RESEARCH ARTICLE For reprint orders, please contact: [email protected]
USA Endometrial Cancer Projections to 2030: should we be concerned? M Aamir Sheikh1, Andrew D Althouse1, Kyle E Freese1,2, Sean Soisson3, Robert P Edwards1, Sharon Welburn2, Paniti Sukumvanich4, John Comerci4, Joseph Kelley4, Ronald E LaPorte2 & Faina Linkov*,1,2 ABSTRACT Aim: As the incidence of endometrial cancer (EC) increased considerably since 2007, this study aimed to project the burden of EC to the year 2030. Methods: Multivariate linear regression was used to project EC incidence by modeling trends in EC incidence from 1990 to 2013, while accounting for temporal changes in obesity, hysterectomy and smoking. Results: The best-fitting model predicting EC rates included a time effect plus effects for hysterectomy (12-year lag), severe obesity (3-year lag) and smoking (9-year lag). The bestfitting model projected an increase to 42.13 EC cases per 100,000 by the year 2030, a 55% increase over 2010 EC rates. Conclusion: The projected increase of EC over next 16 years indicates the need for close monitoring of EC trends. Background The incidence and mortality from adenocarcinoma of the endometrium is on the rise in developed nations [1] . The American Cancer Society (ACS) estimated that there will be approximately 52,630 new cases of endometrial cancer (EC) in 2014, and over 8590 women will die from this disease [2] , making it the most common female genital tract malignancy and the fourth most common cancer in US women. Obesity is an independent risk factor for EC development [3] and it increases the risk of EC more than it does for other cancers [4–7] . Studies have consistently shown that both pre- and post-menopausal women with EC are more likely to be overweight than other women [8] . Previous research has demonstrated 4–11-fold increases in the relative risk of EC for severely obese women compared with those with a normal BMI [9] . Current adiposity, advanced age, excess weight at the age of 18, metabolic syndrome and adult weight gain are all associated with substantial increases in EC risk [10–13] . Physical inactivity has also been found to be an independent risk factor associated with EC development [14] . Additional factors explored in relationship to EC development include parity, oral contraceptive use, unopposed estrogen therapy, early menarche, late menopause, PCOS and diabetes [15,16] . Cigarette smoking was found to be significantly associated with a reduced risk of EC, especially among postmenopausal women [17] , presumably due to enhanced estrogen metabolism in smokers. For EC, it is likely that there is more than one system involved linking obesity and cancer predisposition [18] . The ‘unopposed estrogen hypothesis’ of EC development posits that increased exposure to endogenous or exogenous estrogen that is not opposed by progesterone explains the relationship between obesity and EC risk [19–22] ; however, additional mechanisms have been implicated
KEYWORDS
• endometrial cancer • future projections • incidence • obesity • prevention
Department of OB/GYN & Reproductive Sciences, Magee-Womens Research Institute, University of Pittsburgh School of Medicine, M240 Scaife Hall, 3550 Terrace St, Pittsburgh, PA 15261, USA 2 Department of Epidemiology, University of Pittsburgh Graduate School of Public Health, 130 De Soto St, Pittsburgh, PA 15261, USA 3 Department of Genetic Epidemiology/Division of Public Health, University of Utah, Salt Lake City, UT 84112, USA 4 Department of OB/GYN, Division of Gynecologic Oncology, University of Pittsburgh Medical Center, 200 Lothrop St, Pittsburgh, PA 15213, USA *Author for correspondence: Tel.: +1 412 641 2501; Fax: +1 412 641 6241; [email protected] 1
10.2217/FON.14.192 © 2014 Future Medicine Ltd
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Research Article Sheikh, Althouse, Freese et al. in EC development in recent literature. Kaaks et al. suggested that alterations in endogenous hormone metabolism might provide the main links between EC risk, and excess body weight and physical inactivity [23] . Recent prospective research suggests three major mechanisms leading to EC, including inflammatory, insulin and steroid hormone pathways [24] . Out of all uterine cancer cases reported in 2012, the ACS estimates that only 3% were sarcomas, the rest being carcinomas, which are divided into two types. Type I endometrial carcinomas are typically associated with obesity (50% of affected women are obese [25]) and are estrogen dependent. Type II endometrial carcinomas include papillary serous, clear cell and other histological types. Although they are not completely estrogen independent as previously believed [15] , they tend to be more rare and aggressive than Type I carcinomas. Type I ECs are typically low grade and associated with less aggressive histopathological features [25] . Previously published literature identified differences in risk factors leading to the development of Type II (nonobesity associated, 10–20% of cases) versus Type I endometrial tumors [26–29] . Lower lifetime estrogen exposure reduces a woman’s risk of developing Type I endometrial tumors. This protective factor has been observed among women with reproductive factors such as late menarche, early menopause, prior oral contraceptive pill (OCP) use, high parity