Tests in development to detect circulating tumor cells that escape from solid tumors and travel through the blood, spreading cancer to new sites, may serve as an alternative to conventional tissue biopsy for early cancer diagnosis and gene-expression analysis over the next decade. According to Massimo
Cristofanilli, MD, FACP, Director of the Jefferson Breast Care Center and Deputy Director of Translational Research at the Kimmel Cancer Center at Thomas Jefferson University and Hospitals in Philadelphia, blood tests called “liquid biopsies” will provide oncologists with more accurate information of the cancer’s biology, its aggressiveness, and whether treatment is working than information currently gleaned from tissue biopsy analysis.

“Tissue biopsies have been disappointing because right now they are not helping to cure patients. There must be some limitation in the tissue analysis and the information we get from the tissue,” said Dr. Cristofanilli. “It may be that we are missing an additional piece of information that comes from the blood.”

In 2004, Dr. Cristofanilli published a study¹ showing that breast cancer patients with more than five circulating tumor cells in the blood had more aggressive forms of the disease and significantly shorter progression-free survival (2.7 vs 7 months) and overall survival (10.1 vs > 18 months) than women with fewer than five circulating tumor cells per blood draw. In addition, the presence of circulating tumor cells more accurately predicted a patient’s prognosis than either the site of metastatic disease or the tumor’s estrogen receptor status.

Currently, the only circulating tumor cell test approved by the U.S. Food and Drug Administration to monitor disease progression in patients with metastatic breast, prostate, or colorectal cancer is CellSearch. The test’s drawback is that it only counts circulating tumor cells and cannot capture them, which would allow oncologists to monitor treatment effectiveness. However, newer tests are in development that will allow cells to be both counted and sequenced as biomarkers for use in personalized treatment.

The ASCO Post talked with Dr. ­Cristofanilli about the accuracy of liquid biopsies in detecting and analyzing cancer, their potential use as a tool for cancer screening in healthy people, and how they can provide accurate prognostic information in patients with recurrent disease.

Real-Time Evaluation

How accurate are liquid biopsies in detecting malignant cells in the peripheral blood of patients with cancer?

The information is very accurate. When you look at the blood of patients with cancer it gives you a real-time evaluation and deeper understanding of not only the disease biology based on modification of the genes, but also the metastatic process and how that process modifies with treatment.

The circulating tumor cell test has been available for about 10 years. In retrospect, I think this was a very innovative concept for which we can now imagine that solid tumors also have a liquid phase allowing for detection and enumeration, and quantification of cancer cells in the blood—a totally different environment for those tumors. The enumeration actually provides information about the disease outcome. Every time a patient undergoes a liquid biopsy, the number of circulating tumor cells found in the blood reflects what’s going to happen to the patient in the following month or years.

Over the next 5 to 10 years, we are going to develop a number of different sensitive circulating tumor cell technologies with which we won’t have to access the tumor tissue any longer, and we will have a chance to be informed about the patient’s disease and other factors, including the patient’s immune system before and during treatment. We will be able to detect disease progression without using imaging tests, which have been essentially guiding our treatment decisions and monitoring response for years.

Convenience Factor

In terms of its value in cancer care, would a liquid biopsy be not only more informative than a tissue biopsy, but also more convenient for the patient?

It definitely would be easier on the patient. I suspect it would also be easier on the health-care system, because instead of having to do many imaging studies to track cancer progression and treatment effectiveness, we would have a biologic way to monitor the disease at a less expensive cost.

Sequencing Technologies

How would liquid biopsy be used to sequence circulating tumor cells in the peripheral blood?

In addition to being able to detect circulating cancer cells, we will be able to detect and monitor immune cells, such as circulating cancer-associated macrophage-like cells or specific subsets of lymphocytes that can indicate a more aggressive disease. Another example is if a patient with breast cancer is estrogen receptor–positive and receiving endocrine therapy, we will be able to detect the number of circulating tumor cells and see whether that patient harbors a PIK3CA mutation, suggesting more sensitivity to certain targeted therapies. Then we can monitor the patient over time while she is receiving treatment, see if the cancer cells are disappearing and if another mutation appears, and determine the predominant mechanism of resistance.

