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MADRID – Liquid biopsies to track genetic changes in a patient’s tumor by serial blood specimens rather than multiple tissue biopsies seem poised to enter routine clinical use. But several experts speaking at a session on the topic agreed that liquid biopsy technologies largely remain too unproven to enter everyday practice right now.
“I have no doubt [liquid biopsy] will become routine, but right now the evidence is lacking,” said Alberto Bardelli, Ph.D., summarizing a session he cochaired at the European Society for Medical Oncology Congress.
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Alberto Bardelli, Ph.D.
“I think the potential is very high to use liquid biopsy to monitor residual disease in patients with breast cancer or other tumor types. There is also the possibility of using CTCs [circulating tumor cells] to interrogate the genome of single tumor cells or to grow the cells and use them functionally” to, for example, help identify effective treatments against the tumor, said Dr. Bardelli, a molecular biologist at the University of Torino, Italy.
Liquid biopsies are generally divided into two categories. One approach involves the isolation and analysis of individual, living tumor cells that slough off a primary tumor or metastasis and can be isolated from a patient’s peripheral blood, although tumor cell concentrations are very low, on the order of one tumor cell in a million normal blood cells or even 10- to 100-fold more dilute than that.
In 2004, the Food and Drug Administration approved CellSearch, a commercial test that quantifies CTCs in patients with metastatic breast cancer to predict the likelihood of survival. CellSearch remains the only FDA-approved liquid biopsy assay for cancer, though its use has expanded to patients with prostate or colorectal cancer as well as breast cancer.
Circulating tumor DNA
The second option is to isolate and analyze the DNA that slips out of dead tumor cells and enters a patient’s circulation. One advantage of focusing on circulating tumor DNA (ctDNA) is that it is more than 100 times as common in a patent’s blood as tumor cells; however, tumor DNA is limited to providing a broad-brush average of what is going on genetically in a primary tumor and its metastases at any time, rather than giving the specificity of a genome isolated from a single, circulating tumor cell.
Both approaches seem to have value, and both seem on course to continue in development and be used in complementary ways.
An example of the potential benefit of analyzing ctDNA came in a study published last year, in which investigators identified genetic alterations that they could use to follow patients with metastatic breast cancer. They found ctDNA in the blood of 29 out of 52 women, and saw a strong, inverse relationship between increased levels of ctDNA and survival. Patients with a below-average level of ctDNA had significantly better survival, while patients with relatively higher ctDNA levels had significantly worse survival, the British researchers reported last year (New Engl. J. Med. 2013;368:1199-209). The study results also showed that quantifying ctDNA provided better correlation with changes in tumor burden than did quantifying CTCs or measuring an immune marker for breast cancer, CA 15-3.
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Dr. Carlos Caldas
More recently, these investigators expanded the mutation panel they use to identify ctDNA, and now can find a single-nucleotide or structural variant in the DNAs of 48 of these 52 patients, Dr. Carlos Caldas, one of the investigators, said in a talk at the meeting. Dr. Caldas added that he and his associates have now seen a patient from this series with triple-negative breast cancer and an elevated level of ctDNA who then showed a dramatic reduction in ctDNA level following several treatment cycles. This drop in ctDNA level tracked with the patient’s complete pathological response to treatment.
“This is preliminary evidence that you can use ctDNA as a very early marker of treatment response,” said Dr. Caldas, professor of cancer medicine at the University of Cambridge, England.
Other advantages of measuring ctDNA, especially compared with tracking a tumor using CTCs, is that it is simple and relatively inexpensive, with no need for special isolation technology, and it reflects the patient’s total tumor burden, noted Dr. Gerald Prager, an oncologist at the Medical University of Vienna. He cited a recent example of the power of ctDNA analysis in a report on 106 patients with colorectal cancer, who underwent ctDNA analysis for KRAS and BRAF mutations. Comparison of results from the ctDNA analysis and conventional mutation determinations showed 100% sensitivity and specificity for detecting tumors with the BRAF V600E mutation, and 98% specificity and 92% sensitivity for detecting any of seven KRAS point mutations (Nature Med. 2014;20:430-5).