Gene Tests May Refine Treatment of Cancer : Health: Patients, experts say, should take advantage of a new technology that can help their doctors care for them better.
The marvels of molecular biology are bearing fruit a bit too late for David Corp.
Told last spring that he had what appeared to be an early case of lymphoma (lymph cancer), the 43-year-old Lakewood resident nonetheless faced 30 weeks of chemotherapy because his doctor could not be sure surgery had removed all the cancer cells.
He made it through 18 sessions before the powerful anti-cancer drugs began damaging his heart function so much that his doctor stopped the treatments in late December.
Although Corp says he is happy with his medical care, and his prognosis is good, he, like other cancer patients, wishes he could have avoided the unpleasant side-effects and restrictions of chemotherapy altogether.
“For 18 weeks, I was pretty much tied to the doctor,” he said. “We didn’t go camping, we didn’t take any vacations. If they could have tested my blood and told me that the cancer was all gone and been able to know that in advance, that would have been great.”
Indeed, if Corp’s cancer had appeared five years from now, doctors might have been able to rule out chemotherapy by using a sort of genetic microscope to look for stray cancer cells--finding even just one cancer cell hiding among 999,999 normal cells in his lymph system. No abnormal cells? No chemotherapy.
Other genetic tests would be able to determine whether the cancer had defects that would make its spread more likely.
It probably will be two to five years before patients routinely encounter such extremely sensitive gene-based tests in the doctor’s office, researchers say. This is partly because studies still need to be done on how to interpret their results.
Nonetheless, early evidence about the genetic triggers behind cancer is strong enough that some researchers believe patients should urge their doctors to perform the tests anyway.
“I think it’s appropriate for a patient to ask a doctor for a number of different genetic tests on their cancer,” said Dr. Dennis J. Slamon, director of clinical research at UCLA’s Jonsson Comprehensive Cancer Center.
Privately, other researchers acknowledge that if they or a loved one had a cancer in which a genetic link is known, they too would insist on having the tests done.
Genetic abnormalities pointing to poor cancer survival have been found for various cancers, including lymphomas, leukemias, a nervous system cancer called neuroblastoma, a childhood eye cancer called retinoblastoma, and breast, lung, stomach, bone, kidney, pancreatic, neck and colon cancer.
It is these genetic characteristics, many researchers are saying, that probably explain the potentially fatal difference between two cancers that look alike in every other way. (Cancer kills more than 500,000 Americans every year.)
Although the Food and Drug Administration has not approved tests of a cancer’s genetic characteristics for commercial use, a few large labs will perform them on a research basis on request.
Thus, the anti-cancer tools of the research community are available through private-practice physicians--if doctors know to order them or if patients know to ask for them.
“We do these tests all the time. There are quite a few doctors using them. And they ought to be: They are absolutely indicated for certain tumors,” said Dr. James B. Peter, president of Specialty Laboratories Inc. in Santa Monica.
Besides looking for specific gene defects associated with fast cancer growth, Specialty and other labs can measure how quickly the cancer cells are reproducing and how much of the chemical DNA--the genetic blueprint of life--is in them.
Rapid reproduction of the cells or abnormally large amounts of DNA (deoxyribonucleic acid) would indicate a faster-growing cancer, Peter said. The tests can even be done on minute quantities of tumor tissue preserved years earlier.
These tests, which are considered state-of-the-art and may cost hundreds of dollars, although without FDA approval and further research on their efficacy, they are not technically considered part of the standard care in oncology, doctors say.
Indeed, a doctor who used them to make therapeutic decisions, hypothetically, could risk a malpractice suit--as might a doctor who didn’t use them, because in a few cases they show widely accepted utility.
“I actually am surprised about how quickly commercial laboratories are beginning to test these things,” UCLA’s Slamon said.
At USC, pathologist Michael Press is setting up a lab to do tests for two gene alterations that appear to be the most reliably linked so far to breast cancer’s prognosis. The lab will conduct the tests for private-practice clinicians on request.
The defects the lab seeks are aberrant patterns in the cell’s DNA. The major component of chromosomes, DNA carries in its structure the biological signals that make a human different from a mouse or a petunia. Each unique signal--composed of a specific arrangement of chemicals on the DNA chain--is a gene.
Cancer, scientists have concluded, is rooted in a defective pattern within a gene in the DNA. These faulty patterns, or oncogenes, can be inherited from parents or can occur because of exposure to radiation, chemicals or other environmental factors.
