From Blueprint to Battle Plan


The idea that one type of treatment will cure all cancers was long ago dismissed as being ridiculously simplistic.

Theories on how to best treat cancer have evolved so far, in fact, that some researchers now suggest that the best approach is to examine the genetic makeup of each individual's tumor before choosing treatments from among their arsenal.

This approach, which is best applied to solid tumors--such as breast and colon cancers--is becoming practical with the help of the Human Genome Project, the massive effort to map the entire genetic blueprint. Having a complete picture of the normal human genome will allow scientists to, among other things, take DNA samples from tumors to look for changes or abnormalities that have triggered the disease.

"Tumor classification according to genotype may improve diagnosis, prognostication and therapy," said Joe Gray, director of the division of molecular cytometry at the UC San Francisco Cancer Center.

"Where I think we're headed in the long run is a very close linkage between diagnosis and therapy," he said. "We'll start treating solid tumors as a collection of genetic diseases."

Not everyone believes, however, that this technology is advanced enough to benefit patients today. The American Society of Clinical Oncology recently issued the first set of guidelines on tumor marker tests (the term for the antigens, genes and other elements associated with the presence of cancer) that urges doctors to be cautious about using the tests, particularly when the tests will yield information about a condition for which there is no successful treatment.

"The guidelines are not intended to replace physician judgment regarding particular patients or special situations," said Dr. Robert C. Bast Jr., chairman of the society's Tumor Marker Panel. "However, so many tumor markers have appeared that [appear] to be of actual value to patients. In reviewing all the available data, we found that the cost of and the information derived from these tests may not always have clinical benefit to the patient."

Gray agrees that the tests may yield information that, at present, is not ultimately helpful to the patient. But the information will help researchers in their quest for better therapies for cancer.

For example, he said, the research has already affirmed two beliefs about cancer. One is that cancer develops through chaotic accumulations of genetic changes. The second, Gray said, is that "tumors that appear the same clinically may be significantly different genetically."

For example, patient A's breast cancer may be very different, genetically, from patient B's breast cancer. Even though some tumors appear similar when analyzed with standard pathology techniques, the new tumor marker tests show that genetic defects can accumulate as cancers grow, giving each cancer a distinctive genetic fingerprint.

"We may not be able to treat all tumors with the same therapy and expect them to behave the same way, because they are different genetically," Gray said.

Besides the information supplied by the Human Genome Project, a technological advance has made tumor genotyping possible. The technique, called fluorescence in situ hybridization, or FISH, makes use of slices of DNA or special DNA "chips" to map the patient's DNA and look for particular abnormalities.

Gray compares the approach to a mechanic dismantling a car and using the car's blueprint to determine what parts are missing or damaged.

Research so far has shown that the DNA in some cells can be thoroughly abnormal.

"It illustrates the incredible scrambling of the DNA that occurs as these tumors progress," he said. "There is an amazing amount of variability in the cells. I think this is a manifestation of how tumors evolve. As the genome gets scrambled, you can accumulate more abnormalities."

Some gene abnormalities are already well understood, while many more remain a mystery. Scientists know that too many copies of certain genes called oncogenes might overstimulate cells. Too few copies of a particular gene might decrease the expression of tumor suppressor genes.

The presence of oncogenes or tumor suppressor genes might determine how well a particular therapy works to cure the cancer.

"We can also use this information to develop very specific therapies for this type of tumor, such as a toxin that can bind specifically to the cancer cell and kill it," Gray said.

One area where genetic information is already being used to make treatment decisions is in breast cancer. Some physicians use commercially available tests to look for the gene c-erb B-2 and opt for a much more aggressive type of chemotherapy if it is present.

Solid tumor genetics, however, is only in its infancy, he said. To make it widely applicable, scientists must be able to identify a broader range of DNA damage that gives rise to cancer. Moreover, even if abnormalities are identified, there are limited therapies that address the various types of DNA damage.

"One of the things coming out of this is we really don't know all of the abnormalities going on in these tumors, so our arsenal for therapeutics is limited," Gray said.

Indeed, because of the preliminary nature of the work, current oncology society guidelines urge doctors to avoid recommending well-known tumor marker tests for breast cancer, including C-erb B-2, p-53 and CA15-3. Because of rapid changes in this field, however, the society will reexamine and revise the guidelines yearly.

Eventually, cancer therapy should become highly individualized.

"I think where we're going is to identify which of the existing therapeutic agents to apply. But what we need to do is develop more therapeutic agents," he said.

Another advantage to the burgeoning technology is its use in prevention. The same DNA comparison techniques can be used to identify very early changes in cells that precede the growth of a tumor.

"These things can be applied to the earliest hyperplasias [cell changes] and cancers," Gray said.

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