Colorectal Cancer Immunotherapy. Keytruda. Pembrolizumab. 8
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. Richard Boland, MD. Colon cancer tumors that had microsatellite instability had a better natural history. These were two competing phenomena. A – People with colon cancers that had microsatellite instability were more likely to survive their tumors. B – we were not likely to help these patients by treating them with standard chemotherapy. So 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. 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. So little by little we’re growing on this. And microsatellite instability tumor marker has served as a beacon in precision medicine treatment of colon cancer. So 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. They are the “new new thing” in colon cancer treatment. So this is very important to emphasize this point – 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. Richard 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. Correct. 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. So 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. C. Richard Boland, MD. Also perhaps just an additional point on microsatellite instability – is it linked to the location of colon cancer tumor? Yes. So 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. 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. So 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. Exactly, yes!
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