Ashley S. Felix

Etiologic heterogeneity in endometrial cancer: Evidence from a Gynecologic Oncology Group trial☆

OBJECTIVE Although the epidemiology of typical endometrial carcinomas (grades 1-2 endometrioid or Type I) is well established, less is known regarding higher grade endometrioid or non-endometrioid carcinomas (Type II). Within a large Gynecologic Oncology Group trial (GOG-210), which included central pathology review, we investigated the etiologic heterogeneity of endometrial cancers by comparing risk factors for different histologic categories. METHODS Based on epidemiologic questionnaire data, risk factor associations, expressed as odds ratios (OR) with 95% confidence intervals (CI), were estimated comparing grade 3 endometrioid and Type II cancers (including histologic subtypes) to grades 1-2 endometrioid cancers. RESULTS Compared with 2244 grades 1-2 endometrioid cancers, women with Type II cancers (321 serous, 141 carcinosarcomas, 77 clear cell, 42 mixed epithelial with serous or clear cell components) were older; more often non-white, multiparous, current smokers; and less often obese. Risk factors for grade 3 endometrioid carcinomas (n=354) were generally similar to those identified for Type II cancers, although patients with grade 3 endometrioid tumors more often had histories of breast cancer without tamoxifen exposure while those with Type II tumors were more frequently treated with tamoxifen. Patients with serous cancers and carcinosarcomas more frequently had breast cancer histories with tamoxifen treatment compared to patients with other tumors. CONCLUSIONS Risk factors for aggressive endometrial cancers, including grade 3 endometrioid and non-endometrioid tumors, appear to differ from lower grade endometrioid carcinomas. Our findings support etiologic differences between Type I and II endometrial cancers as well as additional heterogeneity within Type II cancers.

Endometrial Cancer Risk Factors by 2 Main Histologic Subtypes The NIH-AARP Diet and Health Study

On the basis of clinical and pathologic criteria, endometrial carcinoma has been distinguished as types I (mainly endometrioid) and II (nonendometrioid). Limited data suggest that these subtypes have different risk factor profiles. The authors prospectively evaluated risk factors for types I (n = 1,312) and II (n = 138) incident endometrial carcinoma among 114,409 women in the National Institutes of Health (NIH)-AARP Diet and Health Study (1995-2006). For individual risk factors, relative risks were estimated with Cox regression by subtype, and P(heterogeneity) was assessed in case-case comparisons with type I as the referent. Stronger relations for type I versus Type II tumors were seen for menopausal hormone therapy use (relative risk (RR) of 1.18 vs. 0.84; P(heterogeneity) = 0.01) and body mass index of ≥30 vs. <30 kg/m2 (RR of 2.93 vs. 1.83; P(heterogeneity) = 0.001). Stronger relations for type II versus type I tumors were observed for being black versus white (RR of 2.18 vs. 0.66; P(heterogeneity) = 0.0004) and having a family history of breast cancer (RR of 1.93 vs. 0.80; P(heterogeneity) = 0.002). Other risk factor associations were similar by subtype. In conclusion, the authors noted different risk factor associations for Types I and II endometrial carcinomas, supporting the etiologic heterogeneity of these tumors. Because of the limited number of Type II cancers, additional evaluation of risk factors will benefit from consortial efforts.

Recent changes in endometrial cancer trends among menopausal-age US women

BACKGROUND Changes in endometrial cancer incidence rates after the precipitous decline in menopausal hormone therapy (MHT) use in 2002 have not been evaluated. METHODS Using data from the Surveillance, Epidemiology, and End Results Program from 1992 to 2009 (SEER 13), we identified 63428 incident endometrial cancer cases among women ages 20-74. We compared annual percent change (APC) in endometrial cancer incidence rates from 1992 to 2002 to rates from 2003 to 2009. RESULTS In contrast to the constant endometrial cancer rate pattern observed from 1992 to 2002 (APC 0.0%), rates increased after 2002 in women 50-74 years old (2.5%; PAPC comparison<0.01). Endometrial cancer incidence increased over the entire time period among women ages 20-49 (1992-2002: 1.1%; 2003-2009: 2.1%; PAPC comparison=0.21). Post-2002 increases in incidence among women ages 50-74 were specific to Type I endometrial tumors (1992-2002: -0.6%; 2003-2009: 1.6%; PAPC comparison<0.01). DISCUSSION The increase in endometrial cancer incidence rates after 2002 may be related to the widespread decrease in estrogen plus progestin MHT use, which has been reported to lower endometrial cancer risk in overweight and obese women.

