Key Takeaway 3: Determining Tumor Mutational Status

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Tanios S. Bekaii-Saab, MD: In terms of full profiling of the tumor, so genomic sequencing of tumors, we do only those in stage IV cancer. Stage II and stage III, certainly not—most of them will never need the information we get from genomic sequencing. When we do genomics and next-generation genomic sequencing, we want to ensure that we have elements that are important for decision making. If your practice does not have access to next-generation sequencing, you have to have at least the following on hand: microsatellite status [MSS], RAS alteration, KRAS, NRAS, BRAF V600E, as well as HER2 amplification. I think HER2 amplification is a very important component of how we decide or stratify for treatment options. In addition to that, of course, we have to figure out whether the disease is left and right, and there are a number of other elements that go into the equation to select the best therapy.

In our practice, we try to sequence all the patients. I think the important aspect of this is that we uncover other alterations that may be relevant in terms of choice of therapies or other therapies down the line. It helps us in planning whether patients could be directed toward gene-directed therapy, molecular-targeted therapy, immune-directed therapy. One example is MSI [microsatellite instability]—high, although they can relate to tumor mutational burden and be used in immune therapy. There are certain alterations that are less common than Lynch or somatic MSI-high, such as POLE, POLD, and CHEK and others that you will not uncover unless you expand your profile. For those patients, the tumor mutational burden can be quite high, and they seem to benefit equally from the application of immune therapy.

I want to start with a small panel, just a direct panel, and they’ll expand it later on. The reality is, for these things, most of them don’t change much across. I mean, there is heterogeneity, and we know 10%, 15% can be heterogeneous intratumorally or between 1 lesion and the next. But the reality is, for most of these alterations, they stay consistent through the lifetime of the tumor. I think it’s important to have all these alterations figured out from the day you essentially see the patient if possible. At a minimum, microsatellite status, RAS, BRAF, HER2, preferably an expanded sequencing.

I will add 1 other element. I think it’s very important to try to get RNA sequencing when it’s available through the platform. There are a couple of platforms that essentially include RNA sequencing with this. I think they’re very important because some of the fusions, such as NTRK fusions, which are important at some point of treating the patients. NTRK fusions, although rare, can be missed if the platform does not include an RNA sequencing. In fact, you may miss up to 30% of these fusions, like NTRK fusions. We have a drug—an agent, I should say—that targets NTRK fusions that’s approved to the clinic.

The other element to this is I hear occasionally from physicians is, “Why do I need to keep on looking consistently for an MSI-high or for an NTRK fusion if they’re incredibly rare?” Totally understand. However, if you think about it, MSI-high is present in 4% of patients; NTRK fusions, 0.7%. If we don’t check consistently every patient that comes through the door, your 4% becomes 1% and your 0.7% becomes 1 in 10,000, just roughly. I think consistency is very important, because we want to make sure every patient who gets through the door to our clinic has every option explored for them and placed in the armamentarium sequentially. At some point we’re going to need 1 or the other, depending on their genetic profile.

Transcript Edited for Clarity