BOSTON, Dec. 19 -- An experimental lab-on-a-chip can accurately detect cancer cells circulating in the blood, researchers here said.
The chip -- slightly more than 1.5 square inches in area -- detected circulating cancer cells in 115 of 116 blood samples from patients with metastatic cancer for a sensitivity of 99.1%, according to Daniel Haber, M.D., director of the Massachusetts General Hospital Cancer Center, and colleagues.
And it found no cancer cells in the blood of healthy volunteers, for a specificity of 100%, the researchers reported in the Dec. 20 issue of Nature.
"Clearly this has tremendous potential for early diagnosis," Dr. Haber said, but it also has the potential to allow physicians to monitor the success or failure of treatment more closely and to begin to solve some of the puzzles that surround metastasis.
Circulating tumor cells are found in patients even before a cancer has begun to spread, but they are rare -- as few as one in a billion hematologic cells even in the metastatic case -- and hard to isolate, the researchers said.
Current approaches use complicated analytic techniques -- including centrifuging and washing samples -- that generate very low yield and purity, they said.
In contrast, their "microfluidics" approach is highly sensitive, has a 99% yield, and a purity approaching 50%, compared with less than 1% for other methods, the researchers said.
The development of the chip "bring[s] us closer to having a fully automated instrument that can detect circulating tumor cells with exquisite sensitivity," said Jonathan Uhr, M.D., of the University of Texas Southwestern Medical Center in Dallas, writing in an accompanying comment.
Dr. Uhr said such a device "would allow routine monitoring of blood for tumor cells as part of a medical examination, and could result in early detection and treatment."
The researchers said that a number of engineering challenges remain before the system can be used for clinical applications, although it could be used now for research.
Microchips have been used for a range of analytic chores, such as flow cytometry, but have not been applied to tasks where milliliter-sized samples of whole blood must be analyzed, he and colleagues noted.
On theoretical grounds, they concluded that a microchip array of 78,000 tiny silicon posts -- coated with an antibody to a molecule specific to tumor cells -- would overcome that barrier.
The posts were coated with an antibody to anti-epithelial-cell adhesion-molecule, or EpCAM, which is found on tumor cells, but not on blood cells.
Tests showed that when the researchers processed blood samples spiked with tumor cells, the EpCAM-coated posts captured them easily, although the posts also captured some white blood cells.
To test the chip in the real world, the researchers tested 116 blood samples from 68 patients with metastatic epithelial cancers including non-small-cell lung, prostate, pancreatic, breast, and colon, as well as 20 samples from healthy volunteers.
Except for one sample that was smaller than average -- 0.9 milliliters compared with 2.7 milliliters -- the system found circulating tumor cells in all samples from patients, but none in the samples from healthy volunteers.
In addition, circulating tumor cells were isolated in seven out of seven patients with early-stage prostate cancer.
In a separate analysis, Dr. Haber and colleagues tested sequential samples from nine patients undergoing treatment and found that the percentage change in the number of tumor cells they captured correlated well with percentage change in tumor size. (The Pearson's correlation coefficient was 0.68, which was significant at P=0.03.)
"Much of cancer [drug] treatment now is trial and error," Dr. Haber said. The chip might potentially allow doctors to find the correct treatment more quickly.
One advantage of the system, Dr. Haber said, is that captured cells remain alive, opening the door to more detailed understanding of how they function and perhaps what causes some to become the root of new cancers while the majority commit cell suicide.
"We'd like to study exactly what they are," he said.
|The study was supported by the NIH and a Doris Duke Distinguished Clinical Scientist award. Dr. Haber reported no conflicts.|
Primary source: Nature
Nagrath S, et al "Isolation of rare circulating tumour cells in cancer patients by microchip technology" Nature 2007; 450: 1235-41.