and shorter time since last full-term pregnancy [30] . Unopposed hormone replacement therapy (estrogen only) and tamoxifen treatment have also been linked to increased risk for Type I EC [31] . Increases in the rates of EC in the past decade was mainly driven by increases in Type I tumors [32] . Obesity is on the rise and reaching epidemic proportions in the USA [33] . Obesity could be an important contributor to the increase in the number of obesity-associated malignancies, such as EC [34] . It is estimated that 70–90% of EC patients are overweight or obese, with obese women (BMI >30 kg/m2) having a threefold increased risk due to excessive circulating estrogen [35,36] . Crosbie et al. reported that for every 5 kg/m2 increase in BMI, women had a 1.6-fold increased risk of EC so that at a BMI of 42 kg/m2, affected women would have a ninefold increased risk of EC compared with normal weight women [9] . Because advancing age is an established risk factor for EC, EC incidence and mortality rates
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in the USA over time may be affected by aging of the population. The US’ population is expected to increase to approximately 365 million by 2030 and will include 72 million older adults (age ≥65 years) [37] . Since 76% of Type I EC patients are postmenopausal [28] , the increased proportion of older adults in the total population may play an important role in increasing EC rates. Many studies worldwide have attempted to project future incidence and prevalence of cancer; for example, Bray et al. projected the future burden of cancer in the United Kingdom using a model of prevalence as a function of incidence, survival and population demographics [38] . To our knowledge, there are no existing projections of future EC rates. In this study, we will explore how changes in obesity prevalence can predict changes in EC incidence over time, with time lags of varying length considered to evaluate how many years pass before changes in obesity rates are reflected in EC incidence. A similar approach will be taken into account for changes in the rate of hysterectomy and smoking, as they are important factors that may potentially influence the population risk of EC. Specifically, correcting the incidence rate for hysterectomy prevalence provides more accurate estimates of EC risk over time [39] . The overarching goal of this investigation is to estimate the incidence of EC in the USA through the year 2030 while accounting for past and projected changes in populationlevel confounders that may influence EC rates. Methods & materials Multivariate linear regression models were used to project EC incidence through the year 2030 while incorporating population-level changes in obesity prevalence, smoking prevalence, hysterectomy rates and the age composition of the population. EC rates per 100,000 females from 1990 to 2013 (Table 1) formed the basis of our model (site code: ICD-O-3 C54.0, C54.1, C54.2, C54.3, C54.8, C54.9 and C55.9). EC rates and US population data (including data on expected population growth) were obtained from the National Institute of Health (NIH), Surveillance Epidemiology and End Results program (SEER-9, data coverage 1973– 2010) and the US Census Bureau [40] . The proportion of females over age 65 was used as proxy for the aging population. Estimated obesity rates from 1970 to 2008 [41] , smoking rates from 1974 to 2009 [42] and hysterectomy rates from 1970
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USA Endometrial Cancer Projections to 2030
Research Article
Table 1. Endometrial cancer incidence from 1990 to 2013. Year
EC incidence
Rate per 100,000
1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013
33,000 33,000 32,000 31,000 31,000 32,800 34,000 34,900 36,100 37,400 36,100 38,300 39,300 40,100 40,320 40,880 41,200 39,080 40,100 42,160 43,470 46,470 47,130 49,560
25.88 25.54 24.50 23.48 23.25 24.38 25.05 25.47 26.11 26.82 25.17 26.39 26.84 27.15 27.06 27.19 27.15 25.51 25.93 27.03 27.69 29.89 29.56 31.08
Source: US’ female population collected from United States Census Bureau; endometrial cancer incidences obtained from the yearly Cancer Statistics by the National Cancer Institute.
to 2010 [43–47] were also evaluated as potential predictors of EC incidence from 1990 to 2013. Both ‘obesity rate’ (BMI >30 kg/m2) and ‘severe obesity rate’ (BMI >40 kg/m2) were considered as potential predictors. Since there may be a delay between population changes in these factors and their respective influence on EC rates, potential time lag was considered for each factor as we developed the best-fitting model. Projecting EC rates required future projection of the EC risk factors as well, although not all data through 2030 were needed due to the time lag imposed for each variable. Obesity projections from the Behavioral Risk Factor Surveillance System (BRFSS) data [41] were used as to populate the estimated rates of obesity and severe obesity through 2030. Recent projections suggest that smoking rates have roughly stabilized, so we assumed a smoking rate of 18.5% being stable over next two decades. Hysterectomy rates have slightly declined in recent years [46] but in the absence of better information were assumed to remain consistent at 261 per 100,000 (rate in 2010, the last year for which data were available).
