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Gynecol Oncol. Author manuscript; available in PMC 2016 October 01.
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Published in final edited form as:

Gynecol Oncol. 2015 October ; 139(1): 70–76. doi:10.1016/j.ygyno.2015.08.022.

Associations between etiologic factors and mortality after

endometrial cancer diagnosis: The NRG Oncology/Gynecologic
Oncology Group 210 Trial
Ashley S Felix, PhD1,2,3, D Scott McMeekin, MD4, David Mutch, MD5, Joan L Walker, MD4,
William T Creasman, MD6, David E Cohn, MD7, Shamshad Ali, MA8, Richard G Moore, MD9,
Levi S Downs, MD10, Olga B Ioffe, MD11, Kay J Park, MD12, Mark E Sherman, MD13, and
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Louise A Brinton, PhD1

1Hormonal and Reproductive Epidemiology Branch, Division of Cancer Epidemiology and
Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD
2Cancer Prevention Fellowship Program, Division of Cancer Prevention, National Cancer
Institute, National Institutes of Health, Bethesda, MD
4Department of Obstetrics and Gynecology, University of Oklahoma, Oklahoma City, OK, USA
5Washington University School of Medicine, St. Louis, MO
6Department of Obstetrics and Gynecology, Medical University of South Carolina, Charleston, SC
7Division of Gynecologic Oncology, The Ohio State University College of Medicine, Columbus,
OH
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8NRG Oncology Statistics and Data Management Center, Roswell Park Cancer Institute, Buffalo,
NY
9Program in Women's Oncology, Department of Obstetrics and Gynecology, Women and Infants
Hospital/Brown University, Providence, RI
10Gynecologic Oncology, University of Minnesota, Minneapolis, MN
11Anatomical Pathology, University of Maryland, College Park, MD
12Surgical Pathology, Memorial Sloan Kettering Cancer Center, New York, NY
13Breastand Gynecologic Cancer Research Group, Division of Cancer Prevention, National
Cancer Institute, National Institutes of Health, Rockville, MD
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Abstract

Corresponding author: Ashley S. Felix, PhD, 1841 Neil Avenue, 300-C Cunz Hall, Columbus, OH 43210, Felix.20@osu.edu,
Telephone: 614-688-1477.
3Current affiliation: Division of Epidemiology, The Ohio State University College of Public Health, Columbus, OH
Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our
customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of
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discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Conflict of Interest The authors have no conflict of interests to disclose with the exception of Dr. Richard Moore who wishes to
disclose funding received from NRG Oncology/GOG by his Institution (Women and Infants Hospital) for patient accrual.
 Felix et al. Page 2

Background—Few studies have analyzed relationships between risk factors for endometrial
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cancer, especially with regard to aggressive (non-endometrioid) histologic subtypes, and

prognosis. We examined these relationships in the prospective NRG Oncology/Gynecologic
Oncology Group 210 trial.

Methods—Prior to surgery, participants completed a questionnaire assessing risk factors for

gynecologic cancers. Pathology data were derived from clinical reports and central review. We
used the Fine and Gray subdistribution hazards model to estimate subhazard ratios (HRs) and 95%
confidence intervals (CIs) for associations between etiologic factors and cause-specific subhazards
in the presence of competing risks. These models were stratified by tumor subtype and adjusted
for stage and socioeconomic status indicators.

Results—Median follow-up was 60 months after enrollment (range: 1 day – 118 months).
Among 4,609 participants, a total of 854 deaths occurred, of which, 582 deaths were attributed to
endometrial carcinoma. Among low-grade endometrioid cases, endometrial carcinoma-specific
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subhazards were significantly associated with age at diagnosis (HR=1.04, 95% CI=1.01–1.06 per
year, P-trend) and BMI (class II obesity vs. normal BMI: HR=2.29, 95% CI=1.06–4.98, P-
trend=0.01). Among high-grade endometrioid cases, endometrial carcinoma-specific subhazards
were associated with age at diagnosis (HR=1.05, 95% CI=1.02–1.07 per year, P-trend<0.001).
Among non-endometrioid cases, endometrial carcinoma-specific subhazards were associated with
parity relative to nulliparity among serous (HR=0.55, 95% CI=0.36–0.82) and carcinosarcoma
cases (HR=2.01, 95% CI=1.00–4.05).

Discussion—Several endometrial carcinoma risk factors are associated with prognosis, which
occurs in a tumor-subtype specific context. If confirmed, these results would suggest that factors
beyond histopathologic features and stage are related to prognosis.
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INTRODUCTION
Accepted prognostic factors for endometrial carcinoma include tumor characteristics, such
as histology, grade, lymphovascular space invasion, and stage (1). Less is known about the
role that etiologic risk factors may have on survival following an endometrial carcinoma
diagnosis, which could be of use to clinicians to guide treatment decisions and inform
surveillance schedules.

High body mass index (BMI), a strong risk factor for endometrial carcinoma development,
has inconsistently been associated with prognosis following an endometrial carcinoma
diagnosis (2–14). A systematic review (15) found that eight studies reported no association
(2–5, 7–10) while four studies demonstrated increased all-cause mortality associated with
high BMI (16–19). Seven studies that were not included in this review found equally mixed
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results: no association for three (11–13) and increased risk of death with higher BMI in four
(14, 20–22). Studies reporting an association between higher BMI and increased mortality
more frequently controlled for stage, histologic subtype, and adjuvant therapy compared
with studies that did not detect relationships, although exceptions are evident. Most studies
did not include sufficient numbers of non-endometrioid carcinomas to fully examine
relationships among rare aggressive subtypes and differences in categorization of BMI,
small sample sizes, and short follow-up times hamper interpretation of the literature.

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Few studies have examined relationships between other endometrial carcinoma risk factors
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and prognosis. Diabetes, a factor related to increased endometrial carcinoma risk, has been
associated with increased mortality in some studies (11, 14, 17, 23, 24). Although smoking
is inversely related to endometrial carcinoma risk, smokers may develop more advanced-
stage tumors and experience increased endometrial carcinoma mortality than non-smokers
(25, 26). Relationships between parity and endometrial carcinoma specific survival have
been mixed (11, 17, 27–32), with one study reporting increased survival among women with
endometrioid carcinomas, but non-significantly decreased survival among women with non-
endometrioid tumors (29). Similarly, relationships between menopausal hormone use and
survival among endometrial carcinoma patients remain unclear and potentially vary by
preparation type (estrogen-only vs. estrogen plus progestin) (33–36).

