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Liquid Biopsies a Quicker Alternative to Standard Approaches in NSCLC

Danielle Bucco

Jared Weiss, MD
Jared Weiss, MD
Liquid biopsies offer an alternative method for detecting molecular mutations in patients with non–small cell lung cancer (NSCLC), according to expert Jared Weiss, MD.

“Every patient with nonsquamous disease should have comprehensive testing and go back to do repeat tissue biopsies when necessary,” explains Weiss.

In an interview during the 2017 OncLive State of the Science SummitTM on Advanced Non–Small Cell Lung Cancer, Weiss, an assistant professor at the UNC Lineberger Comprehensive Cancer Center, discussed utilizing liquid biopsies for patients with lung cancer, the pros and cons of the approach, and when it might be appropriate to rebiopsy patients.

OncLive: When is it appropriate to use a liquid biopsy?

Weiss: Molecular information has become key to optimal treatment of patients with stage IV NSCLC. When we match the target with targeted therapy, we get treatments that are less toxic, more effective, and demedicalize the life of the patient because they are oral and not intravenous. This makes them highly desirable.

Data from the Lung Cancer Mutation Consortium show us that just having a mutation is not good enough. If patients have mutations and it is not actionable, their survival is no better than patients without mutations. In contrast, for patients with actionable mutations, we expect dramatically greater survival than we used to expect. We are counting in years now. 

I discussed when to use liquid testing and when to use tissue testing. These are complementary strategies with unique advantages and disadvantages. For the patient at initial diagnosis, we need a tissue biopsy to establish that the patient has lung cancer and that it is stage IV. There should be tissue at diagnosis when there is optimal stewardship of that tissue, including good communication between whoever is doing the biopsy, the medical oncologist, and the pathologist.

In the frontline setting, it would be optimal if we could have enough tissue to run PD-L1 and molecular testing on that initial biopsy. That is the ideal world. However, we do not always live in an ideal world for a variety of reasons. We often do not have enough tissue. With upfront testing, if the initial tissue is inadequate for comprehensive molecular testing, a liquid biopsy can then come in to supplement this. 

There are different panels being done, but you want to make sure that the panel is sensitive for EGFR, ALK, and ROS1. When you get back an actionable molecular result, you can believe it. If you get back an EGFR result, the right clinical thing to do is to put the patient on an EGFR tyrosine kinase inhibitor (TKI). In contrast, negative results cannot be completely believed. There are all kinds of variables, including the tumor not shedding DNA into the blood in a detectable way, that can yield a negative result, even if that mutation is present inside the patient's cancer. 

In this scenario when tissue is inadequate, a liquid test is done, and it does not yield an actionable result, then it is often appropriate to go back and pursue the tissue again more aggressively. The other place we think about liquid biopsies is to define the mechanism of resistance at progression. For example, if a patient is on erlotinib (Tarceva), gefitinib (Iressa), or afatinib (Gilotrif) and the cancer begins to progress, we know that, 50% or 60% of the time, the molecular mechanism is a secondary mutation, such as T790M, which is detectable and can be treated with a targeted therapy. 

The right thing to do is to find out if T790M is present. One strategy that is gaining favor is to start with a liquid-based test. I tend to prefer a PCR-based test for speed. You can receive the results of the test a few days to 1 week later if you find that T790M is present.

If a patient has positive results, it has been well established that you can [act on] it. A patient can go on the 1 FDA-approved drug, osimertinib (Tagrisso), with expected outcomes that we know are superior to chemotherapy. In contrast, if you do not find T790M, then a tissue biopsy is appropriate. This can be useful to look for T790M and other mechanisms of resistance that may be actionable.

What are the advantages and disadvantages of liquid biopsies? 

Tissue and blood offer distinct advantages and disadvantages. Pre-analytical variables are particularly important for liquid biopsies beyond the scope of our conversation and need to be paid attention to.

With tissue biopsy, the advantages are greater sensitivity for the spot where you put the needle. However, a disadvantage is that you must put a needle into a patient. There are risks, discomforts, and time delays associated with tissue biopsy. Additionally, there can be heterogeneity both within a tumor and within different locations. A tissue biopsy only tells you about where you put the needle.

A liquid biopsy is far more convenient since it is a blood test. It is very easy to get blood and you can see results very quickly since you are not waiting for the biopsy, which includes a lot of processing. You can see results within 1 week.

The problem is that a negative result cannot always be believed. A lot of tumors, particularly those that are restricted to the lung, do not shed their DNA into the blood in a detectable way.

What factors should be taken into consideration for when to rebiopsy patients?

When a decision is made to obtain a rebiopsy, the key question is, “Where to go?” You are looking for a spot that is clearly progressing. It does not help to go to a nonprogressing spot and obtain tissue. That may sound like an obvious point, but we see that happen all the time, mostly because of poor communication. There needs to be a conversation about what you are looking for so that you make sure that the sample is processed in an appropriate fashion.

It is sometimes said that you cannot get molecular results off bone. That is not entirely true. It is possible, but you need to have a conversation with your pathologist to understand what you are looking for and they will tell you how to process it and avoid problems.

What additional factors should one consider when choosing between liquid or tissue-based biopsies?

It depends on what they're asking. If the question is, “What should I do in the frontline setting?” then tissue is preferred if adequate tissue is available. If that tissue is inadequate, it is perfectly reasonable to do a broader liquid test. At that point, a next-generation–based platform might be worth the additional time.

In contrast, I think of this differently at the time of acquired resistance. At that point, you have some time to wait. Usually, patients on targeted therapies are not dramatically progressing in a way that you need to act quickly—making liquid biopsies an option as the first attempt. If you get a positive result, you can go ahead and treat the patient. However, if it is negative, you have to consider that that tumor may not be releasing DNA into the blood in a detectable way. In that case, you can reconsider getting a tissue biopsy.

The balance between acquisition of DNA from a tissue-based pathway and a liquid-based pathway also depends on local resources. If you have an interventional pulmonologist who is happy to progress mediastinal nodes on 1 day’s notice, then it is reasonable to jump to tissue more often because there is less delay. In contrast, if you only have an interventional radiologist who delays things every time you try to get a specimen, then leaning more heavily on liquid biopsies makes more sense. 

What are the main takeaways from your presentation?

The advantages of targeted therapy when you find something actionable are so massive that this should extend to patients with a low probability of having those changes. I have found dozens of patients with EGFR or ALK who do not have any of the clinical characteristics that we talk about.

I will never forget a patient that I inherited from an oncologist when he left my institution. She had 3 or 4 biopsies, which all had complications—even though she was a never-smoker. My advice was to go after tissue a fifth time. This was in the pre–liquid biopsy era. She went for it and she had EGFR mutation that derived dramatic benefit from an EGFR TKI. That is not the average patient. However, there is a massive advantage when you get a molecularly targeted therapy for a patient. In the case of PD-L1, data suggest that 50% of patients will have dramatic clinical improvements with immunotherapy.

What else you would like to highlight?

There are many experimental studies that might further expand these advances. I would like to highlight circulating tumor cell (CTC) capture. The assays that were famous had trouble picking up NSCLC. That has been largely overcome and now, CTCs can be captured in NSCLC. There are ongoing studies trying to look at markers such as PD-L1 in CTCs that I predict will yield fruit.
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