In some cases, it is the presence of a specific altered gene that predisposes a person to cancer.
Other times, there will be more than one copy of a normal gene in the DNA, amplifying its effect with each repetition. This appears to be the case with the repeated, or amplified, genes that promote the growth of breast and colon tumors, among others.
In other cases, a gene protects a person from cancer, and only when it is damaged will cancer occur. That is the case with the RB gene, which, when absent, causes children to get an often-fatal eye cancer, retinoblastoma. RB damage also appears to play an undetermined role in bone, lung, breast and bladder cancers later in life.
That the same genetic alteration turns up in several different types of cancer raises the possibility that understanding a single gene’s pathology will provide a key to finding and treating many types of cancers.
Work by Press, Slamon and others on a gene associated with fast-growing breast and ovarian cancers, called HER-2/neu, illustrates how genetic typing of cancer cells could help a doctor treat patients.
The research has shown that when tumor cells contain repeated copies of the HER-2/neu gene--seen in 25% to 30% of breast cancers--the patient has a poorer prognosis, even if the cancer was detected early and showed no other signs of spreading.
A doctor who found these amplified genes in a woman’s breast-tumor tissue would have a strong indicator that she is at greater risk of dying from the cancer than might be suggested by other cancer hallmarks (such as lack of cancer cells in nearby lymph nodes). Thus, a woman who had no lymph node involvement might still be recommended for chemotherapy.
If the defect were not found, the doctor would have reassurance that less-intense treatment would be unlikely to place the woman among those whose cancers spread despite being caught early.
This same repeated HER-2/neu gene also appears in about 30% of ovarian cancer tumors, and again, it correlates with higher mortality. A study published last year reported that ovarian cancer patients with five copies of the gene lived an average of 243 days after diagnosis, compared to 1,879 for patients with one copy of the gene.
This is particularly significant because, unlike breast cancer, there is no consistently reliable way to determine prognosis for early-stage ovarian cancer.
Further research also has pinpointed at least two other DNA defects that appear to be linked to fast-growing breast cancers, Slamon added. Thus, one woman’s poor prognosis might be due to repeated copies of the HER-2/neu gene in her tumor, while another woman’s might be due to a completely different gene defect.
Extremely sensitive gene-based tests also are being developed to monitor directly the effectiveness of treatment by counting how many cancer cells remain in a tissue sample, said Dr. Carol Westbrook, who runs a hematology-oncology lab that performs such tests at the University of Chicago.
But these tests, so far, are practical only for blood or lymph system cancers, where fluids can be easily sampled. In addition, studies have not been done on how low the concentration of cells would have to be to assure a cancer’s remission.
It is this lack of studies on how to use information that genetic tests can provide that makes their use a sensitive issue. “On the one hand, one wants to be responsible and not provide data to clinicians that might not be of any utility,” USC’s Press said. “On the other hand, you don’t want to be so slow that people are really clamoring for tests that aren’t available.”
At the USC lab, which will concentrate on breast cancer, doctors will receive results only of gene-based tests that have a substantial body of scientific literature showing their clinical utility, Press said. Doctors will receive reports on genetic indicators of the amount of cellular DNA in the tumor cells, how rapidly they are dividing, and whether the two main genes associated with fast-spreading breast cancer are present at amplified levels.
A third chromosomal abnormality that might be linked with breast cancer, but which has not been studied sufficiently, also will be measured. However, data on it will not be reported to doctors until enough research has accumulated to prove this genetic marker’s clinical utility, Press said.
Across the continent, Dr. Bert Vogelstein, a Johns Hopkins University researcher widely acknowledged as the leader in studying oncogenes’ role in colon cancer, is more cautious about use of tests outside research labs.
“The initial studies suggest that--if confirmed in a larger study--the information gained from studying the genetic changes in the colo-rectal tumors could be useful in helping the clinician decide on therapy,” Vogelstein said.
A larger study is at least two years away from completion, he said. And in any case, he emphasized, no single test will ever give physicians the answer to how a tumor will behave. “The genotypic data can only add to the data that’s obtained from the microscope,” Vogelstein said.
Dr. John Minna, chief of the medical oncology branch at the National Cancer Institute, said prognostic indications will be the primary use for gene-based tests over the next few years.
In several years, they may be useful in the early detection of cancer cells in the body--for instance, detecting the 10% of heavy smokers who are most prone to lung cancer. Only after that might the tests advance enough to screen entire families to see which members might have inherited oncogenes, Minna said.