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The best-fitting model was defined as the multivariate model with the greatest adjusted R 2 with a time effect and some combination of the aforementioned candidate variables. Every possible time lag was evaluated for each of the candidate variables in our modeling in 1-year increments from 1 to 19 years (i.e., model candidate variables included: severe obesity prevalence with 1-year time lag, 2-year time lag…19-year time lag; smoking prevalence with 1-year time lag, 2-year time lag … 19-year time lag; hysterectomy rate with 1-year time lag, 2-year time lag…19-year time lag). The combination of factors, which produced the best-fitting model for the 1990–2013 data, was selected as the final model. Severe obesity rates were found to better predict 1990–2013 EC incidence and thus were selected for use in the final modeling instead of regular obesity rates. The final best-fitting model projecting EC rates from 1990 to 2013 incorporated severe obesity prevalence (3-year time lag), hysterectomy rates (12-year time lag) and smoking prevalence (9-year time lag). When adjusting for time and these variables, the proportion of females over age 65 years did not add significant
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Projected EC incidence =
predictive value and thus was not included in our final model. According to the final best-fitting model, the predicted value for EC incidence per 100,000 in a given year from 2014 to 2030 is as follows:
50.209–0.688 * (year – 1970) + 4.198 * (severe obesity prevalence 3 years prior) – 0.005 * (hysterectom ies/100, 000 12 years prior) – 0.425 * (sm oking prevalence 9 years prior)
For example, the projected EC incidence in 2020 would be calculated using the following equation: Projected 2020 EC incidence = 50.209–0.688 * (2020 – 1970) + 4.198 * (severe obesity prevalence in 2017) – 0.005 * (hysterectom ies/100, 000 in 2008) – 0.425 * (sm oking prevalence in 2011)
We also produced a 95% prediction interval from this equation, which can be used to generate a more optimistic projection (lower bound of the interval) and a more pessimistic projection (upper bound of the interval). As a secondary check of model fit, we compared the model’s fitted values against actual EC rates for years 1990–2013; the observed and expected rates fell within 1 case per 100,000 of each other in 20 of the 24 years for which we had EC data, and none of the models’ projected yearly rates varied by more than 1.5 cases per 100,000 from the actual EC rate for that year. Thus, assuming that projected smoking, obesity and hysterectomy data
are reasonably accurate, we are confident that this model will accurately project future EC rates barring major shifts in prevention strategy or changes in diagnostic criteria. Results The projected EC incidence is expected to reach 35 cases per 100,000 women by 2020 and over 42.13 cases per 100,000 women by 2030 (95% prediction interval: 35.24, 49.04 cases per 100,000). That represents a 55% increase over 2010 rates of EC. The final model incorporated a time effect plus severe obesity rates (3-year lag), smoking rates (9-year lag) and hysterectomy rates (12-year lag) to predict EC rates from 2014 to 2030; the results of this model are shown in Table 2 along with lower and upper bounds for a 95% prediction interval (Figure 1) . This projected increase in EC rates is principally driven by the projected increase in severe obesity prevalence by 2030; each 1% increase in the rate of severe obesity is associated with a projected increase of 4.19 EC cases per 100,000. Smoking and hysterectomy rates have statistically significant negative relationships with EC incidence, but these are modest effects compared with the effect of obesity. Discussion EC incidence is expected to rise sharply over the next decade. Our projections indicate that there will be an estimated 42.13 incident cases of EC
Table 2. Projected rates of endometrial cancer incidence from 2014 to 2030.
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Year
Projected EC rate per 100,000 females
Lower bound for projected EC rate per 100,000 females
Upper bound for projected EC rate per 100,000 females
2014 2015 2016 2017 2018 2019 2020 2021 2022 2023 2024 2025 2026 2027 2028 2029 2030
31.85 32.66 33.53 33.71 34.35 34.94 35.68 36.31 37.14 37.72 38.29 38.86 39.43 40.00 40.99 41.56 42.13
29.96 30.64 31.37 31.12 31.47 31.76 32.22 32.55 33.12 33.36 33.60 33.83 34.06 34.29 34.79 35.01 35.24
33.73 34.68 35.69 36.30 37.24 38.13 39.13 40.07 41.17 42.07 42.97 43.88 44.80 45.71 47.20 48.11 49.04
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USA Endometrial Cancer Projections to 2030
Cases per 100,000 females
60 55
Projected Lower bound Upper bound
Actual EC rates 1990–2013
50
Research Article
Projected EC rates 2014–2030
45 40 35 30 25 20 1990
1995
2000
2005
2010
2015
2020
2025
2030
Year
Figure 1. Past and projected endometrial cancer rates per 100,000.
