Violaine Randrian, MD, PhD, on Lynch Syndrome, Genetics, and Immunotherapy

As you may know, Lynch syndrome is a genetic predisposition, meaning it's defined by a germline mutation in an MMR protein. The different proteins affected are MLH1, MSH2, MSH6, and PMS2. Patients affected by Lynch syndrome actually develop tumors in gastrointestinal sites, endometrial sites, urological, or pancreas-biliary. The question we asked in that study is, could the different variants affected actually impact the response to immune checkpoint blockade? Because right now, immune checkpoint blockades are the reference treatment in metastatic cancers affecting the Lynch syndrome patients. What we observed is that yes, but no. I'm going to develop that. First part is yes, because when we take the whole cohort, we have a retrospectively collected cohort at Memorial Sloan Kettering throughout 10 years, including Lynch syndrome patients with advanced tumors treated by at least one dose of immune checkpoint blockade, and we considered only the first tumor treated by immune checkpoint blockade. Our primary outcome was overall survival. Secondary outcomes were progression-free survival and radiological response rates. Of course, we were also interested in tumor mutational burden and MSI score. When we looked at our primary outcome, which was overall survival, indeed, PMS2 carriers were doing less well than the others. They had a median overall survival of about 21 months, while the other ones were plateauing with about 9 to 10 years of overall survival in advanced tumors. When we looked at median progression-free survival, it was pretty much the same. PMS2 patients had significantly shortened median PFS of 7.2 months, while the others were far longer. Again, with the radiological response rates, we could see a gradient. Only 9% of the PMS2 carriers experienced complete response in that setting, while MSH6 carriers were about 22% to experience that, and the other germline carriers were above 40% of complete response rates, which is amazing in the advanced tumor setting. But we actually saw in our cohort that many of the PMS2 variant carriers actually displayed MSS tumors. They were not MSI-high for 63% of them. So we chose to select only the MSI-high tumors, and then all the effects on the PMS2 carriers were erased. They had the same overall survival, they had the same median progression-free survival, and they experienced about 30% complete response rates. So this means that tomorrow, for PMS2 carrier patients diagnosed with an advanced tumor, we really need to analyze its tumor thoroughly with MSI score and MMR staining to make sure that the tumor is MMR-D/MSI-high. If this tumor is confirmed MSI-high, he has an outstanding prognosis, as good as the other patients. If it's MMR-P/MS-stable tumors, he's not going to respond to immune checkpoint blockade and we should have him under standard-of-care treatment. So that's a small question maybe, but so important for patients that are affected by Lynch syndrome.