The clinical behavior of endometrial carcinomas vary substantially by histologic subtype; in

particular, non-endometrioid carcinomas portend a worse outcome and certain types such as
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serous carcinomas spread on peritoneal surfaces, much like their ovarian/tubal primary
counterparts (37). Given that the behavior of different endometrial carcinoma subtypes
varies, we hypothesize that risk factors that might influence survival for these tumors would
also likely vary. Due to the low prevalence of aggressive tumor subtypes in single institution
cohorts, we utilized data from the NRG Oncology/Gynecologic Oncology Group (GOG)
210 trial, which included a large number of women with rare but aggressive endometrial
tumors, to examine associations between established etiologic risk factors for disease
development and prognosis in a large trial of clinically and pathologically well-characterized
endometrial carcinoma patients.

METHODS
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NRG Oncology/GOG 210 study population

This study population has been previously described (38). The NRG Oncology/GOG 210
molecular staging trial of endometrial carcinoma opened to accrual on September 22, 2003
at 62 U.S. institutions and closed on December 1, 2011. Women with endometrial carcinoma
diagnosed by endometrial biopsy or dilation and curettage were approached to participate in
this trial. Eligibility required that candidates be suitable for surgery with staging and not
have undergone prior retroperitoneal surgery or pelvic/abdominal radiation. Patients with all
stages, grades and epithelial histology types (e.g. endometrial carcinoma or carcinosarcoma)
were eligible for inclusion in the trial. Prior to hysterectomy and bilateral salpingo-
oophorectomy, patients who consented to participate in the trial completed a self-
administered questionnaire as previously described (38). On September 23, 2007, eligibility
criteria in NRG Oncology/GOG 210 changed from unrestricted enrollment to targeted
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enrollment of poor prognosis tumor subtypes and cancers occurring among non-obese and
non-white patients (38).

Of 6,124 cases enrolled between October 23, 2003 and November 30, 2011, 5,492 (89.7%)
completed and returned the questionnaire. We excluded women for the following reasons:
incomplete surgical staging (n=20), final diagnosis not endometrial carcinoma (n=53),
benign diagnoses (n=6), diagnosis of a second primary (n=2), misclassified pathologic
diagnosis based on central pathology review (n=49), inadequate material for pathology

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review (n=22), protocol deviations (n=17), and improper pre-protocol treatment (n=1). We
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excluded cases with missing grade (n=23), mixed epithelial cancers (n=556), mucinous
cancers (n=18), unusual histologic types (including squamous cell, undifferentiated, and de-
differentiated histologies) (n=111), and missing stage (n=5), leaving 4,609 patients for
analysis. For this analysis we excluded mixed epithelial cancers as the components of these
tumors were not recorded in the 60% of cases with admixtures of endometrioid and
adenocarcinoma histology. This study was approved by institutional review boards at the
National Cancer Institute and participating study centers.

Risk factor assessment

Prior to surgery, participants self-completed a questionnaire which assessed information on
demographic characteristics (age, race, annual income, highest level education attained) and
established endometrial carcinoma risk factors including anthropometric measures,
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reproductive and menstrual characteristics, exogenous hormone use, smoking status, and
medical conditions.

Tumor characteristics and outcome assessment

Pathologic information was available from participating NRG Oncology/GOG institutions
and through specialized reviews [previously described in (38)] performed by the NRG
Oncology/GOG Pathology Committee. Diagnoses of serous, carcinosarcoma, clear cell,
grade 3 endometrioid adenocarcinoma, and tumors involving the cervix or with non-nodal
metastases were centrally reviewed. Surgical stage and tumor grade were determined post-
operatively and coded according to the International Federation for Gynecology and
Obstetrics (FIGO) 1988 criteria (39). Final tumor subtype categories included low-grade
(grades 1 and 2) endometrioid, high-grade (grade 3) endometrioid, serous, clear cell, and
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carcinosarcoma. Information on vital status, date, and cause of death was obtained from
medical records and supplemented with cancer registry information. Follow-up information
was available through December 31, 2013. Time to event (in months) was calculated as the
difference between enrollment date and date of death, date last seen, or December 31, 2013,
whichever occurred first.

Causes of death were categorized as related to disease-only (n=582), treatment-only (n=11),

treatment and disease (n=1), neither treatment nor disease (n=159), cancer treatment from a
subsequent trial (n=3), or unknown (n=98). For the purposes of our analysis, we categorized
the 582 disease-only deaths as endometrial carcinoma-specific deaths and the remaining 272
deaths as non-endometrial carcinoma deaths.

Statistical Analyses
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The competing risks of endometrial carcinoma-specific and non-endometrial carcinoma

mortality were modeled using the Fine and Gray model, (40) a semi-proportional model that
provides the cumulative incidence of each event while simultaneously considering the
competing risk of the other outcome. The Fine and Gray model provides estimates of the
cumulative incidence function as subhazard ratios (HRs) and 95% confidence intervals
(CIs), analogous to the Cox proportional hazards model. Time since enrollment was used as

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the underlying time metric and proportional subhazards were assessed by including the risk
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factors as time varying covariates and evaluating the Wald p-value (41).

We first examined relationships between known prognostic factors, including age, stage,
tumor subtype, and adjuvant therapy, with cause-specific subhazards in minimally adjusted
models. We then examined relationships between etiologic factors and endometrial
carcinoma-specific mortality stratified by tumor subtype. We built a regression model
including endometrial carcinoma risk factors that were considered a priori: age at diagnosis,
race, parity, BMI, measured in kg/m2 (one year before diagnosis), diabetes, smoking status,
breast cancer diagnosis and tamoxifen use, oral contraceptive use, and menopausal hormone
use. These models were also adjusted for stage, highest education level attained, and annual
income. Linear trend tests were performed for BMI, parity, and duration of OC use by
including the ordinal form of each categorical variable in the model. As no significant linear
trends were observed for parity or duration of OC use, we present dichotomous categories
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for these exposures. Adjuvant therapy was not included as an adjustment factor in the cause-
specific subhazards models as it was not a significant predictor in minimally adjusted
models. Missing values for each covariate were modeled as a separate category.