per 100,000 women by the year 2030, a 55% increase over 2010 rates (27.03 cases per 100,000 women). An optimistic projection (lower bound of the 95% prediction interval) estimates an increase by 2030 to 35.24 cases per 100,000 women, while a pessimistic projection (upper bound of the 95% prediction interval) suggests that by 2030 incidence could be as high as 49.04 cases per 100,000 women, an 81% increase over 2010 rates. EC incidence in the past has shown an irregular trajectory, which can be attributed to many factors such as the introduction of unopposed hormone replacement therapy for breast cancer treatment in the 1970s [32] . The use of unopposed hormone replacement therapy sharply increased the incidence of EC in 1970s [48] . Later, due to an increase in the number of women who underwent hysterectomy from the 1980s to 2006, there was a rapid decline in the incidence of EC [49] . Our findings are consistent with the fact that over the past several years the incidence and mortality associated with EC have been on the rise [32] . We expected to see a relationship between the increasing percentage of older US population [50] and an increase in projected EC rates based on previous research. However, our data did not show this, most likely because of collinearity between the increasing age of the population and increasing obesity rates over time masking the effects of the aging population. Although our results did not show a significant relationship between the aging population and EC rates, it cannot be ruled out. A projection study done by
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Smith et al. concluded that the overall cancer incidence for older adults is due to increase by 67% by 2030, compared with the year 2010. Since approximately 70% of all EC incidence occurs after the age of 50, we believe that this portion of the US population will also influence future EC rates [51] . In addition to the aging population, we used the study by Finkelstein et al. to generate the obesity estimates in this paper estimated that by 2030, 51% of the US population would be obese and 11% will be severely obese [41] . Since EC has been linked to obesity in many studies, the obesity endemic is also likely to increase EC incidence, a belief supported by the models presented in this paper. With increasing number of smoking prevention campaigns, including smoking restriction at workplaces, it is possible that smoking will be further decreased over the next two decades. While overall smoking reduction is good for health on population level, it might result in increased EC rates, something that our healthcare systems must be prepared for. EC is associated with high cost treatment modalities that mainly includes surgery, but may also include chemotherapy, hormonal therapy and radiation therapy. EC patients and survivors also rely on the expertise of many different health practitioners to treat other obesityassociated comorbid conditions, including heart disease and diabetes. The NCI estimates that expenditures relating to EC in the USA in the middle of the last decade totaled US$1.8 billion [52] . For the same time period, it was estimated that the total cost of treating obesity in the USA
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Research Article Sheikh, Althouse, Freese et al. was just under US$170 billion [53] . Therefore, projections of both obesity and EC indicate that costs are likely to increase dramatically by 2030. The projected surge in EC incidence is driven primarily by obesity, so weight loss interventions are the first logical step in mitigating the projected increases. Weight loss interventions such as bariatric surgery have also been linked with reversal of endometrial hyperplasia [54,55] . In addition, the use of intrauterine device (IUD) is one of the most widely used forms of contraception throughout the world and its use has been linked to decreased EC risk [56] . Furthermore, intrauterine progesterone delivered through IUD appears to eradicate some cases of presumed stage IA, grade 1 endometrioid cancer [57] . Also, the use of the combined oral contraceptive pill is associated with a decreased risk of EC [58] . Clearly, additional research should investigate these mitigating factors in relation to EC. While we have attempted to account for future effects of population trends in obesity, smoking and hysterectomy, it is necessary to understand that this model does not incorporate some other factors that may affect the rate of EC, such as new forms of diagnosis and/or prevention, the emergence of other risk factors or changes in the frequency of women who receive hysterectomies for benign diagnoses, which has been shown to complicate interpretation of the actual rates of EC [49] . Therefore, one of the limitations of our model is that it depends on the assumption that the aforementioned factors will not substantially affect EC incidence and the accuracy of projections for smoking, obesity and hysterectomy that we have incorporated into the modeling. While the results presented here are projections, they emphasize the fact that preventive
efforts to control obesity and obesity-associated malignancies, such as EC, postmenopausal breast cancer, and many others, must be at the forefront of research and medical practice in order to reduce the burden on the healthcare community and the population as a whole. While our data analysis for was limited to EC rates in the US and may not be generalizable to all nations, it should be noted that EC is a growing problem globally [59] and that these rates may portend increases elsewhere as well. Assessing the future of cancer incidence and the mortality rates is essential to formulate a strategy to effectively manage this disease in the upcoming years. From apportioning resources for screening, diagnostic and therapeutics to prevention, having accurate projections can help transform the way we manage cancer [38,60] . Future perspective The drastic increase in EC incidence over the past 7 years fueled by the ongoing obesity epidemic and aging of the US population indicates the need for close monitoring of EC trends. Apart from spreading awareness of this malignancy and its association with severe obesity, there is an urgent need to develop EC risk monitoring, management and prevention techniques over the next two decades. Financial & competing interests disclosure The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
EXECUTIVE SUMMARY ●●
The incidence and mortality from endometrial cancer (EC) is on the rise in developed nations.
●●
Obesity is one of the key risk factors associated with EC.
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This study suggests that EC incidence is expected to rise sharply over the next decade.
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Our projections indicate that there will be an estimated 42.13 incident cases of EC per 100,000 women by the year 2030, a 55% increase over 2010 rates (27.03 cases per 100,000 women).
●●
An optimistic projection (lower bound of the 95% prediction interval) estimates an increase by 2030 to 35.24 cases per 100,000 women, while a pessimistic projection (upper bound of the 95% prediction interval) suggests that by 2030 incidence could be as high as 49.04 cases per 100,000 women, an 81% increase over 2010 rates.
●●
Assessing the future of cancer incidence and the mortality rates is essential to formulate a strategy to effectively manage this disease in the upcoming years.
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USA Endometrial Cancer Projections to 2030 No writing assistance was utilized in the production of this manuscript.
Ethical conduct disclosure The authors state that they have obtained appropriate
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Hormone receptor expression patterns in the endometrium of asymptomatic morbidly obese women before and after bariatric surgery. Gynecol. Oncol. 133(1), 78–82 (2014). 56 Benshushan A, Paltiel O, Rojansky N,
Brzezinski A, Laufer N. IUD use and the risk of endometrial cancer. Eur. J. Obstet. Gynecol. Reprod. Biol. 105(2), 166–169 (2002). 57 Montz FJ, Bristow RE, Bovicelli A, Tomacruz
R, Kurman RJ. Intrauterine progesterone treatment of early endometrial cancer. Am. J. Obstet. Gynecol. 186(4), 651–657 (2002). 58 Purdie DM, Green AC. Epidemiology of
endometrial cancer. Best Pract. Res. Clin. Obstet. Gynaecol. 15(3), 341–354 (2001). 59 Sankaranarayanan R, Ferlay J. Worldwide
burden of gynaecological cancer: the size of the problem. Best Pract. Res. Clin. Obstet. Gynaecol. 20(2), 207–225. (2006). 60 Mistry M, Parkin DM, Ahmad AS, Sasieni P.
