Abstract
Background
Romania has the third highest preventable mortality rate in the European Union that is more than double the average rate in the European Union in 2018. Breast cancer (BC) is a significant driver of global preventable mortality but a few studies from Romania have quantified the degree to which BC influences mortality and morbidity. This study aimed to determine differences in BC mortality between Romania and the European Union. The study also examined urban/rural BC mortality across the eight regions of Romania.
Methods
Age-standardized BC mortality rates among women were calculated by urban/rural places of residence and by subnational region for 2000–2020, using data provided by the Romanian National Center for Statistics in Public Health, National Institute of Public Health. Age-standardized all-cause, all-cancer, and BC mortality rates were explored for Romania and the European Union for 2000–2017, using data obtained from Eurostat. Urban and rural age-standardized BC mortality rates among women were compared across regions of Romania to national and European rates to examine differences in BC mortality across the country and between urban and rural areas. Joinpoint Trend Analysis was employed to further analyze patterns in mortality rates.
Results
Age-standardized national BC mortality rate in Romania decreased from 39.60/100,000 women in 2000 to 38.35/100,000 women in 2020, however rates increased in several regions of the country. While BC mortality rates decreased more in urban areas (by 11.1%) than in rural areas (by 1.6%), urban areas still had a higher BC mortality (46.24/100,000 women in 2020) than rural areas (29.37/100,000 women in 2020) throughout the study period.
Conclusion
The higher BC mortality in Romania compared to other countries in the European countries, the higher mortality rates in urban than rural areas, and the regional variation in mortality rates call for future studies to investigate the possible health care system and care seeking behaviors and the environmental determinants that may have contributed to observed mortality profile. Improving the quality of incidence data in the country through efficient cancer registries could also lead to a better understanding of the variation in mortality rates, which is the premise for more targeted health policies.
Keywords: Breast cancer, Romania, Urban–rural inequalities, Mortality, Regional inequalities
Background
Health indicators of Romania lag behind those of the European Union (EU). In 2021, the average life expectancy in Romania was 72.9 years, which was about 7 years lower than the European Union’s (EU) average of 80.1 years [1]. The average 2021 life expectancy of females in Romania was 76.7 years, almost five years younger than the EU’s average of 82.8 years [1].
Cancer poses a significant burden on preventable deaths in Romania, whose five-year survival rates lag behind the EU [2]. Romania has the third highest preventable mortality rate in the EU, of 306/100,000 compared to the EU average of 160/100,000 in 2018 [2]. Furthermore, the treatable mortality rate, of which breast cancer (BC) play a key role, was 210/100,000 in Romania, more than double the EU average of 92/100,000 in 2021 [2]. In 2022, however, the age-standardized incidence rate of BC in Romania, 113.1/100,000 women is lower than the EU average, 142.8/100,000 women [3]. Moreover, in 2022, the age-standardized mortality rate of BC in Romania, 36.2/100,000 women exceeded that of the EU, 34.1/100,000 women. In a study of nine Central and Eastern European countries, Romania was found to have the second highest years of life lost (46,516 years), years of productive life lost (8,826 years), and present value of future lost productivity (€46 M), behind only Poland [4].
BC is an important public health problem, as Romania has the lowest rate of BC screening in the EU [5]. Only 0.2% of women aged 50–69 years were screened in 2015, the last year for which data is available [5]. Lack of screening has led to 79% of Romanian women never having had a BC exam, according to a 2019 survey published by the Romanian National Institute of Statistics [6]. As of 2022, in contrast to all other EU countries, Romania had only a pilot mammography program, and less than 10% of women reported undergoing mammography between 2018 and 2020 [7]. BC-related mortality has steadily increased in Romania in the last two decades, in contrast to a visible decreasing trend in EU [8].
Romania has a significant rural population, with 46% of the population living in rural communities in 2020, though this also varies between a low of 9.4% in Bucharest Ilfov Region and a high of 57.2% in the South Region [9]. Investment in healthcare varies widely between urban and rural areas of Romania, and compared to the EU average of 3.0%, Romania only allocated 1.6% of its total health spending to prevention activities in 2017 [2]. Furthermore, Romania spent an average of 1,261 euros per person on health in 2020, less than half of the EU’s average of 3,381 euros [2]. Low healthcare expenditures have led to delays in dissemination of new technologies and medications compared to wealthier EU countries [2].
This study aimed to determine differences in BC mortality between Romania and the EU 27. The study also examined urban/rural disparities in BC outcomes across the eight nomenclature of territorial units for statistics for basic regions level 2 (NUTS2) regions of Romania.
