Abstract
Objective:
The majority of endometrial cancer patients are overweight or obese at cancer diagnosis. Obesity is a shared risk factor for both endometrial cancer and diabetes, but it is unknown whether endometrial cancer patients have increased diabetes risks. The aim of our study was to investigate diabetes risk among endometrial cancer patients.
Methods:
Endometrial cancer patients diagnosed between 1997 and 2012 in Utah (n=2,314) were identified. Women from the general population (n=8,583) were matched to the cancer patients on birth year and birth state. Diabetes diagnoses were identified from electronic medical records and statewide healthcare facility databases. Cox proportional hazards models were used to estimate hazard ratios for diabetes after cancer diagnosis.
Results:
Endometrial cancer survivors had a significantly higher risk of type II diabetes when compared to women from the general population in the first year after cancer diagnosis (HR=5.22, 95% CI=4.05, 6.71), >1–5 years after cancer diagnosis (HR=1.67, 95% CI=1.31, 2.12), and >5 years after cancer diagnosis (HR=1.65, 95% CI=1.29, 2.11). Endometrial cancer patients who were obese at cancer diagnosis had a three-fold increase in type II diabetes risk (HR=2.99, 95%CI=2.59, 3.45). Although endometrial cancer patients diagnosed at distant stage had a higher risk of diabetes, cancer treatment did not appear to contribute to any diabetes risks.
Conclusions:
In conclusion, endometrial cancer survivors had a higher risk of diabetes than women in the general population. These results suggest that long term monitoring for diabetes is indicated for endometrial cancer survivors.
Keywords: Endometrial cancer, diabetes, survivorship
Introduction
In the United States, endometrial cancer is the fourth most commonly diagnosed cancer among women, with an estimated 63,230 new cases diagnosed in 2018 [1]. The age-adjusted incidence rate for 2011 to 2015 was 16.9 per 100,000 for women < 65 years of age and 88.6 per 100,000 for women ≥65 years of age [2]. Endometrial cancer was the sixth most common cause of cancer death in 2018, with an estimated 11,350 deaths [1]. The death rate has been increasing on average by 1.5% per year among white women and 2.1% per year among black women from 2006 to 2015 [1]. As of 2017, an estimated 757,190 endometrial cancer survivors live in the United States [3]. Long-term chronic disease risks are of concern among endometrial cancer patients, since the majority are obese at diagnosis [4, 5]. We previously reported on increased risks of cardiovascular disease and genitourinary outcomes among endometrial cancer survivors [4, 5].
In the United States, 9.4% of the population had diabetes in 2015 [6]. Diabetes was the seventh leading cause of death in the United States, with 83,564 deaths due to diabetes in 2017 [7]. Diabetes history contributes to an increased risk of all-cause mortality and cancer-related deaths among endometrial cancer survivors [8, 9]. Given that individuals diagnosed with diabetes are likely to spend nearly 2.3 times more on healthcare costs ($16,752/year vs. $9,601/year) [10], the economic burden is exacerbated further for cancer patients with diabetes. Since diabetes is a chronic disease and can lead to complications [10], prevention and control of diabetes among cancer patients is critical.
Hypothesized diabetes-related biological mechanisms driving endometrial cancer etiology and prognosis include increased insulin and insulin-like growth factor (IGF) signaling, dysregulation of ovarian steroid hormones, and chronic inflammation [11]. In addition, previous studies suggest that the association between diabetes and cancer is partly attributable to shared risk factors such as obesity, physical inactivity, and aging [12].
While previous studies suggest an increased risk of endometrial cancer with previous history of diabetes [13–18], limited evidence has been established that the risk for diabetes is increased after diagnosis of endometrial cancer. A recent study in Korea reported no association between endometrial cancer and subsequent diabetes, but the risk of diabetes by diabetes types and risk factors for diabetes were not investigated [19]. Further, there is no previous study, to our knowledge, that examined whether the risk of diabetes after endometrial cancer diagnosis differs in comparison with a general population.
The objectives of this population-based cohort study were to: (1) examine the risk of developing diabetes after cancer diagnosis among endometrial cancer survivors in comparison with a general population, (2) assess risk factors for diabetes among endometrial cancer survivors, (3) examine the risk of developing diabetes stratified by baseline BMI among endometrial cancer survivors in comparison with a general population.
Methods
Women diagnosed with a first primary endometrial cancer from 1997 to 2012 were identified from the statewide Surveillance, Epidemiology, and End Results Program (SEER) Utah Cancer Registry. Additional data for this study were obtained from the Utah Population Database (UPDB), which includes data linked from the Utah Cancer Registry, driver licenses, and birth and death certificates. Additionally, the UPDB links statewide inpatient hospital claims, ambulatory surgery records, and electronic medical records from the two largest healthcare providers in Utah, the University of Utah and Intermountain Healthcare. Utah is considered to have a minimal percentage of residents who seek healthcare out of the state, based on a report by the National Association of Health Data Organizations that reviewed interstate exchange of nonresident data for health research and public health purposes [20]. Also, Utah has a low out migration rate (2.9%) according to the state-to-state migration flow data from the US Census Bureau for 2016 [21].
