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Researchers Seek Ways to Find Early Signs of Cancer

March 28, 2007 at 9:22 AM EST
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DOCTOR: A couple of short breaths, I’ll line you up, and then I’ll be back for the injection.

SUSAN DENTZER: Every few months, an anxious Kathy Lilliman undergoes a CT scan to see if her ovarian cancer has recurred. Lilliman, who’s 52, was diagnosed with the deadly disease almost three years ago. She had never had a blood test for so-called CA-125, a protein that, at high levels, can signal the presence of ovarian cancer.

Her only symptoms had been occasional gastrointestinal troubles, easily attributable to something more benign than cancer.

KATHY LILLIMAN, Cancer Patient: They were just stomach problems, and I was almost going through menopause right then, too. And I would have it one week, I would feel awful. And then the next week, I would be OK.

SUSAN DENTZER: Her doctor first misdiagnosed Lilliman, shown here with her daughter, as having a condition called irritable bowel syndrome. By the time cancer was diagnosed more than a year later, Lilliman had an orange-sized tumor on one ovary, and the disease had already spread to other organs.

Now, after two long bouts of chemotherapy, Lilliman knows the odds are against her. Only about one in three women with advanced ovarian cancer survive beyond five years. Lilliman wishes the cancer had been detected sooner when it could have been removed by surgery alone.

KATHY LILLIMAN: I wouldn’t have to have gone through the chemo. I wouldn’t be worried now about recurring every few years. If they had caught it early, I would have been done with it and be back to my normal life.

SUSAN DENTZER: Detecting cancer earlier in patients like Lilliman is critical, says Lee Hartwell. He’s a Nobel Prize-winning scientist who heads the Fred Hutchinson Cancer Research Center in Seattle.

LEE HARTWELL, Fred Hutchinson Cancer Research Center: Perhaps the most important statistic we know about cancer is that, if you detect it at an early stage, then standard treatments, usually surgery and radiation, will cure the disease. But if the disease is detected late, it’s very unusual to cure the disease.

The role of biomarkers

Anna Barker
National Cancer Institute
We have to treat it in a much more targeted fashion. We have to be able to know when cancer is going to come back or recur. And biomarkers are actually probably the single biggest hope we have to accomplish those goals.

SUSAN DENTZER: Early detection is all the more urgent now that one in three Americans are facing cancer, and the overall number of cases is expected to double within 15 years. So scientists here at Fred Hutchinson and at other labs across the country are searching for better early warning systems for cancer.

They're called biomarkers, substances like CA-125 or the prostate specific antigen, PSA, that can be a sign of prostate cancer. In the future, many more biomarkers could be found through a simple blood, urine or saliva test and signal that a disease process like cancer is under way.

Scientist Anna Barker is deputy director of the National Cancer Institute, a branch of the National Institutes of Health.

ANNA BARKER, National Cancer Institute: Biomarkers are variously defined. It's a complex term that captures an enormous amount of science. But, really, it's measuring the change in a normal cellular process or a malignant or cancer cell process, so that means that biomarkers can be changes in genes, changes in proteins, some combination thereof.

SUSAN DENTZER: Barker says biomarkers will be crucial across the whole range of cancer detection, diagnosis and treatment. That's a key reason NCI and NIH are pumping tens of millions of dollars into biomarker research.

ANNA BARKER: We have to have better ways to detect this disease earlier. We have to treat it in a much more targeted fashion. We have to be able to know when cancer is going to come back or recur. And biomarkers are actually probably the single biggest hope we have to accomplish those goals.

How cancer progresses

Lee Hartwell
Fred Hutchinson Cancer Research Center
When a cancer actually starts in the body, there are further genetic changes that occur progressively. And that's the fundamental basis of the cancer process, is changes in the genes during the course of the disease.

SUSAN DENTZER: Cancer, the uncontrolled growth of cells, is at its root a disease of genes. Some cancer-causing genes can be inherited, like BRCA1 and BRCA-2, which predispose some women to breast and ovarian cancer.

But other normal genes mutate in the body when exposed to environmental influences, such as when lung cells are bathed in tobacco smoke. And the genetic changes in cancer don't stop there, says scientist Hartwell.

LEE HARTWELL: When a cancer actually starts in the body, there are further genetic changes that occur progressively. And that's the fundamental basis of the cancer process, is changes in the genes during the course of the disease.

SUSAN DENTZER: Genes normally function as switches that turn on protein-making factories in cells, and these proteins then carry out the body's basic work. So each genetic change that takes place as cancer develops leads directly to changes in the body's proteins.

LEE HARTWELL: Some changes produce an excess of protein over the normal. It's the same protein; there's just a lot more of it.

