We’ve heard a lot in the news over the last year about how researchers are working to develop a blood test to detect cancer, sometimes referred to as a “liquid biopsy”.
What should we make of all this? A blood test, whether for early detection or to aid in treatment and monitoring, would be a wonderful development. But how close are we really?
As I headed to San Antonio for the annual Breast Cancer Symposium in December, I wondered what we might hear there about progress toward a liquid biopsy for breast cancer. I’ve shared some highlights from the Symposium in a recent post. In this post, I’ll share my impressions from the Symposium on where things stand with work toward a liquid biopsy for breast cancer.
What is a liquid biopsy?
In a traditional biopsy, cells are removed from the area of concern through surgery or using a needle so they can be examined under a microscope. For most types of cancer, a biopsy is the only way to determine for sure if the area of concern is cancer.
A traditional biopsy is of course invasive, and can’t be repeated often, if at all, in order to determine how well treatment is working or whether there are any signs of cancer remaining after treatment has been completed. The possibility of a blood test that could that could do that job has sometimes been described as a “holy grail” in cancer research.
One of the reasons researchers think a liquid biopsy is possible is this: as cells that are growing go through their cycles and gradually die off, they release fragments of DNA into the bloodstream. One type of liquid biopsy would look for such fragments of “circulating tumor DNA” and analyze them to identify any that have specific mutations linking them to the presence of cancer.
The main challenge
At the beginning of the week in San Antonio, I attended an excellent presentation by Dr. Maximilian Diehn of the Stanford University School of Medicine on the current status and outlook for circulating tumor DNA analysis for liquid biopsies.
Dr. Diehn said that the main challenge in developing a liquid biopsy that will be ready for patients is that it needs to be very sensitive. He explained that the total amount of all types of circulating DNA fragments in the bloodstream is not very high to begin with, and that the fraction of that circulating DNA that is possibly from a tumor is often very small.
Standard techniques for genome sequencing have not been able to reach that level of sensitivity, but there are new techniques that are much more sensitive and able to detect very small amounts of circulating DNA. These techniques continue to be refined and some are already being tested in early clinical trials.
How could a liquid biopsy be used in breast cancer?
There are actually a number of different ways in which a blood test for breast cancer could be used. Dr. Diehn talked about five possible uses. Four would aid in the treatment or monitoring of patients who have already been diagnosed with breast cancer. He noted that these possible applications apply for several major types of cancer, including breast cancer.
The first application, which Dr. Diehn said is already starting to move into the clinic, is to use a blood draw to determine what mutations a patient’s tumor has. This would provide important information about treatment options without the need for a surgical biopsy, which in some situations may not be practical or appropriate.
The second use would be to monitor how a patient is doing on treatment. A blood test would be easy to run repeatedly over time to find out how the disease is responding to treatment. This type of test might be used very early during treatment to see whether a particular therapy is going to be beneficial for a patient.
The third possible application is closely related to the first two. The idea would be to identify mutations present in a patient’s tumor that suggest it is likely to be resistant to a particular treatment. This could be very important in deciding on the use of targeted treatments–if there is a mutation present that causes resistance, treatment is less likely to be effective.
These first three applications are already beginning to be testing in clinical trials for patients with metastatic disease.
And what about earlier stage patients? Dr. Diehn was encouraging about prospects for a blood test that could be done after treatment has been completed to get an early indication of whether there is any minimal disease present after treatment. He said that it is “quite likely that we will be able to use circulating tumor DNA in the future to identify which patients are at highest risk” for a recurrence after treatment. He said that for patients that are at higher risk, clinical trials could be designed to test whether additional specific types of treatment such as a targeted therapy or immunotherapy help to improve outcomes for them.
Finally, there is a possible future application for early detection in cancer screening. The idea would be that a blood test could be done as part of a routine annual physical. The blood would be checked for circulating tumor DNA that reveals a pattern of mutations that could identify the type of cancer and where in the body it is located. The blood test could then be followed up with imaging and other tests as appropriate. This potential use is the hardest, Dr. Diehn said, both because the tumors we’re looking for would typically be very small and we wouldn’t even know what mutations we’re looking for because we don’t know if a tumor exists.
In conclusion, Dr. Diehn said that there are existing tests or “assays” ready for testing now for some of these applications, especially the first three. But clinical trials are needed to prove that they really do work as it’s expected they will. And for the other applications, he suggested techniques will need to be further refined to improve detection limits.
Use in treatment decisions for metastatic breast cancer patients
Two studies presented later at the Symposium seemed to provide more evidence in support of the use of liquid biopsies using circulating tumor DNA analysis to help in treatment decisions for patients with metastatic breast cancer. Both studies were related to clinical trials for patients with estrogen receptor-positive metastatic breast cancer.
In the first study, presented by Dr. Sarat Chandarlapaty, investigators analyzed stored blood samples from a completed clinical trial called BOLERO-2. They found that certain mutations in the gene for the estrogen receptor were very common in ER-positive metastatic breast cancer patients. Overall, the drug being studied–everolimus (Afinitor)–when given along with hormone therapy more than doubled progression free survival. But those patients who had estrogen receptor mutations had worse outcomes than those who did not, suggesting perhaps that this was not the optimal treatment choice for patients with the mutations.
In another presentation, Dr. Jose Baselga discussed the first results from an ongoing Phase III clinical trial called BELLE-2. The first results from this study are showing that patients who have a mutation in the PIK3CA gene–discovered through a blood test–had much higher response rates to a treatment combination designed to block the pathway triggered by this mutation than those who did not have the mutation.
So, both of these studies suggested that a blood test could help to identify metastatic breast cancer patients who would or would not benefit from specific treatments. Audience members seemed to respond with a great deal of interest to both of these presentations. It was asked how long it would be before liquid biopsies using circulating tumor DNA analysis would be available for physicians to use in the clinic. The researchers stressed the importance of clinical trials to confirm and validate the findings from these preliminary studies.
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