Liquid Biopsies, ctDNA Could Help Guide Gastrointestinal Cancer Management

Tanios S. Bekaii-Saab, MD

In an interview with OncLive^®, Tanios S. Bekaii-Saab, MD, delved into the role of molecular and genetic testing for patients with gastrointestinal (GI) cancers; how liquid biopsies differ from and complement tissue biopsies; and the potential role for circulating tumor DNA (ctDNA) in this space.

Bekaii-Saab is the David F. and Margaret T. Grohne Professor of Novel Therapeutics for Cancer Research, chair and consultant in the Division of Hematology and Medical Oncology at Mayo Clinic, and co-leader of Advanced Clinical and Translational Science at Mayo Clinic Cancer Center in Phoenix, Arizona.

In a prior article, Bekaai-Saab detailed the evolving treatment paradigm in pancreatic cancer.

OncLive: What role do liquid biopsies play in the diagnostic process of GI cancers?

Bekaai-Saab: One of the biggest limiting factors in GI cancers is having timely availability of tissue, or sometimes even having the availability of tissue [at all]. For example, in pancreatic and biliary cancers, patients are occasionally diagnosed through endoscopic ultrasonography or brushings, and we only have cells or a small amount of tissue. [In these instances], we may be not have a clear answer on the genetic profile of the tumor.

The other element that's also limiting is timing. More than ever, we know that we need to have a genetic profile of the tumor before we make a decision about subsequent treatment. [Analyzing a tissue sample] takes approximately 3 to 4 weeks when we are able to [collect] tissue, and that certainly limits the decision-making process. This is where liquid biopsies become important in assessing ctDNA. Not all tumors in the GI tract shed [ctDNA] at the same rate or shed enough for us to capture it.

We [also] still miss the element of RNA; some testing platforms are adding the RNA to liquid [biopsies]. [That is primarily important] when thinking about fusions. For example, in cholangiocarcinoma, FGFR fusions play an important role. We know NTRK fusions, albeit rare, are present, and we have agents that target those fusions. [For fusions], RNA sequencing [is necessary] to be able to [detect them] with more sensitivity. [These can also include] ROS1 fusions, RET fusions, and NRG1 fusions.

[There are a lot of instances] where it's important to have RNA. [Some of these fusions] are rare, and they can be missed by liquid biopsies; therefore, integrating RNA [sequencing capabilities] could give us a little bit more of a [comprehensive reading]; however, fusions are mostly picked up by tissue [biopsies].

What is the value of a liquid biopsy while waiting for the results of a tissue biopsy?

When we think about liquid biopsies, they can help facilitate treatment early on. When a patient comes into the clinic for the first time, the first thing we're doing is a liquid biopsy while we also send tissue for testing. Within a week, I'm going to have most of my answers [from the liquid biopsy] while waiting for the tissue [results].

If you find [alterations in the ctDNA] in the blood, [these alterations] will be in tissue. If you don't find them in the blood, you still have to wait for the tissue to determine whether they’re truly absent. The concordance rate—depending on what malignancy and what mutation we're talking about—can be up to 80% to 85%, which is huge. For example, with BRAF mutations, those cancers tend to be more aggressive and shed a lot of ctDNA. BRAF V600E mutations can be depicted a little bit easier in the blood.

We've also shown that [this also] applies to HER2 amplifications. In the [phase 2] MOUNTAINEER trial [NCT03043313], which looked at tucatinib [Tukysa] plus trastuzumab [Herceptin] in [patients with colorectal cancer (CRC)], we showed that the concordance rate between tissue and blood [biopsies] is approximately 80% to 85%. These [biopsy] results can do 2 things for us. First, at Mayo Clinic, we have [the phase 3] MOUNTAINEER-03 study [NCT05253651], which is looking at tucatinib plus trastuzumab and chemotherapy in the first line, so [these testing results] can facilitate patient access to the study. Second, we know that in the presence of HER2 amplifications, patients tend not to respond to EGFR inhibitors. These are patients with CRC who would be technically eligible for EGFR inhibitors, but in the presence of a HER2 amplification, we avoid EGFR inhibitors.

Liquid biopsies are important because they help with RAS mutations. Now that we have more and more studies bringing RAS-targeted strategies to the first line, it becomes more important to have [liquid biopsy results].

What role could liquid biopsies play in combating tumor heterogeneity and tracking changes during a patient’s treatment course?

The other nice thing about liquid biopsies is that you can check longitudinally for changes in the genomic landscape. If you think about tumors, tumor lesions are heterogeneous both within and between lesions. This heterogeneity is the rule, not the exception. If you take a needle and put it in 1 tumor, you may get a little bit of a different answer if it goes a little bit to the right or a little bit to the left. The answer won’t be completely different—the RAS or BRAF mutations are present across the board; however, if you hit 1 lesion and another, you may see some differences. That's a problem because you're not going to take a needle and put it in every lesion in the patient; that's not feasible and would be torture. Liquid biopsies can give the sum of everything that's going on across all the lesions, at least theoretically.

Also, the nice thing about [liquid biopsies] is that you can track progression, and that's what we do. At Mayo Clinic, we do another liquid biopsy [at progression] and see what changed. This is how we understand what's driving RAS-targeted resistance. RAS-targeting and developing strategies that curb resistance are part of the goal in our clinic, [where] we're pretty rich on clinical trials. These [biopsy results] also allow us to move patients to different clinical trials, depending on how things change in their profile.

[There are] a lot of advantages to liquid biopsies. In that sense, there's another element for ctDNA that's also making its way specifically into the earlier stages [of cancer] and in some very select instances in later stages.