Updates on Upfront Treatment of Metastatic Colorectal Cancer - Episode 2

RAS Mutation Testing in mCRC


Zev A. Wainberg, MD: As a practical matter, we know that RAS testing takes longer in certain academic centers versus community centers. And so, we certainly don’t recommend waiting for a patient to start chemotherapy until we have obtained their RAS status. The base chemotherapy is going to be the same, and that’s really the main part of the treatment. So I personally think it’s reasonable to start the patient on their chemotherapy regimen, whatever your choice is—FOLFOX [folinic acid, fluorouracil, and oxaliplatin] or FOLFIRI [folinic acid, fluorouracil, and irinotecan]—and, dependent on RAS status, you can add in the EGFR inhibitor or VEGF inhibitor, depending on whether they’re wild type or mutated. I don’t think we have to wait for that result to start the patient who’s sitting around and is waiting on standard of care chemotherapy. As a matter of practice, even in academic centers, sometimes it can take far too long for these tissue results to come back. We should start patients on chemotherapy, unless we are required to wait as part of a clinical trial.

For right-sided tumors, we know that the role of EGFR inhibitors is less clear. We know that the benefit of EGFR inhibitors is much greater on left-sided tumors versus right-sided tumors. So the question has come up: Should we even bother knowing RAS status on the right side if you have no intention of using that drug on the right side?

I would say yes for 2 reasons. First, I do think EGFR inhibitors have a role in treating right-sided tumors, albeit a much smaller role than in left-sided tumors. And also, knowing RAS status helps you plan out a treatment program for the next few years, whether for clinical trial options or otherwise. So even though there’s less benefit from EGFR inhibitors in right-sided tumors, I still think it’s good to know whether they’re RAS wild type or RAS-mutated.

So RAS status is very important to know. It isn’t just important to know for deciding what to treat the patient with now, but also it helps you make plans for treating the patient over the next few years. When we look at trying to get a complete picture of what’s going on with the patient, we should try to know RAS status, not only because we may choose to use an EGFR inhibitor or not—that’s a personal choice, depending on the situation of the patient and the data that support it—but independent of that, it helps determine what’s going to be that patient’s treatment course down the road, whether it be in the second-line or third-line or eligibility for clinical trials. So I’m a big believer in knowing the status. Even if you’re going to use bevacizumab all the way through, you should still know what the RAS status is. It provides a complete package. So I do think it’s essential to know that status, even if, hypothetically, you have no intention of using the drug until later.

Retesting RAS at progression is still controversial. There’s new data that suggest that there are certain clones that are lost, and some patients who develop resistance to an EGFR inhibitor, for example, have now acquired some of the remainder cells, the required RAS mutation. That’s been shown in a number of preclinical and clinical trials. I don’t do it routinely unless it’s mandated on a clinical trial to retest the RAS status.

More and more, we’re seeing the use of these liquid profiling assays, which are a bit easier to do. You may get the results faster, and for something like RAS status, the newer liquid next-generation sequencing testing is very comprehensive. The sensitivity of picking up a RAS mutation in the blood is pretty good as it relates to something like KRAS. So more and more, I think we’re going to start seeing those incorporated in various time points during the patient’s progression, to see how it correlates with their initial status.

Transcript Edited for Clarity