Shrouded In History
The mysterious origins of ovarian tumors are a stubborn block to reliably detecting or even predicting ovarian cancer. by Lori OliwensteinOvarian cancer is a secretive malignancy, a cancer that grows in the deepest recesses of a woman's body, often without giving the faintest hint that it is there. It is extremely lethal, killing more than half the women in whom it is diagnosed within five years. In fact, although it is only the fifth most common cancer among women, it is responsible for more deaths each year than any other cancer of the female reproductive tract-including
endometrial and cervical cancers.
Its silence and its virulence go hand in hand. "If you detect ovarian cancer early, while it's still at Stage 1A, the cure rate is nearly 100 percent," explains Agustin Garcia, M.D., assistant professor of clinical medicine at the Keck School of Medicine. "But if you don't detect it until it's in Stage 4, the cure rate is 20 percent-at best."
There's the rub. There is still no reliable way to detect-or for that matter, to prevent-ovarian cancer before it has begun its insidious insurrection. And so, for about three-quarters of women with the disease, the odds of survival drop precipitously even before they know there is anything wrong with them.
Which is why researchers at the Keck School of Medicine and the USC/Norris Comprehensive Cancer Center are taking a many-pronged approach to subduing this gynecologic marauder. And they are starting almost from scratch, since ovarian cancer's silence means it is not an easy foe to track.
"Ovarian cancer is not like breast cancer or cervical cancer, where we can study its early development easily," notes Garcia. "We don't even really know which is the normal cell that becomes cancerous."
For a long time, cancer researchers have assumed that ovarian cancer originates in the layer of cells that line the ovarian surface. But in truth, notes Louis Dubeau, M.D., Ph.D., professor of pathology at the Keck School, to date no one has managed to identify exactly which cell it is that turns cancerous, or what prompts that shift to malignancy.
Finding ovarian cancer's cellular roots is not just an academic exercise, Dubeau adds. "If we don't even know where to look for it, it's going to be hard to find it early enough to treat it while it's still treatable."
Dubeau believes the disease's origins are in microscopic structures that are embryologically related to fallopian tubes, endometrium and endocervix. He admits his theory is controversial, but one with some significant evidence behind it-evidence strong enough to help it gain increasing numbers of supporters. "Ovarian cancers do not look like any of the cells present in the ovaries," he explains. "But they are similar to cancers that arise from these other parts of the female genital tract. Indeed, ovarian cancers are virtually indistinguishable-at the microscopic level-from fallopian tube cancers, endometrial cancers or cancers of the cervix."
Interestingly, he points out, the fallopian tubes, endometrium and the cervix have the same embryonic origin, while the ovary comes from an entirely different line of cells. Thus it is difficult to understand how cancerous cells from the ovaries might come to look like cells from these organs-unless they come from cells derived from the same lineage.
"Numerous remnants of the embryological structure that give rise to fallopian tubes, endometrium and the cervix are present within, as well as outside, the ovary," explains Dubeau. Under normal conditions, these bits of vestigial tissue would sit quietly, doing nothing and responding to nothing. In women predisposed to ovarian cancer or in those with abnormal hormone levels, these tissue may respond to hormonal stimulation and eventually give rise to cancer.
This theory would not only explain the mysterious origins of ovarian cancers, but would also explain why prophylactic oophorectomy-removing otherwise-healthy ovaries in order to lessen the risk of developing cancer-is not as effective as might be thought. "Prophylactic oophorectomy does not protect 100 percent," says Dubeau. "Years later, some of these women will go on to develop cancers that look like ovarian cancer. But if my hypothesis is right, that's because we haven't completely protected against ovarian cancer-we haven't made sure to take out these tissue remnants along with the ovaries. All it would take is for a surgeon to be aware, and to extend the operation a little bit."
Detective Work
The real goal of tracing the ovarian cancer family tree is not to make an admittedly radical procedure better, but for physicians to know just what it is they are looking for when they are looking for the earliest stages of the disease. The real goal is to help physicians develop safe, effective and useful ways to detect ovarian cancer before it really begins, because early detection allows it to be cured by surgery in the vast majority of cases.
But having good, sound reasons to develop a screening test that is low-cost, low-risk and able to pick up a high percentage of early-stage cancers and actually doing it are two entirely different things, says Garcia. And the difference, once again, lies in figuring out the details of the malignancy's murky past. "We need to know the natural history of the tumor to know when we can jump in and do something about it before it has advanced too far," he says.
There are a few things already known about ovarian cancer risk. For one thing, women carrying any of the so-called breast cancer (BRCA) genes also have a higher risk of developing ovarian cancer. "And there are likely other genes that increase risk that have not yet been identified," adds Garcia. "But as of now, we can only find such a genetic susceptibility in 5 to 10 percent of patients."
We also know that the risk of ovarian cancer in young women is negligible; ovarian cancer risk is highest for women over the age of 60. We know that women who have had breast cancer are twice as likely to develop ovarian cancer as are women who have not. And we know-thanks to groundbreaking work in 1993 by USC professors of preventive medicine Malcolm Pike, Ph.D., Brian Henderson, M.D., and Ronald Ross, M.D.-that a single pregnancy or oral contraceptive use for five years cuts a woman's risk of getting the disease by 40 to 50 percent.
This sort of knowledge helps in narrowing down the number of women who need to be closely monitored for the disease, but it does not reveal which of the high-risk individuals are actually carrying cancerous cells inside of them. And so the search for a reliable way to detect or even predict ovarian cancer goes on.
