Forging Ahead: Advances in the Fight Against Ovarian Cancer
Forging Ahead: Advances in the Fight Against Ovarian Cancer
Medically reviewed by Dr. C.D. Buckner 7/1/2013
On Christmas Day 1809, Jane Todd Crawford had an astonishing 22-pound tumor extracted from her abdomen. As the first documented case of ovarian tumor removal, the event holds a significant place in medical history. And there is no doubt that, in the 200 years since, ovarian cancer research has made significant leaps. In the past 30 years, specifically, advances in the screening, diagnosis, and treatment of ovarian cancer tell us that we’ve made important progress. Yet there are many unanswered questions and still much to be learned about the disease.
Making Sense of Screening
Ovarian cancer is considered an elusive disease, quietly progressing undetected and usually evading diagnosis until it reaches advanced stages. Unreliable and inconsistent screening is thought to be one of the primary reasons why mortality rates from ovarian cancer have not improved as much over the past 30 years as those from other cancers have.1,2
According to the National Cancer Institute, nearly three-quarters of women diagnosed with ovarian cancer already have advanced disease (spread beyond the primary site) by the time they are diagnosed.3 As a result, scientists have begun to focus more on understanding how screening tools can identify the disease earlier, when survival is maximized.
One of the most common and heavily researched screening tools today is elevation of the blood protein CA-125. Robert Bast, MD, vice president for translational research at the University of Texas M. D. Anderson Cancer Center, first discovered the biomarker in 1981, and he believes that although the CA-125 blood test is on par with mammography in terms of cost-effectiveness and potential years of life saved, it is far from perfect.
One of the biggest problems with using CA-125 as a screening tool is the tendency of the marker to be elevated in women who do not have ovarian cancer—a phenomenon referred to as a false positive. “The problem is that ovarian cancer is neither rare nor common. It’s somewhere in between,” says Dr. Bast. “It strikes about one in 2,500 women over the age of 50, so any false positives can result in a lot of testing, maybe even surgery. Ordinarily, CA-125 in that population [women over 50] has a false-positive rate of about 1 percent, but that’s not good enough because 1 percent of 2,500 is 25. That’s 25 women who you think have ovarian cancer for every one woman who does. You really need an ultrasound and maybe an operation, but a single CA-125 value isn’t specific enough.”
Dr. Bast notes that another problem with relying solely on CA-125 is that levels tend to fluctuate over time and start to rise approximately two years before early diagnosis can be made. Therefore at-risk women need to be screened repeatedly—usually once a year for several years. Even then, though, he points out that CA-125 will not consistently predict cancer progression, making research about the usefulness of screening measures even more necessary.
Some the most promising evidence to support screening comes from the UK Collaborative Trial of Ovarian Cancer Screening, which followed 200,000 women in London, England. Study researchers recently demonstrated that routine use of CA-125 or vaginal ultrasound resulted in 48 percent of ovarian cancers being diagnosed at Stage I or II.4 Carmel Cohen, MD, professor of gynecological oncology at the Mount Sinai School of Medicine in New York City and scientific director of the Ovarian Cancer Research Fund, believes that the importance of this finding cannot be understated.
“Skeptics say, ‘Screening is fine, but we don’t have any proof that it saves lives; we need mortality data,’” says Dr. Cohen. “That’s a weak argument because, all things being equal, Stages I and II survive better than Stages III and IV.”
Because a singular test has yet to be proven definitive in detecting ovarian cancer early, researchers are also considering alternative methods, such as examining patterns of abnormal proteins (called proteomic techniques). High levels of osteopontin, a protein expressed in bone and other tissues, in conjunction with elevated CA-125, for example, may be more indicative of disease than looking at either separately.1,2 Assessing panels of as many as six proteins simultaneously may become the standard. Proteomic research is complex and still in its infancy, but it appears to hold promise.
But will screening really have an impact on prognosis? In an attempt to answer that question, Dr. Bast and his research team are conducting a smaller-scale version of the UK screening trial to see how useful CA-125 and ultrasound screening are in early diagnosis and the impact of this type of screening on disease course and outcome.
“Some people say, ‘Screening is hopeless; CA-125 is not good.’ But it’s like a lot of things—it’s how you use it,” says Dr. Bast. “It looks like you can detect ovarian cancer and you don’t need to do an inordinate number of ultrasounds or an unacceptable number of operations to do it. What we really need to know, though, is: do we save lives, or do we at least prolong survival for women who are screened and whose cancers are detected?”
Refining Who’s Really at Risk
A wealth of new evidence has broadened our understanding of risk factors that may increase a woman’s chance of developing ovarian cancer. This is critical information because awareness of risk increases patients’ likelihood of receiving early treatment.
Doctors have long known that being over the age of 50; having a family history of ovarian, breast, or colorectal cancer; and having no history of childbirth are the most common risk factors for the disease. More recent research, however, has focused on reproductive and hormonal factors.
