Well, it didn’t take long to get into the New Year, did it?
There I was this earlier this week, starting my New Year right by getting exercise on my elliptical when I heard the announcement that Johnson & Johnson was partnering with researchers at Massachusetts General Hospital’s cancer center and other major cancer centers to evaluate the potential of a new technology which can isolate single cancer cells circulating in the blood of patients with known cancers.
The news in itself is an impressive step forward in this type of research. Being able to isolate a single cancer cell in a sample of blood is in a sense one of the holy grails of cancer research. Scientists have been working diligently on developing these techniques for a number of years, and to now have a technology that may in fact move that dream closer to a clinical reality where it actually improves the treatment of patients with cancer is exciting.
However, there is always a caution that comes along with these types of announcements.
First, and perhaps the most obvious, is the fact that this is an announcement of a research deal. Nothing more, nothing less. It is not a new breakthrough. It is not something that has been proven effective in improving cancer detection and treatment. Not that it is anything less than stunning to develop and demonstrate that this technology works-but as with all research it is a giant step to go successfully from the laboratory phase of development to the clinical phase of making a real difference in patients’ lives.
So that in essence is what the fuss is all about: the researchers have signed a contract with a company to further develop this research and determine whether in fact it can be applied successfully to large numbers of patients in a more efficient and less expensive manner.
I think it is also important to remember that there are many researchers who have been working on other techniques to accomplish the same goal, some for many years.
Back in 2006, I attended a world cancer conference (co-sponsored by the American Cancer Society) and wrote the following after a presentation suggesting that we would-within 10 years-be able to measure proteins in the blood to detect cancer at the earliest possible moment:
“The prediction that within ten years we will have inexpensive, accurate molecular probes available to measure 2000 proteins in the blood that will serve as markers of changing cellular patterns predicting the onset of disease is astounding to me.
“It is far beyond where I thought we were in the development phase, and the impact of patients measuring their blood test every six months at home, and having the data analyzed and reported to their physician, who will be able to effectively treat a disease before it becomes visible or detectable by currently available means is almost beyond my belief and comprehension.”
Today’s announcement brings us one step closer to the realization of the dreams of many scientists and clinicians, namely the ability to accurately identify small numbers of cancer cells circulating in the blood of patients with cancer, and being able to extract those cells intact for further study and analysis.
The implications of such a test are numerous and enormous.
For example, it could potentially predict whether or not a cancer was recurring, or whether a particular cancer was more likely to spread elsewhere in the body. It could allow analysis of cancer cells to predict which cancer treatments might work best for an individual’s cancer, and it could predict whether or not a cancer was responding to treatment before other tests such as MRI scans could detect such changes.
However, along with enthusiasm there must be caution, because as I mentioned above it is a long way from the bench to the bedside or the clinic. Our research successes don’t always move easily or quickly into processes that positively impact cancer treatment. In other words, the road going forward is almost certain not to be as straightforward as many would hope.
There is also the intriguing question of whether or not this test-or one like it-will make that prediction from 2006 come true (although I would note that the lecturer back then was referring to proteins, and this newer test isolates actual cancer cells. Nonetheless, the principle is similar if not exactly the same). One could imagine that this test could be used to find cancer cells before a cancer is otherwise detectable, moving us much further down the line when in it comes to the early detection of cancer.
That discovery could come along with its own set of issues.
More and more, researchers are becoming concerned that as our ability to find cancers earlier becomes better and better, we are also finding more cancers that would never have caused anyone any problem (hard to believe, but it is now likely that such cancers exist).
What would be the impact of finding a cancer so early that we couldn’t even see it? Would we treat it with aggressive chemotherapy or radiation? You can see where I am going with this discussion: finding cancer early is frequently-but not always-a good thing. What we really need now is a test that will help us understand which cancers will likely cause harm and require treatment, while helping us “ignore” those which are never destined to cause a problem.
So our technology advances, and with it comes the burden of determining whether or not such new technologies really make a difference.
Right now, if you talk to a number of experts, you will hear them lament that we are seeing many tests that are being touted as important in answering various questions about the future behavior of an individual’s cancer but we are not seeing the type of validation we need to know whether or not such claims are in fact clinically relevant. There are so many markers and genetic tests out there that even the most knowledgeable experts in the clinical treatment of patients with cancer are having a hard time separating the proverbial wheat from the chaff.
So with today’s announcement comes a hope that the researchers and the company that will be working on the further development of this promising new technology will always keep the message in mind that just having a test that does something isn’t necessarily going to help us move forward in our progress in treating cancer. What we don’t need are more tests that measure this or measure that. What we desperately need are tests that make a difference in the lives of our patients.
Keeping focused on the genuine impact-as opposed to the “gee whiz” impact-is critically important at moments like today. We can all be excited and enthusiastic, however our real hope is that the excitement we feel today translates into genuine impact and success in cancer treatment tomorrow.
J. Leonard Lichtenfeld, MD, MACP is Deputy Chief Medical Officer for the national office of the American Cancer Society. He directs the Society’s Cancer Control Science Department, which produces the Society’s widely recognized guidelines for the prevention and early detection of cancer and guidelines for nu trition and physical activity for cancer survivors. Dr. Lichtenfeld is a board certified medical oncologist and internist who was a practicing physician for nearly 20 years.
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CTC technology has great potential – for drug selection – ten or twenty years down the road, and they should continue to try and make strides. However, there is a problem with growing or manipulating tumor cells in any way. When looking for cell-death-related events, which mirror the effect of drugs on living tumors, cells are generally not grown or amplified in any way. The object is occurrence of programmed cell death in cells that come into contact with therapeutic agents.
How do you aggregate a sufficient number of cancer cells to make accurate determinations? Detectable tumor cells in the peripheral blood are present only in extremely small numbers. This precludes allowing a sufficient number of cells to incubate for a few days in the presence of chemotherapeutic agents. Analysis of a relatively small number of isolated cancer cells cannot yield the same quality information as subjecting living cells to chemotherapeutic agents, begging the question of whether or not it can accurately predict which drugs will work and which will not.
CTCs are free-floating cancer cells that can remain in isolation from a tumor for over twenty years. What is the relationship of such long-lasting cells to the tumor cells that need to be attacked through tested substances?
Then there is the question of heterogeneity. Tumors in the body are genetically variable. What is the relationship between CTCs and primary tumors or their already established metastases? It has already been established that the gene expression profile of a metastatic lesion can be different compared to that of the primary. The status of the marker Her2/neu in CTCs sometimes differs from that of the original primary tumor, which would point to different prescriptions for Herceptin.
The number of cells discovered in the CTC technique has turned out to be a good prognosticator of how well empiric treatments are working, but less certain in the ability to use it for drug selection. The “problem” is in isolating and analyzing single cancer cells. The supposition is that common cancers can be detected and cured through analysis at a genetic level of a small number of cells or even a single wayward cell.
Genetic or IHC testing examines dead tissue that is preserved in paraffin or formalin. How is that going to be predictive to the behavior of living cells in spontaneously formed colonies or microspheres? Can it describe the complex behavior of living cancer cells in response to the injury they receive from different forms of chemotherapy? There is a big difference between living and dead tissue.
Some molecular tests do utilize living cells, but generally of individual cancer cells in suspension, sometimes derived from tumors and sometimes derived from CTCs. Don’t forget, this was tried with the human clonogenic assay, which had been discredited long ago.