Endometrial Cancer
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Cancer of the corpus uteri, or endometrium, is the fourth most common invasive cancer among women in the United States. An estimated 40,100 American women will be diagnosed with uterine cancer in 2003, and approximately 6,800 will die from the disease. The incidence of endometrial cancer declined during the 1970s and 1980s; however, from 1988 to 1999 there has been an 0.6 percent increase per year. Average incidence rates for white women were 26 per 100,000 from 1992 to 1999, while African American incidence rates were significantly less at 17.7 per 100,000. Average mortality rates are opposite, with the mortality rate for white women at 3.9 per 100,000 and mortality rates for African Americans nearly double that at 7.0 per 100,000.
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 endometrial cancer included: developing animal models and imaging methods, and conducting clinical studies for detection and prevention. The PRG identified a VSSR as essential to all of the gynecological cancers for support of studies in cancer biology, identification of genetic and molecular signature, specific molecular pathways, and surrogate biomarkers in percursor lesions, metastatic, and recurrent tumors. The PRG also designated research in quality of life issues and disparity reduction and elimination as high-impact priorities for gynecologic cancers.
Biology
The Cancer Genome Anatomy Project (CGAP). CGAP currently includes about 84,000 cDNA sequences of normal endometrium and malignant endometrial tumors with 3 known and 3,857 unknown unique genes.
Microsatellite Instability (MSI). Approximately 20 percent of endometrial cancers demonstrate MSI, which is the abnormal expansion or contraction of small repetitive DNA sequences due to defects in the DNA mismatch repair pathway. MSI is a common feature of hereditary nonpolyposis colorectal cancer (HNPCC). Among HNPCC families, endometrial cancers are the second most common tumors. In hereditary cases of endometrial cancer, mutation of the MSH2 or MLH1 mismatch repair gene is causative of HNPCC and the MSI phenotype.
However, most endometrial cancers with MSI are the result of somatic inactivation of the hMLH1 gene by promoter hypermethylation. Findings of recent studies are helping scientists understand the initiation of tumors through methylation, a primary cause of MSI in endometrial tumors, and to distinguish pathways of endometrial cancer development. Several other studies in endometrial cancer have examined genes that are inactivated by promoter methylation including the APC tumor suppressor and the progesterone receptor. MSI and mutations of the gene PTEN I occur in complex atypical hyperplasia, the precursor to endometrial cancer. Recently, it was discovered that some normal endometrial glands lack PTEN. These PTEN deficient glands reappear through repeated menstrual cycles. These important insights into the initiation of endometrial cancer may help in the development of targeted therapies that will benefit patients with this disease.
Gene Expression Profiling. Recent gene expression profiling studies of endometrial cancers have shown a number of expression differences between the different histologic types of endometrial cancers and also with normal endometrium.
Stromal Interactions. Researchers are currently investigating whether alterations in stromal cells, extracellular matrix (ECM) as well as changes within the cell itself initiate or affect tumor development. Experiments with endometrial adenocarcinoma cells showed that introduction of stromal factors and appropriate ECM induced differentiation of more normal cells and that basement membrane proteins exert effects on the regulatory function of stromal cells.
Tumor Suppressor Genes. NCI is also supporting efforts to isolate a novel tumor suppressor gene that is involved in the development of uterine papillary serous carcinoma (UPSC), the most aggressive type of endometrial cancer. The research has identified a specific mutation in approximately 65 percent of UPSCs.
Risk Factors
An increased risk for endometrial cancer has been associated with estrogen-only hormone therapy, diabetes, obesity, age, lack of physical activity, HNPCC, and other medical conditions, but possible mechanisms remain obscure. Cigarette smoking and high intake of complex carbohydrates appear to reduce risk. Ongoing research in cancer etiology is looking into contributing factors, including specific medical conditions, and linkage to subsequent risk for endometrial and other cancers.
Obesity. Recent increases in endometrial cancer incidence may be linked to the increase in obesity in Americans. Risk can be increased two- to four-fold in obese women compared to women of healthy weight. NCI is sponsoring two studies on obesity and endometrial cancer associated risk. The Four Corners Breast and Endometrial Cancer Study is investigating the effects of obesity and weight changes in Hispanic, Native American, and non-Hispanic white women. Another study is looking at the effects of phytoestrogen consumption on endometrial cancer risk in obese white, African American, and Latino women.
