Cancer Progress and Priorities: Uterine Cancer

Uterine corpus cancer is the most common invasive gynecologic cancer among 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.

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 (Fig. 1; ref. 1). This likely reflects prevalence differences in risk factors, including obesity and reproductive patterns. In the United States, 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; ref. 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 and 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 (Fig. 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 (Fig. 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 United States, age-adjusted mortality is 4.6 per 100,000 women, whereas in Europe, mortality ranges between 2 and 4 per 100,000 (refs. 3, 6; Fig. 4). Similar to recent incidence increases, endometrial cancer mortality rates are also on the rise (4, 7). Overall, 5-year survival is approximately 82%, which represents a marked increase since the 1960s 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 with white women; however, that gap has narrowed significantly over time (13–17). Moreover, 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 with 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, 5-year survival is the same or better (17, 21).

A strong risk factor for endometrial cancer is obesity, accounting for 40% to 50% of all U.S. cases (refs. 22, 23; see Table 1 and Fig. 5). Overall body size appears to be more important than body fat distribution (24). Women with obesity-associated diseases such as diabetes (25, 26), hypertension (27), and polycystic ovary syndrome (28) are also at elevated risk, although obesity may contribute to these relationships. Metabolic syndrome has also been associated with significant risk elevations, although to a lesser extent than obesity (29).

Nulliparous women are at substantially higher risks than parous women (30, 31), with infertility additionally contributing to risk (32). Other established reproductive risk factors include young ages at menarche and/or old ages at menopause (30, 33), potentially reflecting increased numbers of lifetime ovulatory cycles (34). Breastfeeding has also recently emerged as a possible protective factor (35, 36).

The use of combination oral contraceptives has been linked with marked risk reductions which persist for more than 30 years after discontinuation. Intrauterine devices also appear to reduce endometrial cancer risk (37, 38).

Menopausal hormones have been strongly linked with risk increases, particularly for extended usage of high-dose unopposed estrogens (39). Progestins cause regression of estrogen-induced endometrial hyperplasia, the presumed precursor of most endometrial cancers (40), leading to estrogens commonly being prescribed with a progestin (particularly among nonhysterectomized women). Sequential progestin use, i.e., <10 days per month, is associated with only slight risk reductions compared with unopposed estrogen use (41). However, continuous combination therapy reduces risk compared with nonhormone usage (39, 42). Associations of hormone usage are strongly modified by body mass index (BMI; refs. 39, 43).

Clinical trials have demonstrated increased endometrial cancer risk among tamoxifen-treated breast cancer patients, with risks highest shortly after exposure, among those receiving high cumulative doses, and for histologies usually associated with a poor prognosis (44, 45).

Cigarette smoking (46, 47) and moderate-to-active physical activity levels (48–50) have been associated with reduced risks, relations that are independent of other risk factors, including obesity.

It remains less clear whether risk reductions associated with high levels of fruit and vegetable consumption and/or of micronutrients are independent risk factors (51–54). Higher dairy product intake (55), coffee consumption (56), and consumption of green, but not black, tea (57) may lead to risk reductions. High-fat diets (53, 54) and alcohol consumption (58) have not generally been associated with risk. Use of the antidiabetic drug metformin (59) or aspirin (60) appears to slightly reduce risk.

Less accepted as potential risk factors are several occupational exposures (61, 62); talcum powder use (63–65); thyroid diseases, cholecystectomy and endometriosis (66–68); antidepressants, statins, and acetaminophen (69–71); endocrine disruptors (72); tubal ligation (73); and electromagnetic radiation (74).

Elevated endometrial cancer risks have been noted among women with a first-degree family history of endometrial cancer (75, 76). This could reflect familial obesity (genetic or environment) or inherited risk, such as Lynch syndrome, an autosomal-dominant cancer predisposition syndrome attributed to germline mutations in one of several mismatch repair genes. Specific mutations have been estimated to result in cumulative lifetime endometrial cancer risks ranging between 12% and 61% (77–81), with MSH6 showing the highest risks (ref. 82; Table 1). However, the higher range estimates may reflect reliance on data from clinical cancer genetic cohorts that are biased to include patients with family histories of cancer. Although Lynch syndrome is associated with a high cumulative lifetime risk of endometrial cancer, the relative rarity of the condition translates to an attributable fraction of only 5%.