We performed a sensitivity analysis comparing associations between etiologic factors and

cause-specific subhazards stratified by enrollment period (i.e. 2003–2007 vs. 2007–2011)
for each tumor subtype. We tested for formal interactions by including a multiplicative
interaction term between each variable and a binary variable indicating the enrollment
period. Statistical analyses were performed using SAS (version 9.3, SAS Institute, Cary,
NC, USA) and Stata software (version 11, STATA Corp., Texas, USA). All P values were
two-sided; statistical significance was set at P less than 0.05.
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RESULTS
Among the 4,609 endometrial carcinoma patients eligible for inclusion in the current
analysis, median follow-up was 60 months after diagnosis of endometrial carcinoma (range:
1 day – 118 months). In the multivariable analysis considering established prognostic
factors, endometrial carcinoma-specific subhazards were significantly associated with age at
diagnosis (HR=1.03, 95% CI=1.02–1.04 per year, P-trend <0.001), stage (HR comparing
stage IV to stage I=7.94, 95% CI=5.25–12.00, P-trend <0.001), and tumor subtype
(P<0.001) (Table 1). Relative to women diagnosed with low-grade endometrioid tumors,
endometrial carcinoma-specific subhazards were increased among women diagnosed with
high-grade endometrioid (HR=3.95, 95% CI=2.78–5.62), serous (HR=4.88, 95% CI=3.45–
6.90), carcinosarcoma (HR=7.52, 95% CI=5.05–11.20), and clear cell tumors (HR=4.39,
95% CI=2.51–7.68). Adjuvant therapy was not associated with endometrial carcinoma-
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specific subhazards (P=0.61).

Similarly, non-endometrial carcinoma subhazards were significantly associated with age at

diagnosis (P= HR=1.08, 95% CI=1.06–1.09 per year, P trend <0.001), stage (HR comparing
stage IV to stage I=1.82, 95% CI=1.05–3.16, P-trend =0.01), and tumor subtype (P=0.03),
while adjuvant therapy was not significantly related (P=0.06).

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Table 2 presents associations between established endometrial carcinoma risk factors and
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endometrial carcinoma-specific subhazards stratified by tumor subtype with adjustment for

all risk factors, education, annual income, and stage. Analyses related to non-endometrial
carcinoma mortality are presented in supplemental tables, given the uncertainty related to
deaths in this category. Among low-grade endometrioid cases, endometrial carcinoma-
specific subhazards were significantly associated with age at diagnosis (HR=1.04, 95%
CI=1.01–1.06 per year, P-trend) and BMI (HR comparing class II obesity vs. normal
BMI=2.29, 95% CI=1.06–4.98, P-trend=0.01).

Only age at diagnosis was related to endometrial carcinoma-specific subhazards (HR=1.05,

95% CI=1.02–1.07 per year, P-trend<0.001) among high-grade endometrioid cases. Among
serous cases, endometrial carcinoma-specific subhazards were decreased with parity relative
to nulliparity (HR=0.55, 95% CI=0.36–0.82) and a history of breast cancer that did not
include tamoxifen treatment compared with lack of both exposures (HR=0.09, 95%
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CI=0.01–0.71), although the confidence interval was wide. We observed increased

endometrial carcinoma-specific subhazards associated with parity among carcinosarcoma
cases (HR=2.01, 95% CI=1.00–4.05).

Finally, among clear cell cases, increased endometrial carcinoma-specific subhazards were
observed for underweight (HR=4.87, 95% CI=1.64–14.48) and class III obesity (HR=11.96,
95% CI=3.51–40.75) compared with normal-weight; however the confidence intervals were
wide due to the small number of cases and events for this tumor subtype. We also observed
decreased endometrial carcinoma-specific subhazards related to a history of breast cancer
with tamoxifen treatment compared with lack of both exposures (HR=0.07, 95% CI=0.01–
0.48); however this finding was based on 1 death among 9 exposed clear cell cases.
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Relationships between etiologic factors and non-endometrial carcinoma subhazards are

shown in Supplemental Table 1. Non-endometrial carcinoma subhazards were associated
with age at diagnosis among women with all tumor subtypes, except clear cell. Further, non-
endometrial carcinoma subhazards were associated with certain factors among the tumor
subtypes as follows: parity, BMI, diabetes and smoking among low-grade endometrioid
cases; smoking among high-grade endometrioid cases; and BMI among serous cases.

Supplemental Tables 2–6 show associations between risk factors and endometrial
carcinoma-specific subhazards by enrollment period. Only among serous cases did the
relationship between endometrial carcinoma-specific subhazards and risk factors (MHT use)
significantly differ in the pre-amendment vs. post-amendment period (Supplemental Table
4).
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DISCUSSION
Our study confirms the established findings that non-endometrioid histologic subtype,
advanced stage and older age are associated with worse prognosis. In the U.S. population,
low-grade endometrioid carcinomas comprise approximately 72% of malignant endometrial
tumors, and despite an overall favorable prognosis, these tumors account for 26% of cancer-
specific deaths (42). Accordingly, identifying non-traditional factors associated with worse

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prognosis in this group is particularly important, as these women may benefit from more
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intensive medical management.

In agreement with some (14, 16–22), but not all prior analyses (2–5, 7–13), our findings
demonstrate that obesity is associated with an increased risk of death among women with
low-grade endometrioid tumors. Furthermore, older age was related to increased risk of
death, a finding well supported by the literature (43–51). The possible reasons for the worse
prognosis for older or obese low-grade endometrioid endometrial carcinoma patients are
speculative. Given that BMI and circulating estrogen levels are positively correlated among
postmenopausal women, we hypothesize that tumors among heavier women have increased
capacity to grow in metastatic environments. In addition, BMI is posited to represent a pro-
inflammatory state and insulin resistance, which may drive carcinogenesis through
mechanisms independent of hormones. The associations of worse prognosis with age could
represent residual confounding related to more advanced disease within stage.
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Relationships of risk factors with endometrial carcinoma-related deaths among non-

endometrioid cases were less clear in our analysis. Parity was related to a lower risk of death
among women with serous carcinomas, but increased risk of death among women with
carcinosarcomas. These effects on behavior could reflect differences in the biology between
the pure serous carcinoma and the carcinosarcomas, which demonstrate mixed epithelial and
stromal differentiation. It is of further interest that carcinosarcomas are viewed by some
researchers as a form of “metaplastic carcinoma” and descriptive studies suggest that the
epithelial component may appear endometrioid in some cases and non-endometrioid in
others, suggesting these tumors may arise via separable etiological process, akin to the Type
I versus Type II distinction among endometrial carcinomas (52). Moreover, the molecular
profile of carcinosarcomas suggests two distinctive profiles – one that is endometrioid-like,
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with mutations in PTEN and ARID1A and one that is serous-like, with mutations in TP53
and PPP2R1A(53).

