A Closer Look
Putting Circulating Tumor Cells to the Test
Doctors have known for 140 years that tumor cells can escape into the blood of patients with cancer, and it has taken almost as long to find ways to capture these circulating tumor cells, or CTCs. But at least a dozen experimental tools for isolating the cells have emerged recently, creating new possibilities for using CTCs to understand how cancers spread and also to improve the care of patients.
To clarify the changing landscape and foster collaborations, NCI recently convened a meeting of cancer biologists, clinicians, and technologists—the people who develop the tools for capturing these elusive cells. More than 500 participants came to the NIH campus in September to hear presentations on cutting-edge technologies and exchange ideas about where the field needs to go.
The focus of the meeting was translational science—moving technologies from the lab to the clinic—and many presenters said that CTCs could play an important role in medicine. Doctors, they said, may one day be able to select treatments for patients and then monitor the effectiveness of those treatments simply by drawing and analyzing blood. In short, testing CTCs could be a kind of “liquid biopsy.” There was also considerable interest in using the cells to learn about the metastases that cause most cancer deaths.
“Everybody understands how important research on these cells is; first and foremost, for patients, but also for other reasons, such as health economics,” said Dr. Howard Scher of Memorial Sloan-Kettering Cancer Center, who presented at the meeting. “If doctors can use CTCs to tell patients that a drug is not going to work ahead of time, then you’ve spared the patients toxicity and allowed them to move on to something else.”
But Dr. Scher cautioned that discovering and capturing these cells is only the first step. For CTCs to be used as biological markers for cancer, the prognostic value of these cells first needs to be validated, he continued, noting that the FDA has a path for biomarker development that has several stages similar to clinical trials for drugs.
FDA officials were at the meeting and gave presentations on the regulatory aspects of developing these new technologies, which are critical for moving the tools into the clinic, noted Dr. Avraham Rasooly of NCI’s Division of Cancer Treatment and Diagnosis and the FDA Center for Devices and Radiological Health, who was one of the organizers.
The agency has cleared a technology called CellSearch for capturing and counting CTCs in patients with metastatic breast, prostate, and colorectal cancers as a prognostic tool. CTC counts above certain thresholds (five or more per sample in breast and prostate cancer; three or more per sample in colorectal cancer) are associated with a poor prognosis and may be an indication the disease is progressing.
Many of the experimental tools in development are designed to go beyond prognosis and into the realm of personalized medicine. And for good reason: With a growing number of targeted cancer medicines, doctors want to know the genetic subtype of a patient’s tumor, and this information could, in theory, come from CTCs.
“The future of targeted therapies in cancer is completely dependent on a patient’s genetic profile, and you also need to be able to do serial monitoring of patients over time,” Dr. Daniel Haber of Massachusetts General Hospital (MGH) said at the meeting. “When a patient stops responding to therapy, you need to know why and the principal mechanism of resistance.”
His group, co-led by Dr. Mehmet Toner, a biomedical engineer at MGH, has developed the CTC-Chip, a microfluidic device that can capture CTCs from blood. (See movie above.) The team has shown, in principle, that they could use CTCs from the blood of patients with lung cancer to detect mutations in the gene EGFR, which are biomarkers for whether a patient is likely to respond to a certain type of therapy.
In another study, the group is asking whether CTCs can be detected in men with prostate cancer before the disease spreads. Currently, there is no way to identify patients at risk of relapse. The trial includes men whose cancers have not yet spread; their blood will be drawn before and after surgery, and then sampled periodically as the trial proceeds.
“If we could use CTCs to predict which patients are going to relapse, then doctors could consider additional treatments beyond surgery for those patients,” said Dr. Sunitha Nagrath, one of the investigators.
In the Clinic
At the Lombardi Comprehensive Cancer Center at Georgetown University, Dr. Minetta Liu uses the CellSearch test in conjunction with routine imaging in her clinical practice. In a recent study of women with metastatic breast cancer, she and her colleagues found a strong correlation between CTC counts and radiographic evidence of the disease progressing. Their findings provide further evidence that counting CTCs in blood can predict the effectiveness of systemic treatments.
“We are all clearly interested in these cells, and patients are always eager for additional information about their health,” said Dr. Liu.
Being able to assess a treatment’s effectiveness from a simple blood draw could limit the number of time-consuming radiology studies a patient would have to undergo, she continued, while also providing additional reassurance about the effectiveness of a particular treatment regimen. Similarly, testing CTCs could prompt doctors to change treatments earlier than would be suggested by an imaging study alone.
This is important, Dr. Liu stressed, because for women with metastatic breast cancer the focus of treatment is to preserve an individual’s quality of life. “In the absence of a cure, the ability to maximize treatment benefit and minimize toxicity and discomfort are of the greatest importance,” she said.
Some patients may benefit from new therapies as their tumors evolve over time. A trial has just been launched to see whether CTCs can be used to identify women with metastatic breast cancer who are candidates for trastuzumab (Herceptin), even if previous tests did not suggest that they should receive the drug. Women whose tumors have abnormal levels of the protein HER2 are candidates for the drug.
“This trial represents a shift in the current thinking about how to manage metastatic disease,” said the lead investigator, Dr. Massimo Cristofanilli of the University of Texas M.D. Anderson Cancer Center. Using a modified version of the CellSearch system, the study will not just count CTCs but try to use them as biomarkers to inform therapy by assessing HER2 expression in them, added Dr. Cristofanilli, who will soon join the Fox Chase Cancer Center.
“We may be able to offer what is very effective treatment to patients who wouldn’t receive Herceptin because the primary tumor was HER2-negative,” noted Dr. Jeffrey Smerage of the University of Michigan, another investigator in the trial.
At Stanford University, researchers are asking whether the analysis of CTCs can match patients and drugs early in treatment. The team will profile certain genes in CTCs using blood drawn from men with prostate cancer before and after they receive an experimental drug. As the trial progresses, it will be clear who the responders are, and the researchers will then look for associations with CTC gene profiles.
“We’re trying to find out which genes are being expressed in the CTCs and whether they might help us choose a therapy,” said Dr. Stefanie Jeffrey, a breast cancer surgeon at Stanford and a lead investigator of the study. “Hopefully, we’ll be able to find out from the profile before patients are even on the drug whether they are likely to respond.”
The trial is using a device called the MagSweeper to capture CTCs for analysis. As with so many of the technologies, Dr. Jeffrey developed the tool with a multidisciplinary team that included engineers and genome scientists. Some of their preliminary studies have suggested that not all CTCs are alike and that some may have characteristics of stem cells.
“I think we’ll learn that this is a lot more complex than we initially thought based on our paradigm of cancer cells being shed by a tumor,” Dr. Jeffrey said. “The field is just now burgeoning, and we still have a great deal to learn.”
Dr. Thomas Ashworth, the Australian physician who observed CTCs in a patient with cancer in 1869, could not have foreseen where his discovery would lead.
“What’s most exciting is that the technology is reaching a point where we can ask some questions, and trials are actually being done in multiple diseases,” said Dr. Scher. The most important question, he added, may be: “How will testing CTCs help us make medical decisions?”
—Edward R. Winstead