Interesting Article - Blood Screening Trumps Biopsy in Cancer Mutation Hunt

RoseC

This is kind of interesting. I only wish they COULD detect cancer from blood tests, tests that would be more accurate than biopsies.

 

Blood Screening Trumps Biopsy in Cancer Mutation Hunt

By Meg Tirrell - Apr 6, 2013 3:30 PM ET

A simple blood sample turned up cancer-causing mutations more frequently than a tumor biopsy in a study that suggests the approach could help deliver a clearer picture of the disease and better tailor patients’ treatments.

In a study of Bayer AG (BAYN)’s drug Stivarga, researchers analyzed tissue and blood samples from patients with gastrointestinal stromal tumors, or GIST, to find cancer-driving mutations. They found that blood samples were more likely to reveal them than biopsies, in results presented today at the American Association for Cancer Research meeting in Washington.

As cancer treatments increasingly home in on known genetic causes of the disease, researchers need better tools to determine just what mutations each patient has, said George Demetri, director of the Ludwig Center at Dana-Farber Cancer Institute and Harvard Medical School, who led the trial. Samples taken from tumors may not reveal all the underlying mutations at once, he said in an interview.

“A biopsy is by definition a subset of the tumor cells,” Tyler Jacks, director of the Koch Institute for Integrative Cancer Research at the Massachusetts Institute of Technology, said in a telephone interview. He wasn’t associated with the research. “What’s cool about this idea is the use of the blood sample as a surrogate to what’s happening in the tumor.”

The screen, called BEAMing technology, is sensitive enough to detect even rare mutations circulating in the blood stream in the form of free DNA, genetic material shed from tumors. Demetri said he expects the testing technology could become a standard part of caring for cancer patients within five to 10 years.

Stivarga Trial

The analysis was done as part of Leverkusen, Germany-based Bayer’s trial of Stivarga, a cancer therapy approved in February for GIST and last year for colorectal cancer. Researchers took DNA from tumor tissue and analyzed it for mutations in two genes known to drive cancer-causing proteins targeted by Bayer’s drug and medicines from Pfizer Inc. (PFE) and Novartis AG (NOVN), Sutent and Gleevec.

Stivarga is approved for use in GIST after patients’ cancer has stopped responding to Sutent and Gleevec. Bayer jointly promotes Stivarga with Onyx Pharmaceuticals Inc. In the study, researchers took blood samples from patients once their cancer had progressed and analyzed them for mutations, including so- called secondary mutations that cause resistance to those drugs.

They found secondary mutations in 48 percent of blood samples, versus 12 percent of tissue samples.

“The problem for the last decade of research is when you take out one tumor and sample one corner of the tumor and then sample another, you may see two different mutations in that same tumor,” Demetri said in an interview. “What we were looking for was technology that, with a simple blood test, we’d be able to sample all the mutated DNA in a person’s body.”

Technology Limitations

The technology has some limitations, Demetri said. It detects expected mutations, while is unable to turn up unknown drivers of cancer. Newer versions of the technology are being worked on now that would enable researchers to seek out unidentified cancer-causing mutations, which could be helpful for drug development.

The test may help identify which patients should receive which drugs, Demetri said, enabling some to skip treatments that won’t work for them or others to be given just the right therapy for the driver of their cancer.

“Dynamic monitoring and understanding what’s happening to the tumor over time, how it’s evolving, is important,” Jacks said. “This technology allows you to do that.”

To contact the reporter on this story: Meg Tirrell in New York at mtirrell@bloomberg.net

To contact the editor responsible for this story: Reg Gale at rgale5@bloomberg.net

gdpawel

Caveat about blood assays

Getting tumor cells from blood maybe feasible for solid tumors, though ususally only when the tumor is very advanced, and then only in small numbers. It seems plausible that you can get enough specimen from circulating tumor cells for solid tumors. It may be possible using PCR (Polymerase Chain Reaction) or similar technology for specific agents.

Only minute quantities of DNA are necessary for PCR. DNA can be amplified from a single cell. PCR amplification techniques raise considerable concerns regarding contamination from one specimen to another, creating the potential for false positive results. Clinical interpretation of PCR results may also be challenging.

But, PCR may be useful when culture is difficult due to the low numbers of the organisms, for lengthly culture requirements, or when there is difficulty in collecting an appropriate sample. Don't know if the results would be indicative of what would happen inside the human body.

They usually proliferate (grow) cancer cells from a small sample and subject those cells to chemo. Cells 'grown' in the lab will not behave the same way as the actual cancer cells do in your body's own environment. Because they test on subcultured cells (as opposed to fresh tumor cultures) and test the cells in monolayers (as opposed to three dimensional cell clusters), the cell grown in the lab will not behave the same way as the actual cancer cells do in your body's own environment.

Older technology assay tests failed because scientists looked to see which drugs inhibited the cancer cells' growth (cell-growth endpoint), not which chemotherapies actively killed the tumor cells (cell-death endpoint). Cancer wasn't growing faster than other cells, it's just dying slower. The newer assay testing technology connects drugs to patients by what 'kills' their cells, not by what 'slows' them down.

All of the work in the past twenty years in the cell culture field has been carried out largely on three dimensional (3D) clusters of cells (not monolayers). Work is done exclusively with three dimensional, floating, tumor spheroids. When you test the cells as three dimensional spheroids, they are many-fold resistant in vitro, just as they are in vivo (multicellular resistance). Even Johns Hopkins and the Washington University at St. Louis has discovered that 3D analysis is more accurate.

Basically, CTC labs use "negative selection" to isolate alleged circulating tumor cells. What that means is methods to "selectively" remove circulating normal cells, such as monocytes, lymphocytes, neutrophils, circulating endothelial cells, etc. The problem is that these normal cells outnumber circulating tumor cells by a factor of a million to one, and no "negative selection" procedure (or combination of procedures) can possibly strip away all the normal cells, leaving behind a relatively pure population of tumor cells. 

What you have to do is to use a "positive selection" procedure, meaning selectively extracting the tumor cells out of the vastly larger milieu of normal cells. The problem is, when you do this, there is only a teeny tiny yield of tumor cells.

Here's from Wikipedia:

Circulating tumor cells are found in frequencies on the order of 1-10 CTC per mL of whole blood in patients with metastatic disease. For comparison, a mL of blood contains a few million white blood cells and a billion red blood cells.

So, from a typical 7 ml blood draw into a purple top tube, you are going to get, on average, 7 to 70 tumor cells -- total. This may be sufficient for certain molecular type tests (although the degree to which this tiny sample of cells is representative may be questioned), but it isn't nearly sufficient to test even a single drug in a cell culture assay, where one requires millions of cells for quality testing, including requirements for negative and positive controls.

Regardless of all of this, most of the cells that leave home don't survive the journey in the blood or lymph systems and many cancerous cells that eventually do lodge in a distant organ simply remain dormant, leaving it up to the immune system to take care of them.

Full-blown metastasis is an extremely challenging trade and the great majority of cancer cells are not up to the task. Even those malignant characters that manage to slither their way into the blood or lymph system, usually fail to do anything further.

Most tumor cells lack the streamlined form of the blood and immune cells that are designed for cross-body trafficking, shear forces in the smaller vessels may rip the intruders apart. These free-floating cancer cells can remain in isolation from a tumor for over twenty years.

Source: Cell Function Analysis