Similar to the etiology of carcinosarcomas, some pathology investigators have posited that
clear cell carcinoma is not readily classifiable as a Type I or Type II tumor (54). Data
suggest that these tumors have some specific genetic abnormalities that distinguish them
from endometrioid carcinomas, and these tumors portend a worse prognosis (42). Perhaps
the better prognosis of clear cell carcinomas associated with use of estrogen plus progestin
menopausal hormones is an indicator of a more indolent Type I phenotype.

The underlying causes of non-endometrial carcinoma death, while unknown in our study
population, are likely to be driven by cardiovascular events, the leading cause of death
among women with endometrial carcinoma (55). In line with this notion, we observed that
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older age, elevated BMI, smoking, and diabetes – exposures that affect longevity more
generally – were associated with non-endometrial carcinoma mortality among endometrial
carcinoma patients.

Our results demonstrate that etiologic risk factors known to influence endometrial
carcinogenesis have prognostic impact following a diagnosis. Overall, women with low-
grade endometrioid tumors have excellent prognosis; however, incorporating information on

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additional prognostic factors may identify women who can safely avoid adjuvant therapy.
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Several endometrial carcinoma prediction models have been developed for overall survival
(56, 57), lymph node metastasis (58–60), loco-regional or distant recurrence (61), and
receipt of radiotherapy (62). On the whole, these models only incorporate information on
pathologic characteristics obtained from surgery with the exception of a recent risk-scoring
model that included patient-level characteristics. (57). Our results, along with those from
AlHilli et al. (57) suggest that patient-level factors are relevant for endometrial carcinoma
prognosis, and that histology-specific risk-scoring models integrating these factors may be
more accurate for individualized treatment planning and follow-up. Conversely, women
with high-grade endometrioid and non-endometrioid tumors have a poor prognosis
regardless of stage or age. An identification of non-traditional factors related to prognosis
may enhance our understanding of the underlying biology of these tumors as well as suggest
tailored treatment strategies.
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Our study had several strengths including a large overall sample of patients, standardized
review of histologic diagnoses by a panel of experts, and information on numerous
epidemiologic risk factors. Furthermore, our ability to examine associations separately by
tumor subtype is a major advantage over previous studies which either considered overall
estimates or stratification by broad categories (Type I and Type II). Finally, we
demonstrated that these risk factors are independently related to outcomes after adjustment
for clinical factors such as stage and measures of socioeconomic status, which are known to
influence endometrial carcinoma survival (1, 63). Despite the large overall sample size,
some exposure categories for non-endometrioid subtypes had small numbers, resulting in
imprecise estimates. Further, changes in enrollment criteria affected the distribution of
tumor subtypes we observed in our study as compared with national estimates; however, our
sensitivity analyses did not demonstrate major differences in relationships between risk
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factors and prognosis before and after these changes occurred. Finally, we lacked
information on causes of death other than endometrial carcinoma which limits our ability to
interpret relationships observed for this outcome.

In conclusion, we observed that factors associated with the incidence of endometrial

carcinoma are related to endometrial carcinoma-specific mortality following a diagnosis.
Additional studies, particularly those performed within pooling projects, are needed to
confirm our findings. A better understanding of factors related to endometrial carcinoma
progression and survival is needed to improve approaches for treatment and provide insights
that may improve long-term prognosis.

Supplementary Material
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Refer to Web version on PubMed Central for supplementary material.

ACKNOWLEDGEMENTS
This study was supported by National Cancer Institute grants to the Gynecologic Oncology Group Administrative
Office (CA 27469), the Gynecologic Oncology Group Statistical and Data Center (CA 37517) and the NRG
Oncology Grant number: U10 CA180822. In addition, this research was supported in part by funds provided by the
intramural research program of the National Cancer Institute, National Institutes of Health.

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The following institutions participated in this study: Roswell Park Cancer Institute, University of Alabama at
Birmingham, Duke University Medical Center, Abington Memorial Hospital, Walter Reed Army Medical Center,
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Wayne State University, University of Minnesota Medical School, Northwestern University, University of
Mississippi, University of Colorado-Anschutz Cancer Pavilion, University of California at Los Angeles, Fred
Hutchinson Cancer Research Center, Penn State Milton S. Hershey Medical Center, University of Cincinnati,
University of North Carolina, University of Iowa Hospitals and Clinics, University of Texas Southwestern Medical
Center, Indiana University Medical Center, Wake Forest University Health Sciences, University of California
Medical Center at Irvine – Orange Campus, Magee Women's Hospital – University of Pittsburgh Medical Center,
University of New Mexico, Cleveland Clinic Foundation, State University of New York at Stony Brook,
Washington University School of Medicine, Cooper Hospital/University Medical Center, Columbus Cancer
Council/Ohio State, University of Massachusetts Memorial Health Care, Fox Chase Cancer Center, Women's
Cancer Center of Nevada, University of Oklahoma Health Sciences Center, University of Virginia, University of
Chicago, Mayo Clinic, Case Western Reserve University, Moffitt Cancer Center and Research Institute, Yale
University, University of Wisconsin Hospital, Women and Infants' Hospital, The Hospital of Central Connecticut at
New Britain General, GYN Oncology of West Michigan, PLLC and Community Clinical Oncology Program.

