore, it is very important to appropriately screen these patients going forward with colonoscopies, which are recommended every 1 to 2 years in these patients.

In addition, women with CRC are also at a risk for endometrial cancer and ovarian cancer; therefore, at the completion of childbearing and, even prior to that, we usually recommend annual endometrial biopsies as well as transvaginal ultrasounds to screen for these gynecologic malignancies within this high-risk population.

Other malignancies associated with Lynch syndrome include gastric cancer, pancreatic cancer, and small bowel cancer. What is interesting from Dr Le’s data is that probably some of these patients, who also have this defective MMR, may benefit from immunotherapy.

TARGETED ONCOLOGY:How is immunotherapy currently incorporated in the treatment paradigm for CRC?

Stadler:Currently, immunotherapy is only available in the setting of clinical trials. Certainly, in our stage IV patients who are recognized as being MMR deficient, consideration of participation of any trial using immunotherapy is very reasonable.