Abstract
Using a microchip device, scientists were able to capture and culture circulating tumor cells for genetic analysis and drug testing, which identified new tumor mutations that were susceptible to targeted agents.
Researchers have shown that rare tumor cells circulating in a patient's blood can be cultured and genetically analyzed. The approach, described in Science in July, demonstrates that it may be possible to use a simple blood draw to track a cancer as it evolves and adjust treatment accordingly (Science 2014;345:216–20).
Scientists isolated circulating tumor cells (CTC)—cancer cells shed by solid tumors—from the blood of 36 patients with metastatic estrogen receptor–positive breast cancer. CTC cell lines from six patients were successfully grown in the lab and screened for mutations in 1,000 cancer-associated genes, revealing new mutations that were not present in the primary tumors.
Tumors have learned to adapt to effective treatments by changing their genetic makeup, says co–senior author Daniel Haber, MD, PhD, director of the Massachusetts General Hospital (MGH) Cancer Center in Boston. Indeed, CTCs from three patients treated extensively with estrogen-blocking aromatase inhibitors tested positive for an uncommon estrogen receptor mutation. Another patient's cancer developed new mutations in both PI3K and FGFR.
Subsequent testing found various targeted drugs could inhibit cancer growth in patient-derived cell lines and in mice with tumors developed from each patient's CTCs.
The existence of CTCs has been known for nearly 150 years. They are exceedingly rare, with a single cancer cell drifting among a billion healthy blood cells. To date, they have been useful only in predicting a patient's prognosis.
In the study, CTCs were captured using the MGH-developed CTC-iChip, which Johnson & Johnson (J&J) will develop for commercial use. The device can capture CTCs in nearly 80% of patients with metastatic cancer, whereas CellSearch (Janssen Diagnostics, a J&J subsidiary)—the only FDA-approved test for isolating CTCs—is successful only about half the time, says Haber. In addition, the new device harvests living tumor cells, as opposed to CellSearch, which fixes CTCs for counting.
CTCs isolated and cultured from the peripheral blood of a patient with breast cancer. Cytokeratin is shown in red; Ki67 in yellow; CD45 in green; and nuclei in blue.
CTCs isolated and cultured from the peripheral blood of a patient with breast cancer. Cytokeratin is shown in red; Ki67 in yellow; CD45 in green; and nuclei in blue.
The microchip works by first removing small blood components. The remaining white blood cells and CTCs are aligned single file using a microfluidic process. White blood cells are magnetically tagged and deflected, leaving behind untouched CTCs. Previous research shows the CTC-iChip can capture CTCs from the blood of patients with advanced cancers of the prostate, lung, pancreas, and colon (Sci Transl Med 2013;5:179ra47).
It takes only 30 minutes to process a blood sample, but the CTC culturing process can take 1 to 3 months. Even then, not all CTCs can be grown in the lab. “The technology isn't perfect yet,” says Haber, whose team is working to improve the device's capture rate and speed up culturing. Haber expects it will be 1 to 2 years before the device is moved into clinical testing.
Jeffrey Smerage, MD, PhD, who conducts research on CTCs at the University of Michigan Comprehensive Cancer Center in Ann Arbor, agrees the technology is not ready for routine clinical use.
Smerage, who was not involved in the study, says researchers must still determine how methods used to grow CTCs influence their gene expression and whether CTCs and metastatic tumors are biologically the same. Even so, the findings make Smerage “very optimistic” about the possibility of using CTCs to guide therapy.
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