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Tip Sheet: Gynecologic Cancer - More Awareness Needed

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Duke Health News 919-660-1306

Background

Cancers of the female reproductive system tend to be hidden, but researchers at Duke University Medical Center are working to find ways to detect and treat the potentially lethal diseases.

Only one of the gynecologic cancers, cervical cancer, can be detected easily in early stages, and even with an effective screening method, thousands of women die from cervical cancer each year, mostly because they don't get regular Pap smears. While there's no screening test for uterine cancer, symptoms like unexplained bleeding can lead to a diagnosis early in the course of the disease. Ovarian cancer, on the other hand, has no early screening method and only produces symptoms late in the disease, when effective treatment is difficult.

Researchers at the Duke Comprehensive Cancer Center are engaging in a find-and-fight assault against these women's cancers. It's a battle that ranges from collecting thousands of tumor samples from women throughout North Carolina to wielding heat to help dissipate cancerous growth.

The Duke researchers already have participated in a number of important findings that have clarified how these diseases get started and keep going, and how best to fight them. Duke scientists were the first to identify two key genes - BRCA1 and BRCA2 - that are involved in both ovarian and breast cancer. Duke also participated in national clinical trials that brought the two primary chemotherapy drugs to widespread use for ovarian cancer. Now patients have the option of joining new clinical trials that will paint a more detailed picture of these cancers.

In addition to research, Duke is one of 30 medical centers in the country offering fellowships in gynecologic oncology, a recognized medical specialty that provides doctors extra training in managing the care of patients with cancer of the ovaries, uterus, cervix, vulva, vagina and Fallopian tubes.

The American Cancer Society predicts the number of new invasive cancers and U.S. deaths in 1999 due to the three most common of these diseases to be:

Here are a few research projects from Duke Comprehensive Cancer Center and Duke University Medical Center that could help women improve their health:

Banishing a Foe

While there are relatively few new cases of invasive cervical cancer each year, Duke's Dr. Gustavo Rodriguez thinks there are still too many - and too many deaths from the disease.

"It's almost unheard of to diagnose invasive cervical cancer in a patient having yearly Pap smears," said Rodriguez, assistant professor of gynecologic oncology.

"Unfortunately, not all women get their yearly exams. We need to change that."
In fact, he said that regular screening - a yearly Pap smear to collect and examine cells from the cervix - reduces cervical cancer mortality by 90 percent to 95 percent. But half of women diagnosed with cervical cancer have never had a Pap smear, and another 10 percent haven't had one in the five years prior to their diagnoses, he said.

"Women need to know to ask for a Pap smear if they haven't had one, and practitioners need to stop assuming that someone else is taking care of that crucial aspect of their patients' health," he said. "There's really no reason for women not to be screened, yet women still walk in with advanced cervical cancer."

Some reasons why women don't get Pap smears include poor access to care and simply not knowing that they should be screened. Risk factors for developing cervical cancer include having had more than one sexual partner, exposure to the sexually-transmitted human papilloma virus (HPV) and a suppressed immune system.

Financial problems should not keep women from seeking the care they need, said Rodriguez. "In North Carolina, our state-funded Cervix Dysplasia Clinic can provide screening and care to the underserved and indigent who meet our criteria, and the Department of Health is also a resource," he said.

Cervical cancer and the cellular changes preceding it can be detected when cells from the cervix are examined under a microscope. Treatment is available to prevent pre-cancerous changes from progressing into full-blown cancer, Rodriguez said.

Cause and Prevention in Ovarian Cancer
Only 5 percent to 10 percent of ovarian cancers are related to the inherited genes BRCA1 and BRCA2 - originally known as the "breast cancer genes." Finding other, possibly preventable risk factors is part of the goal of Duke's Gynecologic Oncology Program and the Cancer Detection, Prevention and Control Research Program.

"There's no good screening method for ovarian cancer right now, so the best possibility is to try to prevent the disease," said Dr. Andrew Berchuck, professor of gynecologic oncology. He and his colleagues want to identify the factors that affect the risk of developing ovarian cancer.

One new tool, the N.C. Ovarian Cancer Study, collects information and blood and tumor samples from 700 ovarian cancer patients in 48 counties in the state. This pool will be compared to information and blood samples from an equal number of similar women without cancer to highlight behavior, environment or other differences that could be linked to developing ovarian cancer.

Researchers know that family history of the disease is a strong risk factor, but other factors, including the number of lifetime ovulations and infertility, are also associated with ovarian cancer risk.

Ovulation-limiting actions like pregnancy, breast feeding and using birth control pills reduce ovarian cancer risk, and may even help prevent the disease directly. On the other hand, some things out of women's control increase risk, such as an early start to menstruation or a late menopause. The disease is also more prevalent in white women than in women of other races, and in women age 50 to 74.