ClinicalTrials.gov Identifier: NCT00340808

REFERENCES
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1. Creasman WT, Odicino F, Maisonneuve P, et al. Carcinoma of the corpus uteri. FIGO 26th Annual
Report on the Results of Treatment in Gynecological Cancer. Int J Gynaecol Obstet. 2006; 95(Suppl
1):S105–43.
2. Anderson B, Connor JP, Andrews JI, et al. Obesity and prognosis in endometrial cancer. Am J
Obstet Gynecol. 1996; 174(4):1171–8. discussion 1178–9. [PubMed: 8623844]
3. Studzijnski Z, Zajewski W. Factors affecting the survival of 121 patients treated for endometrial
carcinoma at a Polish hospital. Arch Gynecol Obstet. 2003; 267(3):145–7. [PubMed: 12552325]
4. Everett E, Tamimi H, Greer B, et al. The effect of body mass index on clinical/pathologic features,
surgical morbidity, and outcome in patients with endometrial cancer. Gynecol Oncol. 2003; 90(1):
150–7.
5. Kodama J, Seki N, Ojima Y, et al. Correlation of presenting symptoms and patient characteristics
with endometrial cancer prognosis in Japanese women. Int J Gynaecol Obstet. 2005; 91(2):151–6.
[PubMed: 16162346]
6. Khan M, Mori M, Sakauchi F, et al. Risk of endometrial cancer mortality by ever-use of sex
Author Manuscript

hormones and other factors in Japan. Asian Pac J Cancer Prev. 2006; 7(2):260–6. [PubMed:
16839220]
7. Gates EJ, Hirschfield L, Matthews RP, Yap OW. Body mass index as a prognostic factor in
endometrioid adenocarcinoma of the endometrium. J Natl Med Assoc. 2006; 98(11):1814–22.
[PubMed: 17128692]
8. Temkin SM, Pezzullo JC, Hellmann M, Lee YC, Abulafia O. Is body mass index an independent
risk factor of survival among patients with endometrial cancer? Am J Clin Oncol. 2007; 30(1):8–14.
[PubMed: 17278888]
9. Munstedt K, Wagner M, Kullmer U, Hackethal A, Franke FE. Influence of body mass index on
prognosis in gynecological malignancies. Cancer Causes Control. 2008; 19(9):909–16. [PubMed:
18392944]
10. Jeong NH, Lee JM, Lee JK, et al. Role of body mass index as a risk and prognostic factor of
endometrioid uterine cancer in Korean women. Gynecol Oncol. 2010; 118(1):24–8. [PubMed:
20400173]
Author Manuscript

11. Nicholas Z, Hu N, Ying J, et al. Impact of Comorbid Conditions on Survival in Endometrial

Cancer. Am J Clin Oncol. 2012
12. Crosbie EJ, Roberts C, Qian W, et al. Body mass index does not influence post-treatment survival
in early stage endometrial cancer: results from the MRC ASTEC trial. Eur J Cancer. 2012; 48(6):
853–64. [PubMed: 22100903]
13. Ruterbusch JJ, Ali-Fehmi R, Olson SH, et al. The influence of comorbid conditions on racial
disparities in endometrial cancer survival. Am J Obstet Gynecol. 2014

Gynecol Oncol. Author manuscript; available in PMC 2016 October 01.

 Felix et al. Page 10

14. Ko EM, Walter P, Clark L, et al. The complex triad of obesity, diabetes and race in Type I and II
endometrial cancers: prevalence and prognostic significance. Gynecol Oncol. 2014; 133(1):28–32.
Author Manuscript

[PubMed: 24680588]
15. Arem H, Irwin ML. Obesity and endometrial cancer survival: a systematic review. Int J Obes
(Lond). 2012
16. von Gruenigen VE, Tian C, Frasure H, et al. Treatment effects, disease recurrence, and survival in
obese women with early endometrial carcinoma : a Gynecologic Oncology Group study. Cancer.
2006; 107(12):2786–91. [PubMed: 17096437]
17. Chia VM, Newcomb PA, Trentham-Dietz A, Hampton JM. Obesity, diabetes, and other factors in
relation to survival after endometrial cancer diagnosis. Int J Gynecol Cancer. 2007; 17(2):441–6.
[PubMed: 17362320]
18. Modesitt SC, Tian C, Kryscio R, et al. Impact of body mass index on treatment outcomes in
endometrial cancer patients receiving doxorubicin and cisplatin: a Gynecologic Oncology Group
study. Gynecol Oncol. 2007; 105(1):59–65. [PubMed: 17150247]
19. Mauland KK, Trovik J, Wik E, et al. High BMI is significantly associated with positive
progesterone receptor status and clinico-pathological markers for non-aggressive disease in
Author Manuscript

endometrial cancer. Br J Cancer. 2011; 104(6):921–6. [PubMed: 21343929]

20. Arem H, Park Y, Pelser C, et al. Prediagnosis body mass index, physical activity, and mortality in
endometrial cancer patients. J Natl Cancer Inst. 2013; 105(5):342–9. [PubMed: 23297041]
21. Arem H, Chlebowski R, Stefanick ML, et al. Body mass index, physical activity, and survival after
endometrial cancer diagnosis: Results from the Women's Health Initiative. Gynecol Oncol. 2012
22. Gunderson CC, Java J, Moore KN, Walker JL. The impact of obesity on surgical staging,
complications, and survival with uterine cancer: a Gynecologic Oncology Group LAP2 ancillary
data study. Gynecol Oncol. 2014; 133(1):23–7. [PubMed: 24680587]
23. Coughlin SS, Calle EE, Teras LR, Petrelli J, Thun MJ. Diabetes mellitus as a predictor of cancer
mortality in a large cohort of US adults. Am J Epidemiol. 2004; 159(12):1160–7. [PubMed:
15191933]
24. Campbell PT, Newton CC, Patel AV, Jacobs EJ, Gapstur SM. Diabetes and cause-specific
mortality in a prospective cohort of one million U.S. adults. Diabetes Care. 2012; 35(9):1835–44.
[PubMed: 22699290]
Author Manuscript

