ctDNA Emerges as Promising Biomarker for Lymphoma

David M. Kurtz, MD, PhD

Circulating tumor DNA (ctDNA) has piqued the interest of researchers as an emerging method to detect and diagnose various malignancies, including lymphoma. David M. Kurtz, MD, PhD, said that this technology will be coming to the clinic soon, and may be as routinely used as a PET or CT scan is to detect disease.

“ctDNA is different,” said Kurtz. “This is something that we need to educate all providers about and decide how we are going to use this moving forward in our routine clinical paradigms.”

Utilizing liquid biopsies to collect ctDNA in conjunction with next-generation sequencing (NGS) is a method that is being used across multiple tumor types including breast cancer, non—small cell lung cancer, and sarcoma. In lymphoma specifically, ctDNA can be used to monitor the disease throughout therapy, including at relapse and at the completion of therapy, according to Kurtz.

OncLive: What is the current clinical use of cell-free DNA?

In an interview with OncLive, Kurtz, instructor of medicine, postdoctoral fellow, Divisions of Oncology and Hematology, Stanford Cancer Center, Stanford University, discussed the clinical use of ctDNA in lymphoma. Kurtz: Cell-free DNA is an emerging technology for detecting and diagnosing malignancies, including lymphomas and other solid tumors. It represents a small fraction of total healthy cell-free DNA that we are looking for that is called ctDNA. Of all the cell-free DNA molecules that you may find in a patient's plasma, about 1% or less are derived from the patient's lymphoma. What we in the lab have worked on over the last 5 years are methods to detect a patient’s lymphomas using ctDNA. There are several different methods for detecting ctDNA.

Can you go into more detail about detecting ctDNA?

What are some of the challenges with this method?

There are a number of different uses for ctDNA in lymphomas. This includes monitoring a patient's disease during the course of therapy, monitoring for disease relapse at the completion of therapy, and also looking to investigate the actual biology of how a patient's lymphoma evolves under the pressure of treatment, and eventual relapse.For detecting a patient’s lymphoma using ctDNA, we need to know what mutations drive the lymphoma. We start by taking a biopsy of a patient’s tumor or a sample prior to therapy and sequence that using an NGS platform. Once we have identified the molecular bar code that represents a patient's lymphoma, we can then track that over time from their blood plasma. By getting a simple blood draw, we can isolate DNA from the plasma and sequence that. Using this prior knowledge of the molecular fingerprint, we can track their disease over time as they respond to the therapy and hopefully achieve a remission. For patients in whom we are worried about recurrence, we can sequence blood plasma samples during the period of monitoring for disease recurrence and try to detect that disease earlier than a clinical exam, or imaging studies like PET scans or CT scans. There are 2 groups of challenges—technical challenges and logistic challenges. The technical challenge that I previously mentioned was that ctDNA is often less than 1% of all the cell-free DNA that is in the blood plasma. Detecting things at these low levels requires a lot of work in the lab to optimize the techniques and reduce the noise of sequencing. That is what we have been working on for the past 5 years. We have a pretty good assay now called CAncer Personalized Profiling by deep Sequencing (CAPP-Seq). We are ready to move forward in the clinic.

That brings me to the logistic challenge of implementing these into the clinic. This is the hurdle that the field is facing now. One of the biggest logistical questions is using ctDNA to select therapy for patients—can we use this to identify patients who are not responding to frontline therapy and escalate their treatment to more aggressive therapies, such as an autologous bone marrow transplant or chimeric antigen T-cell therapy? Could we even potentially find patients who are responding very well to therapy and abbreviate their course, giving fewer than 6 cycles of R-CHOP as our standard therapy for diffuse large B-cell lymphoma? Deciding how to implement this is a big challenge.

What is your takeaway message for ctDNA in lymphoma?

There is also the challenge of paying for the NGS, which is an expensive technology. Prices are coming down, but there is going to be a major challenge in implementing this in the right time points and in a cost-effective way for our patients. I hope that providers know that the idea of ctDNA is here to stay. There have been a lot of biomarkers that have come in with a lot of “sizzle” and “heat” that have not really panned out as things that we can implement in the clinic.

This is something that will be coming to a clinic near you in the future. It is an emerging technology that is going to be written into clinical trials in the next 1 to 2 years, and hopefully become as common of a method for detecting disease, and monitoring patient's disease as a PET/CT scan might be in the clinic today. This is the exciting challenge of the field in the next 5 to 10 years.

These are the things that we are excited about in our group at Stanford University, and we are excited to work with everyone in the field moving forward.