Cancer incidence in the United Kingdom: projections to the year 2030. Br. J. Cancer 105(11), 1795–1803 (2011).
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USA Endometrial Cancer Projections to 2030: should we be concerned? M Aamir Sheikh1, Andrew D Althouse1, Kyle E Freese1,2, Sean Soisson3, Robert P Edwards1, Sharon Welburn2, Paniti Sukumvanich4, John Comerci4, Joseph Kelley4, Ronald E LaPorte2 & Faina Linkov*,1,2 ABSTRACT Aim: As the incidence of endometrial cancer (EC) increased considerably since 2007, this study aimed to project the burden of EC to the year 2030. Methods: Multivariate linear regression was used to project EC incidence by modeling trends in EC incidence from 1990 to 2013, while accounting for temporal changes in obesity, hysterectomy and smoking. Results: The best-fitting model predicting EC rates included a time effect plus effects for hysterectomy (12-year lag), severe obesity (3-year lag) and smoking (9-year lag). The bestfitting model projected an increase to 42.13 EC cases per 100,000 by the year 2030, a 55% increase over 2010 EC rates. Conclusion: The projected increase of EC over next 16 years indicates the need for close monitoring of EC trends. Background The incidence and mortality from adenocarcinoma of the endometrium is on the rise in developed nations [1] . The American Cancer Society (ACS) estimated that there will be approximately 52,630 new cases of endometrial cancer (EC) in 2014, and over 8590 women will die from this disease [2] , making it the most common female genital tract malignancy and the fourth most common cancer in US women. Obesity is an independent risk factor for EC development [3] and it increases the risk of EC more than it does for other cancers [4–7] . Studies have consistently shown that both pre- and post-menopausal women with EC are more likely to be overweight than other women [8] . Previous research has demonstrated 4–11-fold increases in the relative risk of EC for severely obese women compared with those with a normal BMI [9] . Current adiposity, advanced age, excess weight at the age of 18, metabolic syndrome and adult weight gain are all associated with substantial increases in EC risk [10–13] . Physical inactivity has also been found to be an independent risk factor associated with EC development [14] . Additional factors explored in relationship to EC development include parity, oral contraceptive use, unopposed estrogen therapy, early menarche, late menopause, PCOS and diabetes [15,16] . Cigarette smoking was found to be significantly associated with a reduced risk of EC, especially among postmenopausal women [17] , presumably due to enhanced estrogen metabolism in smokers. For EC, it is likely that there is more than one system involved linking obesity and cancer predisposition [18] . The ‘unopposed estrogen hypothesis’ of EC development posits that increased exposure to endogenous or exogenous estrogen that is not opposed by progesterone explains the relationship between obesity and EC risk [19–22] ; however, additional mechanisms have been implicated
KEYWORDS
• endometrial cancer • future projections • incidence • obesity • prevention
Department of OB/GYN & Reproductive Sciences, Magee-Womens Research Institute, University of Pittsburgh School of Medicine, M240 Scaife Hall, 3550 Terrace St, Pittsburgh, PA 15261, USA 2 Department of Epidemiology, University of Pittsburgh Graduate School of Public Health, 130 De Soto St, Pittsburgh, PA 15261, USA 3 Department of Genetic Epidemiology/Division of Public Health, University of Utah, Salt Lake City, UT 84112, USA 4 Department of OB/GYN, Division of Gynecologic Oncology, University of Pittsburgh Medical Center, 200 Lothrop St, Pittsburgh, PA 15213, USA *Author for correspondence: Tel.: +1 412 641 2501; Fax: +1 412 641 6241; [email protected] 1
10.2217/FON.14.192 © 2014 Future Medicine Ltd
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Research Article Sheikh, Althouse, Freese et al. in EC development in recent literature. Kaaks et al. suggested that alterations in endogenous hormone metabolism might provide the main links between EC risk, and excess body weight and physical inactivity [23] . Recent prospective research suggests three major mechanisms leading to EC, including inflammatory, insulin and steroid hormone pathways [24] . Out of all uterine cancer cases reported in 2012, the ACS estimates that only 3% were sarcomas, the rest being carcinomas, which are divided into two types. Type I endometrial carcinomas are typically associated with obesity (50% of affected women are obese [25]) and are estrogen dependent. Type II endometrial carcinomas include papillary serous, clear cell and other histological types. Although they are not completely estrogen independent as previously believed [15] , they tend to be more rare and aggressive than Type I carcinomas. Type I ECs are typically low grade and associated with less aggressive histopathological features [25] . Previously published literature identified differences in risk factors leading to the development of Type II (nonobesity associated, 10–20% of cases) versus Type I endometrial tumors [26–29] . Lower lifetime estrogen exposure reduces a woman’s risk of developing Type I endometrial tumors. This protective factor has been observed among women with reproductive factors such as late menarche, early menopause, prior