Metabolic Syndrome and Risk of Endometrial Cancer in the United States: A Study in the SEER–Medicare Linked Database

Background: Metabolic syndrome and its component feature, central obesity, are associated with endometrial cancer risk. It remains unclear whether associations with the other metabolic factors that comprise metabolic syndrome are independent of the obesity–endometrial cancer association. Furthermore, the link with specific endometrial cancer subtypes remains ill-defined, despite evidence of etiologic heterogeneity among these tumors. Methods: In a case–control study within the SEER–Medicare linked database, we examined whether metabolic factors, individually or combined, were associated with endometrial cancer. Cases (n = 16,323) were women diagnosed with endometrial cancer from 1993 through 2007. Controls (n = 100,751) were a 5% sample of female Medicare enrollees residing in the same SEER registry area as cases. Metabolic syndrome was defined using ICD-9-CM codes from inpatient/outpatient diagnoses 1 to 3 years before case diagnosis and a comparable time period in controls. ORs and 95% confidence intervals (CI) were estimated using logistic regression. Results: Endometrial cancer risk was associated with metabolic syndrome [OR (95% CI): 1.39 (1.32–1.47)] and its component factors: overweight/obesity [1.95 (1.80–2.11)], impaired fasting glucose [1.36 (1.30–1.43)], high blood pressure [1.31 (1.25–1.36)], and high triglycerides [1.13 (1.08–1.18)]. After adjusting for overweight/obesity, the increased risks associated with the metabolic syndrome factors remained. Heterogeneity of associations by subtype were not identified (Pheterogeneity = 0.82). Conclusions: Among women age 65 and older in the United States, metabolic syndrome, and its component factors, increased endometrial cancer risk similarly across endometrial cancer subtypes. Impact: Strategies to reduce the prevalence of metabolic syndrome factors might have a favorable effect on endometrial cancer incidence. Cancer Epidemiol Biomarkers Prev; 24(1); 261–7. ©2015 AACR.

The etiology of uterine sarcomas: a pooled analysis of the epidemiology of endometrial cancer consortium.

Background:Uterine sarcomas are characterised by early age at diagnosis, poor prognosis, and higher incidence among Black compared with White women, but their aetiology is poorly understood. Therefore, we performed a pooled analysis of data collected in the Epidemiology of Endometrial Cancer Consortium. We also examined risk factor associations for malignant mixed mullerian tumours (MMMTs) and endometrioid endometrial carcinomas (EECs) for comparison purposes.Methods:We pooled data on 229 uterine sarcomas, 244 MMMTs, 7623 EEC cases, and 28 829 controls. Odds ratios (ORs) and 95% confidence intervals (CIs) for risk factors associated with uterine sarcoma, MMMT, and EEC were estimated with polytomous logistic regression. We also examined associations between epidemiological factors and histological subtypes of uterine sarcoma.Results:Significant risk factors for uterine sarcoma included obesity (body mass index (BMI)⩾30 vs BMI<25 kg m−2 (OR: 1.73, 95% CI: 1.22–2.46), P-trend=0.008) and history of diabetes (OR: 2.33, 95% CI: 1.41–3.83). Older age at menarche was inversely associated with uterine sarcoma risk (⩾15 years vs <11 years (OR: 0.70, 95% CI: 0.34–1.44), P-trend: 0.04). BMI was significantly, but less strongly related to uterine sarcomas compared with EECs (OR: 3.03, 95% CI: 2.82–3.26) or MMMTs (OR: 2.25, 95% CI: 1.60–3.15, P-heterogeneity=0.01).Conclusion:In the largest aetiological study of uterine sarcomas, associations between menstrual, hormonal, and anthropometric risk factors and uterine sarcoma were similar to those identified for EEC. Further exploration of factors that might explain patterns of age- and race-specific incidence rates for uterine sarcoma are needed.

