A new genetic test that has been applied to certain aggressive forms of lymphoma is offering clinicians a clearer picture of patients' chances of survival. It is also joining the ranks of critical new developments in oncology that are pointing the way to more targeted treatments for cancer.

"Not so long ago, no one had any idea what made a cancer cell a cancer cell," says Dr. Ian Magrath, Medical and Scientific Director of the International Network for Cancer Treatment and Research in Brussels. "Now we have, in many cases, rather precise information about the pathways to cancer, and the process has become less mystical."

The new test, developed by Pat Brown of Stanford University and used by researchers at the National Cancer Institute in collaboration with other major centers, offers clinicians a genetically-based survival index for people who have undergone chemotherapy for diffuse large-B-cell lymphomas, the most common type of adult lymphoma.

Below, Dr. Magrath talks about the new genetic test for lymphoma, and its larger implications.

Why is it important to predict a lymphoma patient's chances for survival?
There are many reasons. From the oncologist's perspective, predicting outcome may be important in choosing optimal therapy, or deciding whether the patient is eligible for a particular research study. If, for example, a patient has an excellent chance of survival, and falls into a "low risk" group, then the physician could recommend a standard, well-tolerated therapy. If, however, the patient does not have excellent survival chances (with traditional therapies), and is in a "high risk" group, one might, propose to the patient some form of experimental therapy rather than the standard therapy.

Also, in order to make informed decisions, patients ought to be given some idea of what to expect, both in terms of effectiveness of therapy, and toxic side effects. An elderly patient, for example, with a very low chance of survival, may decide not to receive chemotherapy, or may opt for a less toxic treatment approach, even if other, more toxic therapies may offer a slightly better chance of survival.

What does this new genetic test measure?
The test, which is called DNA microarray, provides a good representation of the gene expression pattern of a tumor and and at the same time, provides a comparative picture of the pattern of gene expression in the tumor cells compared to that in normal cells.

How does it work?
In very broad terms, genetic material (RNA) is extracted from the tumor cells and "translated" into DNA (genes), which is "tagged" with a colored fluorescent material, let's say red. The same extraction process is done in normal cells, and this DNA is tagged with green dye.

The DNA from the tumor cells and normal cells are mixed together, and added to a "microarray". The microarray is a glass slide on which tiny pieces of DNA made from each gene that one is interested in are stuck in a regular pattern (the array).

The red and green DNA from tumor cells and normal cells stick to their corresponding pieces of DNA on the slide. If there is more red than green DNA for a particular gene (i.e., the genes expression is higher in the tumor cells than in the normal cells), then there will be more red DNA stuck to the particular spot than green. And vice versa.

The relative amounts of DNA stuck to the spots can be determined in a matter of minutes by measuring the amount and color of the flourescent light emitted from each spot, and an overall picture of the expression of each of the genes in the microarray can be obtained. This information is stored in a computer and can be manipulated in whatever way one wishes.

What is the primary purpose of this test?
Since the pattern of gene expression is ultimately responsible for the shape, size, and behavior of the tumor cell, it contains all of the information one might wish to know about it, including the type of tumor and even what the likelihood is that it will respond to a particular treatment.

Why is this genetic test more accurate than current methods?
Present tests include subjective elements, like looking at (lymphoma) tissue under the microscope and coming to determinations based on what one sees. While more objective tests (in effect, measurement of the expression of a small number of genes) can be done, one has only a few genes for study from among thousands of possibilities. With microarray techniques, there is no subjective element, since all the data are converted to numbers and patterns by the computer, one can measure the expression of tens of thousands of genes simultaneously, thus the microarray test gives much more information.

We may have here a quantum leap forward in our ability to collect large amounts of information that has enormously greater functional implications than what is possible from just looking at the appearance of a cell.

How might this test affect the development of molecularly targeted cancer therapies?
We are moving toward an era in which the genetic changes that characterize a cancer also provide the target at which new drugs are aimed. Since the molecular or genetic changes are generally unique to the tumor cell, they provide clinicians with an Achilles heel, whereby the tumor can be killed without serious effects on normal cells. With several molecular techniques, including microarray analyses, one can determine whether the targets for particular drugs are, in fact, present in the tumor cells, and then apply the correct therapy. At the present time, such approaches are in their infancy, but I do not doubt that they will become more and more feasible.

How will this test be used in clinical settings?
The test will be used to provide additional information to tests already in use, such as examination (of cancer cells) with a microscope, and testing for the expression of a small number of genes. It is still a research tool, but information obtained so far in a number of tumors, including, for example, lymphomas, lung cancer, brain tumors, breast cancer and sarcomas, suggests that it will provide both more accurate and precise diagnosis.

The test may also provide more information about prognosis. Such information may complement existing prognostic information such as tumor stage (extent of disease), and is likely to be used in conjunction with it.

How significant an advancement is this test?
The use of microarray will have all kinds of impacts, some of which we may not yet be able to foresee. Scientists and physicians are dealing with larger quantities of information than ever before, and will have to learn how to handle these large amounts of information. I am sure it will have a significant impact on patient care, because it will improve diagnostic precision and the ability to predict outcome of therapy. At the basic research level it will play a role in the development of new drugs, and ultimately all of this should translate into improvements in survival rates.

You have worked both in clinical and research settings for many years, and have witnessed the growing relevance of genetics in cancer diagnosis and treatment. Are these particularly exciting times to be an oncologist?
Yes. In the first half of the 20th century, there were no clear ideas as to how to treat cancer, except to cut the tumor out or to try to destroy it with X rays. In the second half of the century, we learned to kill tumors with poisons that kill some cancer cells more easily than normal cells. Now we are beginning to develop highly specific treatment approaches to cancer. Drugs that are targeted to cancer cells are likely to be no more toxic than antibiotics. Of course, cancer cells, like microorganisms, are highly adaptable and can become resistant to treatment, but now, instead of despairing, we'll be able to see precisely what's changed - at least at the level of gene expression - very quickly, so that it should be possible to develop strategies to overcome the resistance, or prevent it from happening.

Dr. Ian Magrath is the Director (Medical and Scientific) of the International Network for Cancer Treatment and Research in Brussels.