The eligibility criteria were: 1) women aged ≥18 years at cancer diagnosis, 2) diagnosed with a first primary endometrial cancer (SEER International Classification of Diseases for Oncology, 3rd edition [ICD-O-3] codes: C54.0–C55.9) between 1997 and 2012. The classification of type I endometrial cancer histology was defined as adenocarcinoma, endometrioid, mucinous adenocarcinoma, and adenocarcinoma with squamous differentiation (ICD-O-3 morphology codes: 8140, 8380, 8382, 8480, 8482, 8560, and 8570). Type II endometrial cancer histology was defined as clear-cell carcinomas and papillary serous carcinomas (ICD-O-3 morphology codes: 8310, 8441, and 8460) [22]. Each endometrial cancer survivor was matched with up to five women from the general population by birth year, and birth state (Utah/non-Utah). Birth state was included in the matching variables because additional information would be available on women born in Utah in the UPDB. Women in the general population comparison group were considered ineligible if they had been diagnosed with any invasive cancer. All research projects using the UPDB were approved by the Utah Resource for Genetic and Epidemiologic Research (RGE) and the Institutional Review Board (IRB) at the University of Utah.
Only new diabetes diagnoses after endometrial cancer diagnoses were considered in this study, thus we excluded diabetes cases before endometrial cancer diagnosis as a prevalent case. All diabetes cases were identified with an ICD-9 diagnosis code and date. Type I and type II diabetes were classified by ICD-9 codes (ICD-9 codes: 250.00 – 250.93). Secondary diabetes mellitus and abnormal findings related to diabetes (ICD-9 codes: 790.2 – 790.29, 791.5, 791.6, V45.85, V53.91, and V65.46) were classified as ‘other’ in the analysis. The majority of other diabetes cases (84% in the cancer patients cohort vs. 83% in the general population cohort) were other abnormal glucose (ICD-9 code: 790.29).
The Charlson Comorbidity Index (CCI) [23] was used to calculate baseline comorbidities using medical records prior to the date of endometrial cancer diagnosis. For the general population cohort, the CCI prior to the date of diagnosis of the case they were matched with, was taken as the baseline CCI. To avoid double adjustment, malignancy and metastatic solid tumor comorbidities were excluded in the CCI calculation.
Endometrial cancer patients were excluded if the cancer stage (n=165) or cancer grade (n=348) was missing, if they were diagnosed with diabetes before cancer diagnosis (n=71), or if they were diagnosed with diabetes both before and after cancer diagnosis (n=552). A total of 2,314 endometrial cancer survivors and 8,583 women from the general population were included in the final analysis (Figure 1). If women were diagnosed with diabetes, the follow-up period was calculated from the cancer diagnosis date (date of cancer diagnosis of the cancer patients they were matched to) to the date of diabetes diagnosis. If they were not diagnosed with diabetes, their follow-up period was calculated from the cancer diagnosis date to the date of death or last date of residence in Utah. The last residence date in Utah was determined by UPDB through the individual’s last contact with various data sources, including Utah birth/death certificate, driver’s license division, and voter registration.
Figure 1.
Study Inclusion/Exclusion Criteria.
We previously compared self-reported diabetes from a subset of the endometrial cancer patients (n=221) and EMR/statewide data that was used in this study to investigate concordance for various diseases including diabetes. Patients’ self-report was considered as the gold standard and the sensitivity and specificity for diabetes were 88.6% and 90.9%, respectively [4].
Statistical Analysis
Chi-square tests were used to compare demographic characteristics between the endometrial cancer survivors and the general population cohort. Cox proportional hazard models [24] were used to estimate the hazard ratios (HRs) and 95% confidence intervals (CIs) for the risk of diabetes among endometrial cancer survivors in comparison with the general population cohort. The follow up period was stratified into 0–1 year, >1–5 years, >5 years from endometrial cancer diagnosis. We adjusted for race, baseline body mass index (BMI), baseline CCI, birth state, and birth year. Hazard ratios for diabetes (all diabetes and type II diabetes) stratified by baseline BMI were also estimated using Cox proportional hazard models adjusted for matching factors (birth state, birth year), baseline CCI, race, and age at diagnosis. Proportional hazards assumptions were tested for all Cox proportional hazards models. If the proportional hazard assumption was violated, Cox proportional hazards regression models with cubic spline functions were used and we reported the estimate from the cubic spline function.
Cox proportional hazard models were also used to examine risk factors for type II diabetes only among endometrial cancer survivors. Potential risk factors investigated included age at cancer diagnosis, year of cancer diagnosis, race, baseline BMI, family history of diabetes, stage, grade, cancer treatment and baseline CCI. Family history of any cancer, endometrial cancer, and diabetes included first, second and third degree relatives. Adjustment variables for each potential risk factor were selected based on an assessment of the three properties of confounders based on prior knowledge. The stratified analyses and risk factors analyses were not conducted in type I diabetes due to the small number of type I diabetes cases (n = 23).
Weight and height were identified for the closest date ≥ 1 year before endometrial cancer diagnosis from the driver’s license division. For women from the general population, the most recent BMI results at least 1 year before the endometrial cancer diagnosis date of the matched cancer patient was included. We chose the cutoff date to assess height and weight to minimize the possibility of the cancer diagnosis impacting the weight. The median years and interquartile range between the date of baseline BMI and cancer diagnosis/matched date were 3.76 (3.7) among endometrial cancer survivors and 4.1 (4.8) among women in the general population cohort. Approximately 27% of all participants were missing baseline BMI values. Thus, baseline BMI were imputed for individuals missing BMI with a linear regression model including the following covariates: cancer diagnosis, baseline CCI, race, and age at endometrial cancer diagnosis. We compared the HRs with and without imputation to assure that the inferences did not change due to the imputed BMI.
