Evolving NSCLC Treatment Paradigm - Episode 2

Molecular Testing in Stage IV Lung Cancer

Alexander Drilon, MD:Paying attention to selecting the most appropriate test for profiling patients’ tumors on a molecular level is critical in this day and age, and that’s because we’ve really moved beyond single-gene testing that we used to do in the early 2000s, when we knew about fewer genes likeEGFR—for example, in 2003 and 2004—and then later, theALKrearrangement. Now we have a whole slew of other potential drivers likeROS1andRETfusions,METexon 14 alterations,BRAFV600E, andHER2. And so, it’s important to choose a test that’s comprehensive and that’s able to detect all of these alterations in patients who have non—small cell lung cancers. My personal preference is not to practice single-gene testing anymore and to go for a multiplex comprehensive approach.

At our center, we use DNA-based next-generation sequencing [NGS], recognizing that not all NGS assays are the same. And, of course, the caveats are that because it’s a big test that looks for hundreds of genes, it can sometimes take a few weeks to come back. And for patients who are sick, it’s critical to find out early on, maybe within the first week, whether or not those cancers have a driver. And so, a strategy that we’ve adopted at our center is to do rapid-phase testing, where we look forEGFRandALKusing mutation-specific immunohistochemical antibodies, and that way you might get an answer within the first 1 to 2 days and be able to institute targeted therapy early. And then the rest of the sample we send for comprehensive NGS. So, I think NGS is the way to go in this day and age.

Regarding the amount of time it takes for these assays to come back: First, depending on the test, there are some good commercial assays that can come back within 3 weeks, for example, and there are others that may take 4 or 5 weeks. But, in general, you don’t get an answer within the first 14 days, which is why it’s important to either focus on rapid-phase testing or also use a complementary approach like plasma-based cell-free DNA that can get you an answer within 7 to 10 days for some assays.

Justin Gainor, MD:The current standard of care in the United States is to perform genetic testing on newly diagnosed patients with advanced non—small cell lung cancer. We know that among patients withEGFRmutations [and]ALK, andROS1rearrangements, that these patients derive substantial benefits to treatment with the corresponding targeted therapies. So, one would expect that, based upon these benefits, testing would be 100%. Unfortunately, that still isn’t the case in the United states, and that could be for a variety of reasons. In speaking to my colleagues, many times patients who come to academic centers don’t have comprehensive genetic profiling and for a variety of reasons. Sometimes it can be because there’s no tissue available. Biopsies or fine needle aspirates were performed as the biopsy procedure, and there’s limited tissue available to perform the corresponding genetic analysis.

Sometimes patients don’t have a disease that’s accessible to a core needle biopsy for a variety of reasons. Nonetheless, I do think it should be our goal, and it should be the standard to perform genetic analyses on all newly diagnosed patients and to do so expeditiously. For patients who don’t have tissue available to perform genetic analyses, I think one can approach this in 2 different ways. The first is to actually repeat a biopsy. I think if one has sufficient suspicion that a patient may have a targetable genetic alteration, that certainly makes sense, especially if a lesion is amenable to a repeat biopsy.

We know that in patients who are never-smokers, more than 50% of those patients are going to have a genetic alteration that can dramatically transform how those patients are managed. For patients who don’t have a disease that’s amenable to a repeat biopsy, be it because of comorbidities or the location of their tumors, an emerging tool is actually to perform a liquid biopsy—so, to look at circulating-tumor DNA as a means to identify targetable genetic alterations. It should be emphasized, though, that liquid biopsies are not a substitute for baseline genetic sequencing if you actually have the tumor material available. Liquid biopsies can be a helpful complement, especially if the baseline tissue has been exhausted. The reason I say this is because circulating-tumor DNA assays are not nearly as sensitive as doing genetic sequencing on a baseline tumor biopsy. A negative CT-DNA assay isn’t truly a negative test; it could just be that a patient isn’t shedding. And so, negative results on a CT-DNA assay are really nondiagnostic, and you should keep an open mind that that patient may indeed actually still have a targetable genetic alteration.

Transcript edited for clarity.