Kasi Analyzes Role of Liquid Biopsies in CRC Ahead of 2019 ISGIO Annual Conference

Pashtoon M. Kasi, MD, MBBS, MS

Pashtoon M. Kasi, MD, MBBS, MS

The 2019 International Society of Gastrointestinal Oncology (ISGIO) Annual Conference will cover a variety of topics in the space of gastrointestinal (GI) cancers, including the role of liquid biopsies. Liquid biopsy assays are being used in a number of different cancer types, and now they are demonstrating utility in colorectal cancer (CRC), according to Pashtoon M. Kasi, MD, MBBS, MS.

Liquid biopsies have several advantages over tissue biopsies, such as a less invasive procedure, in a patient as opposed to tissue. These assays can detect aberrations and mutations in the blood that can help inform treatment decisions. By identifying these mutations, physicians will have a better understanding of which patients will respond better to select agents.

By looking at circulating tumor DNA (ctDNA) with liquid biopsy assays, Kasi says physicians may be able to predict response to treatment in patients, and determine who will relapse after treatment. Liquid biopsy assays can detect minimal residual disease (MRD) in the blood, and this will help demonstrate which patients still harbor residual disease after treatment.

One challenge with liquid biopsies, however, is that not all ctDNA will be detected within a single assay. There is a certain sensitivity with these assays, therefore, some residual disease may not appear in the results while it is present in the blood. This can make it more challenging to rely on the liquid biopsy assays to predict relapse in these patients.

In an interview withTargeted Oncology, Kasi, assistant professor of oncology and senior associate consultant in the Division of Hematology/Oncology at the University of Iowa, Holden Comprehensive Cancer Center, discussed the current role and utility of liquid biopsy in CRC, and what he’s looking forward to bringing up during the 2019 ISGIO Annual Conference.

TARGETED ONCOLOGY: What are you looking forward to at the 2019 ISGIO Meeting?

Kasi:So far, we have had some work in the stage IV setting where there is a lot of shedding of cancer DNA in the plasma, or the blood of the patient, so [there are] a lot of commercially available assays available now for ctDNA. There are several [trials] looking at ctDNA in patients with stage IV CRC, and we’ve had some supportive data at ASCO, as well as ESMO.

What’s new and exciting in the world of CRC is now the role of MRD. This is what 1 of the debates at ISGIO will actually focus on: Can you use ctDNA or liquid biopsy, meaning the ctDNA in particular, to direct adjuvant therapy in CRC? [MRD] could be cells, it could be exomes, or other things that you can measure in the persons’ blood. However, in this context, we are focusing on CRC and talking about early-stage CRC. We want to know if they have any residual disease floating around. We [debate] if that could be used to either monitor or do surveillance, or if we can use it to guide therapy in patients with CRC.

As far as we know, in patients with stage III and for a select subset of patients with stage II, all of this made it onto the actual pathology report. These are things we look at in the patient specimen to help us guide and choose chemotherapy.

There was a lot of debate about this in the last couple of years, especially surrounding the duration of chemotherapy and some discussions regarding who benefits more with either doublet versus single-agent chemotherapy. All those things are evolving on the actual pathology of the report of the patient. The question now is can you use liquid biopsy here to direct adjuvant therapy in patients with CRC.

TARGETED ONCOLOGY: Have you seen any research recently looking at this?

Kasi:In the post-surgical MRD population, we have had a number of studies available that all pretty much occurred within this year. Initially, I personally didn’t foresee that these assays and results were already making an impact or can be even close to trials or be available to order in real-time. Interestingly, there are several articles that I continue to see with some of these references. Those will be helpful to show some of the drastic differences that I have been observing.

For most of the studies, what they have done is, after whatever curative intent surgery or treatment the patient received, they had ctDNA collected from the patient to see if you could use that to tell who will have their cancer come back and who had been cured. Not surprisingly, in the patients where there was still ctDNA in circulation, the cancer pretty much came back in every single patient in the different cohorts that had been shown by multiple investigators in multiple studies that have come up with their assays for MRD detection post completion of standard of care therapy. As opposed to the ones who are negative, there are still some who have recurrence of the disease because some of that, as you can imagine, is from the assays having a certain sensitivity, so it can only go so far deep. It depends on the amount of ctDNA that is circulating. Someone may be negative at the time, but later, maybe their cancer will come back while the test was negative, and the person still had some cancer left behind. That’s been the main question. What is that level of sensitivity that these assays? How can we integrate it into practice or, for that matter, trials before we bring it to practice?

TARGETED ONCOLOGY: What other questions remain in regard to these assays?

Kasi:No assays are going to be perfect, so the question right now is within the circles of CRC. What is the acceptable level of detection where we would still be comfortable using the assay if it didn’t detect where it is supposed in a proportion of patients? It’s a topic that is evolving but takes higher priority because you’re potentially deciding on adjuvant therapy based on if they have any ctDNA; you’re making the decision based on the assay itself.

I would say, it’s very exciting to know that many investigators in this space have already come forward. Some of the trials will start sometime later this year, and some of the assays have already been published showing their value, so the trials we have now are for more than a few assays that are looking at the same question in the same space of patients with CRC, and we will have the opportunity to potentially use them more as we gain more data comparing how these assays work because they all have a different approach on how they would be able to detect the MRD better.

TARGETED ONCOLOGY: What else do you hope is covered at the meeting in regard to liquid biopsy?

Kasi:One point that is relevant to to the whole space of liquid biopsies is the fact that there is a lot of utility for liquid biopsies in patients with cancer. One is using it for MRD detection or detection of any residual disease that is left behind. In terms of other areas where some of the experts are already ready for prime time, [we’re looking at] utilizing this for initial molecular profiling. You could potentially use liquid biopsy to identify relevant aberrations or mutations that would help guide treatment.

The other big bucket is treatment monitoring. In terms of predicting response to treatment or identifying the patients who are not responding early, you could potentially limit the amount of exposure to a drug that’s not going to work for them or have early evidence that the drug [won’t work].

Many studies have shown that the capabilities of DNA to detect any of this better than imaging. With imaging, there needs to be a certain size to see improvement, whereas ctDNA can have a lead time by several months in predicting relapse or recurrence, or even response.

It’s been very exciting that now from initial molecular profiling to serial profiling to detect acquired mechanisms of resistance to predict early response or failures; now a lot of that is directed to this MRD space, so you can use that information in those patients who are likely to recur because they already have floating DNA. Some people estimate it’s in the order of ours when you see a patient several weeks before their surgery, they shouldn’t have any ctDNA in their blood. The fact that they are able to detect that is always an ominous sign.