ctDNA Testing Now Valuable Tool in CRC, Next Steps Underway

Pashtoon M. Kasi, MBBS, MD, MS

Circulating tumor DNA (ctDNA) detection via liquid biopsy can be used to noninvasively detect biomarkers as well as monitor patients with colorectal cancer (CRC), but more research is needed to determine its optimal role, explained Pashtoon M. Kasi, MBBS, MD, MS.

“The interesting thing about liquid biopsies, or ctDNA testing, is it can play a role in all phases of a patient's journey with cancer,” said Kasi, a medical oncologist and assistant professor at the Carver College of Medicine at the University of Iowa. “You can see the value of this noninvasive technology throughout the continuum of care.”

In an interview with OncLive, Kasi discussed the use of ctDNA testing throughout treatment for patients with CRC and ongoing research on liquid biopsies.

OncLive: What are the latest updates related to liquid biopsies, especially in CRC?

Kasi: When talking about liquid biopsies, it’s important to know the assay that you are ordering. Some assays may not identify the necessary gene impression or aberration. If that report comes back as negative, that doesn't necessarily mean that the test is negative. That could mean there is not enough shedding or the assay does not, at this point in time, have the capacity to detect it. A lot of these commercially available assays are panel-based and, therefore, are not focused on one tumor. As an oncologist focusing on any type of cancer, it's important to know if it is guideline-recommended, potentially actionable aberrations are present.

Several trials are looking into the value of using [liquid biopsies] to identify quiet mechanisms of resistance. For CRC in particular, we know when anti-EGFR therapies, such as cetuximab (Erbitux) or panitumumab (Vectibix) fail, there are acquired RAS mutations that are present. Historically, it has been shown that you can identify these mutations in tissue as well as in liquid, depending on the methodology used.

At present, it is not practice to rebiopsy these patients, because we were not going to do anything different. However, serial analyses have shown that clones decay over time. You could potentially "recycle" or rechallenge patients with the same treatment that stopped working if the acquired aberration faded away. Because it's not invasive—it's just a blood test—you can now do these repeated assays that you didn't have the opportunity to do before. Currently, the likelihood of the rechallenged treatment working is low. If [the acquired aberrations] are absent, there are patients who respond who could potentially benefit from this approach.

The commercially available assays are also identifying microsatellite instability—high (MSI-H) status. Immunotherapy is now approved as the first tumor agnostic approvals. With this being available as an option, advances for patients with CRC is coming in this subset of patients. The MSI-H or the mismatched repair deficient tumors, which constitutes about 4% of these tumors in the metastatic setting.

For these patients, immunotherapy has unprecedented ongoing durable responses and identification of them in a prompt, timely fashion is of value. Liquid biopsies are not meant to replace tissue testing, rather it is a means to complement ongoing tissue testing. They also fill the void when you may not have tissue specimen in-house. There are situations where a biopsy may not be feasible or safe.

Is tumor sidedness playing a bigger role in treatment decisions?

While the differences in terms of sidedness were recognized for decades, it wasn't until recently that we identified its value as a predictive marker. The interesting thing is that sidedness still plays a role beyond [any] mutations. Furthermore, sidedness is also a continuum in terms of arbitrarily dividing two-thirds of the colon or going up to the splenic sector. The transition point is not black and white.

One example of genomic classification is called consensus molecular subtyping. That has shown, based on gene expression profiling, that CRC is segregated into 4 consensus molecular subtypes. The rise and fall in terms of the numbers and subtypes is a continuum when you move from the right side of the colon, to the left, and to the rectum. Ongoing research is needed; we do not completely understand it.

There have been biomarker-driven studies in CRC. Could you give an overview of the BEACON study, which looked at patients with BRAF-mutant disease?

This year, we saw the BEACON study, which is the combination of BRAF, MEK, and EGFR inhibition for patients with BRAF-mutant CRC. The study met all of its primary and secondary endpoints and is already in the guidelines. Now, there is a first-line study called the ANCHOR-CRC study, which looks at the same combination in the first-line setting. It would be of value to know the mutational or the mismatched repair status [upfront] before you start the first line of therapy.

What do these studies inform about the role of ctDNA in CRC treatment?

Most of the research right now is showing increasing promise in the advanced metastatic setting. An increasing number of assays are being developed for early-stage disease that are more sensitive to determine whether someone should receive chemotherapy.

Some of these trials are incorporating the watch-and-wait approach for CRC. For someone not offered surgery, liquid biopsies could be used to identify these true, complete clinical responders to not have any cancer left behind. In terms of the direction right now, a lot of the research is in the metastatic setting.

However, all the trials and data that have been presented, including some of the studies that were recently published, are looking at the role of liquid biopsy assays in the early-stage and adjuvant settings where you can identify patients who may need a more aggressive approach. [Liquid biopsies] can also be used as a dynamic marker of response and then as a means of surveilling patients after they have been offered curative intent therapy.