Methods
This study utilized the following 4 data sources: 1) data on new and existing BC cases from the databases of aggregated health indicators of the Center for Statistics in Public Health at the National Institute of Public Health (NIPH) collected from reports of family physicians and oncology specialists, based on their clinical data records, by the District Public Health Directorates, that forward the data on annual basis to the NIPH; 2) crude incidence, crude prevalence, and number of deaths of BC by district, region, age and rural–urban health indicators from the Romanian National Institute of Statistics; 3) the Romanian National Institute of Statistics online database (Tempo) [9] that provided the population data by age, region, and urban–rural residence; and 4) the Statistical Office of the European Union online database (Eurostat) [1] that provided the standardized mortality rates for the European countries.
All-cause, all-cancer, and BC mortality age-specific and age-standardized rates for Romania and EU27 (European Union excluding the United Kingdom) for 2000–2017 were obtained from Eurostat. Number of new BC cases and number of BC cases registered at the end of each year was collected from the data collected by the National Center for Statistics in Public Health, National Institute of Public Health, reported by each District Public Health Directorate in Romania based on data supplied by oncology specialists. A BC death is defined as a woman who died with BC as the first cause of death.
Absolute number of BC deaths by age group, urban/rural region, and subnational region for 2000–2020 were provided by the National Center for Statistics in Public Health, National Institute of Public Health, Bucharest, Romania. Age-standardized all-cause, all-cancer, and BC mortality rates were calculated using the number of deaths by age-group and female population by age-group per region and by rural urban area in Romania from 2000 to 2020. Direct age standardization was conducted according to the methodology described in Naing using the current European standard population based on 2011–2030 population projections of EU Member States and European Free Trade Association countries as the reference population [10].
The current European standard population based on 2011–2030 population projections of EU Member States and European Free Trade Association countries as the reference population is precisely what is commonly referred as “the European standard population” and was published by Eurostat in 2013, in the document entitled: European Commission. Revision of the European Standard Population — Report of Eurostat’s task force. Luxembourg: Publications Office of the European Union, 2013. Theme: Population and social conditions. Collection: Methodologies and Working papers. ISBN 978–92 - 79–31,094 - 2. ISSN 1977–0375. 10.2785/11470. Cat. No: KS-RA- 13–028-EN-N [11].
For the comparisons of BC mortality between Romania and the other EU countries we have extracted the Romania national country standardized mortality rates and the EU average standardized mortality rates published in the mortality database of Eurostat.
Our analysis included two comparisons: a) comparing BC mortality in the EU and in Romania at the national level, and b) comparing BC mortality between regions and urban–rural areas of Romania at the subnational level. Regarding the first comparison of BC mortality in the EU and Romania at the national level, we used the standardized mortality rates for BC according to Code 50 in the International Classification of Disease Revision 10 for the period of 2000–2017 [12], as 2017 was the last year with the necessary data available for the majority of countries in the Eurostat database. Regarding the second comparison of regions and urban–rural populations of Romania, we used data from the Romanian National Center for Statistics in Public Health for the period 2000–2020.
Regarding the geographical area, we used EU 27 data (the United Kingdom excluded) and intra-country data disaggregated by rural–urban area and by NUTS2 Region. Romania has the eighth largest land area in the EU and the sixth largest population in the EU (21.9 million citizens registered, of which 19.1 million reside in Romania in 2023) [9]. Currently, 46% of the population lives in rural areas, the largest percentage of any EU country [13]. Romania is comprised of 42 counties and 8 NUTS 2 regions: North-East (NE), South-East (SE), South (S), South-West (SW), West (W), North-West (NW), Center (C), and Bucharest-Ilfov (BI).
The Regulation (EC) no 1059/2003 of the European Parliament and of the Council on the establishment of a common classification of territorial units for statistics (NUTS) defines the eight regions (NUTS 2) and the 42 counties of Romania (NUTS3). The Romania’s territory is composed by urban and rural areas, according to Law no. 351/2004 regarding the approval of the National Territorial Development Plan.
According to this law, the town is a concentration of people, with an administrative function and a way of life specific to urban areas, and with a professional structure of the population where those employed in non-agricultural branches are predominant. The commune is an administrative-territorial unit which comprises the rural population united through a community of interests and traditions. It may include one or several villages. Generally, most of the workforce is predominantly involved in agriculture and the public services are poorer and less represented than in urban areas.
Analyses were performed using SPSS Version 28.0.0.0. Comparisons of raw numbers and structure of deaths, crude mortality rates analysis, standardized mortality rate, mortality change, and mortality difference were calculated using methodology first described in Furtunescu et al. [14] P-values for linear trend were calculated for age-standardized mortality rates after testing for linearity by examining residuals. Age-standardized Mortality Rate Ratios (MRR) and P-values for trend were calculated using negative binomial regression in SPSS [15].
