Molecular Testing and EGFR-Mutant Non-Small Cell Lung Cancer - Episode 12

Emerging Biomarkers in Lung Cancer


Philip C. Mack, PhD: There’s a wide variety of new mutations that could potentially have an impact on our therapeutic course for a patient with adenocarcinoma. Think about the pie chart that’s often shown for adenocarcinoma that breaks the patients up into categories based on whether there’s a KRAS mutation, an EGFR mutation, or another mutation. We are going to be adding significantly to that pie chart. However, the slices that we are going to be adding to that can be very thin. For instance, NTRK1 mutations are very actionable. However, they may represent significantly less than 1% of the population.

In terms of the future of mutation testing, what we need to do is next-generation sequencing—multiplex type tests that pick up these rare mutations. There’s no purpose in screening patients individually for an NTRK1 mutation if the odds of them having it are going to be 1 in 100 or even 1 in 1000. However, if you were performing a wide panel that can pick up these mutations, then you would come across these potential mutations that can benefit a lot from modern therapies. Other potential mutations that could be of benefit include the FGFR3 fusions and several signal transduction mutations that can have an impact on combinations of therapies.

In my mind, the future of mutation testing is to take a very wide look at the number of different mutations, even if they represent very rare mutations, as long as they’re actionable. We owe it to our patients to try to identify them so that they can receive targeted therapy.

Additionally, I think we’ll start to see the ability to use liquid biopsies for tracking patients over time in the future. A patient will start on a course of therapy, and as that patient goes through their course, we can perform liquid biopsies at regular intervals, allowing us to look for any changes in tumor biology that may impact the activity of that therapy. Then we can potentially intercede at an earlier stage.

One could envision a time in the future when we’re using liquid biopsies to look for changes in the tumor biology that allow us to adjust our therapy accordingly to keep those patients in a state of tumor control. Right now, there is no cure for metastatic lung cancer. So, the goal is to see if we can put patients in a state in which we can keep their tumor growth under control for long periods—hopefully with good quality of life. A liquid biopsy approach and molecular biology in a serial fashion can enable this.

Technological advancements for mutation detection in lung cancer are mostly looking at 2 different parameters. The first is sensitivity. For instance, how small of an allele percentage can we detect in the liquid biopsy that’s still relevant to the treatment course? In some cases, tumors shed such a small amount of circulating tumor DNA into peripheral circulation that we may run into stoichiometric issues with the tumor blood. There may be only 1, 2, or even 0 copies of the tumor DNA in a single tube of blood for that particular marker. This makes it very interesting to try to detect something that rare.

Alternatively, we are looking at a wider range of mutations, not just the primary mutations that we know about—EGFR, ALK, etc—and have therapeutics for. We should be looking at companion mutations to those markers that can influence the activity of our best drugs. For instance, only about 75% of patients actually benefit from an EGFR inhibitor, even though they have an EGFR mutation. What are the additional factors involved in whether that patient is going to benefit or not—or how durable the benefit will be? We’re beginning to isolate different factors that can give us a lot of insight into this. It gives us the potential to prescribe additional therapeutics on top of an EGFR inhibitor that may be of benefit. That will be a real breakthrough. Again, the ultimate goal is to keep tumor growth under control for long periods of time.

Transcript Edited for Clarity