Insights From:Alan P. Venook, MD, University of California
Alan P. Venook, MD: Progress in colon cancer, the treatment of metastatic colorectal cancer in terms of personalized medicine, has been slow. We know a couple of markers that tell us what not to use, and now more recently, one that we know is proactive and tells us what to use. In terms of how it fits, for the longest time, KRAS at codons 12 and 13 and now what are called all-RAS, or NRAS, are a series of different mutations in the RAS gene. These are all biomarkers that largely tell us which patients are very unlikely to benefit from the EGFR antibodies. They give us some prognostic information as well. So, those are two biomarkers that tell us what not to use.
The BRAF mutation is an important biomarker, which we now understand to be a particularly negative factor. This is something that should guide us to treat patients differently than standard, because patients on average do poorly if they’re treated with standard therapy with a BRAF mutation. BRAF mutations do not exist in patients with RAS mutations. We’re starting to get a portfolio of these mutations.
MSI-High, the so-called microsatellite instability, is a marker of a genetic predisposition to cancer, a familial cancer risk gene that has some bearing in stage 2 colon cancer. But in terms of metastatic colorectal cancer, its importance relates to the use of checkpoint inhibitors. So, the hype, the ridiculous excitement these days, is in the checkpoint inhibitors, which in fact are a major advance in many diseases. In metastatic colorectal cancer, about 3% of patients with metastases are what’s called MSI-High. Those patients have a reasonably good chance of benefiting from the checkpoint inhibitors, and some of those who benefit can benefit a lot. Really what we have are the RAS mutations, BRAF, and the MSI status as biomarkers.
Soon to come I think will be HER2, or ERBB2. Because, in fact, it is amplified in about 3% to 5% of patients with colorectal cancer—usually patients with left-sided colorectal cancer—and those patients do get benefit from the antibodies to HER2, trastuzumab, or pertuzumab. So, in the whole range of things, those are the tests that can be informative. Again, not any of which are dramatically predicting for great efficacy in a lot of patients, but we’re starting to pick apart the disease a bit and get some clarity on that.