For a while, notes Garcia, there was some excitement over a molecule called CA125, a specific ovarian tumor marker found in the blood of patients with the cancer. The initial hope was that it might be used the same as PSA (prostate-specific antigen) is used in prostate cancer; that the level of the molecule in the blood would be a strong indicator of the possibility of cancer, and a sign as to whether further diagnostic testing is necessary.
But, as Garcia recently noted in a review article in the journal Current Practice of Medicine, CA125 has not quite lived up to those initial hopes. While the marker seems to be useful in the later stages of ovarian cancer, helping physicians monitor how the tumor is responding to any of a number of therapies being employed against it, it is only elevated in about half of early stage ovarian cancers.
And a screening test that is not extremely accurate can be worse than having no screening test at all, Garcia says. After all, screening tests just tell you whether it is likely the person has the disease or a predisposition to the disease. In order to diagnose ovarian cancer, you have to do surgery to obtain a biopsy. And that puts a lot of pressure on the screenings to be as accurate as possible in the first place. "It's a pretty big surgery, after all," Garcia points out. "The test has to be really, really good, or you'll do many big, unnecessary surgeries."
That does not mean that the concept of screening has been dismissed, however. In fact, observes Garcia, the Keck School of Medicine and the USC/Norris are now beginning to start some clinical research into various screening methods, including CA125 and some other molecular markers-as well as the use of ultrasound-that, when paired together, might be more accurate in pinpointing early cancers. The Ovarian Cancer Working Group at USC is heading up this effort, led by Lynda Roman, M.D., principal investigator for the Gynecologic Oncology Group at the USC/Norris, with funding provided by the L.A.-based Lynne Cohen Foundation, as well as other sources.
Second Time Around
As it turns out, the importance of accurate screening and detection does not end at the initial diagnosis of ovarian cancer. Ovarian cancer's deadly reputation is due to its tendency to metastasize, to wander throughout the abdomen, spreading rapidly and affecting a variety of organs. Even after the cancer is diagnosed and the ovaries removed, there is still the concern that there may be stray cancer cells roaming throughout the region, ready to settle down and begin their uncontrolled proliferation in another site.
But if Dubeau's intriguing theories are right, the very enzyme that gives the cells their taste of immortality will soon be giving physicians a way to track down recurrences of the tumor. Dubeau recently received a $1.2 million grant from the National Cancer Institute (NCI) and support from the Lynne Cohen Foundation to study whether telomerase, the enzyme in question, might be used to predict a woman's risk of recurrence of ovarian cancer.
"Telomerase is essential for continual cell growth," says Dubeau. "It is the reason why cancer cells can grow indefinitely."
Each time a normal cell divides, the ends of its chromosomes-its telomeres-become slightly shorter. When the telomeres get down to a certain, predetermined length, the cell can no longer divide.
But in cancer cells, the gene for the enzyme telomerase is somehow switched on; the telomerase allows the telomeres to maintain their length and thus to divide ad infinitum.
Telomerase is so important because it is found in high levels in virtually every single type of cancerous cell-including ovarian cancer. In 1998, Dubeau and his colleagues showed that ovarian cancer cells not only express abnormally high levels of the protein, but that an assay (or laboratory test) relying on telomerase was better able to diagnose the disease accurately than the conventional way of looking at collected cells under a microscope. Indeed, Dubeau showed in test-tube experiments that his assay for telomerase could pick up cancer in a sample containing only 10 to 50 cancerous cells among thousands of normal cells.
The NCI-funded study will take this to the next step, looking at the assay's ability to pick up the telomerase produced by stray ovarian cancer cells left behind after surgery, even when other tests are unable to find any remaining traces of the disease.
Dubeau and his USC colleagues hope to recruit as many as 500 ovarian cancer patients from USC, the University of California, Los Angeles, the Mayo Clinic, Memorial Sloan Kettering Cancer Center, M.D. Anderson Cancer Center, the Scripps Institute, Utah Medical Center, Tulane University and Harvard University. Eligible patients will be those who are undergoing so-called second look surgeries, in which the patient's abdomen is reopened some six months after the initial, tumor-removing surgery, and a detailed visual examination is conducted.
These surgeries have long been part of the gold standard for ovarian cancer treatment: The physician looks for signs of new tumor growth in hopes of detecting any seeds of the disease before they become too advanced. But the problem is, in at least half of the patients whose abdomens show no sign of the disease, the cancer springs back to life anyway.
Telomerase, says Dubeau, might be able to do what second-look surgeries cannot: Pick out those patients most likely to relapse, so that they can be followed more closely and treated more aggressively. And so, Dubeau plans to have the surgeons doing these second-look surgeries take a simple washing of the abdomen while doing the visual exam; the cells collected by those washings will then be tested at USC for telomerase activity. If cells are found with high levels of the enzyme, it may well indicate that some cancer cells resisted treatment.
The patients will be followed for up to two years, to see if those who appear to have a "clean" abdomen on exam but who show telomerase activity actually go on to develop a recurrence of their disease. "The hypothesis is that these are the patients who will recur," says Dubeau. "If our hypothesis is verified, then in the future, these sorts of patients would be treated far more aggressively."
"It whispers-- so listen," warns the National Ovarian Cancer Coalition of the disease so many women are forced to fight. But if USC researchers have anything to say about it, that whisper will soon be amplified into a shout that can be heard around the world-in plenty of time to save plenty of lives.
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