Ovarian Cancer
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In 2003, approximately 25,400 women in the United States are expected to be diagnosed with ovarian cancer, and approximately 14,300 are expected to die of the disease. Incidence rates decreased by 0.7 percent per year between 1989 and 1999. Ovarian cancer is responsible for the highest mortality rates of all gynecologic cancers. Incidence and mortality rates are highest in white women compared to other racial and ethnic groups.
When detected early, ovarian cancer is highly treatable, with a 5-year survival rate of 95 percent. Ovarian cancer is often asymptomatic in its early stages, and symptoms that do occur are often not of the type that would alert most women or their health care providers. Thus, most diagnoses occur at advanced stages of disease, when survival rates are 81 percent for regionally advanced stages and 31 percent for stages with distant metastases.
The Report of the Gynecologic Cancers Progress Review Group in 2001 described research priorities and the resources needed to bridge gaps in understanding and overcoming barriers to progress. Recommendations specific to ovarian cancer included: early detection and prevention strategy development, proteomic technology development, elucidation of mechanisms of tumorigenesis and metastasis, as well as clinical trial optimization for new agents, and surrogate markers. The PRG deemed a VSSR essential for all three gynecologic cancers for the support of studies in cancer biology, identification of genetic and molecular signature, specific molecular pathways, and surrogate biomarkers in precursor lesions, metastatic, and recurrent tumors. The PRG also designated research in quality of life issues and disparity reduction and elimination as a high-impact priority for gynecologic cancers.
Risk Factors
The lifetime risk of ovarian cancer is 1.8 percent, and its annual incidence is about 61.8 per 100,000 women who reach ages 75-79. The causes of ovarian cancer are unclear. One theory suggests that constant, uninterrupted ovulation increases the risk of ovarian cancer. This could explain why pregnancy, breast feeding, and oral contraceptive use are associated with a decreased risk of ovarian cancer. Other theories speculate that increased pituitary gonadotropin levels contribute to an increased risk of the disease or that alterations in ovarian blood flow or the transtubal transportation of carcinogens may be involved in the initiation of ovarian cancers.
Exogenous Hormones. Follow up after 20 years of participants in the Breast Cancer Detection Demonstration Project who used estrogen-only menopausal hormone therapy showed a significantly greater risk, dependent on duration of use, for developing ovarian cancer. Women on estrogen-progestin hormone therapy did not demonstrate a change in risk, but this arm of the study was a small sample size and therapy was of relatively short duration.
Inherited Risk Factors. Three inherited ovarian cancer susceptibility syndromes have been described: (1) familial site specific ovarian cancer, (2) familial breast/ovarian cancer, and (3) Lynch II syndrome (combination of breast, ovarian, endometrial, gastrointestinal, and genitourinary cancers). It is believed that 5B10 percent of ovarian cancers are caused by inherited mutations in the BRCA1 or BRCA2 genes.
BRCA1 and BRCA2 Mutations. There are large variations in risk for ovarian cancer in carriers of BRCA1 mutations, indicating that other factors play a role. Recent NCI-funded studies have found that the risk for developing ovarian cancer increases to between 16and 60 percent with a BRCA1 mutation and between 15 and 25 percent with a BRCA2 mutation. Despite these risks for developing ovarian cancer, patients with BRCA mutations were found to survive 20 months longer than patients without the mutation, possibly caused by differences in disease pattern due to the mutation, rather than early detection.
Registries. A Family Registry for Ovarian Cancer (FROC) is being established using histories of families that are positive and negative for ovarian cancer. The variables of interest include race/ethnicity, invasiveness and type of tumor, age at diagnosis, and BRCA1 prevalence. The Breast and Ovarian Family Cancer Registry collected information and specimens from over 6,000 families with the diseases, potentially valuable in the study of the cooperative effects between genetics, the environment, and lifestyle.
Diet. Analyses of questionnaires from women, enrolled in the Nurses= Health Study (NHS) showed a link between ovarian cancer and frequent egg consumption, but no change in risk with antioxidant vitamin consumption from foods or foods and supplements. Women who consumed 2.5 servings of fruits and vegetables per day during adolescence decreased ovarian carcinoma risk by 46 percent, suggesting that antioxidant vitamins are protective when consumed earlier in life.
Genetic Polymorphisms. Scientists supported by NCI are investigating the effects of polymorphisms in genes regulating steroid metabolism, catecholestrogen formation, and detoxification of oxidative damage. A study with population-based controls found that deficiencies in a metabolic enzyme that cause galactose to accumulate in the ovary were not related to ovarian cancer development.
Other Risk Factors. A multicentered, nested case-control study found a direct relationship between circulating levels of IGF-I and an inverse relationship between BMI and risk for ovarian cancer. A different study found a decreased risk with cigarette smoking, alcohol consumption, and complex carbohydrates; and increased risk with upper body obesity, inactivity, and higher intake of fat.
