Immunotherapy Advances for MSI-High Colorectal Cancer: Keytruda and Precision Treatment

Jump To Section

• Why MSI-High Tumors Respond Better to Immunotherapy
• When Chemotherapy Fails for MSI-High Colon Cancer
• Keytruda and Other Immune Checkpoint Inhibitors
• How Colon Cancer Location Predicts MSI Status
• The Future of DNA Methylation and microRNA Testing
• Personalizing Colorectal Cancer Therapy
• Full Transcript

Why MSI-High Tumors Respond Better to Immunotherapy

Dr. C. Richard Boland, MD reveals that colorectal cancers with microsatellite instability (MSI) have two critical characteristics: they often follow a less aggressive course naturally, yet paradoxically resist standard chemotherapy. "These tumors were more likely to survive their tumors but less likely to respond to traditional treatments," explains Dr. Boland. Recent breakthroughs show MSI-high tumors demonstrate dramatic responses to immune checkpoint inhibitors like Keytruda (pembrolizumab), making MSI testing essential before treatment planning.

When Chemotherapy Fails for MSI-High Colon Cancer

Historically, all Stage 3 colorectal cancer patients received chemotherapy despite varying responses. "Most Stage 3 patients didn't get dramatic tumor shrinkage, yet all endured chemotherapy's toxicity," notes Dr. C. Richard Boland, MD. MSI testing now identifies patients who gain minimal benefit from cytotoxic drugs. Dr. C. Boland, MD, emphasizes: "Some patients get all the toxicity without therapeutic response if they have MSI-high tumors." This underscores the importance of biomarker testing before treatment initiation.

Keytruda and Other Immune Checkpoint Inhibitors

Immunotherapy drugs like Keytruda (pembrolizumab), Yervoy (ipilimumab), and Opdivo (nivolumab) represent a paradigm shift for MSI-high colorectal cancers. "These are the 'new new thing' in colon cancer treatment," states Dr. Boland. Unlike chemotherapy, which attacks cancer cells directly, checkpoint inhibitors remove immune system brakes, allowing the body to recognize and destroy MSI-high tumors more effectively. Clinical trials show significantly improved outcomes with these targeted therapies compared to traditional approaches.

How Colon Cancer Location Predicts MSI Status

Tumor location provides crucial clues about genetic markers. Dr. C. Richard Boland, MD explains: "90% of sporadic MSI-high tumors and two-thirds of Lynch syndrome cancers occur in the proximal colon." This anatomical pattern helps clinicians prioritize testing. "Any proximal colon cancer should prompt MSI evaluation," advises Dr. Boland. The strong correlation between right-sided tumors and MSI status enables more efficient precision medicine implementation in clinical practice.

The Future of DNA Methylation and microRNA Testing

While MSI testing currently guides immunotherapy decisions, Dr. Boland anticipates broader molecular profiling. "We're entering an era of DNA methylation signatures and microRNA analysis," he explains. These advanced tests will better predict responses to specific chemotherapies and targeted drugs beyond immunotherapy. Dr. C. Boland, MD, envisions comprehensive tumor profiling becoming standard: "We'll match genetic signatures with optimal treatments as precision medicine evolves."

Personalizing Colorectal Cancer Therapy

Dr. C. Richard Boland, MD stresses the importance of tailored treatment strategies. "The goal is identifying who benefits from chemotherapy versus immunotherapy," he states. For MSI-high patients, checkpoint inhibitors often provide superior outcomes with fewer side effects than traditional regimens. Dr. Boland concludes: "By matching tumor biology with targeted therapies, we're realizing true personalized medicine in colorectal cancer care." This approach minimizes unnecessary toxicity while maximizing therapeutic effectiveness for each patient.

Full Transcript

Dr. Anton Titov, MD: Colon and rectal cancer treatment with immune checkpoint inhibitors. How to select patients for cancer immunotherapy? Immune checkpoint inhibitors in colon cancer treatment: Keytruda (pembrolizumab), Yervoy (ipilimumab), Opdivo (nivolumab), Ofatumumab (Arzerra).

Dr. C. Boland, MD: Colon cancer tumors that had microsatellite instability had a better natural history. These were two competing phenomena. People with colon cancers that had microsatellite instability were more likely to survive their tumors. We were not likely to help these patients by treating them with standard chemotherapy.

Dr. C. Boland, MD: That was the first step into personalized medicine. But now it's going to be possible - we are still at early stages - to assess DNA methylation signatures and micro RNA signatures of tumors that will help us know that this chemotherapy is more likely to work, and that therapy is less likely to work. As time goes by, we will be matching tumor genetic signatures with the specific treatments.

Dr. C. Boland, MD: The only thing that we have right now is medications targeting EGF receptor amplification. That only adds a little bit of benefit in colon cancer treatment. But in the last year it was shown that colon cancer tumors that have microsatellite instability were very likely to have a very huge response to immune checkpoint inhibitors.

Dr. C. Boland, MD: So little by little we're growing on this. The microsatellite instability tumor marker has served as a beacon in precision medicine treatment of colon cancer. It looks like people who have colon cancer tumors with microsatellite instability are not going to benefit from traditional cytotoxic chemotherapy. But they might get a very big benefit from immune checkpoint inhibitor medications.

Dr. C. Boland, MD: They are the "new new thing" in colon cancer treatment. This is very important to emphasize - that some people with colon cancer will get all the toxicity of chemotherapy, but they will not get as much therapeutic response if they have microsatellite instability in colon cancer.

Dr. C. Boland, MD: On the other hand, immune checkpoint inhibitors were used in other cancers. But now we would know, by testing for microsatellite instability marker, if immune checkpoint inhibitors might benefit this group of colorectal cancer patients.

Dr. Anton Titov, MD: Correct.

Dr. C. Boland, MD: Historically, oncologists always knew that if they treated a population of patients with Stage 3 colorectal cancer, those patients would have better survival. They knew that most of the Stage 3 colon cancer patients did not get the dramatic tumor response. Yet all patients were treated, and all had the risk of the toxicity of chemotherapy.

Dr. C. Boland, MD: Now, if we can pick those people who are going to respond to chemotherapy and give them chemotherapy, and if we can remove people who are not going to respond to chemotherapy, and find out what treatment will work for them - then we'll really be able to exploit the idea of precision therapy and personalized medicine.

Dr. Anton Titov, MD: Also perhaps just an additional point on microsatellite instability - is it linked to the location of colon cancer tumor?

Dr. C. Boland, MD: Yes. Microsatellite instability occurs in virtually all Lynch syndrome tumors. Two-thirds of Lynch syndrome colon cancer tumors are in the proximal colon. Interestingly, the tumors that have increased methylation of MLH1 gene and acquired microsatellite instability - not hereditary colon cancer tumors - 90% of such colon cancer tumors are located in the proximal colon too.

Dr. C. Boland, MD: So anytime you see a colon cancer that's in the proximal colon, you want to think of checking for microsatellite instability of the tumor, because then you may consider a more specific treatment for such tumor. Microsatellite instability is a tumor marker linked to the location of colon cancer.

Dr. Anton Titov, MD: But the reverse is also true - location of the tumor might alert the doctor to the type of tumor marker to look for, because microsatellite instability affects selection of chemotherapy medication that is likely to help such colon cancer patient.

Dr. C. Boland, MD: Exactly, yes!