Pages

Friday, 22 January 2016

Tumor DNA in Bloodstream May Yield New Cancer Insights

For many people with cancer, the needle biopsy — an invasive procedure that isolates tumor tissue for analysis — is an uncomfortable part of diagnosis and treatment. Recent research reveals that the information obtained from this biopsy might be less accurate than previously thought.

By Jim Stallard 
on Monday, August 11, 2014

Experimental pathologist Jorge Reis-Filho says “liquid biopsies” could provide more comprehensive ways to assess tumors.
Summary
Experimental pathologist Jorge Reis-Filho explains how tumor DNA obtained from the blood could lead to noninvasive — yet highly sensitive — ways of detecting and monitoring cancer in the body.
For many people with cancer, the needle biopsy — an invasive procedure that isolates tumor tissue for analysis — is an uncomfortable part of diagnosis and treatment. Recent research reveals that the information obtained from this biopsy might be less accurate than previously thought.
As researchers identify genetic changes that trigger cancer and promote its growth, there is a growing awareness that effective treatments could be undermined by tumor heterogeneity — the variation among cancer cells both within the primary tumor and within distinct tumors formed by a cancer’s spread, or metastasis, to distant sites. For example, genetic mutations present in one biopsy sample might be absent from another biopsy taken from a different part of the tumor. This type of discrepancy complicates clinical decisions and confounds research efforts.
Now scientists are looking for less invasive and more comprehensive ways to examine tumors. One approach might be to rely on “liquid biopsies,” which analyze tumor cells or tumor cell DNA that has entered the bloodstream simply by drawing a blood sample from the patient.
Memorial Sloan Kettering experimental pathologist Jorge Reis-Filho, who studies the genetic alterations that drive the malignant behavior of breast cancer cells, discussed with us the potential of analyzing circulating tumor DNA (ctDNA) or circulating tumor cells (CTCs) in a blood sample and explained ways that ctDNA might provide insights for treatments that go beyond current conventional clinical tests.
What are the differences between CTCs and ctDNA and what can they reveal about a tumor?
CTCs have been recognized over the last decade as clinically useful cancer biomarkers in certain cases, but researchers have recently begun to focus on ctDNA as a potentially superior source of genetic information.
One limitation of CTCs is that they require elaborate methods for detection and retrieval. First, they need to be isolated from other blood material, which is difficult because they are very rare. Then extracting the DNA to study the genetic makeup of the cells is itself a cumbersome process. In addition, it is unclear what causes cells to break off from a tumor. We don’t know whether CTCs represent the entire makeup of cancer cells in the tumor or only a subpopulation, so it has yet to be defined how many CTCs need to be analyzed with molecular methods in each patient.
ctDNA, on the other hand, is much easier to isolate. When cells die, including cancer cells, some of the DNA they shed ends up in the [blood] plasma. This DNA in the circulation can be extracted from plasma and used for the characterization of the genetic makeup of tumor cells. In patients with advanced disease, tumor DNA can be collected even from a single vial of blood. As this is minimally invasive, multiple vials can be collected and the DNA extracted can provide important insights into the biology of the tumor.
More important, ctDNA may actually provide a more global — and therefore more accurate — picture of the cancer in the body. We have shown that at least in some patients, sequencing the ctDNA can capture all genetic alterations found in cancer cells in different parts of the body, because the cells dying and releasing DNA would come from all parts of the primary tumor and metastases.

What has made the study of ctDNA such a focus of interest recently?

The big change has been the introduction of next-generation sequencing, a new technology that allows us to sequence entire genomes of tumor cells to detect mutations with great accuracy. For example, we have a test here called MSK-IMPACT, which can look for hundreds of cancer-related mutations at once with very high sensitivity. We have used this test to detect every clinically relevant mutation present in ctDNA from cells all over the body. Just a few years ago, this type of analysis would have pertained to the realm of science fiction.
Being able to detect the entire range of mutations could be of great help in planning therapy. If ctDNA sequencing can detect all mutations present in the different cancer cells from a patient, we have a better chance to select the optimal drug or combination of drugs for that particular patient.

How could analysis of ctDNA be used to monitor disease progression and treatment?

As with CTCs, there have been studies showing that disease progression can be tracked by monitoring ctDNA levels, particularly by how concentrated the ctDNA is in the blood. As cancer progresses, the levels go up. In addition, in the last two years, research here at MSK and elsewhere has shown that next-generation sequencing of ctDNA from the plasma of breast cancer patients could identify genetic alterations that arise at different stages of the disease and potentially tell us whether a tumor will recur.
When it comes to treatment, we are beginning to see that genomic analysis of ctDNA over time makes it possible to track how cancer cells evolve in response to therapy. We recently published a study demonstrating this approach in a single patient with advanced breast cancer that had spread to the liver and bone. Genetic analysis from the primary tumor had revealed a mutation in a gene called AKT, so the patient was enrolled in a clinical trial testing a targeted therapy. We also sequenced DNA from the liver metastasis and from plasma samples collected both before the patient started the trial and at multiple points after receiving the drug.
We saw that the mutations in the cancer cells changed as the patient first responded to the drug and then relapsed. The changes in genetic composition mirrored the response to the drug as indicated by PET scans of the tumor and metastases. Significantly, however, we detected increases in the amount of ctDNA in plasma that preceded the detection of disease progression by imaging analysis or biochemical tests.
Although this analysis was done in a single patient, it does establish an important proof of principle that we might use this technique to track new mutations as they arise in response to targeted therapy. Analyzing ctDNA could give us a fuller picture of disease progression and drug resistance.

What applications do you see for this technology in the near future?

The use of ctDNA from plasma is still in its infancy. We can’t lose sight of all that we don’t yet know. With circulating tumor cells, a lot of initial hopes have not yet been fully realized; however, the experience accrued with the analysis of CTCs may prove instrumental for the use of ctDNA in clinical practice. The lessons we have learned over the last decade about the development of molecular tests for treatment decision-making, coupled with technological developments, are cause for optimism that this type of liquid biopsy will lead to noninvasive — yet highly sensitive — ways of detecting and monitoring cancer in the body.
https://www.mskcc.org/blog/tumor-dna-bloodstream-may-yield-new-insights

This post is on Healthwise