25. Daniell HW. More advanced-stage tumors among smokers with endometrial cancer. Am J Clin
Pathol. 1993; 100(4):439–43. [PubMed: 8213639]
26. Modesitt SC, Huang B, Shelton BJ, Wyatt S. Endometrial cancer in Kentucky: the impact of age,
smoking status, and rural residence. Gynecol Oncol. 2006; 103(1):300–6. [PubMed: 16631234]
27. Lochen ML, Lund E. Childbearing and mortality from cancer of the corpus uteri. Acta Obstet
Gynecol Scand. 1997; 76(4):373–7. [PubMed: 9174435]
28. Salvesen HB, Akslen LA, Albrektsen G, Iversen OE. Poorer survival of nulliparous women with
endometrial carcinoma. Cancer. 1998; 82(7):1328–33. [PubMed: 9529025]
29. Albrektsen G, Heuch I, Wik E, Salvesen HB. Parity and time interval since childbirth influence
survival in endometrial cancer patients. Int J Gynecol Cancer. 2009; 19(4):665–9. [PubMed:
19509568]
30. Albrektsen G, Heuch I, Wik E, Salvesen HB. Prognostic impact of parity in 493 uterine sarcoma
patients. Int J Gynecol Cancer. 2009; 19(6):1062–7. [PubMed: 19820369]
31. Wagenius G, Bergstrom R, Strang P, et al. Prognostic significance of flow cytometric and clinical
variables in endometrial adenocarcinoma stages I and II. Anticancer Res. 1992; 12(3):725–32.
Author Manuscript

[PubMed: 1622130]
32. Hachisuga T, Fukuda K, Hirakawa T, Kawarabayashi T. The effect of nulliparity on survival in
endometrial cancer at different ages. Gynecol Oncol. 2001; 82(1):122–6. [PubMed: 11426973]
33. Orgeas CC, Hall P, Wedren S, Dickman PW, Czene K. The influence of menopausal hormone
therapy on tumour characteristics and survival in endometrial cancer patients. Eur J Cancer. 2009;
45(17):3064–73. [PubMed: 19493676]
34. Robboy SJ, Bradley R. Changing trends and prognostic features in endometrial cancer associated
with exogenous estrogen therapy. Obstet Gynecol. 1979; 54(3):269–77. [PubMed: 471366]

Gynecol Oncol. Author manuscript; available in PMC 2016 October 01.

 Felix et al. Page 11

35. Smith DC, Prentice RL, Bauermeister DE. Endometrial carcinoma: histopathology, survival, and
exogenous estrogens. Gynecol Obstet Invest. 1981; 12(4):169–79. [PubMed: 7250780]
Author Manuscript

36. Petitti DB, Perlman JA, Sidney S. Noncontraceptive estrogens and mortality: long-term follow-up
of women in the Walnut Creek Study. Obstet Gynecol. 1987; 70(3 Pt 1):289–93. [PubMed:
3627576]
37. Stewart CJ, Doherty DA, Havlat M, et al. Transtubal spread of endometrial carcinoma: correlation
of intra-luminal tumour cells with tumour grade, peritoneal fluid cytology, and extra-uterine
metastasis. Pathology. 2013; 45(4):382–7. [PubMed: 23635815]
38. Brinton LA, Felix AS, McMeekin DS, et al. Etiologic heterogeneity in endometrial cancer:
evidence from a Gynecologic Oncology Group trial. Gynecol Oncol. 2013; 129(2):277–84.
[PubMed: 23485770]
39. Zaino RJ. FIGO staging of endometrial adenocarcinoma: a critical review and proposal. Int J
Gynecol Pathol. 2009; 28(1):1–9. [PubMed: 19047915]
40. Fine JP, Gray RJ. A Proportional Hazards Model for the Subdistribution of a Competing Risk.
Journal of the American Statistical Association. 1999; 94:13.
41. Zhou B, Fine J, Laird G. Goodness-of-fit test for proportional subdistribution hazards model. Stat
Author Manuscript

Med. 2013; 32(22):3804–11. [PubMed: 23625840]

42. Hamilton CA, Cheung MK, Osann K, et al. Uterine papillary serous and clear cell carcinomas
predict for poorer survival compared to grade 3 endometrioid corpus cancers. Br J Cancer. 2006;
94(5):642–6. [PubMed: 16495918]
43. Kosary CL. FIGO stage, histology, histologic grade, age and race as prognostic factors in
determining survival for cancers of the female gynecological system: an analysis of 1973–87
SEER cases of cancers of the endometrium, cervix, ovary, vulva, and vagina. Semin Surg Oncol.
1994; 10(1):31–46. [PubMed: 8115784]
44. Hoffman K, Nekhlyudov L, Deligdisch L. Endometrial carcinoma in elderly women. Gynecol
Oncol. 1995; 58(2):198–201. [PubMed: 7622105]
45. Zaino RJ, Kurman RJ, Diana KL, Morrow CP. Pathologic models to predict outcome for women
with endometrial adenocarcinoma: the importance of the distinction between surgical stage and
clinical stage--a Gynecologic Oncology Group study. Cancer. 1996; 77(6):1115–21. [PubMed:
8635132]
Author Manuscript

46. Mundt AJ, Waggoner S, Yamada D, Rotmensch J, Connell PP. Age as a prognostic factor for
recurrence in patients with endometrial carcinoma. Gynecol Oncol. 2000; 79(1):79–85. [PubMed:
11006036]
47. Alektiar KM, Venkatraman E, Abu-Rustum N, Barakat RR. Is endometrial carcinoma intrinsically
more aggressive in elderly patients? Cancer. 2003; 98(11):2368–77. [PubMed: 14635071]
48. Truong PT, Kader HA, Lacy B, et al. The effects of age and comorbidity on treatment and
outcomes in women with endometrial cancer. Am J Clin Oncol. 2005; 28(2):157–64. [PubMed:
15803010]
49. Jolly S, Vargas CE, Kumar T, et al. The impact of age on long-term outcome in patients with
endometrial cancer treated with postoperative radiation. Gynecol Oncol. 2006; 103(1):87–93.
[PubMed: 16545441]
50. Ahmed A, Zamba G, DeGeest K, Lynch CF. The impact of surgery on survival of elderly women
with endometrial cancer in the SEER program from 1992–2002. Gynecol Oncol. 2008; 111(1):35–
40. [PubMed: 18707756]
51. Benedetti Panici P, Basile S, Salerno MG, et al. Secondary analyses from a randomized clinical
Author Manuscript

trial: age as the key prognostic factor in endometrial carcinoma. Am J Obstet Gynecol. 2014;
210(4):363 e1–363 e10. [PubMed: 24361787]
52. McCluggage WG. Malignant biphasic uterine tumours: carcinosarcomas or metaplastic
carcinomas? J Clin Pathol. 2002; 55(5):321–5. [PubMed: 11986333]
53. McConechy MK, Ding J, Cheang MC, et al. Use of mutation profiles to refine the classification of
endometrial carcinomas. J Pathol. 2012; 228(1):20–30. [PubMed: 22653804]
54. Lax SF, Pizer ES, Ronnett BM, Kurman RJ. Clear cell carcinoma of the endometrium is
characterized by a distinctive profile of p53, Ki-67, estrogen, and progesterone receptor
expression. Hum Pathol. 1998; 29(6):551–8. [PubMed: 9635673]

Gynecol Oncol. Author manuscript; available in PMC 2016 October 01.

