Role of Liquid Biopsies Still Needs Refining in Breast Cancer

Aditya Bardia, MD, MPH

There will likely be an increased use of liquid biopsies in the field of breast cancer in the coming years, especially as more data and targeted therapies become available, according to Aditya Bardia, MD, MPH.

“As long as we have an actionable result, as long as we have a targeted therapy that we could select based on liquid biopsy, I think we are going to see an increased use,” he said.

While the diagnostic approach has become a more standard option to help inform treatment decisions in lung cancer, more data are still needed to determine the role of liquid biopsies for patients with breast cancer, he explained.

To date, no prospective trials have demonstrated the clinical utility of liquid biopsies in breast cancer, however, Bardia believes there will be an increased use of liquid biopsies as additional targeted agents move through the pipeline and more evidence showcase the potential benefits of this type of analysis.

In an interview with OncLive, Bardia, medical oncologist at Massachusetts General Hospital, discussed the potential role of circulating tumor cells (CTC) and circulating tumor DNA (ctDNA) testing in patients with breast cancer.

OncLive: What is the current role of liquid biopsies in cancer?

Bardia: Liquid biopsies can be divided into 2 broad categories. One would be CTCs, so essentially looking at tumor cells in the blood. The second would be ctDNA. That is looking at tumor fragments in the blood. Most of the evidence about the prognostic role of liquid biopsy comes from studies done with CTCs. There have been multiple studies that have demonstrated that patients who have elevated levels of CTCs have a worse prognosis compared to those that do not have the effect of those detectable CTCs. These studies were done in breast cancer, prostate cancer, bladder cancer, and they have consistently shown that elevated levels of CTCs are associated with worse prognosis.

What are the advantages of using liquid biopsies?

The main advantage of liquid biopsy is that it’s relatively noninvasive. If you compare liquid biopsy to tissue biopsy, for tissue biopsy you need a site, be it the bone, the lung, or the liver, to biopsy, which can be a relatively invasive procedure. The advantage of liquid biopsy is that it is a blood test; it’s relatively noninvasive. If you can get the same information with a liquid biopsy as compared to a tissue biopsy, then that is a major advantage from a patient perspective.

The other advantage of liquid biopsy is that’s it’s much easier to monitor tumor evolution. It’s much easier to obtain multiple blood draws as opposed to getting multiple tissue biopsies.

How can results from a liquid biopsy be used to inform treatment decisions for a patient?

The liquid biopsies, particularly plasma-based genotyping, can be helpful in selection of genotype-matched therapy. For example, if a patient has an EGFR mutation in a liquid biopsy, one could utilize that for selection of an EGFR-directed therapy. If a patient has a PI3K mutation, one could select that for either triage to a PI3K inhibitor trial or if a PI3K inhibitor is FDA approved, one could utilize that for selection of a PI3K inhibitor. Essentially, liquid biopsy could be used for selecting matched-therapy based on the genotype.

What are the challenges associated with liquid biopsies?

One of the major challenges of liquid biopsy is the interpretation of the results. It’s really like finding a needle in the haystack. If you detect something in the blood, is it something that is functionally relevant? Is it a driver mutation as opposed to a passenger mutation? Those are important considerations. Just because you’re detecting something in the blood, it does not mean that it is important or that it is driving the tumor.

Why do you think there has been some resistance to using liquid biopsies in breast cancer?

The major challenge is demonstrating the clinical utility. If we look at the concerns, one concern would be, as I mentioned earlier, the functional significance of what we see in the blood. If an alteration is present, is it a driver alteration versus a passenger alteration? There are also concerns that if you’re seeing something in the blood, it might not be related to the tumor. You could be picking up alterations that are present in normal cells or are a part of clonal hematopoiesis from the white blood cells or the bone marrow precursors. If you’re picking up those abnormalities that are not related to the cancer, then you could go down a path that would not be beneficial for treating the cancer.

The other disadvantage with liquid biopsy at this time is that we don’t have demonstrated clinical utility. In breast oncology, the field has been, if you will, burnt by the CTC studies, which looked at patients that had elevated CTCs. If they continued to have elevated CTCs despite treatment, they were randomized to continue the same treatment versus randomized to a different treatment. That trial showed that there was no survival advantage if you were to switch therapy based on the CTC count. One could argue that yes, you are detecting these alterations in the blood, but does it improve outcomes? That is something that has not been shown yet in breast cancer, and that is why there is some skepticism about using liquid biopsy as part of the routine standard of care.

Can you discuss some of the recent trials that looked at liquid biopsies?

Most of the liquid biopsy studies have been done as a biomarker or add-on study to an existing trial. In breast oncology, with the development of PI3K inhibitors, most of the trials also had blood banked to look at PI3K mutations in the blood. A second reanalysis looked at whether the PI3K mutation was present in the blood versus not and what impact that had on the survival with the use of a genotype-directed therapy.

At this time, we don’t have a prospective trial that has demonstrated clinical utility of ctDNA in breast oncology. As far as CTCs go, there are again a number of secondary analyses as well as in the adjuvant settings which have shown that patients with elevated CTCs have worse prognosis. There was a trial by the ECOG group in the adjuvant setting which showed that patients who had elevated CTCs in the adjuvant setting were much more likely to have a relapse as compared to patients who did not have elevated CTCs.

Now we need studies that can demonstrate the clinical utility of either finding the ctDNA or CTC, and that would eventually increase the utilization of liquid biopsies in practice.

Where could liquid biopsy have the most significant benefit?

I think the role of liquid biopsies would be for therapy selection, therapy monitoring, and understanding the mechanisms of resistance. From a therapy selection standpoint, genotype-based liquid biopsy or plasma-based genotyping would be very helpful because based on the genotype, one could select a matched targeted therapy. From a monitoring perspective in patients who have a certain mutation and are receiving a targeted therapy, you could monitor that mutation as a pharmacodynamic biomarker to see if the therapy is working as far as innovating that pathway is concerned. Finally, in terms of resistance, if you look at the liquid biopsy at the time of disease progression, you could find new mutations, particularly acquired mutations, that are leading to therapy resistance. That could potentially inform why the treatment stopped working, but it could also guide to the next therapy. A good example of this is the discovering of acquired HER2 mutations in patients who are receiving endocrine therapy. If you notice that a patient has acquired a HER2 mutation, it would explain why the endocrine therapy stopped working, and you could use a matched therapy directed against the HER2 mutation.

Do you think liquid biopsies could one day have as much of a role in breast cancer as they do in lung cancer?

I think thoracic oncology was the first field that demonstrated the role of liquid biopsy. Liquid biopsies are routinely used in the management of patients with metastatic lung cancer. In breast cancer, with the development of targeted therapies, be it the PI3K inhibitors or the AKT inhibitors or HER2 inhibitors, I think we would see more utilization of liquid biopsies. As long as we have an actionable result, as long as we have a targeted therapy that we could select based on liquid biopsy, I think we are going to see an increased use.

What should the community know right now about liquid biopsies?

The key with liquid biopsy is the interpretation of the result and how to act upon the result. If you are seeing a specific alteration, is it something that is functional? Is it something that is driving the tumor? That is an important determination to make. The second is to find the matched therapy. If that matched therapy is not available as the standard of care, then look for that matched therapy in a clinical trial or have access to an academic center that does a lot of precision medicine trials. That’s going to be key.