Cancer Progress and Priorities: Uterine Cancer.

Two risk prediction models, one developed in U.S.-based cohorts ( 99 ) and the other in a European cohort ( 100 ), demonstrated moderate discriminatory ability for established endometrial cancer risk factors (respective discrimination assessed by the area under the curve of 0.68 and 0.77). In the latter model, the addition of pre-diagnostic serum biomarkers only modestly (1.7%) increased discrimination ( 101 ).

Although considered an indolent tumor, the rapid increase in both endometrial cancer incidence and mortality warrants additional etiologic and prevention research. While progress has been made in identifying risk factors for the most common endometrial cancer subtype, this has not translated into effective primary prevention strategies. Future efforts should be directed at reducing the prevalence of modifiable risk factors ( e.g., obesity). Additional research is needed to identify risk factors for aggressive endometrial cancer subtypes, particularly among black women. To favorably impact survival, research on screening modalities to identify endometrial cancer at early stages is needed. Currently, screening in the general population is not recommended, but efforts to identify high-risk women could be beneficial.

Estrogens are strongly related to risk ( Table 1 ) ( 88 – 90 ), with one study showing generalized uterotropic activity of both parent estrogens and metabolites ( 91 ). Circulating androgens, the main source of estrogens in postmenopausal women, have also been linked with increased risk ( 88 – 90 , 92 , 93 ). Consistent with an association between diabetes and endometrial cancer risk, insulin and c-peptide have been demonstrated to be elevated among women with endometrial cancer ( 94 ). Insulin-like growth factor 1 (IGF)-1 and the IGF binding proteins are less consistently linked with risk ( 95 , 96 ). Risk has also been related to circulating levels of inflammatory biomarkers ( 97 ) and with several obesity-related hormones ( 98 ).

Important heterogeneity has been noted between type I (predominantly endometrioid adenocarcinomas with a hormonally driven etiology) and type II (mainly non-endometrioid malignancies that occur frequently among older and non-white women) cancers. Several epidemiological studies have found that type II cancers are less strongly linked to classic risk factors, such as obesity, nulliparity and hormones ( 44 , 83 ). Stronger relationships of hormonal, reproductive, and anthropometric risk factors have been found for endometrioid endometrial cancers compared with serous, clear cell, mucinous, or mixed tumors ( 44 , 83 – 86 ). Furthermore, the Cancer Genome Atlas (TCGA) study has identified four molecular subtypes of endometrial cancer: polymerase Ɛ (POLE) ultramutated, microsatellite instability hypermutated, copy-number low, and copy-number high clusters ( 87 ). A comprehensive evaluation of endometrial cancer risk factors according to TCGA subtype has not yet been conducted.

Endometrial cancer screening is not recommended for women in the general population ( 111 ). Studies evaluating the use of endometrial biopsy and/or transvaginal ultrasound have generally shown low detection specificity ( 112 ). Nonetheless, the American Cancer Society Cancer recommends annual screening for Lynch syndrome patients with endometrial biopsy beginning at age 35 years. Development of early detection blood-based biomarkers are being explored ( 113 ).

Uterine corpus cancer is the most common invasive gynecologic cancer among United States (U.S.) women. Studies of endometrial cancers, which comprise approximately 90% of all uterine cancers, have identified numerous risk factors, many of which appear to reflect high levels of estrogens in the absence of sufficient progesterone. Recent advances have indicated that the disease is etiologically heterogeneous, consisting of at least two major subgroups. This heterogeneity extends to important racial differences in both incidence and survival, possibly partially attributable to genetic factors.

Primary prevention efforts focused on weight loss or use of medications are attractive prevention strategies. For high-risk patients, bariatric surgery is associated with a 44% reduced risk of developing endometrial cancer ( 109 ). Among Lynch syndrome patients, there is some evidence that oral contraceptive use may reduce risk ( 110 ).

Uterine cancer incidence is highest in North America and Northern Europe, intermediate in Southern Europe and temperate South America, and lowest in Southern and Eastern Asia and most of Africa ( Figure 1 ) ( 1 ). This likely reflects prevalence differences in risk factors, including obesity and reproductive patterns. In the U.S., uterine cancer is the fourth most frequently diagnosed cancer, with estimates of 63,230 diagnoses in 2018 (lifetime risk of 1 out of every 40 women) ( 2 ). The average annual age-adjusted incidence of uterine cancer from the Surveillance, Epidemiology and End Results Program (SEER) was 25.7 per 100,000 women between 2010–2014 ( 3 ). The disease is rare before the age of 45 years, but risk rises sharply among women of all races in their late 40s to middle 60s ( Figure 2 ). Worldwide, uterine cancer ranked in 2012 as the sixth most common cancer, with 319,600 estimated cases ( 4 ). Dramatic changes in the incidence of uterine cancers have occurred over time. A marked increase in U.S. incidence peaked around 1975, a trend later linked with the widespread use of menopausal estrogens in the late 1960s and early 1970s ( Figure 3 ). After a subsequent period of steady or declining incidence rates in many countries, endometrial cancer is again on the rise, mirroring increases in obesity prevalence ( 4 , 5 ). In the U.S., age-adjusted mortality is 4.6 per 100,00 women, while in Europe mortality ranges between 2–4 per 100,000 ( 3 , 6 ) ( Figure 4 ). Similar to recent incidence increases, endometrial cancer mortality rates are also on the rise ( 4 , 7 ). Overall, five-year survival is approximately 82%, which represents a marked increase since the 1960’s when it was 60% ( 8 , 9 ). The distribution of uterine cancer stage, a strong prognostic factor, has remained stable ( 8 , 10 – 12 ). Five-year survival is 95.3% for localized, 67.5% for regional, and 16.9% for distant-stage diseases ( 9 ).

Historically, endometrial cancer incidence was lower among black compared to white women; however, that gap has narrowed significantly over time ( 13 – 17 ). However, once hysterectomy rates are taken into account, incidence in blacks surpasses that of whites ( 18 ). Although the associations for established endometrial cancer risk factors among black and white women are similar ( 19 ), prevalence differences may partially explain the markedly higher incidence increases among blacks. Endometrial cancer mortality is twice as high among black compared to white women (8.1 vs. 4.2 per 100,000 women) and has been attributed to aggressive clinical characteristics, lower socioeconomic status, higher prevalence of comorbid conditions, poor patient-provider interactions, and inferior treatment ( 20 ). Although less frequently studied, Asian and Hispanic women have lower risks of endometrial cancer compared with white women; however, five-year survival is the same or better ( 17 , 21 ).