The Status of Liquid Biopsies in Metastatic Cancer

This article was written by Joan Mancuso.

As a woman living with metastatic breast cancer, I’ve always dreaded getting a tissue biopsy of a metastasis. Even though the biopsy yields information about the tumor’s pathology and potentially affects my treatment options, I consider it a necessary evil. Tissue biopsies are usually uncomfortable, and I get anxiety about the potential danger that goes hand in hand with an invasive procedure to sample the tumor. For those reasons, liquid biopsies from blood draws are very appealing.

At this year’s annual meeting of the American Society of Clinical Oncology, I attended a session about liquid biopsies. It was given by Dr. Luis A. Diaz who is associate professor of clinical oncology at Johns Hopkins University. Dr. Diaz spoke about several uses of liquid biopsy tests, such as monitoring therapeutic response and tumor resistance for those of us living with metastatic cancer, as well as the pros and cons of such tests at this point in time.

According to Dr. Diaz, “the field of liquid biomarkers has really exploded.” It started with protein biomarkers and began to include circulating tumor cell (CTC) tests about 10 years ago, he said. Two protein biomarkers for breast cancer are CA15-3 and CA27-29, for example.

In his presentation, Dr. Diaz discussed how circulating tumor DNA (ctDNA) tests are much more specific than protein biomarkers in monitoring tumor burden and identifying somatic mutations leading to tumor resistance. And many of us know that tumor markers are not useful in keeping track of cancer for everybody.

Unlike germline mutations, which are hereditary, somatic mutations occur after conception. These mutations are present in the blood in small fragments that come only from the tumor, which is different from normal sources such as the bone marrow, gastrointestinal tract and skin, for example, Dr. Diaz said. However, one caveat is that the mutations sometimes do occur in the later decades of life when cancer may not be present, he noted.

Monitoring therapeutic response

ctDNA tests can follow changes in a metastatic patient’s tumor burden and help determine how well the patient is responding to therapy, Dr. Diaz said. He was involved in a study which showed that ctDNA tests over time in pancreatic cancer were more accurate in tracking the cancer than a protein biomarker (CA19-9), in a patient who had an excellent response to aggressive, combination chemotherapy.

A comparison of the two tests showed that the CA19-9 marker continued to drop until the patient’s cancer recurred, but the ctDNA tests showed three spikes. The first spike corresponded to the killing of cancer cells a few months after the patient started treatment (meaning that the cells were shedding into the blood). The second and third spikes corresponded to the patient resuming chemotherapy after taking two breaks from treatment. According to Dr. Diaz, the ctDNA tests showed “real time” response, which was not seen with the biomarker or by imaging.

Acquired tumor resistance

ctDNA tests can help scientists understand how metastatic tumors acquire resistance to targeted therapies over time, Dr. Diaz said. And the test results can help those of us living with metastatic cancer determine whether to change our course of treatment.

Dr. Diaz took part in a study that involved a colorectal cancer patient who was taking an epidermal growth factor receptor (EGFR) blocker for that cancer. Over time, the patient’s tumor started to become resistant to the inhibitor. (In breast cancer, a different EGFR blocker—lapatinib—is used for patients who have the HER2 positive subtype.)

In the study, blood was drawn periodically and evaluated. After awhile, it became clear that somatic mutations were emerging which were not seen initially. The same effect was observed in another study where a patient with non-small-cell lung cancer acquired resistance to a different EGFR inhibitor, Dr Diaz said.

These observations point to potential opportunities to change systemic therapy or enroll in a clinical trial for metastatic breast cancer or a basket trial, all based on the identification of a new mutation. In a basket trial, patients with different types of metastatic cancers (e.g., breast, lung, colorectal and ovarian) who have the same type of mutation enter into a clinical trail to evaluate a drug that targets that mutation.

Challenges to liquid biopsies

If CTC tests are useful in monitoring treatment response and discovering somatic mutations that lead to resistance without using an invasive tissue biopsy, why do some oncologists still resist using the tests?

Dr. Diaz noted the pros and cons of two different categories of tests. He said that the digital PCR test is “cheap and fast,” but “you need to know [which mutation] you’re looking for ahead of time.” The results of the test are highly accurate but limited because there’s no chance of discovering other mutations. Relatively speaking, digital PCR is a simple test: It doesn’t require extensive bioinformatics, meaning the collection and analysis of the complex biological data involving genetic codes does not have to be rigorous.

Although the next-generation sequencing test can be used to reveal somatic mutations that may not be suspected ahead of time, it has a high error rate, Dr. Diaz noted. The test is expensive and the turn around time is 1-2 days at best. In order to move ahead, the test needs technological improvements in combination with very advanced bioinformatics, to separate a false positive from a bona-fide mutation, Dr. Diaz said.

The future

Digital genomics has improved biomarker sensitivity, but broad commercialization will require overcoming cost, setting regulations and working with insurance payers, as well as demonstrating significant benefit through clinical trials, according to Dr. Diaz.

Low-cost, effective CTC tests would improve the quality of life for metastatic cancer survivors. The quicker they come to market, the better for us.




Joan is a helpline volunteer, member of SHARE Leaders, and a consumer reviewer at the Department of Defense Breast Cancer Research Program. She also facilitates SHARE's metastatic breast cancer support group, Living with Uncertainty.