Liquid Biopsies Identify Mechanisms of Resistance in Gastrointestinal Cancers

Aparna Parikh, MD

In an effort to overcome resistance to targeted therapies in gastrointestinal (GI) cancers, investigators have begun using liquid biopsies. This strategy collects circulating tumor DNA, which can identify heterogeneous resistance mechanisms both prior to and during therapy.

In a study presented at the 2017 ESMO World Congress on Gastrointestinal Cancer, plasma was collected at disease progression from 35 patients who had molecularly-defined GI cancers—24 with colorectal, 8 with biliary, and 3 with gastroesophageal. To identity mechanisms of resistance, molecular alterations in each individual patient were compared to their circulating tumor DNA.

Patients were routinely rebiopsied and circulating tumor DNA specimens were evaluated to determine if change in levels predicted response to targeted therapy.

Investigators concluded that systematic analysis of circulating tumor DNA at disease progression can identify heterogeneous mechanisms of acquired resistance in this population of patients.

In an interview with OncLive at the GI congress, lead investigator Aparna Parikh, MD, Massachusetts General Hospital, discussed the potential impact of liquid biopsies in overcoming resistance to targeted therapies in gastrointestinal cancer.

OncLive: Please provide an overview of this study.

Parikh: Knowing that patients often develop drug resistance to targeted therapy, we started to look over treatment course, looking to see how patients did with the use of liquid biopsies. Tissue biopsies may not capture the entirety of the tumor. In terms of heterogeneity, if you were to biopsy different tumor lesions, as well as different spots in the primary tumor, you may not capture the molecular underpinnings of the tumors.

We started to do liquid biopsies in our clinical practice under research protocol to follow patients over time to monitor how they were doing with targeted treatments. At the time of developing drug resistance, we do another liquid biopsy. What this work showed us was that in the blood, you can follow how patients do and start identifying mechanisms of resistance in the blood.

What we ended up finding, was that even in patients who had a biopsy at progression, the liquid biopsies could show an underlying mechanism of resistance—and sometimes multiple resistance mechanisms—in 64% of the patients.

So how would this tool be put into practice in GI cancers?

Once you understand the mechanism of resistance, there is not always necessarily a drug for it, but with a newer generation FGFR inhibitor, you can actually target the mechanisms of resistance. With the example that we provided in the talk, just allowing us to see what the mechanism of resistance was, particularly 1 that seemed to be merging, we took a break with therapy, radiated a lesion, and then were able to resume the patient on targeted therapy. With that particular patient, we were able to go back on the drug and he had a response again. Understanding what the resistance mechanism is, even if there isn’t a drug available for that target, we might be able to come up with other strategies to overcome resistance.

I think as Dr. Heinz-Josef Lenz pointed out in his discussion, it may not just be 1 drug fits all, it may be a combination strategy. But, at least the liquid biopsy is allowing us to understand what those drivers of resistance are.

What needs to be done in order to move liquid biopsies out of the research setting?

The nice thing about what we are doing in our program is that we are doing it for all patients on targeted therapies. What we are also doing now in our group is looking at patients who have surgical resection and seeing if you can measure circulating tumor DNA in the blood after surgery, particularly curative intent surgery—using that as a marker of minimal residual disease. We are also now using this approach for patients that are on chemotherapy, so not necessarily a targeted agent, and immunotherapy to see what happens.

I think if you have the resources to do it, and were doing it under a single protocol, we are now basically doing it for all of our patients. We are also using it in the setting of radiation to see what happens to circulating tumor DNA in the blood over the course of radiation. So, I think there is a lot of different applicability, and just understanding the limitations of the liquid biopsy techniques, and as Dr. Lenz also mentioned in his discussion, maybe the use of circulating tumor RNA in the blood as well.

There is a lot of different applications so we'll just have to see which technology is the right technology and how to best use these, particularly under an environment where resources are constrained.

What do you hope that community oncologists took away from your presentation?

I think my take-home message was that liquid biopsies are feasible, and in our data—as well as other work that is being presented—we showed that they are more sensitive than tissue biopsies.

I don't want to take away from the importance of tissue biopsies, because they are important, but they may grossly underrepresent the heterogeneity of the tumor. So, it is important to understand the feasibility of the approach, and the sensitivity of the liquid biopsy in adjunct or as a replacement for tumor biopsies.

Are there any challenges that remain in the adoption of this technique?

A lot of the kinks, particularly getting a blood draw prior to the start of treatment, that was a missed opportunity for many patients. Patients would get a blood draw after treatment started, but not necessarily before, so you’d miss that window of opportunity to understand what happened prior. But, these kinks are being worked out.

We are working closely with Guardant Health, and they have a nice system in place where, for certain copays for patients, they’ll help with the cost of that, too. Right now, it has worked out well, but we do not have an in-house blood-based sequencing platform yet. The Corcoran Lab at Massachusetts General Hospital has a…platform—which is used really for research purposes. Right now, we are really relying on Guardant Health.

I am not sure where the liquid biopsies are going to be covered in the reimbursement space as they are used in clinical practice moving forward, that is to be determined. It has worked out okay thus far, but we will have to see as time evolves.

Parikh A, Goyal L, Hazar-Rethinam M. Systematic liquid biopsy identifies novel and heterogeneous mechanisms of acquired resistance in gastrointestinal (GI) cancer patients. Ann Oncol 2017; 28 (suppl_3): mdx262. doi: 10.1093/annonc/mdx262.

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View more from the 2017 World Congress on GI Cancer

Hopefully, as drug development goes forward, we will be able to use these in a more practical way for our patients.