All P values were two-sided, and p-values <0.05 were considered statistically significant. All analyses were conducted using SAS version 9.4 (SAS Institute, Inc., Cary, NC).
Results
A total 2,314 endometrial cancer patients and 8,583 women from the general population were included in the final cohorts (Table 1). Endometrial cancer patients had a higher proportion of obesity than the general population cohort (41.4% vs.16.0%, p <0.0001). Women in the general population cohort were more likely to have normal weight than endometrial cancer survivors (49.9% vs. 28.7%, p< 0.0001). Family history of endometrial cancer was more common among endometrial cancer patients. (17.5% vs. 12.1%, p < 0.0001). Although we matched on birth year, the distribution was slightly different between the two cohorts after excluding the women in the general population cohort who had cancer (p = 0.0247). The proportion of individuals with diabetes was higher in the endometrial cancer cohort than the general population cohort (29.5% vs. 15.8%, p< 0.0001).
Table 1.
Demographic characteristics of endometrial cancer patient and general population cohorts in Utah
| Endometrial Cancer (n=2,314) | General population (n=8,583) | P-value a | |
|---|---|---|---|
| Birth year | |||
| <1920 | 113 (4.9) | 439 (5.1) | 0.0247 |
| 1920–1929 | 281 (12.1) | 924 (10.8) | |
| 1930–1939 | 462 (20.0) | 1560 (18.2) | |
| 1940–1949 | 660 (28.5) | 2407 (28.0) | |
| 1950–1959 | 514 (22.2) | 2049 (23.9) | |
| >1960 | 284 (12.3) | 1204 (14.0) | |
| Race | |||
| White | 2207 (95.4) | 7805 (90.9) | <0.0001 |
| Other | 96 (4.2) | 401 (4.7) | |
| Unknown | 11 (0.5) | 377 (4.4) | |
| Hispanic | |||
| No | 2142 (92.6) | 5555 (64.7) | <0.0001 |
| Yes | 154 (6.7) | 487 (5.7) | |
| Unknown | 18 (0.8) | 2541 (29.6) | |
| Vital status | |||
| Alive | 1624 (70.2) | 7309 (85.2) | <0.0001 |
| Dead | 690 (29.8) | 1274 (14.8) | |
| Baseline body mass index, kg/m2 | |||
| <18.5 | 30 (1.3) | 241 (2.8) | <0.0001 |
| 18.5–24.9 | 663 (28.7) | 4282 (49.9) | |
| 25 – 29.9 | 662 (28.6) | 2685 (31.3) | |
| ≥30 | 959 (41.4) | 1375 (16.0) | |
| Follow-up period, year | |||
| 0–1 | 172 (7.4) | 10 (0.1) | <0.0001 |
| >1–5 | 536 (23.2) | 1859 (21.7) | |
| >5–10 | 780 (33.7) | 3233 (37.7) | |
| >10–15 | 532 (23.0) | 2277 (26.5) | |
| 15+ | 294 (12.7) | 1204 (14.0) | |
| Baseline Charlson Comorbidity Index | |||
| ≥1 | 559 (24.2) | 2002 (23.3) | 0.4021 |
| 0 | 1755 (75.8) | 6581 (76.7) | |
| Family history of any cancer b | |||
| No | 1048 (45.3) | 3958 (46.1) | 0.4798 |
| Yes | 1266 (54.7) | 4625 (53.9) | |
| Family history of endometrial cancer b | |||
| No | 1909 (82.5) | 7547 (87.9) | <0.0001 |
| Yes | 405 (17.5) | 1036 (12.1) | |
| Family history of diabetes b | |||
| No | 1104 (47.7) | 4073 (47.5) | 0.8272 |
| Yes | 1210 (52.3) | 4510 (52.6) | |
| Diagnosis of diabetes after diagnosis of endometrial cancer | |||
| No | 1632 (70.5) | 7225 (84.2) | <0.0001 |
| Yes | 682 (29.5) | 1358 (15.8) | |
| Diabetes type | |||
| Type I | 7 (0.3) | 16 (0.2) | <0.0001 |
| Type II | 474 (20.5) | 843 (9.8) | |
| Other | 201 (8.7) | 499 (5.8) | |
| Follow up time, years | |||
| 0–1 | 221 (9.6) | 139 (1.6) | <0.0001 |
| >1–5 | 222 (11.4) | 515 (6.1) | |
| >5–10 | 239 (18.4) | 704 (11.4) |
Two-sided chi-square test
Includes first, second and third degree relatives.
Includes secondary diabetes mellitus, abnormal glucose, impaired fasting glucose, impaired glucose tolerance test (oral), other abnormal glucose, glycosuria, and acetonuria.
Approximately 58% of the endometrial cancer survivors were diagnosed with cancer from 50 years to 69 years of age (mean 60.5) (Table 2). The majority of endometrial cancer patients were diagnosed at local stage (77.5%), endometrioid adenocarcinoma histology (66.6%) and Type I endometrial cancer (84.6%). Nearly 95% of the endometrial cancer patients received surgical treatment and 8% received chemotherapy.
