Liquid Biopsies Are Shaping Future of Molecular Testing

Sreeni Chittoor, MD, FACP

The role of liquid biopsies is finding traction in the non—small cell lung cancer (NSCLC) space, as the noninvasive procedure allows for identification of molecular markers and potentially, prediction of high-risk recurrence, said Sreeni Chittoor, MD, FACP.

Though liquid biopsy has been met with some resistance for clinical use, Chittoor is certain it will continue to be more widely integrated as part of precision medicine for community oncologists. 

"Liquid biopsies are here to stay, whether you like it or not," Chittoor said. "It is a rapidly evolving area. NSCLC is heterogeneous, so regardless of how difficult it may be, it is imperative that every patient with lung cancer has molecular testing performed because we have druggable molecular targets."

In an interview with  OncLive  during the 2019 State of the Science Summit on Precision Medicine, Chittoor, a medical oncologist and hematologist at Texas Oncology, discussed the role of liquid biopsies in NSCLC and the advantages of using this type of assay compared with tissue-based genotyping across cancer types. 

OncLive: How would you define the current role of liquid biopsy in NSCLC?

Chittoor: As a community-based oncologist, what I do is based on FDA approvals. Therefore, that being said, the FDA has approved liquid biopsies for activating EGFR mutations, such as exon 19 deletion. Also, use of liquid biopsies for individuals who progress on first-line EGFR TKIs were approved. This is essentially to look for the most common [EGFR] mutation, T790M, which is seen in about 50% to 60% of patients in this population. 

However, the National Comprehensive Cancer Network (NCCN) has guidelines recommending broader molecular testing. There are two different panels called LUNGSEQ Panel and 50SEQ Panel. Basically, with LungSEQ, there are different molecular markers being looked at, which in addition to  EGFR, includes  ROS1, ALK, BRAF, NTRK, RET, MET, AKT1, PTEN, and  HER2. 

This is relevant because we have drugs that will target these particular alterations.  Nearly every molecular marker I spoke about is a trackable, druggable target. For example, a new drug, alpelisib (Piqray), was approved to target those with  PIK3CA mutations.

As community oncologists, we are more or less forced to learn what is out there regardless of how long the [biomarker] menu is. It's a lot to assimilate, considering there are only 24 hours in a day and there are a lot of physical and emotional demands when you take care of patients every day. 

How do you handle the educational aspect when there is so much to  learn in this space?

When all is said and done, if you don't [learn it], you're going to be behind. You're not going to provide appropriate care that the patient needs. Keeping up with the rapid pace of discovery in molecular medicine is a daunting task, but we have to step up to the plate and get on with it. 

Could you expand on some of the opportunities you mentioned and how you choose which test to use in each individual patient? 

Going back to metastatic NSCLC and molecular abnormalities, the genes I spoke of earlier are the ones we focus on because they are druggable targets.

If a patient has an  EGFR  activating mutation, say exon 19 deletion, we have a choice [to make]. The NCCN recommendation is to use osimertinib (Tagrisso) in the first-line setting. Osimertinib, a third-generation  EGFR  TKI, was compared head-to-head with first- and second-generation TKIs and found that there was a significant improvement in progression-free survival with osimertinib—and almost doubled the duration of response. The data are so strong that it makes us think twice before we decide what drug we want to give. The other big advantage with osimertinib is that it crosses the blood-brain barrier, which is a plus. 

What information can you add about the other targets you mentioned?

We have these wonderful drugs that we can use to target specific molecular abnormalities. When you have a molecular target, you want to use a drug that effectively addresses that target. You get the best response when you do that rather than use a “shotgun” therapy. 

For patients with  BRAF  mutations, we have [combination regimens], such as dabrafenib (Tafinlar) and trametinib (Mekinist). Looking at  those with HER2 positivity, we obviously have trastuzumab (Herceptin).

If someone has an ALK rearrangement, the choice now for these patients is actually alectinib (Alecensa), because it also crosses the blood-brain barrier and has been shown to be superior to crizotinib (Xalkori). 

Now, if you're looking at  ROS1  rearrangements, you have crizotinib and ceritinib (Zykadia), and you have the newly approved entrectinib (Rozlytrek).

What are the advantages of liquid biopsy and how does it compare with tissue biopsy?

Liquid biopsy is noninvasive and it will reveal the tumor heterogeneity of the primary tumor and the metastatic sites. This is unlike a tissue biopsy, meaning that in a tumor, cells may be dividing—some more aggressive than others. If you do a needle biopsy, you're not learning the entire landscape of the tumor, you're just getting a piece of the tumor from that particular 1- or 2-cm mass. In liquid biopsy, you're getting a comprehensive picture of the entire genomic landscape. 

When it comes to monitoring using liquid biopsies, you can monitor for drug resistance as you treat a patient. For example, patients who are being treated for breast cancer but develop resistance to an aromatase inhibitor, liquid biopsy has the potential to find an ESR1 mutation in which aromatase inhibitors will not work. Therefore, you have to switch gears. 

Another example is that in patients with prostate cancer, if ARV7 [is present], the drugs we often use [in patients with prostate cancer] will not work. Therefore, you would be wasting your time [to use them]. 

You can also monitor patients for response using liquid biopsy. For example, if you are treating a patient who is in complete remission, you can check their minimal residual disease status in the maintenance phase. That will give you an idea of how the patient is doing. 

Another advantage of liquid biopsies is that if a patient completes their treatment, you can monitor their circulating tumor (ct)DNA, in order to know if a patient is at a very high-risk of recurrence.

Of course, the turnaround time for tissue biopsies may take 2 or sometimes 3 weeks. With liquid biopsies, it is usually within 10 days.

What research is ongoing with liquid biopsy that you wanted to highlight?

There are three different studies. One is monitoring patients with triple-negative breast cancer after they go into remission for ctDNA noted in the peripheral blood. If it is present, those patients are randomized 2:1 to receive pembrolizumab (Keytruda) versus observation. 

The second study is for patients with stage II/III colon cancer, and is [looking at] whether or not these patients have ctDNA in the peripheral blood. From that, it may tell us who should get intense treatment versus who should not. 

Finally, of course, you have the umbrella Lung-MAP trial, which is looking at multiple groups of patients who are trying to understand who will respond to what and how.

What is your take-home message to your colleagues?

I don't want my colleagues to jump on the bandwagon when they see liquid biopsy trials. The two most important things for any tumor biomarker assay are analytical validation and clinical utility. Analytical validation of test means accuracy, reliability, and reproducibility of the test, while clinical utility means you should have high-level evidence that would support the claim that this particular test will change a patient's outcome. 

Until we have that in place in a meaningful way, we have to be cautious of how we utilize these studies.