Expert Explains Limitations of Molecular Profiling in Lung Cancer

Dara L. Aisner, MD, PhD

Though testing for molecular abnormalities can determine a course of treatment for patients with non—small cell lung cancer, it can also muddle their treatment options if not examined properly, explained Dara L. Aisner, MD, PhD.

“When sorting out the results, it’s not just looking at the top of the report and saying, ‘this is the result or it's negative,’” said Aisner. “It's understanding the testing well enough to understand what a negative really means and what a positive really means.”

OncLive: What did your presentation on molecular profiling focus on?

In an interview during the 2018 OncLive^® State of the Science Summit™ on Advanced Non—Small Cell Lung Cancer, Aisner, an associate professor in the department of Pathology at the University of Colorado School of Medicine, discussed the rapidly progressing field of molecular profiling, the importance of understanding assay results, and how they translate to patient care in lung cancer.Aisner: Some of the things that I wanted to [express] in my presentation are understanding the limitations of testing and understanding that no test is perfect.

If you don't feel like you have the technical expertise, it's very possible to seek it out and get the guidance you need either on a case-by-case basis or in a more systematic way. Getting that kind of assistance can help a lot. I have a lot of examples in which I was consulted on a report and [the physician will focus on] result A, whereas I’ll focus on result D. I know it's at the bottom of the page, but it is the more important finding.

Even more important than those sorts of examples are ones where I get asked [the next steps on] a test that came back all negative. It is important to look at what was tested. What questions are being asked and, more importantly, what questions are not being asked?

Can you elaborate on some of the cases you consulted on?

Another point is that technologies are evolving very rapidly. What is exciting and interesting today is not going to be what we're talking about in a few years. There's a balance to be had between jumping for a test because it's new and “hot,” versus going for data that are well established. There's a real middle ground in between those 2 extremes.A lot of this has to do with the fact that this is a relatively new area for oncologists. When many people who are in practice now went to medical school, this was not part of practice. It's something that we are incorporating into the training of oncologists today, but even in that setting the technology is so complex.

How should these tests be conducted?

This is where the multidisciplinary team becomes important. Having somebody who understands the technical aspects of the test in very fine detail as part of a multidisciplinary team can be advantageous. This is about education, learning how to read the reports, and learning when you need help in digging deeper. As we mature in our use of this type of testing, we will see that people will get better at figuring out how to go from a report to what this means for my patients.The “how” is really the elephant in the room for most people. It's really challenging, because on one hand you want to do what's easiest and fastest. On the other hand, if you don't necessarily know all of the technical details, you don't know if the [test] that is billed will answer all of the questions you want answered.

Does the time of assessing PD-L1 and tumor mutational burden make a difference?

The “how” has to be centered around the goal for the patient. If a patient is frail with poor performance status, getting a huge test that may make them eligible for clinical trials perhaps isn't the right approach. Conversely, if you have [a patient] who is very aggressive about wanting to treat their disease, perhaps you want to be more comprehensive from the outset. It’s not a one-size-fits-all approach.I don't think we have answered that yet. Pretty much all of the studies that have been done have looked at those values before immunotherapy treatment. There have been some discussions about [whether] immunotherapy is more effective in the neoadjuvant versus adjuvant setting.

What are we looking for in these tests?

Similarly, there are questions about immunotherapy timing relative to chemotherapy. If you give somebody chemotherapy and a large portion of their immune cell infiltrate is killed off through the chemotherapy, maybe you aren't maximally leveraging the immune system. The questions of how to time the various agents and how to time the testing are really up in the air.At this point, there are 4 targets that should categorically be evaluated in every patient because there are associated drugs that we know provide benefit. Sometimes, there is a bias toward not testing frail or older patients, but we have seen cases where there is a dramatic effect from a therapy that has significantly less toxicity.

How does testing differ across histologies?

This is where the value comes in. It's not just that the targeted therapy works. It's that it works with lower toxicity. Getting the testing for EGFR mutations, ALK rearrangements, ROS1 rearrangements, and BRAF V600E mutations [is important because] if one of those is positive, it will change the patients’ course of care.There’s a sort of a dichotomy in that when you look at the guidelines for adenocarcinoma testing we talk about testing for EGFR, ALK, ROS1, and BRAF. Fundamentally, there's a cost- benefit decision that has been made. It's worth the effort to look for ROS1 rearrangements even though they occur in only 1% or 2% of patients because the magnitude of the benefit is so significant.

What's the biggest misconception about molecular profiling?

We don't have an accurate assessment of how often those alterations happen in squamous cell carcinoma. If we consider a valuable threshold to be 1%, what [happens] if EGFR mutations occur in more than 1% of squamous cell carcinoma cases? That should carry similar testing weight as a 1% event in adenocarcinoma, provided we can demonstrate that there is a clinical benefit associated with it.The biggest misconception is that a bigger test is better. Sometimes that's true and sometimes it’s not. We know that every approach to testing has its Achilles heel. It's about understanding what that Achilles heel is.