Prevention
Oral Contraceptives. Previous studies have shown that the risk of ovarian cancer is decreased by 40 to 50 percent in women who take oral contraceptives, regardless of whether they had children, a family history of ovarian cancer, or hereditary ovarian cancer syndrome. This effect increases with time, ranging from a 10 to 12 percent decrease in risk after 1 year of use to a 50 percent decrease after 5 years and persisting for 10B15 years after use is discontinued. A study in 840 Israeli women found that additional births were protective in BRCA1/2 mutation carriers; however, only noncarriers had decreased risk with oral contraceptive use.
Fertility Drugs. Women who had never given birth, or had used fertility drugs, even when used for over 12 months, were not at increased risk for ovarian cancer. Increased risks were associated with endometriosis and other unknown causes of infertility. An NCI-funded study is examining medical records of women in Denmark who have received ovulation-stimulating drugs to identify medical conditions that may increase risk of ovarian cancer.
Prophylactic Oophorectomy. Oophorectomy after childbearing in BRCA1/2 mutation carriers decreased risk of ovarian cancer by 96 percent. Side effects of premature menopause are treated medically, and with diet and exercise, but there is little data on risks of premature menopause. NCI Gynecological Oncology Group and CGN are collaborating on a national, prospective follow-up study that will investigate precursor lesions, incidence of cancer prior to ovary removal, and effects on quality of life. Women who don=t have surgery will be monitored using a novel CA-125 measure that follows levels over time to assess alterations in the ovaries.
Early Detection, Diagnosis, and Prognosis
Proteomics. The FDA/NCI Clinical Proteomics Program, in collaboration with Correlogic Systems Inc., have developed a procedure to distinguish patterns of protein expression in blood samples from unaffected women and those with ovarian cancer. A blinded set of test samples correctly identified 50 of 50 bloods from women with cancer and 63 of 66 samples from unaffected women. This technology was able to recognize a cancer signature in the blood of all stage I ovarian cancer cases, albeit in a small sample size. A pilot diagnostic study is following women currently in ovarian cancer remission and archiving serial samples of blood through relapse or continued remission from which to identify changes in proteomic profiles that are indicative of disease recurrence and to compare these results against the results of the existing marker, CA-125. Trials are under way at NCI to evaluate proteomics both alone and in combination with current screening methods for ovarian cancer.
Gene Expression Profiles. Studies in the Director's Challenge program have developed profiles in ovarian cancer cells that can distinguish between morphologic subtypes, high- versus low-grade tumors, and alterations in BRCA1 and BRCA2.
Microarray Technology. Scientists participating in NCI investigator-initiated research have been testing the feasibility of a cDNA microarray technology to identify the overexpression of the biomarker osteopontin. The technology found significant differences between healthy and cancerous cells, tissue and plasma, evidencing an association between osteopontin and ovarian cancer.
Prostate, Lung, Colorectal, and Ovarian Cancer Screening (PLCO) Trial. Screening for ovarian cancers, one component of the PLCO trial, includes a physical examination of the ovaries, a blood test for the tumor marker CA 125, and transvaginal ultrasound in healthy women, ages 55-74.
3D Power Doppler Ultrasound. In a comparison with two-dimensional (2D) imaging, 3D Doppler Ultrasound both allowed for correct identification of all malignancies. Specificity and positive predictive value improved with 3D use, indicating the possibility of clinical advantages for detection.
National Ovarian Cancer Early Detection Program. The program is assessing the detection of precancerous lesions and early changes of the ovaries using a less invasive in-office laparoscopy technique for ovary visualization and tissue sample collection, the "ovarian pap test." The program is currently enrolling 6,000 high-risk, asymptomatic women and women with confirmed or suspected ovarian cancer.
Cancer Genome Anatomy Project. Molecular markers for the detection of ovarian cancer are a high priority of this gene discovery effort. Ovarian cDNA sequences in the CGAP database now number more than 300,000. These sequencing efforts have identified two known unique ovarian specific sequences and nearly 1,000 unknown ovarian unique sequences.
Treatment
New Drug Strategies. The use of drug combinations holds promise in overcoming the resistance to platinum based drugs that develop in many ovarian cancers after initial treatment. The drugs oxaliplatin, epirubicin, liposomal doxorubicin, topotecan, oral etoposide, gemcitabine, and vinorelbine have produced responses in ovarian cancer patients when used alone and are now being tested in two and three drug combinations. Also promising in early studies, is the use of a second, or consolidation round of standard dose chemotherapy for patients whose tumors have responded well to the first round. Data from two large trials has indicated that intraperitoneal therapy may have more side effects but may offer some disease-free and overall survival advantages over intravenous therapy for selected patient populations. Innovative approaches to the treatment of advanced ovarian cancer in development or in early trials include therapeutic vaccines, gene therapy, and antiangiogenic agents.
