Endometrial cancer is the most common gynecologic malignancy in the United States. It is estimated that 69,960 new cases will be diagnosed in 2022. Endometrial cancer is associated with a five-year survival rate of 81%, largely due to the majority of patients presenting with early-stage disease which can be cured with surgery alone. It is often regarded by many as the gynecologic malignancy with the best outcomes, however, recent studies have shown that the mortality rate from endometrial cancer is quickly rising and is approaching that of ovarian cancer. The mortality rate of ovarian cancer (6 deaths per 100,000 women) has been decreasing due to advances in treatment while the mortality rate of uterine cancer (currently 5.1 deaths per 100,000 women) has been steadily rising since 2005. This article will briefly review the epidemiology of endometrial cancer and then will examine opportunities for improving treatment outcomes.
Most patients with endometrial cancer display a characteristic clinical profile - they typically present with either postmenopausal bleeding or heavy irregular menses. Their body mass index (BMI) is usually overweight (BMI 25-30) or obese (BMI>30) and they often exhibit other components of the metabolic syndrome (e.g. hypertension, diabetes). This clinical picture is tied to exposure to excess estrogen. Exposure to excess estrogen can occur in many ways - it may be secondary to chronic anovulation, excessive peripheral conversion of androgens to estrone in adipose tissue in patients who are overweight or obese, and estrogen-producing tumors (e.g. granulosa cell tumors of the ovary). Reproductive factors such as nulliparity, infertility, early menarche or late menopause also increase the risk of endometrial cancer. Use of tamoxifen in postmenopausal women is associated with an elevated risk of endometrial cancer as well (this elevated risk is not seen in premenopausal women).
Only 2%-5% of cases of endometrial cancer are hereditary. Lynch Syndrome and Cowden Syndrome are commonly linked with endometrial cancer. Lynch Syndrome is an autosomal dominant syndrome caused by germline mutations in the mismatch repair genes MLH1, MSH2, MSH6, PMS2, and EPCAM. The lifetime risk of endometrial cancer in women with Lynch Syndrome is 40%-60% depending on the specific mutation and may equal or exceed the lifetime risk of colon cancer in these women. Cowden syndrome is a rarer autosomal dominant syndrome, resulting from a germline mutation in PTEN and is associated with an increased risk of breast, thyroid and endometrial cancer. Some data suggests that patients with a BRCA1 mutation may also have an increased risk of serous uterine cancer.
The standard approach to treatment of endometrial cancer is hysterectomy with bilateral salpingo-oophorectomy. Surgery is typically performed via a minimally invasive route, with robotic-assisted laparoscopy or conventional laparoscopy being the most common routes. Pelvic and/or paraaortic lymphadenectomy has also traditionally been performed in order to identify and triage patients who may benefit from adjuvant chemotherapy and/or radiation. However, systematic retroperitoneal lymphadenectomy has been associated with increased morbidity including lymphoceles and lymphedema, and both short and long-term neuralgia. Gynecologic oncologists at many centers have moved toward performing sentinel lymph node mapping and ultrastaging of sentinel lymph nodes as it is associated with a reduced surgical morbidity but provides the same prognostic information of lymph node status. Alternatives to surgery, particularly for patients with low-risk endometrial cancer who are interested in preserving fertility, include treatment with progestin therapy (e.g. megestrol acetate or levonorgestrel intrauterine device). A thorough evaluation to ensure that the lesion is confined to the uterus is required prior to pursuing progestin therapy.
Traditionally, endometrial cancer has been divided into two subgroups according to histologic subtype - endometrioid (e.g. Type I) which affects 80% of patients, and non-endometrioid (e.g. Type II), which affects 20% of patients. The non-endometrioid endometrial cancers include serous carcinoma, clear cell carcinoma, and carcinosarcoma. Type I endometrioid endometrial cancers are related to excess estrogen exposure and tend to be associated with the precursor lesion of endometrial intraepithelial neoplasia, while the Type II non-endometrioid endometrial cancers have a hormone-independent pathogenesis and generally have a poorer prognosis than the Type I endometrioid endometrial cancers.
The National Cancer Institute has funded the Cancer Genome Atlas (TCGA) to comprehensively classify various types of cancer at a genomic level, and the classifications which have been proposed for endometrial cancer have really advanced the understanding of the behavior of the various types of endometrial cancers. The TCGA has defined four distinct categories for endometrial cancer: 1) DNA polymerase epsilon (POLE) ultra-mutated (very high mutation rates); 2) microsatellite instability (MSI) hypermutated, and frequently associated with MLH1 promoter methylation (MSI-H) 3) copy-number low, endometrioid tumors characterized by high frequency of CTNNB1 mutations and a range of other modest to highly recurrent gene defects; and 4) copy-number high, characterized by TP53 mutation and high frequency of FBXW7 and PPP2R1A mutations. Correlations between these subtypes and survival have been observed. For instance, POLE-mutant tumors have the best prognosis, followed by MSI-H, then copy-number low, and then copy-number high tumors have the poorest outcomes.
Investigators from Post Operative Radiation in Endometrial Carcinoma (PORTEC) group, a multicenter randomized trial designed to examine the role of postoperative radiation in endometrial cancer, have also examined the use of the molecular classification of endometrial cancer proposed by the TCGA to guide treatment. In the PORTEC-3 trial, patients with high-risk endometrial cancer were randomized to receive combined adjuvant chemotherapy and radiation versus radiation alone. The molecular classifications were applied to the study groups and it was found that the patients who fell into the copy-number high and POLE-mutant tumors had excellent survival regardless of treatment modality. It has been proposed that the best method for stratifying patients into prognostically distinct groups for tailored treatment is one that integrates genomic and traditional clinicopathologic prognostic parameters. However, to date, large prospective studies have not been completed to validate this hypothesis.
As mentioned in the introductory paragraph, the mortality rate for endometrial cancer has been steadily rising in recent years, and this points to the need to closely examine what opportunities there are to improve diagnosis and treatment in order reverse this trend. Most cases of endometrial cancer cannot be prevented, but reducing the risk factors and introducing protective factors into one’s lifestyle whenever possible, may lower the risk of developing this disease. Education of women as well as providers on common symptoms of endometrial cancer is critical to improving identification of this malignancy and subsequently outcomes for this disease. Postmenopausal vaginal bleeding is considered to be the classic symptom of this cancer; however, other symptoms which should raise concern for this malignancy include blood in the urine in a postmenopausal woman, abnormal vaginal discharge in a postmenopausal woman, or change in menstrual pattern for a premenopausal women, e.g. increase in menstrual flow or intermenstrual bleeding. More research into the use of the molecular subtypes in guiding treatment is another window of opportunity for improving outcomes from endometrial cancer. Lastly, researchers at the National Cancer Institute have recently demonstrated that the death rate from uterine cancer is highest among non-Hispanic Black women. This is due in part to the more aggressive subtypes of uterine cancer being more common in this group of women. Researchers found that between 2010 and 2017, Black women had twofold higher mortality rates than any other racial and ethnic group for any uterine cancer type as well as for the aggressive non-endometrioid subtypes. This study highlights the racial disparities in uterine cancer mortality and points to the need for more research in diverse populations to identify modifiable factors associated with these disparities and to improve treatment approaches. This research combined with increased recognition of presenting symptoms and greater study of treatment tailored to the molecular subtypes and research in of the molecular subtypes is among the opportunities which will eventually lead to improved outcomes for endometrial cancer.
As appeared in the Summer 2022 issue of Scripts.