oral contraceptive pill (OCP) use, high parity and shorter time since last full-term pregnancy [30] . Unopposed hormone replacement therapy (estrogen only) and tamoxifen treatment have also been linked to increased risk for Type I EC [31] . Increases in the rates of EC in the past decade was mainly driven by increases in Type I tumors [32] . Obesity is on the rise and reaching epidemic proportions in the USA [33] . Obesity could be an important contributor to the increase in the number of obesity-associated malignancies, such as EC [34] . It is estimated that 70–90% of EC patients are overweight or obese, with obese women (BMI >30 kg/m2) having a threefold increased risk due to excessive circulating estrogen [35,36] . Crosbie et al. reported that for every 5 kg/m2 increase in BMI, women had a 1.6-fold increased risk of EC so that at a BMI of 42 kg/m2, affected women would have a ninefold increased risk of EC compared with normal weight women [9] . Because advancing age is an established risk factor for EC, EC incidence and mortality rates
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in the USA over time may be affected by aging of the population. The US’ population is expected to increase to approximately 365 million by 2030 and will include 72 million older adults (age ≥65 years) [37] . Since 76% of Type I EC patients are postmenopausal [28] , the increased proportion of older adults in the total population may play an important role in increasing EC rates. Many studies worldwide have attempted to project future incidence and prevalence of cancer; for example, Bray et al. projected the future burden of cancer in the United Kingdom using a model of prevalence as a function of incidence, survival and population demographics [38] . To our knowledge, there are no existing projections of future EC rates. In this study, we will explore how changes in obesity prevalence can predict changes in EC incidence over time, with time lags of varying length considered to evaluate how many years pass before changes in obesity rates are reflected in EC incidence. A similar approach will be taken into account for changes in the rate of hysterectomy and smoking, as they are important factors that may potentially influence the population risk of EC. Specifically, correcting the incidence rate for hysterectomy prevalence provides more accurate estimates of EC risk over time [39] . The overarching goal of this investigation is to estimate the incidence of EC in the USA through the year 2030 while accounting for past and projected changes in populationlevel confounders that may influence EC rates. Methods & materials Multivariate linear regression models were used to project EC incidence through the year 2030 while incorporating population-level changes in obesity prevalence, smoking prevalence, hysterectomy rates and the age composition of the population. EC rates per 100,000 females from 1990 to 2013 (Table 1) formed the basis of our model (site code: ICD-O-3 C54.0, C54.1, C54.2, C54.3, C54.8, C54.9 and C55.9). EC rates and US population data (including data on expected population growth) were obtained from the National Institute of Health (NIH), Surveillance Epidemiology and End Results program (SEER-9, data coverage 1973– 2010) and the US Census Bureau [40] . The proportion of females over age 65 was used as proxy for the aging population. Estimated obesity rates from 1970 to 2008 [41] , smoking rates from 1974 to 2009 [42] and hysterectomy rates from 1970
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USA Endometrial Cancer Projections to 2030
Research Article
Table 1. Endometrial cancer incidence from 1990 to 2013. Year
EC incidence
Rate per 100,000
1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013
33,000 33,000 32,000 31,000 31,000 32,800 34,000 34,900 36,100 37,400 36,100 38,300 39,300 40,100 40,320 40,880 41,200 39,080 40,100 42,160 43,470 46,470 47,130 49,560
25.88 25.54 24.50 23.48 23.25 24.38 25.05 25.47 26.11 26.82 25.17 26.39 26.84 27.15 27.06 27.19 27.15 25.51 25.93 27.03 27.69 29.89 29.56 31.08
Source: US’ female population collected from United States Census Bureau; endometrial cancer incidences obtained from the yearly Cancer Statistics by the National Cancer Institute.
to 2010 [43–47] were also evaluated as potential predictors of EC incidence from 1990 to 2013. Both ‘obesity rate’ (BMI >30 kg/m2) and ‘severe obesity rate’ (BMI >40 kg/m2) were considered as potential predictors. Since there may be a delay between population changes in these factors and their respective influence on EC rates, potential time lag was considered for each factor as we developed the best-fitting model. Projecting EC rates required future projection of the EC risk factors as well, although not all data through 2030 were needed due to the time lag imposed for each variable. Obesity projections from the Behavioral Risk Factor Surveillance System (BRFSS) data [41] were used as to populate the estimated rates of obesity and severe obesity through 2030. Recent projections suggest that smoking rates have roughly stabilized, so we assumed a smoking rate of 18.5% being stable over next two decades. Hysterectomy rates have slightly declined in recent years [46] but in the absence of better information were assumed to remain consistent at 261 per 100,000 (rate in 2010, the last year for which data were available).