Table 2.
Clinical Characteristics among endometrial cancer patients in a population-based cohort in Utah
| n | % | |
|---|---|---|
| Year of cancer diagnosis | ||
| 1997–2000 | 567 | 24.5 |
| 2001–2003 | 433 | 18.7 |
| 2004–2006 | 409 | 17.7 |
| 2007–2009 | 464 | 20.1 |
| 2010–2012 | 441 | 19.1 |
| Age at cancer diagnosis | ||
| <40 | 131 | 5.7 |
| 40–49 | 293 | 12.7 |
| 50–59 | 696 | 30.1 |
| 60–69 | 636 | 27.5 |
| 70–79 | 370 | 16.0 |
| >80 | 188 | 8.1 |
| Age at cancer diagnosis, mean (SD) | 60.5 (12.8) | |
| Grade | ||
| Grade I (Well differentiated) | 1093 | 47.2 |
| Grade II (moderately differentiated) | 740 | 32.0 |
| Grade III (poorly differentiated) | 403 | 17.4 |
| Grade IV (undifferentiated) | 78 | 3.4 |
| Cancer stage | ||
| Local | 1793 | 77.5 |
| Regional | 394 | 17.0 |
| Advanced | 127 | 5.5 |
| Histology | ||
| Endometrioid adenocarcinoma | 1541 | 66.6 |
| Adenocarcinoma, NOS | 328 | 14.2 |
| Adenocarcinoma with squamous metaplasia | 58 | 2.5 |
| Serous adenocarcinoma | 85 | 3.7 |
| Clear cell adenocarcinoma | 17 | 0.7 |
| Mixed cell adenocarcinoma | 38 | 1.6 |
| Mucinous adenocarcinoma | 36 | 1.6 |
| Carcinosarcoma | 27 | 1.2 |
| Stromal sarcoma | 43 | 1.9 |
| Leiomyosarcoma | 44 | 1.9 |
| Other | 97 | 4.2 |
| Endometrial cancer type | ||
| Type I | 1957 | 84.6 |
| Type II | 84 | 3.6 |
| Other | 273 | 11.8 |
| Treatment | ||
| Surgery only | 1531 | 66.2 |
| Surgery and radiation | 487 | 21.1 |
| Surgery, radiation and chemotherapy | 98 | 4.2 |
| Surgery and chemotherapy | 75 | 3.2 |
| Other (Radiation only / Chemo only/ radiation & Chemo) | 25 | 1.1 |
| No available information | 98 | 4.2 |
| Surgery | ||
| Yes | 2191 | 94.7 |
| No | 25 | 1.1 |
| Unknown | 98 | 4.2 |
| Chemotherapy | ||
| Yes | 187 | 8.1 |
| No | 2029 | 87.7 |
| Unknown | 98 | 4.2 |
In the first year since cancer diagnosis, endometrial cancer survivors had a 5-fold increase in risk of any type of diabetes (overall, type I, type II, and other) compared to the general population (Table 3). The number of individuals diagnosed with diabetes in each period is summarized in Supplementary Table 3A. Endometrial cancer survivors had a significantly higher risk of diabetes when compared to the general population >1–5 years since cancer diagnosis (HR=1.52, 95% CI=1.26, 1.84), and >5 years since cancer diagnosis (HR=1.46, 95% CI=1.22, 1.75) when adjusted for matching factors, race, baseline BMI and baseline CCI. Risks for type II diabetes and other diabetes were significantly higher for endometrial cancer survivors across all follow up periods, while risk for type I diabetes was significant for the overall period and only in the first year after cancer diagnosis.
Table 3.
The risk of diabetes among endometrial cancer survivors compared to the general population cohort in Utah, by years since cancer diagnosis
| Endometrial cancer Survivors N = 2,314 | General Population N =8,583 | Overall | 0–1 year | >1–5 years | >5 years | |||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| N | % | N | % | HR | 95% CI | HR | 95% CI | HR | 95% CI | HR | 95% CI | |
| Diabetes mellitus | 682 | 29.5 | 1358 | 15.8 | 1.91 | (1.73, 2.10) a | 5.02 | (4.01, 6.28) a | 1.52 | (1.26, 1.84) | 1.46 | (1.22, 1.75) |
| Type I | 7 | 0.3 | 16 | 0.2 | 3.93 | (1.03, 14.94) | 11.33 | (1.16, 110.7) | 0.38 | (0.02, 8.08) | - | - |
| Type II | 474 | 20.5 | 843 | 9.8 | 2.05 | (1.82, 2.31) a | 5.22 | (4.05, 6.71) a | 1.67 | (1.31, 2.12) | 1.65 | (1.29, 2.11) |
| Other b | 201 | 8.7 | 499 | 5.8 | 1.69 | (1.42, 2.01) a | 4.55 | (2.51, 8.22) | 1.69 | (1.26, 2.27) a | 1.4 | (1.10, 1.78) a |
Note: All analyses adjusted for race, baseline BMI, baseline CCI score, birth state and birth year.
Proportional hazard assumption was violated; HRs are from Cox models with cubic splines.
Includes secondary diabetes mellitus, abnormal glucose, impaired fasting glucose, impaired glucose tolerance test (oral), other abnormal glucose, glycosuria, and acetonuria.