Alternatively, the lack of circulating tumor cell detection—and of an actionable mutation—might suggest that we could simply use a less toxic endocrine therapy. Currently, we have to serially biopsy the tissue over time to get this information. Also, if the patient has a disease that cannot be measured through a tissue biopsy, we would have to use a sequence of positron-emission tomography/computed tomography scans or other imaging to see the state of the cancer.

These tests might not be necessary if you have a very sensitive blood test that allows you to measure microscopic or minimal residual disease. The real challenge is to be able to obtain such information in all patients with advanced disease. In this regard, I think the future is in the integration of different blood-based detection methods. Circulating tumor cells obviously have the advantages we’ve highlighted, but current methods do not detect tumor cells in 100% of patients and, more importantly, the detection of very few cancer cells limits the ability to do a genomic analysis and find a mutation.

If you also use DNA sequencing technologies to analyze circulating free DNA, you might have a complete understanding of what the tumor representation is within the blood. The circulating tumor cells may reflect more of the stem cell–like cells, the cells that are responsible for the new metastases, and the DNA circulating cells may be reflecting the bulk of the metastatic tumor.

The bottom line is that the blood has everything that you need to know to understand disease biology, select treatment, and predict outcome.

Screening Potential

Eventually, could liquid biopsy become part of routine cancer screening in healthy people? And what is the prognostic value of such a screening test—would you be able to determine whether the circulating cancer cells will progress to aggressive cancer or are safe to leave untreated?

In terms of screening healthy people, we are not at that point yet. Liquid biopsy analyses would have to be sensitive enough to detect when the tumor is really releasing cancer cells. We may imagine that the process of cancer development from in situ to invasive disease could be associated with the activation of innate immunity and such changes might be detected in the blood before they show up on an imaging scan. Another possibility could be the detection of products of tumor metabolism related to the cancer.

In terms of the prognostic value of circulating tumor cells, more data are needed to determine the accuracy of such an approach. The data suggest that if we are able to detect circulating tumor cells along with circulating macrophages, we will have the ability to predict both prognosis and what happens when the disease becomes resistant to treatment and likely to develop metastasis.

But what do you do with that information once you have the biology attached to it? Can you use secondary adjuvant therapy, for example, or is it safe to continue to monitor the cancer? More research needs to be done to tell us how to act on this information.

Current Use

How are you using liquid biopsies in your clinical practice?

Any patient who comes to my clinic with metastatic breast cancer can be evaluated with a number of tests, including imaging studies for staging, tissue biomarkers, and circulating tumor cells, so we can talk with the patient about her options and what the prognostic outcome looks like. Obviously, we try to be precise, and at the same time, we want to educate the patient.

Unfortunately, our approach to metastatic breast cancer has been to provide treatment recommendations even before understanding the implications of such a diagnosis.

We should be able to tell patients everything they need to know about the state of their cancer, particularly when you are having a sensitive conversation about the prognosis of metastatic disease. If I know that the patient has a survival median of 30 months or more vs someone who has 12 months, I think the patient should have that information for a number of reasons. Either the treatment will likely not be effective and the patient needs to decide what to do, or there may be numerous options with which there is a possibility of long-term control. By itself, this makes having information about circulating tumor cells very useful. I have patients who want to know their circulating tumor cell level and want the test run every 3 months to see if there are any changes, because they think this information is helpful in managing their life, and why not?

Once a patient becomes metastatic and has to deal with the devastating news that her disease is terminal, she wants to know exactly what else can be done and how to cope with the reality of her situation. I think we now have the technology to help us help our patients better understand their prognosis. ■

Disclosure: Dr. Cristofanilli is on the clinical advisory board and a consultant for Cynvenio, a cancer diagnostics company based in Los Angeles.

Reference

1. Cristofanilli M, Budd T, Ellis MJ, et al: Circulating tumor cells, disease progression, and survival in metastatic breast cancer. N Engl J Med 351:781-791, 2004.