Other genes get inactivated, so that a protein that's normally produced is not produced anymore. Then, a third type of change is where the proteins produced is actually a different protein and has some abnormal function.

The quest to identify biomarkers

Nicole Urban
Fred Hutchinson Cancer Research Center
At the time that a diagnosis is made, when a woman is symptomatic and has late-stage cancer, about 80 percent of those women do have elevated CA-125. The problem is that it doesn't elevate until the cancer is quite advanced.

SUSAN DENTZER: So a biomarker for cancer could be any of these changes in genes or changes in the body's untold number of proteins. As many as one million of those proteins could turn out to be important in cancer.

That means the quest to identify all the biomarkers associated with cancer will be a Herculean effort, destined to take a decade or more.

Leading the effort at Fred Hutchinson to study biomarkers for ovarian cancer is biostatistician Nicole Urban. For her, the quest is personal as much as professional, since she was diagnosed with ovarian cancer three decades ago.

NICOLE URBAN, Fred Hutchinson Cancer Research Center: It was very early stage. It was also not a very aggressive form of ovarian cancer. I had been very lucky to have been diagnosed early, and so I wanted to do what I could to solve this problem.

SUSAN DENTZER: The problem, Urban says, is that, unlike in her case, three-quarters of ovarian cancers are like Kathy Lilliman's. They're diagnosed after the disease has spread beyond the ovaries and pelvis, drastically raising the odds of death.

NICOLE URBAN: ... whereas, if it's detected early, 90 percent of women survive at least five years, most of them 10 years.

SUSAN DENTZER: The biomarker CA-125, for cancer antigen 125, is a useful but not altogether dependable signal of cancer.

NICOLE URBAN: At the time that a diagnosis is made, when a woman is symptomatic and has late-stage cancer, about 80 percent of those women do have elevated CA-125. The problem is that it doesn't elevate until the cancer is quite advanced.

SUSAN DENTZER: So Urban and her team are now evaluating other proteins linked to ovarian cancer to see if together they serve as clearer indicators of early-stage cancer.

One is produced by a gene called HE4, normally expressed in the male testicles. For unknown reasons, it's almost never found in women, unless they have ovarian cancer. Urban says she thinks a test could ultimately be created to detect HE4 and several other ovarian cancer biomarkers.

NICOLE URBAN: What I would actually hope, in my wildest dreams, is that we would have risk markers, we would have -- so when women go for a mammogram, that at the time that they get their mammogram, they would also have their blood tested, and that there would be markers that would identify women who are at very high risk of being diagnosed with ovarian cancer.

SUSAN DENTZER: Hartwell says the goal should not be just to find biomarkers for all cancers, but also to find them for other devastating diseases, like diabetes.

LEE HARTWELL: I imagine a future in which we will routinely take a blood test, you know, several times a year that looks at tens of thousands of biomarkers. And by comparing our pattern over time, we will detect changes in our health state that allow us to do much more in terms of prevention.

The need for more research

Janet Woodcock
Food and Drug Administration
We've teamed up together to make sure that, not only are the tests developed into medical products, but there's enough information about them and about their value that CMS is able to reimburse for them.

SUSAN DENTZER: But a mind-boggling amount of scientific research will have to be conducted before that hope is borne out.

Among other things, scientists need more sophisticated tests to detect the presence of biomarkers, and then proof from clinical trials that these biomarkers reliably predict disease in large populations of very different patients.

ANNA BARKER: We have to discover biomarkers, we have to validate biomarkers, and then we have to use biomarkers in clinical trials, and then we have to actually make products that patients receive that are actually biomarker-based.

SUSAN DENTZER: Pushing all this science along as fast as possible and turning it into tests and treatments for patients is now a top government priority, says Dr. Janet Woodcock. She's chief medical officer for the Food and Drug Administration.

DR. JANET WOODCOCK, Food and Drug Administration: We think this is so urgent that, amongst the federal sector, the Food and Drug Administration, the National Cancer Institute, and the Center for Medicare and Medicaid Services, or CMS, that we've teamed up together to make sure that, not only are the tests developed into medical products, but there's enough information about them and about their value that CMS is able to reimburse for them.

SUSAN DENTZER: The FDA recently approved for sale one type of biomarker test, the MammaPrint. By analyzing 70 genes in tumor tissues, it can help predict whether women with breast cancer are at risk of recurrence or spread of the disease following treatment. Barker says it's just a harbinger of what's to come.

ANNA BARKER: Well, having actually lost my entire family to cancer -- my mother, my father, my sister, my grandmother, and two aunts -- I can only say that, if biomarkers had been available when any one of them basically was alive, I think they would have probably helped those individuals to have a higher quality of life, certainly, and maybe live longer.

SUSAN DENTZER: And for cancer patients like Kathy Lilliman, that's a future well worth hoping for.