Higher BMI at baseline was a significant risk factor for type II diabetes among endometrial cancer survivors, with a dose-response relation across all follow up periods (p trend <0.0001) (Table 4). Distant cancer stage at diagnosis (HR=2.32, 95%CI=1.05, 5.17) and higher CCI score (>2) (HR=2.06, 95%CI=1.18, 3.62, p trend = 0.026) were significant risk factors for type II diabetes after 1–5 years since cancer diagnosis, but not in the other follow up periods. Individuals with grade IV endometrial cancer were at higher risk for type II diabetes compared to those with grade I endometrial cancer in the first year since cancer diagnosis (HR=2.33, 95%CI=1.07, 5.07). Endometrial cancer survivors of other races (mostly American Indian [37%] and Pacific Islander [40%]) were more likely to be diagnosed with diabetes than white endometrial cancer survivors overall (HR=1.55, 95%CI=1.23, 1.94) and in the first year since cancer diagnosis (HR=2.16, 95%CI=1.45, 3.21). Age at cancer diagnosis, year of cancer diagnosis, family history of diabetes and cancer treatment were not associated with diabetes risk among endometrial cancer survivors.
Table 4.
Risk factors for type II diabetes among endometrial cancer survivors in a population-based cohort in Utah, by years since cancer diagnosis
| Diabetes mellitus |
||||||||
|---|---|---|---|---|---|---|---|---|
| Overall | 0–1 year | > 1–5 years | >5 years | |||||
| HR | (95% CI) | HR | (95% CI) | HR | (95% CI) | HR | (95% CI) | |
| Age at diagnosis a | ||||||||
| < 40 years | Reference | Reference | Reference | Reference | ||||
| 40–50 years | 1.05 | (0.69, 1.59) | 1.20 | (0.55, 2.61) | 0.91 | (0.46, 1.83) | 0.96 | (0.46, 2.00) |
| 50–60 years | 0.91 | (0.61, 1.34) | 0.98 | (0.47, 2.04) | 0.79 | (0.42, 1.50) | 0.91 | (0.46, 1.80) |
| 60–70 years | 0.96 | (0.65, 1.43) | 1.67 | (0.82, 3.41) | 0.61 | (0.31, 1.19) | 0.71 | (0.35, 1.45) |
| 70–80 years | 0.97 | (0.63, 1.48) | 1.50 | (0.70, 3.18) | 0.78 | (0.39, 1.57) | 0.69 | (0.31, 1.54) |
| 80+ years | 1.04 | (0.62, 1.72) | 1.69 | (0.74, 3.89) | 0.88 | (0.38, 2.02) | 0.45 | (0.12, 1.65) |
| Year of diagnosis b | ||||||||
| 1997–2000 | Reference | Reference | Reference | Reference | ||||
| 2001–2003 | 1.09 | (0.85, 1.41) | 1.09 | (0.69, 1.72) | 1.25 | (0.77, 2.03) | 0.99 | (0.66, 1.49) |
| 2004–2006 | 1.01 | (0.76, 1.34) | 0.91 | (0.56, 1.49) | 1.38 | (0.86, 2.22) | 0.78 | (0.47, 9.49) |
| 2007–2009 | 0.82 | (0.60, 1.11) | 1.01 | (0.64, 1.59) | 0.79 | (0.46, 1.35) | 0.52 | (0.24, 6.49) |
| 2010–2012 | 0.71 | (0.50, 1.02) | 0.93 | (0.57, 1.51) | 0.56 | (0.30, 1.06) | - | - |
| Race | ||||||||
| White | Reference | Reference | Reference | Reference | ||||
| Other | 1.55 | (1.23, 1.94) | 2.16 | (1.45, 3.21) | 1.34 | (0.91, 1.97) | 1.37 | (0.92, 2.05) |
| Baseline BMI c | ||||||||
| <18.5 kg/m2 | 1.31 | (0.86, 2.00) | 2.39 | (1.02, 5.56) | 1.38 | (0.67, 2.83) | 0.99 | (0.50, 1.93) |
| 18.5–24.9 kg/m2 | Reference | Reference | Reference | Reference | ||||
| 25–29.9 kg/m2 | 1.80 | (1.56, 2.08) | 2.26 | (1.61, 3.19) | 1.87 | (1.47, 2.39) | 1.60 | (1.30, 1.98) |
| 30+ kg/m2 | 2.99 | (2.59, 3.45) | 3.46 | (2.48, 4.82) | 3.52 | (2.77, 4.46) | 2.43 | (1.94, 3.03) |
| P trend | <0.001 | <0.001 | <0.001 | <0.001 | ||||
| Family history of diabetes d | ||||||||
| No | Reference | Reference | Reference | Reference | ||||
| Yes | 1.13 | (0.93, 1.37) | 1.24 | (0.90, 1.72) | 1.19 | (0.84, 1.69) | 0.93 | (0.66, 1.31) |
| Cancer stage at diagnosis e | ||||||||
| Localized | Reference | Reference | Reference | Reference | ||||
| Regional | 1.11 | (0.86, 1.43) | 1.32 | (0.91, 1.90) | 1.09 | (0.70, 1.72) | 0.75 | (0.42, 1.35) |
| Distant | 1.62 | (1.00, 2.63) | 1.45 | (0.74, 2.85) | 2.32 | (1.05, 5.17) | 1.18 | (0.26, 5.28) |
| Grade e | ||||||||
| I | Reference | Reference | Reference | Reference | ||||
| II | 0.83 | (0.68, 1.02) | 1.05 | (0.75, 1.47) | 0.78 | (0.54, 1.13) | 0.64 | (0.44, 0.94) |
| III | 0.80 | (0.58, 1.10) | 1.04 | (0.63, 1.70) | 0.57 | (0.30, 1.09) | 0.73 | (0.41, 1.31) |
| IV | 1.46 | (0.78, 2.71) | 2.33 | (1.07, 5.07) | 1.04 | (0.29, 3.74) | - | - |
| Treatment f | ||||||||
| Surgery only | Reference | Reference | Reference | Reference | ||||
| Surgery and radiation | 1.14 | (0.91, 1.43) | 1.29 | (0.91, 1.85) | 1.05 | (0.69, 1.58) | 1.01 | (0.67, 1.54) |
| Surgery, radiation and chemotherapy | 0.86 | (0.49, 1.51) | 0.85 | (0.37, 1.95) | 1.37 | (0.60, 3.15) | 0.26 | (0.04, 1.54) |
