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MSI Testing
Testing for Microsatellite Instability in the Era of Immune Checkpoint Inhibitors

Released: July 11, 2017

Expiration: July 10, 2018

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In my discussion of this case study plus recent clinical data and approvals, I will explain why every patient with metastatic colorectal cancer (CRC) should have molecular testing for microsatellite instability (MSI). My patient was a 62-year-old man diagnosed approximately 5 years ago with stage III colon cancer, which was treated with adjuvant FOLFOX followed by monitoring. Approximately 2.5 years later, he developed metastatic disease with wild-type RAS and wild-type BRAF and received chemotherapy with FOLFIRI plus bevacizumab. However, we realized then that he had never had MSI testing of a biopsy sample to determine his eligibility for immunotherapy.

We sent the tissue from the patient’s original biopsy for MSI analysis, which indeed came back MSI high. Although we initially considered clinical trials, by the time we got his results, we were able to treat him off study with the anti–PD-1 antibody pembrolizumab as this immune-checkpoint inhibitor received FDA approval for the treatment of metastatic CRC previously treated with a fluoropyrimidine, oxaliplatin, and irinotecan. I am happy to say he responded very well with minimal toxicity.

Testing for MSI
This case highlights the need for MSI testing, which has gained importance since the FDA also approved pembrolizumab for any patient with an unresectable or metastatic solid tumor that is mismatch repair (MMR) deficient/MSI high who has progressed on previous treatment and for whom there is no satisfactory alternative treatment option. This landmark approval is the first ever tissue/site-agnostic indication for an anticancer therapy based solely on molecular characteristics. MSI-high/MMR-deficient solid tumors are usually immunogenic and have extensive T-cell infiltration, thereby rendering them responsive to immune checkpoint inhibitor therapy. MSI testing is further supported by updated results presented at ASCO 2017 for clinical trials evaluating pembrolizumab or the anti–PD-1 antibody nivolumab in combination with anti–CTLA-4 antibody ipilimumab in MSI-high patients. A high clinical benefit rate of 50% to 80% was sustained on updated analysis, even in highly refractory disease.

An unprecedented aspect of the FDA’s decision was that there was no official companion diagnostic. I suspect that the FDA did not mandate a diagnostic because there is no consensus yet on the best testing method. The most common test is to do IHC for 4 key proteins (MLH1, MSH2, MSH6, PMS2); if all proteins are present, then the tumor is microsatellite stable. If even 1 protein is absent, then the tumor may be microsatellite unstable. Other tests include a fragment analysis of the genes encoding these 4 proteins, as well as next-generation sequencing.

Of importance, MSI status does not guarantee that checkpoint inhibitors will work but that they have a high probability of efficacy. If I did not have biopsy results from a patient who is not responding to therapy, I would not start immune checkpoint inhibitors without first testing for MSI. Fortunately, we are often able to obtain tissue from previous biopsies to perform testing.

Future Directions With Immune Checkpoint Inhibitors in CRC
There are multiple open questions about checkpoint inhibitors in CRC. First, ongoing studies are evaluating whether checkpoint inhibitors should replace first-line chemotherapy in MSI-high metastatic CRC, as well as their role in the adjuvant setting.

A second question is whether there are efficacy differences between patients with somatic vs germline MSI. Although determining if a patient has Lynch syndrome (hereditary nonpolyposis colon cancer) is important for counseling purposes, so far we have been unable to determine if the benefits of immune checkpoint inhibitors differ between patients with germline mutations vs those with somatic mutations.

Conclusion
It is important to underscore that MMR deficiency/MSI high only occurs in approximately 15% of CRC cases. Many of my patients are now asking for immunotherapy; however, most will not have these mutations and are, therefore, unlikely to benefit. As clinicians, we have to manage our enthusiasm for new therapeutic options. However, given the new indication for pembrolizumab and updated clinical efficacy data, all patients with cancer, especially all patients with CRC, should be tested for MSI/MMR to determine whether they might benefit from immune checkpoint inhibitors.

Your Thoughts?
How has your management of patients with CRC changed since the new approval for pembrolizumab and updated supportive results from ASCO 2017? Are you more likely to consider immune checkpoint inhibitors in your patients with CRC? Please leave your thoughts below.

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When do you test your patients with CRC for MSI/MMR deficiency?
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