By identifying more risk factors, Berchuck and study leader Joellen Schildkraut, associate professor in the Cancer Detection, Prevention and Control Research Program and Department of Community and Family Medicine, hope to provide a new starting point for figuring out how ovarian cancer begins, who's most at risk for it, and ultimately how to prevent and better treat the disease.

The Chicken and the Egg Doctors know that using birth control pills protects women from ovarian cancer, but the magnitude of the effect seemed too large to attribute just to preventing ovulation, said Duke's Dr. Gus Rodriguez. Three years of pill use cuts ovarian cancer risk by 50 percent, even though the total number of ovulations only drops by about 7 percent, he explained.
Acting on his hunch, a team led by Rodriguez investigated and reported last year that the bulk of the pills' effect might be due to a process other than ovulation. In monkeys, the researchers from Duke and the Bowman Gray School of Medicine found that the hormone progestin actually induces damaged cells on the surface of the ovaries to begin a cellular suicide program. Some of these surface, or epithelial, cells are damaged each time a mature egg is released. Progestin appears to make these damaged cells die before they can become malignant, suggesting that it could be a useful prevention agent for ovarian cancer.The doctors are now studying the effects of progestin on the most frequent ovulators of all - hens. Chickens appear to be a good model for studying the ovaries, since they ovulate, or produce an egg, about once a day and they develop spontaneous ovarian cancer at a high rate. By 4 to 6 years of age, between 13 percent and 40 percent of hens have ovarian cancer. Researchers led by Rodriguez are in the midst of a two-year study of 2,000 chickens - half of which receive progestin and half of which get a placebo. After the birds are sacrificed, the researchers will compare tissue appearance and the prevalence of ovarian cancer in the two groups.

This study also will be validating the chicken as a model of ovarian cancer, an important step in ovarian cancer research. Right now, there are very few animal models that mimic the human disease, and treatment of ovarian cancer patients is plagued by delayed diagnosis and limited therapy options, say doctors. Having a good animal model could let researchers rapidly identify possible diagnostic markers or develop new treatments, Rodriguez said.

The researchers are also performing laboratory studies to examine the effects of different progestins on normal human ovarian cells.

Saving Today for Big Returns Tomorrow
It doesn't get compounding interest or soar like Internet stocks, but Duke's Gynecologic Cancer Tumor Bank is a long-term investment that might pay out big in the future as researchers try to learn how these cancers get started and ultimately how to stop or prevent them.

Begun in 1985, the bank now holds around 15,000 tissue samples from more than 3,000 patients that could help researchers find causes and cures for gynecologic cancers. Included in the bank are samples of both early- and late-stage uterine and ovarian cancer, blood serum from patients with gynecologic cancers and serum from healthy people.

"In the past 10 years or so there's been a huge explosion in understanding cancer on a molecular level by studying genetic changes," said Dr. Andrew Berchuck, professor of gynecologic oncology. "To do that kind of research, you need a bank of specimens and correlation with response to treatment and ultimate outcome. We have that here."

In fact, the tumor bank provides such a unique opportunity for research that multiple samples have been provided to 12 collaborators outside of Duke, including scientists at government labs, universities and private companies, he said.

Instead of recruiting hundreds of patients to test every new idea, researchers can use the frozen samples to study the effect of a gene mutation, for example, and correlate the findings to survival. In short, the tumor bank lets researchers find answers faster as they look for subtle and not-so-subtle differences between patients' tumors.
"A BMW and a Chevette are both cars, but they are very different under the hood," said Berchuck. "With this tumor bank and the ability to do molecular studies, we're basically looking under the hood of cancers to see what makes them run."

Banking tumor samples is slightly different from preparing samples for pathology exam, but still fairly simple, Berchuck said. As tumor material is removed, desired sections are rapidly frozen, preserving the genetic material and the proteins found in the tumor cells. Pathology samples are mounted to preserve cell structure, but not the molecular detail needed to look at gene mutations or protein expression, Berchuck said.

Is it Hot in Here?

Duke researchers have been turning up the heat to help kill cancer cells for some time. The therapy is called hyperthermia, literally increased temperature, and it seems to be working.Above a certain temperature, cells die simply because of the heat, but the higher temperatures also help by increasing blood flow to the cells. Higher blood flow increases oxygen in the cells, which makes radiation therapy work better. As radiation beams hit the cells, oxygen molecules are broken into highly reactive atoms that damage cancer cells' DNA. Without oxygen in the cells, radiation is less effective.

Dr. Ellen Jones, Butler-Harris assistant professor of radiation oncology, leads the study of hyperthermia in gynecologic cancer at Duke. Jones, who also holds a biomedical engineering doctorate, has studied how heat and radiation interact in tumors.
"During my graduate work at Dartmouth, we learned that heat and radiation are synergistic," she explained. "Two plus two is five instead of four."

Early clinical trials to help treat ovarian and cervical cancer with hyperthermia at Duke are between phases, but Jones is working on the next step. "We're building on our research experience in hyperthermia, extending some of the concepts, and establishing a role for hyperthermia in the clinic," she said.

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