 Felix et al. Page 12

55. Ward KK, Shah NR, Saenz CC, et al. Cardiovascular disease is the leading cause of death among
endometrial cancer patients. Gynecol Oncol. 2012; 126(2):176–9. [PubMed: 22507532]
Author Manuscript

56. Abu-Rustum NR, Zhou Q, Gomez JD, et al. A nomogram for predicting overall survival of women
with endometrial cancer following primary therapy: toward improving individualized cancer care.
Gynecol Oncol. 2010; 116(3):399–403. [PubMed: 20022094]
57. AlHilli MM, Mariani A, Bakkum-Gamez JN, et al. Risk-scoring models for individualized
prediction of overall survival in low-grade and high-grade endometrial cancer. Gynecol Oncol.
2014; 133(3):485–93. [PubMed: 24690476]
58. Bendifallah S, Genin AS, Naoura I, et al. A nomogram for predicting lymph node metastasis of
presumed stage I and II endometrial cancer. Am J Obstet Gynecol. 2012; 207(3):197 e1–8.
[PubMed: 22939725]
59. AlHilli MM, Podratz KC, Dowdy SC, et al. Risk-scoring system for the individualized prediction
of lymphatic dissemination in patients with endometrioid endometrial cancer. Gynecol Oncol.
2013; 131(1):103–8. [PubMed: 23845691]
60. Kang S, Lee JM, Lee JK, et al. A Web-based nomogram predicting para-aortic nodal metastasis in
incompletely staged patients with endometrial cancer: a Korean Multicenter Study. Int J Gynecol
Author Manuscript

Cancer. 2014; 24(3):513–9. [PubMed: 24552891]

61. Kondalsamy-Chennakesavan S, Yu C, Kattan MW, et al. Nomograms to predict isolated loco-
regional or distant recurrence among women with uterine cancer. Gynecol Oncol. 2012; 125(3):
520–5. [PubMed: 22366410]
62. Lee CM, Szabo A, Shrieve DC, et al. Descriptive nomograms of adjuvant radiotherapy use and
patterns of care analysis for stage I and II endometrial adenocarcinoma: A surveillance,
epidemiology, and end results population study. Cancer. 2007; 110(9):2092–100. [PubMed:
17849468]
63. Madison T, Schottenfeld D, James SA, Schwartz AG, Gruber SB. Endometrial cancer:
socioeconomic status and racial/ethnic differences in stage at diagnosis, treatment, and survival.
Am J Public Health. 2004; 94(12):2104–11. [PubMed: 15569961]
Author Manuscript
Author Manuscript

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Research highlights
Author Manuscript

Non-endometrioid histologic subtype, advanced stage and older age are associated
with worse endometrial carcinoma prognosis.

Obesity is related to higher mortality among low-grade endometrioid cases.

Parity is associated with lower mortality in serous cases but higher mortality in
carcinosarcoma cases.
Author Manuscript
Author Manuscript
Author Manuscript

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Table 1

Multivariable subhazard ratios (HRs) and 95% confidence intervals (CIs) for cause-specific mortality by age, tumor characteristics, and adjuvant therapy
among 4,609 women with endometrial carcinoma enrolled in the NRG Oncology/GOG 210 trial, 2003–2011
Felix et al.

Endometrial carcinoma-specific mortality Non-endometrial carcinoma mortality

deaths=582 deaths=272

deaths/N 1 deaths/N 1
HR (95% CI) HR (95% CI)

Age at diagnosis, per year 1.03 (1.02, 1.04) 1.08 (1.06, 1.09)

p-trend <0.001 <0.001

Stage
I 184/3344 1.00 170/3344 1.00

II 43/321 1.95 (1.25, 3.06) 23/321 1.47 (0.92, 2.35)

III 231/738 3.70 (2.69, 5.10) 58/738 1.52 (1.03, 2.24)

IV 124/206 7.94 (5.25, 12.00) 21/206 1.82 (1.05, 3.16)

p-trend <0.001 0.01

Tumor subtype
Low-grade endometrioid 100/2778 1.00 126/2278 1.00

High-grade endometrioid 116/614 3.95 (2.78, 5.62) 34/614 1.16 (0.78, 1.73)

Serous 210/712 4.88 (3.45, 6.90) 71/712 1.70 (1.19, 2.43)

Carcinosarcoma 119/331 7.52 (5.05, 11.20) 32/331 1.62 (1.05, 2.51)

Clear cell 37/174 4.39 (2.51, 7.68) 9/174 0.96 (0.47, 1.96)
chi-square p <0.001 0.03

Gynecol Oncol. Author manuscript; available in PMC 2016 October 01.

Adjuvant therapy
None 155/2619 1.00 154/2619 1.00

Chemotherapy 241/632 1.39 (0.93, 2.07) 39/632 0.56 (0.35, 0.87)

Radiation 85/750 1.12 (0.78, 1.61) 44/750 0.73 (0.52, 1.03)

Chemotherapy and radiation 11/573 1.18 (0.79, 1.75) 33/573 0.63 (0.41, 0.98)

Other 6/35 1.19 (0.35, 4.08) 2/35 0.75 (0.17, 3.23)

chi-square p 0.61 0.06

1
HRs from Fine and Gray semi-proportional competing risk model adjusted for age (continuous), stage (I, II, III, IV), tumor subtype (low-grade endometrioid, high-grade endometrioid, serous,
carcinosarcoma, clear cell), adjuvant therapy (none, chemotherapy, radiation, chemotherapy plus radiation, unknown)
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Table 2

Multivariable subhazard ratios (HRs) and 95% confidence intervals (CIs) for associations between etiologic risk factors and endometrial carcinoma-
specific mortality stratified by tumor subtype in the NRG Oncology/GOG 210 trial, 2003–2011
Felix et al.