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The best-fitting model was defined as the multivariate model with the greatest adjusted R 2 with a time effect and some combination of the aforementioned candidate variables. Every possible time lag was evaluated for each of the candidate variables in our modeling in 1-year increments from 1 to 19 years (i.e., model candidate variables included: severe obesity prevalence with 1-year time lag, 2-year time lag…19-year time lag; smoking prevalence with 1-year time lag, 2-year time lag … 19-year time lag; hysterectomy rate with 1-year time lag, 2-year time lag…19-year time lag). The combination of factors, which produced the best-fitting model for the 1990–2013 data, was selected as the final model. Severe obesity rates were found to better predict 1990–2013 EC incidence and thus were selected for use in the final modeling instead of regular obesity rates. The final best-fitting model projecting EC rates from 1990 to 2013 incorporated severe obesity prevalence (3-year time lag), hysterectomy rates (12-year time lag) and smoking prevalence (9-year time lag). When adjusting for time and these variables, the proportion of females over age 65 years did not add significant
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Research Article Sheikh, Althouse, Freese et al.
Projected EC incidence =
predictive value and thus was not included in our final model. According to the final best-fitting model, the predicted value for EC incidence per 100,000 in a given year from 2014 to 2030 is as follows:
50.209–0.688 * (year – 1970) + 4.198 * (severe obesity prevalence 3 years prior) – 0.005 * (hysterectom ies/100, 000 12 years prior) – 0.425 * (sm oking prevalence 9 years prior)
For example, the projected EC incidence in 2020 would be calculated using the following equation: Projected 2020 EC incidence = 50.209–0.688 * (2020 – 1970) + 4.198 * (severe obesity prevalence in 2017) – 0.005 * (hysterectom ies/100, 000 in 2008) – 0.425 * (sm oking prevalence in 2011)
We also produced a 95% prediction interval from this equation, which can be used to generate a more optimistic projection (lower bound of the interval) and a more pessimistic projection (upper bound of the interval). As a secondary check of model fit, we compared the model’s fitted values against actual EC rates for years 1990–2013; the observed and expected rates fell within 1 case per 100,000 of each other in 20 of the 24 years for which we had EC data, and none of the models’ projected yearly rates varied by more than 1.5 cases per 100,000 from the actual EC rate for that year. Thus, assuming that projected smoking, obesity and hysterectomy data
are reasonably accurate, we are confident that this model will accurately project future EC rates barring major shifts in prevention strategy or changes in diagnostic criteria. Results The projected EC incidence is expected to reach 35 cases per 100,000 women by 2020 and over 42.13 cases per 100,000 women by 2030 (95% prediction interval: 35.24, 49.04 cases per 100,000). That represents a 55% increase over 2010 rates of EC. The final model incorporated a time effect plus severe obesity rates (3-year lag), smoking rates (9-year lag) and hysterectomy rates (12-year lag) to predict EC rates from 2014 to 2030; the results of this model are shown in Table 2 along with lower and upper bounds for a 95% prediction interval (Figure 1) . This projected increase in EC rates is principally driven by the projected increase in severe obesity prevalence by 2030; each 1% increase in the rate of severe obesity is associated with a projected increase of 4.19 EC cases per 100,000. Smoking and hysterectomy rates have statistically significant negative relationships with EC incidence, but these are modest effects compared with the effect of obesity. Discussion EC incidence is expected to rise sharply over the next decade. Our projections indicate that there will be an estimated 42.13 incident cases of EC
Table 2. Projected rates of endometrial cancer incidence from 2014 to 2030.
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Year
Projected EC rate per 100,000 females
Lower bound for projected EC rate per 100,000 females
Upper bound for projected EC rate per 100,000 females
2014 2015 2016 2017 2018 2019 2020 2021 2022 2023 2024 2025 2026 2027 2028 2029 2030
31.85 32.66 33.53 33.71 34.35 34.94 35.68 36.31 37.14 37.72 38.29 38.86 39.43 40.00 40.99 41.56 42.13
29.96 30.64 31.37 31.12 31.47 31.76 32.22 32.55 33.12 33.36 33.60 33.83 34.06 34.29 34.79 35.01 35.24
33.73 34.68 35.69 36.30 37.24 38.13 39.13 40.07 41.17 42.07 42.97 43.88 44.80 45.71 47.20 48.11 49.04
Future Oncol. (2014) 10(16)
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USA Endometrial Cancer Projections to 2030
Cases per 100,000 females
60 55
Projected Lower bound Upper bound
Actual EC rates 1990–2013
50
Research Article
Projected EC rates 2014–2030
45 40 35 30 25 20 1990
1995
2000
2005
2010
2015
2020
2025
2030
Year
Figure 1. Past and projected endometrial cancer rates per 100,000.
