AACR 2009: Measuring Circulating Tumor Cells Is Clinically Useful, New Technique Promises to Be Faster

Zosia Chustecka

April 21, 2009

April 21, 2009 (Denver, Colorado) — The measurement of circulating tumor cells (CTCs) in the blood of cancer patients is a hot topic, and a symposium on the subject attracted a packed audience here at the American Association for Cancer Research (AACR) 100th Annual Meeting.

CTC enumeration is already being used in the clinic, and it provides information that is clinically useful, said symposium chair Howard Scher, MD, chief of genitourinary oncology at the Memorial Sloan-Kettering Cancer Centre, in New York City.

Measuring CTCs before and after treatment gives an indication of whether or not the patient is responding, and trials are underway to see if this correlates with survival, Dr. Scher told Medscape Oncology in an interview. In addition, the CTCs offer a "liquid biopsy" because the tumor cells can be analyzed for genetic mutations, which can then affect what treatment is chosen, he explained.

"As a clinician, I know that what I am treating is a moving target, and so to do a blood test that can help me to understand somebody's prognosis, to select one treatment instead of another, and to show me quickly whether the treatment is working not only improves patient outcomes, but will also prevent patients from being exposed to a treatment that is ineffective, eliminating potential toxicity," Dr. Scher said.

So far, there is only 1 commercially available product to measure CTCs — CellSearch (Veridex LLC) — that is approved by the US Food and Drug Administration for monitoring treatment effects in breast, colorectal, and prostate cancers alongside other measures. Several more devices are under active development, and one that promises to be cheaper and faster was described in a poster highlighted at an AACR press conference.

The new technique is based on a microfilter device developed by a team at the Keck School of Medicine, University of Southern California, in Los Angeles, in collaboration with the California Institute of Technology, in Pasadena. Several of the scientists involved have patents on the technology, and they hope to have it commercially available in 3 to 5 years.

"Capturing these cells is no easy task," said research assistant Anthony Williams, a postgraduate student who worked with Richard Cote, MD, professor of pathology at Keck before he became chair of pathology the University of Miami, in Florida.

"There are only 1 or 2 circulating tumor cells in 1 mL of blood, which contains billions of other blood cells," Mr. Williams explained. So far, existing technology has depended on affinity-binding platforms to detect these cells, using antibodies that react with markers on the surface of the CTCs to capture them. However, the markers might not be present on every cancer cell, Mr. Williams said. For example, one of the markers that is used, epithelial cell adhesion molecule, is found on only 70% of prostate cancer cells — and nonepithelial cancers, such as melanoma, have no such markers.

In contrast, the new technique developed at Keck captures CTCs by virtue of their size. "These cells are much larger than their counterparts," Mr. Williams explained. A big advantage of this method is the speed at which blood is processed — it takes an average of 90 seconds to process 7.5 mL of blood. The currently available technology can take 4 to 5 hours, Mr. Williams said.

"It is faster," said Dr. Scher, but he pointed out that the microfilter technique is still at an early stage of development, and needs more work and analytical validation. For example, the rate at which blood is pushed through the filter will need to be standardized. "To bring it to the point of a clinical test it has to be absolutely consistent around the world," he said.

There might also be another advantage. In clinical trials at Sloan-Kettering, which use both devices on blood samples taken from patients with metastatic prostate cancer, the microfilter found CTCs in 92.9% of patients and CellSearch found them in only 45.6% of patients.

"We are finding more cells, and we are finding cells in more patients," Dr. Scher said, "but we still have to prove what these cells are."

Trials are ongoing at Sloan-Kettering, and clinical trials with the microfilter are also underway at the University of Chicago, in Illinois, Mr. Williams said.

Another new device is the CTC chip. Massachusetts General Hospital, where it was developed, is now working with CellPoint Diagnostics on commercialization, but that is still several years away. This device is based on immunoaffinity, but it uses a different format — the antibody is located on microposts fixed on a glass slide, whereas in the CellSearch system, the antibodies are on glass beads in a solution, explained Jeffrey Settleman, PhD, scientific director at the Massachusetts General Hospital, in Boston. One of the disadvantages with these beads is that the cells adhere and are killed, whereas with the other systems, the CTCs remain "live" and can be further analyzed, he said.

Dr. Settleman told Medscape Oncology that he is rather skeptical about the concept of capturing CTCs by size, because the size of these cells varies enormously across different cells types. He acknowledged that immunoaffinity can miss some cancer cells because it hones in on 1 marker, but he said that different antibodies can be used for different cancer types.

Dr. Scher said that both of the new devices — the microfilter and the CTC4 chip — are very promising, but he emphasized that both systems are still in early development.

An exciting prospect for CTC enumeration devices is that they might eventually be used for diagnosing of cancer. In a speculative scenario, a blood sample taken, for example, to measure cholesterol levels could also be tested for the presence of CTCs and could indicate the presence of a hitherto unsuspected cancer.

"This is the Holy Grail, and we are not there yet," said Dr. Scher. "We need far more sensitive measuring techniques."

The scenario is speculative because, at present, it is not known whether healthy individuals have a baseline level of CTC or similar cells, or whether there is a level that would indicate the presence of cancer, Dr. Settleman noted. This question is being addressed in an ongoing trial at Massachusetts General Hospital and some answers should be forthcoming within the next year, he added.

Dr. Scher reported acting as a consultant and receiving grant/research support from Veridex, Cougar, and Medivation; he also holds stock in Johnson & Johnson.

American Association for Cancer Research (AACR) 100th Annual Meeting: Abstract 2608. Presented April 20, 2009.