Nonsteroidal anti-inflammatory drugs and endometrial carcinoma mortality and recurrence

Background Recent data suggest that the use of nonsteroidal anti-inflammatory drugs (NSAIDs) may be associated with reductions in endometrial cancer risk, yet very few have examined whether their use is related to prognosis among endometrial cancer patients. Methods Study subjects comprised 4374 participants of the NRG Oncology/Gynecology Oncology Group 210 Study with endometrial carcinoma who completed a presurgical questionnaire that assessed history of regular prediagnostic NSAID use and endometrial cancer risk factors. Recurrences, vital status, and causes of death were obtained from medical records and cancer registries. Fine-Gray semiproportional hazards regression estimated adjusted subhazard ratios (HRs) and 95% confidence intervals (CIs) for associations of NSAID use with endometrial carcinoma-specific mortality and recurrence. Models were stratified by endometrial carcinoma type (ie, type I [endometrioid] vs type II [serous, clear cell, or carcinosarcoma]) and histology. Results Five hundred fifty endometrial carcinoma-specific deaths and 737 recurrences occurred during a median of five years of follow-up. NSAID use was associated with 66% (HR = 1.66, 95% CI = 1.21 to 2.30) increased endometrial carcinoma-specific mortality among women with type I cancers. Associations were statistically significant for former and current users, and strongest among former users who used NSAIDs for 10 years or longer (HR = 2.23, 95% CI = 1.19 to 4.18, two-sided P trend = .01). NSAID use was not associated with recurrence or endometrial carcinoma-specific mortality among women with type II tumors. Conclusions In this study, use of NSAIDs was associated with increased endometrial carcinoma-specific mortality, especially in patients with type I tumors. Barring a clear biologic mechanism by which NSAIDs would increase the risk of cause-specific mortality, cautious interpretation is warranted.

Comparison of survival outcomes between patients with malignant mixed mullerian tumors and high-grade endometrioid, clear cell, and papillary serous endometrial cancers.

Introduction: Malignant mixed mullerian tumors (MMMTs) are an aggressive subtype of endometrial cancer (EC). Previous studies compare survival between high-grade endometrioid (EM), clear cell (CC), and papillary serous (PS) ECs; yet few studies compare MMMTs to these aggressive subtypes. The goal of this study was to compare recurrence-free survival (RFS), disease-specific survival (DSS), and overall survival (OS) among EC subtypes. Methods: We conducted a retrospective cohort study of EC cases treated at Magee-Womens Hospital between 1996 and 2008. Kaplan-Meier estimates of RFS, DSS, and OS as well as and log-rank tests were used to compare survival distributions between histologic subtypes. Cox regression was used to estimate hazard ratios for histologic subtypes, adjusted for other significant prognostic factors. Interactions between histologic subtype and prognostic factors were examined to assess effect modification. Results: This cohort included 81 MMMT (15%), 254 high-grade EM (46%), 73 CC (13%), and 147 PS (26%) cases. Compared to high-grade EM (6%) and CC (7%) cases, relatively more MMMT (12%) and PS (12%) cases were nonwhite. Stage differed significantly among the subtypes, with 36%, 34%, 37%, and 51% of MMMT, high-grade EM, CC, and PS cases, respectively, diagnosed at advanced late stage (P < 0.001). Kaplan-Meier curves and log-rank tests showed similar RFS, DSS, and OS between MMMT, high-grade EM, CC, and PS cases stratified by stage. In adjusted Cox regression models, RFS and DSS were not significantly different between MMMT and other subtypes. High-grade EM cases had a significantly better OS compared to MMMT cases (HR, 0.63; 95% confidence interval [CI], 0.41-0.98). Conclusions: This is the first retrospective study to suggest that certain survival outcomes are similar among MMMT, high-grade EM, CC, and PS subtypes. Other large-scale studies are needed to confirm these findings.

Longitudinal evaluation of cancer-associated biomarkers before and after weight loss in RENEW study participants: Implications for cancer risk reduction