The genome-wide association study approach has identified 17 risk loci for endometrial cancer, including 9 recently identified loci (83), which are modestly associated with risk (ORs, 0.8–1.4). Some risk loci are significant only for endometrioid cancers. Few rare variants have been identified through exome-wide association studies (84), but candidate gene studies (85, 86) have identified a number of SNPs in genes that may possibly affect risk.

Important heterogeneity has been noted between type I (predominantly endometrioid adenocarcinomas with a hormonally driven etiology) and type II (mainly nonendometrioid malignancies that occur frequently among older and nonwhite women) cancers (see Tables 1 and 2). Several epidemiologic studies have found that type II cancers are less strongly linked to classic risk factors, such as obesity, nulliparity, and hormones (44, 87).

Stronger relationships of hormonal, reproductive, and anthropometric risk factors have been found for endometrioid endometrial cancers compared with serous, clear cell, mucinous, or mixed epithelial tumors (44, 87–91). Furthermore, The Cancer Genome Atlas (TCGA) study has identified four molecular subtypes of endometrial cancer: polymerase ϵ (POLE) ultramutated, microsatellite instability hypermutated, copy-number low, and copy-number high clusters (92). A comprehensive evaluation of endometrial cancer risk factors according to TCGA subtype has not yet been conducted.

Estrogens are strongly related to risk (Table 1; refs. 93–95), with one study showing generalized uterotropic activity of both parent estrogens and metabolites (96). Circulating androgens, the main source of estrogens in postmenopausal women, have also been linked with increased risk (93–95, 97, 98). 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 (99). Insulin-like growth factor 1 (IGF)-1 and the IGF-binding proteins are less consistently linked with risk (100, 101). Risk has also been related to circulating levels of inflammatory biomarkers (102) and with several obesity-related hormones (103).

Two risk prediction models, one developed in U.S.-based cohorts (104) and the other in a European cohort (105), 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 prediagnostic serum biomarkers only modestly (1.7%) increased discrimination (106).

Projection models indicate that endometrial cancer incidence will continue to rise, mainly as a consequence of rising obesity prevalence (7, 107). Changes in the distribution of other endometrial cancer risk factors also contribute to the projected growth in incidence, including increases in diabetes and metabolic syndrome (108, 109), declines in use of combination hormone therapy (5), and decreases in childbearing and smoking (110, 111). Moreover, hysterectomy for benign conditions has declined in recent decades, particularly among whites, contributing to more at-risk women (18, 112). In the next decade, mortality rates are also projected to increase (113).

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 (114). Among Lynch syndrome patients, there is some evidence that oral contraceptive use may reduce risk (115).

Endometrial cancer screening is not recommended for women in the general population (116). Studies evaluating the use of endometrial biopsy and/or transvaginal ultrasound have generally shown low detection specificity (117). Nonetheless, the American Cancer Society recommends annual screening for Lynch syndrome patients with endometrial biopsy beginning at age 35 years. Development of early detection blood-based biomarkers is being explored (118).

Although considered an indolent tumor, the rapid increase in both endometrial cancer incidence and mortality warrants additional etiologic and prevention research. Although 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 affect 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.

No potential conflicts of interest were disclosed.

Conception and design: A.S. Felix, L.A. Brinton

Development of methodology: A.S. Felix, L.A. Brinton

Acquisition of data (provided animals, acquired and managed patients, provided facilities, etc.): A.S. Felix, L.A. Brinton

Analysis and interpretation of data (e.g., statistical analysis, biostatistics, computational analysis): A.S. Felix, L.A. Brinton

Writing, review, and/or revision of the manuscript: A.S. Felix, L.A. Brinton

Administrative, technical, or material support (i.e., reporting or organizing data, constructing databases): A.S. Felix, L.A. Brinton

Study supervision: A.S. Felix, L.A. Brinton