Low-grade endometrioid High-grade endometrioid Serous n=712 deaths=210 Carcinosarcoma n=331 deaths=119 Clear cell n=174 deaths=37
n=2,278 deaths=100 n=614 deaths=116
Characteristic 1 p2 1 p2 2 p2 2 p2 2 P2
HR (95% CI) HR (95% CI) HR (95% CI) HR (95% CI) HR (95% CI)

Age at diagnosis, per year 1.04 (1.01, 1.06) 0.002 1.05 (1.02, 1.07) <0.001 1.01 (0.99, 1.02) 0.48 1.00 (0.97, 1.03) 0.77 1.05 (0.98, 1.13) 0.16

Ethnicity 0.34 0.13 0.82 0.90 0.23

White 1.00 1.00 1.00 1.00 1.00

Black 1.55 (0.74, 3.26) 1.44 (0.80, 2.61) 1.13 (0.77, 1.64) 1.12 (0.67, 1.87) 0.24 (0.05, 1.25)

Other 1.71 (0.58, 5.06) 2.58 (0.87, 7.70) 1.00 (0.51 (1.96) 1.04 (0.31, 3.47) 2.73 (0.04, 189.77)

Parity 0.88 0.78 0.003 0.05 0.21

Nulliparous 1.00 1.00 1.00 1.00 1.00

Parous 0.94 (0.54, 1.62) 1.09 (0.61, 1.94) 0.55 (0.36, 0.82) 2.01 (1.00, 4.05) 0.25 (0.05, 1.25)

BMI (kg/m2) 0.04 0.92 0.89 0.21 0.001

Normal (18.5–24.99) 1.00 1.00 1.00 1.00 1.00

Underweight (<18.5) 3.61 (0.53, 24.61) 2.94 (0.19, 45.13) 1.47 (0.25, 8.68) 1.04 (0.06, 17.23) NE

Overweight (25–29.99) 1.04 (0.47, 2.30) 1.24 (0.69, 2.22) 0.98 (0.63, 1.54) 0.78 (0.42, 1.44) 4.87 (1.64, 14.48)

Class I Obese (30–34.99) 0.86 (0.38, 1.91) 1.01 (0.52, 1.95) 1.01 (0.63, 1.60) 0.62 (0.30, 1.29) 2.21 (0.29, 16.93)

Class II Obese (35–39.99) 2.29 (1.06, 4.98) 1.02 (0.47, 2.23) 1.14 (0.70, 1.84) 1.05 (0.51, 2.15) 0.55 (0.04, 7.63)

Class III Obese (≥40) 1.92 (0.86, 4.31) 1.30 (0.66, 2.54) 0.79 (0.43, 1.45) 1.55 (0.74, 3.24) 11.96 (3.51, 40.75)
3 0.01 0.63 0.86 0.38 0.17
p-trend

Gynecol Oncol. Author manuscript; available in PMC 2016 October 01.

Diabetes 0.28 0.75 0.95 0.14 0.49

Never 1.00 1.00 1.00 1.00 1.00

Ever 0.73 (0.38, 1.92) 0.92 (0.55, 1.54) 0.99 (0.69, 1.41) 0.66 (0.38, 1.15) 0.56 (0.10, 2.96)

Smoking status 0.36 0.49 0.96 0.51 0.34

Non-smoker 1.00 1.00 1.00 1.00 1.00

Current smoker 1.65 (0.73, 3.74) 1.59 (0.74, 3.41) 1.11 (0.53, 2.31) 1.47 (0.63, 3.44) 0.41 (0.11, 1.45)

Former smoker 0.88 (0.53, 1.44) 1.00 (0.64, 1.57) 1.00 (0.72, 1.37) 1.23 (0.78, 1.95) 0.37 (0.05, 2.75)
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Low-grade endometrioid High-grade endometrioid Serous n=712 deaths=210 Carcinosarcoma n=331 deaths=119 Clear cell n=174 deaths=37
n=2,278 deaths=100 n=614 deaths=116

Breast cancer and tamoxifen 0.15 0.83 0.04 0.35 0.007

use
Felix et al.

No breast cancer/no tamoxifen 1.00 1.00 1.00 1.00 1.00

Breast cancer/no tamoxifen 2.45 (1.00, 5.99) 0.76 (0.27, 2.26) 0.09 (0.01, 0.71) 1.21 (0.39, 3.74) NE

No breast cancer/tamoxifen NE NE 1.00 (0.72, 1.37) NE NE

use

Breast cancer/tamoxifen use 0.98 (0.24, 3.94) 0.77 (0.22, 2.72) 1.15 (0.70, 1.87) 1.55 (0.85, 2.83) 0.07 (0.01, 0.48)

Oral contraceptive use 0.33 0.56 0.43 0.49 0.61

Never 1.00 1.00 1.00 1.00 1.00

Ever 0.79 (0.50, 1.27) 0.88 (0.56, 1.37) 1.15 (0.81, 1.61) 0.83 (0.49, 1.41) 1.38 (0.40, 4.78)

Menopausal hormone use 0.92 0.83 0.34 0.56 0.06

None 1.00 1.00 1.00 1.00 1.00

Estrogen only 0.87 (0.42, 1.68) 1.19 (0.57, 2.45) 0.72 (0.37, 1.40) 1.01 (0.48, 2.13) 0.20 (0.03, 1.25)

Progestin only 1.33 (0.46, 3.86) 0.58 (0.06, 5.93) 0.20 (0.02, 1.83) 1.92 (0.50, 7.30) NE

Estrogen plus progestin 1.07 (0.57, 1.98) 0.87 (0.53, 1.43) 0.84 (0.54, 1.31) 0.75 (0.41, 1.36) 0.09 (0.01, 0.85)

NE=not estimable
1
HRs from Fine and Gray semi-proportional competing risk model adjusted for all variables shown in the table, stage (I, II, III, IV), education (High school/GED, some college/technical school, college
graduate/beyond), income ($20,000–$39,999, $40,000–$69,999, ≥$70,000)
2
Wald chi-square p-value excluding the unknown category
3
p-value (two-sided) for trend was calculated using the Wald test for the ordinal variable based on the categories (excluding underweight) and referent group shown

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