per 100,000 women by the year 2030, a 55% increase over 2010 rates (27.03 cases per 100,000 women). An optimistic projection (lower bound of the 95% prediction interval) estimates an increase by 2030 to 35.24 cases per 100,000 women, while a pessimistic projection (upper bound of the 95% prediction interval) suggests that by 2030 incidence could be as high as 49.04 cases per 100,000 women, an 81% increase over 2010 rates. EC incidence in the past has shown an irregular trajectory, which can be attributed to many factors such as the introduction of unopposed hormone replacement therapy for breast cancer treatment in the 1970s [32] . The use of unopposed hormone replacement therapy sharply increased the incidence of EC in 1970s [48] . Later, due to an increase in the number of women who underwent hysterectomy from the 1980s to 2006, there was a rapid decline in the incidence of EC [49] . Our findings are consistent with the fact that over the past several years the incidence and mortality associated with EC have been on the rise [32] . We expected to see a relationship between the increasing percentage of older US population [50] and an increase in projected EC rates based on previous research. However, our data did not show this, most likely because of collinearity between the increasing age of the population and increasing obesity rates over time masking the effects of the aging population. Although our results did not show a significant relationship between the aging population and EC rates, it cannot be ruled out. A projection study done by
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Smith et al. concluded that the overall cancer incidence for older adults is due to increase by 67% by 2030, compared with the year 2010. Since approximately 70% of all EC incidence occurs after the age of 50, we believe that this portion of the US population will also influence future EC rates [51] . In addition to the aging population, we used the study by Finkelstein et al. to generate the obesity estimates in this paper estimated that by 2030, 51% of the US population would be obese and 11% will be severely obese [41] . Since EC has been linked to obesity in many studies, the obesity endemic is also likely to increase EC incidence, a belief supported by the models presented in this paper. With increasing number of smoking prevention campaigns, including smoking restriction at workplaces, it is possible that smoking will be further decreased over the next two decades. While overall smoking reduction is good for health on population level, it might result in increased EC rates, something that our healthcare systems must be prepared for. EC is associated with high cost treatment modalities that mainly includes surgery, but may also include chemotherapy, hormonal therapy and radiation therapy. EC patients and survivors also rely on the expertise of many different health practitioners to treat other obesityassociated comorbid conditions, including heart disease and diabetes. The NCI estimates that expenditures relating to EC in the USA in the middle of the last decade totaled US$1.8 billion [52] . For the same time period, it was estimated that the total cost of treating obesity in the USA
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Research Article Sheikh, Althouse, Freese et al. was just under US$170 billion [53] . Therefore, projections of both obesity and EC indicate that costs are likely to increase dramatically by 2030. The projected surge in EC incidence is driven primarily by obesity, so weight loss interventions are the first logical step in mitigating the projected increases. Weight loss interventions such as bariatric surgery have also been linked with reversal of endometrial hyperplasia [54,55] . In addition, the use of intrauterine device (IUD) is one of the most widely used forms of contraception throughout the world and its use has been linked to decreased EC risk [56] . Furthermore, intrauterine progesterone delivered through IUD appears to eradicate some cases of presumed stage IA, grade 1 endometrioid cancer [57] . Also, the use of the combined oral contraceptive pill is associated with a decreased risk of EC [58] . Clearly, additional research should investigate these mitigating factors in relation to EC. While we have attempted to account for future effects of population trends in obesity, smoking and hysterectomy, it is necessary to understand that this model does not incorporate some other factors that may affect the rate of EC, such as new forms of diagnosis and/or prevention, the emergence of other risk factors or changes in the frequency of women who receive hysterectomies for benign diagnoses, which has been shown to complicate interpretation of the actual rates of EC [49] . Therefore, one of the limitations of our model is that it depends on the assumption that the aforementioned factors will not substantially affect EC incidence and the accuracy of projections for smoking, obesity and hysterectomy that we have incorporated into the modeling. While the results presented here are projections, they emphasize the fact that preventive
efforts to control obesity and obesity-associated malignancies, such as EC, postmenopausal breast cancer, and many others, must be at the forefront of research and medical practice in order to reduce the burden on the healthcare community and the population as a whole. While our data analysis for was limited to EC rates in the US and may not be generalizable to all nations, it should be noted that EC is a growing problem globally [59] and that these rates may portend increases elsewhere as well. Assessing the future of cancer incidence and the mortality rates is essential to formulate a strategy to effectively manage this disease in the upcoming years. From apportioning resources for screening, diagnostic and therapeutics to prevention, having accurate projections can help transform the way we manage cancer [38,60] . Future perspective The drastic increase in EC incidence over the past 7 years fueled by the ongoing obesity epidemic and aging of the US population indicates the need for close monitoring of EC trends. Apart from spreading awareness of this malignancy and its association with severe obesity, there is an urgent need to develop EC risk monitoring, management and prevention techniques over the next two decades. Financial & competing interests disclosure The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
EXECUTIVE SUMMARY ●●
The incidence and mortality from endometrial cancer (EC) is on the rise in developed nations.
●●
Obesity is one of the key risk factors associated with EC.
●●
This study suggests that EC incidence is expected to rise sharply over the next decade.
●●
Our projections indicate that there will be an estimated 42.13 incident cases of EC per 100,000 women by the year 2030, a 55% increase over 2010 rates (27.03 cases per 100,000 women).
●●
An optimistic projection (lower bound of the 95% prediction interval) estimates an increase by 2030 to 35.24 cases per 100,000 women, while a pessimistic projection (upper bound of the 95% prediction interval) suggests that by 2030 incidence could be as high as 49.04 cases per 100,000 women, an 81% increase over 2010 rates.
●●
Assessing the future of cancer incidence and the mortality rates is essential to formulate a strategy to effectively manage this disease in the upcoming years.
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USA Endometrial Cancer Projections to 2030 No writing assistance was utilized in the production of this manuscript.
Ethical conduct disclosure The authors state that they have obtained appropriate
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