| Surgery and chemotherapy | 1.50 | (0.88, 2.58) | 1.90 | (0.96, 3.76) | 1.67 | (0.61, 4.55) | 0.57 | (0.08, 1.54) |
| Other* | 1.54 | (0.56, 4.19) | 1.11 | (0.27, 4.56) | 3.65 | (0.84, 15.87) | - | - |
| Surgery f | ||||||||
| Yes | 0.67 | (0.25, 1.83) | 0.98 | (0.24, 4.00) | 0.28 | (0.06, 1.22) | - | - |
| No | Reference | Reference | Reference | Reference | ||||
| Chemotherapy f | ||||||||
| Yes | 1.14 | (0.78, 1.66) | 1.27 | (0.77, 2.11) | 1.56 | (0.84, 2.91) | 0.34 | (0.08, 1.40) |
| No | Reference | Reference | Reference | Reference | ||||
| Baseline CCI g | ||||||||
| 0 | Reference | Reference | Reference | Reference | ||||
| 1 | 0.91 | (0.70, 1.18) | 0.72 | (0.47, 1.12) | 1.14 | (0.74, 1.76) | 0.95 | (0.57, 1.58) |
| 2+ | 1.20 | (0.82, 1.76) | 0.73 | (0.39, 1.37) | 2.06 | (1.18, 3.62) | 1.10 | (0.40, 3.03) |
| P trend | 0.773 | 0.126 | 0.026 | 0.986 | ||||
Adjusted for BMI, CCI, race, cancer stage, and year of diagnosis
Adjusted for BMI, CCI, race, and endometrial cancer type
Adjusted for CCI, race, age at diagnosis
Adjusted for BMI, CCI, race, age at diagnosis, endometrial cancer type, year of diagnosis, and age at diagnosis
Adjusted for BMI, CCI, race, age at diagnosis, year of diagnosis, and histology
Adjusted for BMI, CCI, race, age at diagnosis, and year of diagnosis
Adjusted for race, age at diagnosis, and year of diagnosis
Includes radiation only, chemotherapy only and radiation & chemotherapy
When stratified by BMI, endometrial cancer survivors at normal BMI had higher risks for diabetes and type 2 diabetes compared to the general population across all four time periods (Table 5). Within the normal BMI group, the average baseline BMI before imputation were significantly different between endometrial cancer survivors (median=22.8, mean=22.5, standard deviation [SD] =1.75) and women (median=22.3, mean=22.2, SD=1.71) in the general population (t (3679) =−4.46, p < 0.0001). Overweight women in the endometrial cancer survivor cohort also had higher risks for all diabetes and type II diabetes overall, in the 0–1 year and 1–5 years follow up time periods. Overall, the highest HRs for all diabetes and type II diabetes were observed in the first year after cancer diagnosis, with 4 to 5-fold higher risks for diabetes among endometrial cancer survivors compared to the general population.
Table 5.
Diabetes risk stratified by baseline BMI among endometrial cancer survivors compared to the general population, by years since cancer diagnosis
| Normal | Overweight | Obese | ||||
|---|---|---|---|---|---|---|
| HR | (95% CI) | HR | (95% CI) | HR | (95% CI) | |
| Overall | ||||||
| Diabetes mellitus | 1.75 | (1.43, 2.14) | 1.82 | (1.53, 2.17) a | 1.98 | (1.70, 2.31) a |
| Type II | 1.97 | (1.53, 2.55) | 1.94 | (1.56, 2.41) a | 2.06 | (1.72, 2.46)a |
| 0–1 year | ||||||
| Diabetes mellitus | 4.03 | (2.44, 6.64) a | 4.81 | (3.30, 7.00) a | 5.64 | (3.90, 8.15) a |
| Type II | 3.91 | (2.21, 6.92) a | 5.32 | (3.49, 8.10) a | 5.60 | (3.72, 8.43) a |
| >1–5 years | ||||||
| Diabetes mellitus | 1.45 | (1.00, 2.09) | 1.67 | (1.23, 2.26) | 1.56 | (1.23, 1.99) |
| Type II | 1.73 | (1.10, 2.72) | 1.64 | (1.13, 2.39) | 1.44 | (1.08, 1.91) |
| >5 years | ||||||
| Diabetes mellitus | 1.58 | (1.19, 2.09) | 1.24 | (0.94, 1.64) | 1.41 | (1.10, 1.81) |
| Type II | 1.70 | (1.16, 2.48) | 1.12 | (0.76, 1.66) | 1.57 | (1.16, 2.14) |
Adjusted for CCI, race, age at diagnosis, birth state, birth year
Proportional hazard assumption was violated; HRs are from Cox models with cubic splines
Stratified analyses for the risk of diabetes among endometrial cancer patients for Hispanic and non-Hispanic white women are shown in supplementary Table 3B and Table 3C. Although the sample size was small, among Hispanic individuals, endometrial cancer survivors had a high risk of diabetes overall (HR=4.97, 95%CI=1.16, 21.30) compared to the general population (Supplementary Table 3A). Among Non-Hispanic White individuals, endometrial cancer survivors had higher risks for overall diabetes and type II diabetes across all four time periods and other diabetes overall and in the 0–1 year periods compared to the general population (Supplementary Table 3B). There was not a statistically significant difference in these risk among Hispanic endometrial cancer survivors compared to non-Hispanic white endometrial cancer survivors.
