Surgically Unresectable Metastatic Colorectal Cancer Case: 2 - Episode 2
Edward Chu, MD:In 2017, at this point, in patients who have metastatic colorectal cancer, as this patient does, there is probably no specific indication for determining the MSI status of this patient. Because in truth, when we think about first-line systemic therapy of this patient, it will either be oxaliplatin- or irinotecan-based chemotherapy in combination with either 1 of the 2 biologic agents: the anti-VEGF antibody, bevacizumab, or the anti-EGFR antibodies, cetuximab or panitumumab, if the patient’s tumor isRASwild-type.
I think where we would consider MSI testing would be in the disease refractory setting. So, we now know that, based on really impressive resultssmall numbers but very impressive results—published by the Johns Hopkins group, in patients who have metastatic colorectal cancer, whose tumors are MSI-high, and have evidence for microsatellite instability, they will actually have upward of a 30% to 40% response rate to the anti-PD-1 antibody pembrolizumab. Also, I think there are now data supporting the use of the other anti-PD-1 antibody, nivolumab, in patients who have MSI-high disease.
I think in the disease refractory setting, the MSI status is quite important. I think where the field is now heading, unfortunately the number or percent of patients with MSI-high disease is relatively small, on the order of perhaps 10% to 15%. So, the vast majority of our patients with metastatic colorectal cancer have what’s called MSS disease, or microsatellite stable disease. And I think where many folks are going, including our own here at Pittsburgh, we are trying to see whether or not we might be able to employ a strategy combining different immunotherapies or combining immunotherapy with targeted therapy.
Perhaps the best example is this very interesting study that is being conducted using a MEK inhibitor, cobimetinib, in combination with the anti-PD-L1 molecule, atezolizumab. Those results have been very impressive in patients with MSS metastatic colorectal cancer, where the overall response rate is on the order of 30% to 35%.
With respect to determining which test is easiest to perform, I think a lot will depend upon what the capabilities are of the individual laboratory. And I think truthfully, either MSI testing or testing of the MMR genes can get us the same answer. And if, in fact, there’s presence of MSI-high disease or presence of mutations in either one of the mismatch repair genes, we have our answer that that patient has HNPCC, or Lynch syndrome.
With respect to testing, either MSI testing or mutational analysis of the mismatch repair genes can be done. The other point to note is that now there’s a very high association, close to 100%, between IHC expression of the mismatch repair proteins, and MMR mutational events, and MSI-high status.
Transcript edited for clarity.