INTRODUCTION Obesity is a major risk factor for the development of endometrial cancer (EC). An improved understanding of biologic mechanisms associated with weight loss, including alteration in inflammation, hormonal balance, and cancer antigens expression may lead to the development of effective cancer prevention strategies. The goal of this study was to explore longitudinal biomarker changes in obese women who underwent weight loss intervention, testing the hypothesis biomarker levels can be altered through intentional weight loss. METHODS Serum samples from 89 participants with Class II and Class III obesity and 43 non morbidly obese comparisons were obtained in Re-Energize with Nutrition, Exercise and Weight Loss (RENEW) study as previously reported. Twenty-one bead-based xMAP immunoassays were utilized, including cancer-associated antigens, cytokines, chemokines, and hormones. One-way repeated measures ANOVA was used to examine the association between changes in biomarker expression levels over time (baseline, 6 months and 12 months). Linear mixed effects models were used to examine longitudinal relationships between biomarker expression levels. RESULTS Mean levels of VEGF, soluble E-selectin, GH, adiponectin, IL-6, IL-7, CA-125, and IGFBP-1 significantly differed between time periods. In adjusted mixed linear models, decreasing BMI was significantly associated with lower levels of soluble E-selectin and IL-6 and increases in GH, adiponectin, and IGFBP-1. CONCLUSIONS This is one of the first efforts to explore changes in cancer-associated biomarkers in a cohort of weight loss research participants at high risk for EC development. Our findings demonstrate that changes in the expression of markers can be achieved with weight loss intervention.

Serum Estrogens and Estrogen Metabolites and Endometrial Cancer Risk among Postmenopausal Women

Background: Although endometrial cancer is clearly influenced by hormonal factors, few epidemiologic studies have investigated the role of endogenous estrogens or especially estrogen metabolites. Methods: We conducted a nested case–control study within the Womens Health Initiative Observational Study (WHI-OS), a cohort of 93,676 postmenopausal women recruited between 1993 and 1998. Using baseline serum samples from women who were non-current hormone users with intact uteri, we measured 15 estrogens/estrogen metabolites via HPLC/MS-MS among 313 incident endometrial cancer cases (271 type I, 42 type II) and 354 matched controls, deriving adjusted ORs and 95% confidence intervals (CI) for overall and subtype-specific endometrial cancer risk. Results: Parent estrogens (estrone and estradiol) were positively related to endometrial cancer risk, with the highest risk observed for unconjugated estradiol (OR 5th vs. 1st quintile = 6.19; 95% CI, 2.95–13.03, Ptrend = 0.0001). Nearly all metabolites were significantly associated with elevated risks, with some attenuation after adjustment for unconjugated estradiol (residual risks of 2- to 3-fold). Body mass index (kg/m2, BMI) relations were somewhat reduced after adjustment for estrogen levels. The association with unconjugated estradiol was stronger for type I than type II tumors (Phet = 0.01). Conclusions: Parent estrogens as well as individual metabolites appeared to exert generalized uterotropic activity, particularly for type I tumors. The effects of obesity on risk were only partially explained by estrogens. Impact: These findings enhance our understanding of estrogen mechanisms involved in endometrial carcinogenesis but also highlight the need for studying additional markers that may underlie the effects on risk of certain risk factors, for example, obesity. Cancer Epidemiol Biomarkers Prev; 25(7); 1081–9. ©2016 AACR.

Intrauterine devices and endometrial cancer risk: A pooled analysis of the Epidemiology of Endometrial Cancer Consortium

Intrauterine devices (IUDs), long‐acting and reversible contraceptives, induce a number of immunological and biochemical changes in the uterine environment that could affect endometrial cancer (EC) risk. We addressed this relationship through a pooled analysis of data collected in the Epidemiology of Endometrial Cancer Consortium. We combined individual‐level data from 4 cohort and 14 case‐control studies, in total 8,801 EC cases and 15,357 controls. Using multivariable logistic regression, we estimated pooled odds ratios (pooled‐ORs) and 95% confidence intervals (CIs) for EC risk associated with ever use, type of device, ages at first and last use, duration of use and time since last use, stratified by study and adjusted for confounders. Ever use of IUDs was inversely related to EC risk (pooled‐OR = 0.81, 95% CI = 0.74–0.90). Compared with never use, reduced risk of EC was observed for inert IUDs (pooled‐OR = 0.69, 95% CI = 0.58–0.82), older age at first use (≥35 years pooled‐OR = 0.53, 95% CI = 0.43–0.67), older age at last use (≥45 years pooled‐OR = 0.60, 95% CI = 0.50–0.72), longer duration of use (≥10 years pooled‐OR = 0.61, 95% CI = 0.52–0.71) and recent use (within 1 year of study entry pooled‐OR = 0.39, 95% CI = 0.30–0.49). Future studies are needed to assess the respective roles of detection biases and biologic effects related to foreign body responses in the endometrium, heavier bleeding (and increased clearance of carcinogenic cells) and localized hormonal changes.