Hormones. A woman's risk for endometrial cancer is increased by exposure to estrogen unopposed by progesterone, either endogenous or exogenous. Risk factors related to endogenous estrogenic effect include obesity, high fat diet, nulliparity, early menarche, and late menopause. NCI's Estrogen Replacement Therapy Study is a high-priority Phase 3 clinical trial designed to resolve the debate over whether women who have had early-stage endometrial cancer should take estrogen replacement.
Tamoxifen. The SERM, tamoxifen, used to treat ER-positive breast cancer and for the prevention of breast cancer in women at high risk, has been linked with an increased risk of endometrial cancer. New drugs that can be used alone or in combination therapy with tamoxifen for treatment of hormone-dependent tumors are being investigated. Alternate-substituted alkyl PCDFs are a new mechanism-based class of antiestrogens that block estrogen-induced mammary and endometrial cell/tumor growth via crosstalk between the ER and Ah receptor signaling pathways. These compounds have been shown to be relatively nontoxic, inhibit ER-positive and ER-negative mammary tumor growth, and synergize with tamoxifen to inhibit breast cancer growth and block tamoxifen-induced estrogenic activity in the uterus. Preliminary studies also indicate that selective androgen hormone receptor modulators (SahRMs) that inhibit prostate cancer cell growth may provide a new approach for treating women with breast cancer in combination with tamoxifen and SERMs.
History of Breast Cancer. Six hundred forty-eight of 37,583 women participating in the Breast Cancer Detection and Demonstration Project developed endometrial cancer during the average 13.8 years of follow-up. Women with a personal history of breast cancer were more likely to develop endometrial cancer, yet a family history of breast cancer did not increase that risk.
HNPCC. HNPCC, responsible for 5 percent of all colon cancers, increases a woman's risk for endometrial cancer to 60 percent by age 70. Average risk is about 1.5 percent.
Other Factors. Since other medical conditions have been implicated as risks for endometrial cancer, a case-cohort study is being conducted in Denmark that will allow access to medical records for the precise diagnoses of conditions prior to development of endometrial cancer.
Prevention
NCI prevention studies are focusing on altering the effects of hormones necessary for prevention or therapy through route of administration; alternative, less harmful hormones or additionally regimented attenuating hormones; and new chemoprevention methods. A Phase 2 randomized study comparing medroxyprogesterone and ethinyl estradiol and norgestrel is ongoing for the prevention of endometrial cancer in HNPCC patients. Multiple studies are investigating phytoestrogens. Research includes attenuating risk associated with obesity or endometrial cancer incidence. Other NCI studies are looking at nutrition in terms of epidemiology and genetics and cancer.
Early Detection, Diagnosis, and Prognosis
A study conducted in 101 women compared two endometrial biopsy techniques, Tao Brush and Pipelle, using both techniques during the same office visit. Sensitivity for Tao Brush was 95.5 percent, and 86 percent for Pipelle's. Both have specificities and positive predictive values of 100 percent and negative predictive values of 98 percent. Using both biopsy devices increased positive and negative predictive values to 100 percent and reduced costs.
Treatment
The standard treatment for endometrial cancer is surgery; hysterectomy and bilateral salpingo-oophorectomy. In women who have not completed childbearing alternative treatments that address fertility issues are being investigated, such as hormonal therapy, chemotherapy, radiotherapy, and adjuvant therapies.
Hormonal Therapies. A Phase 2 trial is comparing an estrogen blocker and receptor modulator in patients with recurrent, metastatic endometrial cancer. An NSABP study found that progesterone exerts molecular effects in cancerous endometrial cells including cyclin p21 and p27 induction, decreasing proliferation and inhibiting invasion. In progesterone receptor B expressing cells, it induces a secretory phenotype. Array analysis also showed inhibition of a number of cellular adhesion molecules. Another study showed that in poorly differentiated endometrial cancer cells, the introduction of progesterone receptors A and B allowed progestin to re-exert regulatory effects on proliferation.
Targeted Therapies. NCI treatment studies focus on comparison of different chemotherapies, alone or in combination, and with or without radiotherapy. Most trials are in Phase 1 or 2. Side effects of therapy and quality-control issues in radiation equipment are also being investigated. The more aggressive endometrial cancer, type 2, is a HER/neu-overexpressing tumor that should theoretically respond to Herceptin7 treatment. Several studies, one in combination with traditional chemotherapy, are in progress. Erlotinib, an epidermal growth factor receptor inhibitor, and flavopiridol, another kinase inhibitor, are being tested in Phase 1 and 2 studies for advanced endometrial cancers.