Dr. Cohen considers oral contraceptives “one of the cheapest, easiest, most beneficial ways of reducing risk.” In fact, over the course of five years, women taking birth-control pills may decrease their risk by as much as 50 percent compared with those who have never taken them.5 Conversely, infertile women who have never been pregnant and who have taken unusually high dosages of certain ovulation stimulation medications, such as Clomid® (clomiphene citrate), may increase their risk.5 According to the American Cancer Society, postmenopausal women who have been on long-term (five to 10 years) estrogen replacement therapy without progesterone may also incur a greater risk.6
The role of lifestyle factors, such as obesity and cigarette smoking, is also gaining wider attention.5 Recent data from the large-scale Nurses Health Study,7 which examined lifestyle habits of more than 120,000 female nurses, found that women who smoked had a greater risk of a rare type of epithelial ovarian cancer, whereas women who drank caffeine displayed a 20 to 25 percent lower risk of developing ovarian cancer. Although the caffeine finding was not considered significant from a statistical viewpoint, the trend was strong enough to justify further research into whether caffeine use may provide protective effects.
Even though researchers are uncovering more factors that can potentially play a role in cancer development, the word risk is still most commonly equated with the words family history. “When family history includes breast, ovarian, and uterine cancer in cluster, the likelihood is there is some inheritable risk,” says Dr. Cohen, “but we haven’t identified all the genes that are responsible. Therefore women with a strong family history of those cancers really ought to be seeing a genetic counselor or a gynecological oncologist to settle out their risk.”
Is It in the Genes?
As Dr. Cohen notes, genetics likely play a large role in understanding who is at risk of ovarian cancer. Two types of genetic mutations of particularly high importance to ovarian cancer development have emerged: oncogenes and tumor suppressor genes. Oncogenes are mutated genes that cause normal cells to divide too quickly, increasing the likelihood that they will develop into cancer cells. Tumor suppressor genes help prevent mutated cells from becoming cancer cells. Drs. Cohen and Bast use the car as an analogy to describe the way the two different types of genes work: oncogenes punch the accelerator on cell development, and tumor suppressor genes slam on the brakes. Suppressor genes themselves are beneficial; it’s not until they are mutated to grow abnormally and too fast that problems arise.
“When you have an overexpression of an aberrant form of a suppressor gene, it means the suppressor effect is weakened and therefore the patient’s own immune system will be weakened and will not respond to rejection or normal repair of a cell deficit,” Dr. Cohen explains. “There will then be an overgrowth of tissue, which is classified as a cancer.”
Two well-known oncogenes are BRCA1 and BRCA2. While linked to heritable forms of breast cancer, these mutations are also linked to ovarian cancer in about 10 percent of cases. The oncogene HER2/neu is also associated with breast cancer and is overexpressed in about 20 percent of ovarian cancers. Recently, researchers at M. D. Anderson Cancer Center discovered that the oncogene PKCi may be elevated in women with serous ovarian cancers; and, in women with nonserous ovarian cancer, PKCi appears to be elevated in combination with an oncogene called cyclin E.8 Some genetic mutations may be specific to certain subtypes of ovarian cancer. For example, between 20 and 50 percent of borderline epithelial ovarian tumors have mutations of the oncogene K-ras, but this gene is nearly absent in nonborderline epithelial cancers.
In the case of tumor suppressor genes, researchers are becoming increasingly interested in the protein p53,9 especially in advanced ovarian cases. An overexpression of nonfunctional p53 is present in about 40 to 60 percent of Stage III and IV ovarian cancers but in only about 10 to 20 percent of Stage I cases and in virtually no borderline cases. As with other genetic discoveries, though, it is uncertain what detection of these mutations means for treatment and prognosis.
“In any cancer you can almost always find abnormal p53 functioning,” says Dr. Cohen. “The question of what to do about it becomes the next issue.”
Treatment of ovarian cancer has done little to change cure rates, but survival has been prolonged. Dr. Bast calls it a “half-full, half-empty” problem. “There has been a significant improvement in median survival for ovarian cancer patients, and rates are highly significant if a patient undergoes optimal surgery followed by optimal chemotherapy,” he says. “The median survival is still only about five years, but when I was going through medical school, it was only a year or two.”
He attributes this improvement to three particular therapeutic advances. First, he cites the response rate to a class of chemotherapies called platinum drugs (which include the medication Platinol® [cisplatin]), which has increased from about 20 percent in the 1980s to about 70 percent today. Second, he says, are taxane drugs (such as Taxol® [paclitaxel]), which have helped extend survival by six to 12 months. Finally, he points to a class of drugs called angiogenesis therapies (including the drug Avastin® [bevacizumab]), which may prolong survival by about six months.
According to Krishnansu S. Tewari, MD, gynecologic oncologist and associate professor at the Chao Family Comprehensive Cancer Center, University of California, Irvine, “One of the most exciting areas of clinical research in ovarian cancer involves angiogenesis, which is the process through which a tumor is able to connect with the patient’s body through blood vessel formation. [Angiogenesis] allows the cancer to receive nourishment and grow. Blocking the pathway of angiogenesis holds great promise in ovarian cancer therapy.”