Discussion
We observed that endometrial cancer survivors had increased risks of developing both type I and II diabetes after cancer diagnosis compared to women in the general population. The highest diabetes risks were observed within the first year after cancer diagnosis, and risks persisted throughout the follow up period. The highest risk of diabetes within the first year may be associated with medical surveillance before and after cancer treatment. Hwang et al. [19] also reported that the strongest risk of diabetes was among cancer patients in the first 2 years after cancer diagnosis, but the association was not significant (HR=1.17, 95%CI=0.77, 1.76) among endometrial cancer survivors. However, our study supports the hypothesis that endometrial cancer diagnosis is associated with a higher risk of developing diabetes. Prior studies reported on the association between diabetes history and the subsequent risk of endometrial cancer [13–18], but very few studies evaluated risk of diabetes after cancer diagnosis.
Among endometrial cancer survivors, overweight/obesity was a strong risk factor for type II diabetes as expected, with a dose-response relation across all follow up periods. Our results support previous findings that overweight/obesity is an important risk factor for diabetes in the general population [25, 26]. Later cancer stage, higher CCI score, and higher cancer grade were also suggested as risk factors for type II diabetes in our study, but only in select follow up periods. The increased risk of diabetes among higher stage/grade cancer patients may be associated with cancer treatment.
Paclitaxel/carboplatin, one of the most common chemotherapy combinations for endometrial cancer [27] may induce hyperglycemia [28]. In addition, medications to manage side effects resulting from chemotherapy may also induce hyperglycemia [29]. However, our results suggest that there is no association between cancer treatment and the risk of type II diabetes among endometrial cancer survivors. Age at diagnosis of endometrial cancer and family history of diabetes were not significant risk factors for type II diabetes. Although family history of diabetes has been associated with diabetes risk in general populations [30], it was not associated with diabetes risk among endometrial cancer survivors in our study.
In stratified analysis by BMI, higher risk for diabetes was observed among cancer survivors compared to the general population cohort in all BMI groups throughout the follow up periods. The highest risk for diabetes were observed immediately after cancer diagnosis within the first year in all BMI groups but surveillance after a cancer diagnosis. The association persisting in the later follow up years suggests that the diagnosis of endometrial cancer is associated with diabetes risk regardless of BMI groups. Thus, even if endometrial cancer patients were at normal BMI at diagnosis, they had a higher risk of diabetes than women from the general population who are of similar age. Perhaps this observation is due to residual confounding within the normal BMI subgroup since the BMI was slightly higher among endometrial cancer patients within the normal BMI subgroup. Our results suggest that monitoring endometrial cancer patients for diabetes is important over the long-term. Further, it is crucial that healthcare providers are aware of the increased diabetes risk even if the endometrial cancer patient’s body weight is within normal range.
The potential biological mechanisms between diabetes and cancers have been discussed in previous studies. The insulin-cancer hypothesis postulates that endometrial cancer cell proliferation is activated by chronic insulin resistance (i.e. reduced sensitivity of insulin-responsive tissues to insulin) [31] and its risk factors such as inflammatory mediators, adipokines, and excessive androgens. Even though endometrial cancer is not directly correlated with insulin, the increased level of insulin may result in adverse effects including cancer cell proliferation [32]. Another potential mechanism is that obesity and diabetes alter the regulation of sex hormones including estrogen which activates IGF-1 receptor on endometrial cancer cells and enhances cellular proliferation [31]. Diabetes could also advance tumorigenesis by increases in pro-inflammatory cytokines (e.g. interleukin (IL)-6 and tumor necrosis factor (TNF)-α), which mediate the increase in dysregulation of metabolic pathways resulting in insulin resistance and inflammatory response [33].
