Further Evidence Needed Supporting Clinical Utility of Liquid Biopsies in GI Cancers

John Strickler, MD

Liquid biopsies offer a potential precision medicine approach in patients with gastrointestinal (GI) cancers, as they provide clinicians with information to guide treatment decisions in a minimally invasive way. However, more data are needed to support the clinical utility of these assays, said John Strickler, MD.

“Currently there are commercially available cell-free DNA (cfDNA) assays, which we can use in the clinic and we know that those assays have analytical and clinical validity,” said Strickler, assistant professor of medicine, Duke Cancer Institute. “We order them in select circumstances. But in terms of showing clinical utility—that’s still a work in progress.”

One of the biggest challenges in cancer care as a whole is finding ways to overcome resistance mechanisms that develop in response to targeted therapies, he explained. In an effort to identify these mechanisms, investigators can perform repeat biopsies at the time of disease progression and use that information to decide on new treatment approaches to overcome that resistance.

However, it has become clear that several heterogeneous resistance mutations can emerge within the same patient.

“One mutation by itself might be druggable,” said Strickler. “But, we can't target all 15 mutations at the same time.”

OncLive: How are liquid biopsies being used to help better understand genomic drivers of acquired resistance?

Are any clinical trials further evaluating liquid biopsies in GI cancers?

In an interview with OncLive, Strickler discussed how liquid biopsies are being used to help guide treatment decisions for patients with GI cancers and shed light on other research efforts that are being made to improve outcomes.Strickler: In general, we're using these liquid biopsies in distinct scenarios—in cases where tissue is not available or we think that the tumor might have evolved over some period of time, so much so that the initial tissue biopsy is no longer representative of the tumor that we are now treating. [We’re also using these biopsies when] rebiopsy is either not feasible or not in the best interest of the patient. We can currently use the liquid biopsies in these select circumstances to hopefully guide treatment for our patients.2019 will be a big year for beginning to use liquid biopsies and incorporating them prospectively into clinical trials. What we’ll see in the near future is the use of the liquid biopsies to select patients for certain therapies or to select those who might be candidates for adjuvant chemotherapy, for example. This is something that we're excited about because this could change practice for patients with GI cancers.

What are some current themes or hypotheses coming out of this research?

Where do you see future research headed with these assays?

Beyond liquid biopsies, what exciting advances have been made in GI cancers as a whole?

Also, some interesting work done by my colleague Ryan B. Corcoran, MD, PhD, of Massachusetts General Hospital, looked at drivers of resistance to targeted therapies. It used the liquid biopsy as a potentially better way to sample the complete tumor burden to identify alterations that could be targeted with specific therapies, or to identify alternations that would not be from a simple lesion biopsied with a single needle. Sometimes, there are scenarios where performing a genomic profiling on the complete tumor burden provides a more accurate picture than a biopsy of just a single lesion.The first is that there may be certain types of variants detected in blood that would potentially predict benefit from targeted therapies. We've reviewed some cases of HER2 amplification as a potential targetable alteration that can be picked up in blood. Also, patients may have developed resistance to an anti-EGFR antibody and then we used the liquid biopsy to identify patients who might be candidates for an EGFR antibody rechallenge, which is essentially finding signals in the blood that the patient may benefit from rechallenging with a therapy that they previously progressed on.Currently, we know that [liquid biopsies] have good analytical and clinical validity, but there are not a lot of data on the clinical utility outside of individual case reports—at least in GI cancers. Therefore, where I see this headed is more well-performed, well-conducted studies showing that when we use the blood-based assay in sample cfDNA, we can actually change outcomes for our patients for the better.Increasingly in the treatment of GI cancers, we're making breakthroughs on 2 levels. The first type of breakthrough is in the form of more incremental advancements, where we're finding new therapies that provide modest survival benefit. That is 1 group of discoveries that has been ongoing for the last several years.

On top of that, we're finding that there are individual therapies that are a paradigm shift for our patients. It may be a rare patient population, but when we find that biomarker, we are able to completely change the survival for those patients in a fairly dramatic way. [This is the case] whether it be microsatellite instability-high disease, predicting benefit from immunotherapy, ERBB2 or HER2 amplification to predict benefit from HER2-targeted therapies, or, in even more rare cases, NTRK fusions to predict benefit from TRK inhibitors.

What kind of challenges need to be overcome in order to move the needle forward?

There are exciting clinical trials in the space. Some trials are incorporating novel diagnostic assays, such as cfDNA profiling, to potentially select patients for therapies. There are also new trials coming into the immunotherapy space to potentially find ways to make patients sensitive to therapies that they normally would not respond to. There are several exciting different areas of research for us in the clinical research space, and we look forward to bringing these trials into the clinic.There are several challenges for patients with GI malignancies. One challenge is the fact that many patients have mutations that confer resistance to targeted therapies. The classic example is a KRAS mutation, which is still very difficult to target with investigational or FDA-approved therapies.

Additionally, we see, particularly in colorectal cancer, heterogeneity of resistance. This means that a patient will not just develop 1 mechanism of resistance. Sometimes, they can develop 10 to 15 simultaneous resistance mutations. That presents a challenge for us in the GI world and it is an issue that we will continue to work to address.