Dr. Tewari notes that Avastin not only has been shown to prevent angiogenesis but has been approved by the Food and Drug Administration for the treatment of multiple cancers, including breast, colorectal, lung, and—outside the United States—kidney cancer.
“Currently, our Gynecological Oncology Group is studying the ability to block angiogenesis in patients with both newly diagnosed and relapsing ovarian cancer,” adds Dr. Tewari. “Although these clinical trials in ovarian cancer using bevacizumab are ongoing, many suspect this will represent bevacizumab’s finest hour.”
The success of any treatment depends in large part on each woman’s individual expression of the disease, which makes it difficult to identify one drug that would uniformly treat all cases equally well.
“We’re trying to refine the treatments that we give to ovarian patients based not only on the stage and how [the disease] looks under the microscope but by virtue of its molecular behavior,” says Dr. Cohen. “For example, clear-cell carcinoma is a subcategory of ovarian cancer. It is a very, very aggressive disease and is hard to control with chemotherapy that is more useful in a papillary serous carcinoma.”
The highly individual nature of each woman’s disease has researchers looking to adapt treatments to the molecular structure of a patient’s cancer. For instance, one way of individualizing treatment is to target the unique ways in which the cells communicate with one another.
“We know now that certain proteins give messages to other areas of the cell to do certain jobs, which can be divided into cell proliferation and suppression, broadly,” explains Dr. Cohen. “If you can identify a drug or substance that will interrupt that pathway by quieting the protein that makes that message, you have a way of controlling the replication of that cell group.” However, as Dr. Cohen notes, it’s not as straightforward as simply silencing a gene or protein because that communication pathway might have both positive and negative functions.
“You have to find a treatment that will affect the message under adverse conditions and not constructive conditions because you might shut off its beneficial effects. It’s like damming the Mississippi River near Chicago. If you do that, the country south of Illinois will die of drought,” he says. “You have to be selective about choosing drug interventions, and those take a very long time to perfect.”
“I think what really needs to be done at the present time is to sort out differences from patient to patient,” adds Dr. Bast. “We’ve always known that patients are different, and their cancers differ from person to person. The challenge is being able to predict who will respond and who won’t respond to different chemotherapies. Now, with some of the new technologies where you can sequence genes and look at which are turned on and which aren’t, we’re beginning to be able to group patients in ways we never could before.”
Taking a New View?
It used to be that ovarian cancer was thought to develop in a linear pattern, starting in the ovaries and expanding outward. Based on this model, staging would indicate the distance and the widespread pattern of metastasis, from the pelvis to the abdomen and beyond. Recently, though, scientists have contemplated different models for how ovarian cancer develops and spreads. Some of the most compelling evidence comes from studies of women with the BRCA1/BRCA2 gene(s) who undergo prophylactic oophorectomy. In these women small, high-grade carcinomas in the fallopian tube have been detected that are not present in the ovaries, suggesting that, perhaps in this population of women, the disease can begin in the fallopian tube and spread to the ovaries as it advances.10 Although this represents only a small number of cases, occurrences such as these add another element to the puzzle that scientists are still piecing together.
“[Our view] certainly is evolving, but I’m not sure anyone has a good estimate of how many ovarian cancers arise from outside the ovary or even from the abdomen cavity itself,” says Dr. Bast. “Sporadic disease may not be identical to high-risk disease, at least in the fraction of the cases where it actually does arise in the fallopian, endometrium, or the abdominal cavity itself. That has implications for early detections, and it suggests that we may need to depend on blood tests and less on imaging.”
Accurate classification has important implications for treatment, and understanding how ovarian cancer cells behave will inform research on risk factors and genetics as well as treatment development. Scientists from Johns Hopkins University have proposed a model in which tumors are divided into two groups: those that are slow growing and confined to the ovary and those that grow rapidly and are poorly differentiated.10 Using this classification system, the scientists were able to isolate genes associated with each tumor type, which may assist them in earlier detection using genetic methods rather than waiting until the disease is detectable through more-traditional methods such as ultrasound.
Drs. Bast and Cohen also note that in the field of gynecological oncology there are differing views as to whether early-stage disease is really the same type of ovarian cancer as later-stage disease. Some researchers believe that early-stage ovarian cancer may represent a completely different type of cancer that’s more gradual and may not progress past Stage I or II. Ultimately, determining the most accurate model is complicated by the fact that, as Dr. Cohen summarizes, “ovarian cancer is not a monolithic, homogenous disease.”
The Road Ahead
Considerable progress has been made in advancing our understanding and treatment of ovarian cancer, but many questions remain. As the research described here makes clear, however, each day holds the opportunity for breakthrough. Regardless of how long or rocky the road ahead of us is, there is value in knowing that today’s innovations are doing more than just building the science of detection or treatment. They are building the science of hope.
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