To our knowledge, this study is the first study that examined risk of subsequent diabetes after endometrial cancer diagnosis in comparison with a general population. Our study has many strengths, including the population-based study design with a very large cohort of approximately 2,300 endometrial cancer survivors and 8,500 women from the general population. Another strength of this study is the long follow-up period, which was >5 years for the majority of our study sample. Diabetes diagnoses were ascertained via medical records from the two largest healthcare providers in Utah, statewide inpatient hospital and ambulatory surgery records, which reduces recall errors due to self report and survival bias which is often an issue in cancer survivor cohorts. In addition, Utah has a small percentage of residents who seek health care out of state and a low out migration rate [20, 21]. Although the number of women diagnosed with type I diabetes was small, this is reflective of the general population which is expected to have very low type I diabetes prevalence (0.6%, 95%CI=0.5, 0.8) among individuals ≥45 years. Specifically, they reported that the weighted prevalence (%, 95%CI) for type I diabetes were 0.5 (0.3, 0.6), 0.6 (0.4, 0.7), and 0.6 (0.5, 0.8) in 20–44 aged, 45–64 aged, and ≥65 aged adults in the United States [34].
This study had several limitations such as possible errors in ICD coding and missing less severe cases of diabetes. The sensitivity (88.6%) and specificity (90.9%) using EMR and statewide healthcare databases to identify diabetes diagnoses among endometrial cancer patients in the study was fairly high [4]. Because we used ICD-9 codes and medical records as the source for diabetes diagnosis, we cannot eliminate the possibility of coding errors, although we would not expect such errors to be differential in cancer patients and the general population. We did not have details on pre-diabetic diagnoses because we used medical record ICD codes as the source for diabetes diagnosis. Additionally, the women in the study may have been diagnosed with diabetes in hospitals not covered by our data sources. However, approximately 99.6% of the endometrial cancer patients and 98.5% of the general population cohort did have records in these data sources, particularly since we have statewide coverage for inpatient stays and ambulatory surgery [4]. Another limitation was the missing baseline BMI for some of our study subjects. Approximately 27% of all participants had missing baseline BMI, which were imputed. However, we assured that the inferences did not change due to the BMI imputation. Similarly, we had limited information about cancer treatment, thus we could not investigate associations between specific treatment agents and diabetes among endometrial cancer survivors. Potential confounders such as physical activity, diet, and levels of stress were not assessed, although BMI may act as a proxy for physical activity. Lastly, endometrial cancer survivors may be more likely to be diagnosed with diabetes during cancer treatment and follow up period due to surveillance bias. However, the association between endometrial cancer and diabetes risk persisted in the later follow up years (>5 years) at a time point where medical surveillance is recommended to return to that of the general population.
While few studies examined the risk of subsequent diabetes after endometrial cancer and their mechanism, the importance of preventing and managing diabetes among cancer survivors has been suggested in previous studies. Diabetes is not only associated with an increased mortality rate among endometrial cancer survivors [8, 9, 35], but it may also affect the efficacy of chemotherapy among cancer patients [36]. Diabetes diagnosis may also increase the risk of infections [37], which in turn may affect the cancer treatment plan. In particular, cancer patients with diabetes were less likely to self-manage their diabetes through exercise, diet, monitoring blood sugar when receiving chemotherapy [38].
Even though the prognostic impact of higher BMI on endometrial cancer survival has been conflicting, a meta-analysis including 665,694 endometrial cancer patients from 18 studies reported an elevated all-cause mortality rate in obese women with a dose-response relationship [39]. Physical activity was also associated with lower all-cause 5-year mortality [35]. Physical activity and better adherence to lifestyle recommendations (i.e. physical activity, diet, smoking) played a significant role in improving the health-related quality of life measured by the RAND 36 health status inventory (p < 0.001) among endometrial cancer survivors [40].
In conclusion, endometrial cancer survivors had a higher long-term risk of type I and II diabetes compared to women in the general population. Obesity was the strongest risk factor for diabetes among endometrial cancer survivors. Although endometrial cancer patients diagnosed at distant stage had a higher risk of diabetes, cancer treatment did not appear to contribute to any diabetes risks. These findings emphasize the importance of obesity intervention and diabetes prevention and long-term monitoring strategies among endometrial cancer survivors.
Supplementary Material
Highlights.
Endometrial cancer survivors in all BMI groups had an increased risk of diabetes.
29.5% of endometrial cancer patients were diagnosed with diabetes after diagnosis of endometrial cancer.
Obesity was the most important risk factor for type II diabetes among endometrial cancer survivors.
Overall, endometrial cancer survivors had a twofold higher risk of type II diabetes compared to the general population.
Acknowledgements
This work was supported by grants from the NIH (R21 CA185811, R03 CA159357; M.Hashibe, PI), the Huntsman Cancer Institute, Cancer Control and Population Sciences Program (HCI Cancer Center Support Grant P30CA042014), and a NCRR grant (R01 RR021746, G. Mineau, PI) with additional support from the Utah State Department of Health and the University of Utah. We thank the Pedigree and Population Resource of the Huntsman Cancer Institute, University of Utah (funded in part by the Huntsman Cancer Foundation) for its role in the ongoing collection, maintenance and support of the Utah Population Database (UPDB). We also acknowledge partial support for the UPDB through grant P30 CA2014 from the National Cancer Institute, University of Utah and from the University of Utah’s Program in Personalized Health and Center for Clinical and Translational Science. We thank the University of Utah Center for Clinical and Translational Science (CCTS) (funded by NIH Clinical and Translational Science Awards), the Pedigree and Population Resource, University of Utah Information Technology Services and Biomedical Informatics Core for establishing the Master Subject Index between the Utah Population Database, the University of Utah Health Sciences Center and Intermountain Health Care.
Footnotes
Disclosure of Potential Conflicts of Interest
No potential conflicts of interest were disclosed.
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