Joinpoint regression analyses were performed using Joinpoint Trend Analysis Software Version 5.2.0. The standard error of age-standardized national Romanian BC mortality was used as the reference standard error. The best joinpoint regression models were selected using weighted Bayesian Information Criterion. After model selection, annual percentage change (APC) was extracted from each model. P-values were examined at an alpha level of 0.05.
The Institutional Review Boards of the University of Vermont and the National Institute of Public Health, Romania have reviewed this study and determined that it is exempt from IRB review.
Results
Differences between Romania and the EU
Number of deaths
In 2000, 77,298 deaths due to BC were registered in the EU (EU27), of which, 2,949 (3.8%) were reported in Romania. In 2017, 84,613 deaths due to BC were registered in the EU, of which 3,500 (4.1%) were reported in Romania. From 2000 to 2020 there were 67,339 deaths due to BC in women 20 years or older in Romania.
Mortality Rates
Age-standardized all-cause mortality rates in the entire Romania resident population were higher in Romania than the EU throughout the study period. In 2002, the rate in Romania was 1,641.5/100,000 compared to the EU rate of 1,022.7/100,000 (Fig. 1). In 2017, the last year for which data is available, age-standardized all-cause mortality rate was 1,192.7/100,000 in Romania compared to 820.8/100,000 in the EU (Fig. 1).
Fig. 1.
Line graphs of standardized all-cause, all cancer, and BC mortality rate per 100,000, Romania, 2000–2020 and EU 27, 2002–2017 according to Eurostat data
Age-standardized all-cancer mortality rate of women was higher in the EU than in the entire Romanian resident population from 2002–2017, but the trends for each geography were different. In 2002, the age-standardized all-cancer women mortality rate was 180.5/100,000 in Romania compared to 227.5/100,000 in the EU (Fig. 1). In 2017, age-standardized all-cancer women mortality rate grew to 195.5/100,000 in Romania while the EU rate decreased to 205.4/100,000 (Fig. 1).
Age-standardized BC mortality rate in women was initially higher in the EU than in Romania, though this ranking reverses at the end of the study period (Fig. 1). In 2002, the age-standardized BC mortality rate was 38/100,000 women in the EU and 36.3/100,000 women in Romania. However, in 2017, the age-standardized BC mortality rate was 32.4/100,000 women in the EU and 35.9/100,000 women in Romania (Fig. 1).
Differences in BC mortality of subnational populations in Romania
Age-standardized BC mortality rates in women are higher in urban areas than in rural areas for the entire women population at national level and in nearly all regions for 2000–2020 (Figs. 2 and 3, Table 1). This is not surprising as 55% percent of the population lived in 2000 in urban areas and 56.4% in 2020, however cumulatively, 65% of BC deaths over the years of the study took place in urban areas.
Fig. 2.
Changes in breast cancer mortality by rural—urban areas, Romania, 2000–2020. Standardized mortality rates
Fig. 3.
Changes in breast cancer mortality by regions and rural–urban areas, Romania, 2000–2020
Table 1.
Breast cancer deaths and age-standardized rates for national, urban, rural, and urban–rural mortality rate ratio during the period of (2000–2020)
| Year | No. Deaths | Age-Standardized Mortality per 100,000 Women | Age-Standardized Urban Mortality per 100,000 Women | Age-Standardized Rural Mortality per 100,000 Women | Urban–Rural Mortality Rate Ratio |
|---|---|---|---|---|---|
| 2000 | 2948 | 39.60 (38.17, 41.03) | 51.99 (49.59, 54.40) | 29.86 (28.14, 31.58) | 1.74 |
| 2001 | 2999 | 40.60 (39.15, 42.06) | 55.47 (52.98, 57.97) | 28.92 (27.21, 30.63) | 1.92 |
| 2002 | 3013 | 39.83 (38.00, 41.25) | 53.31 (50.91, 55.71) | 28.69 (27.00, 30.37) | 1.86 |
| 2003 | 3007 | 39.67 (38.25, 41.08) | 53.52 (51.12, 55.93) | 28.70 (27.01, 30.40) | 1.86 |
| 2004 | 3084 | 40.74 (39.30, 42.18) | 54.29 (51.89, 56.69) | 29.47 (27.75, 31.19) | 1.84 |
| 2005 | 3168 | 41.19 (39.75, 42.62) | 53.49 (51.18, 55.80) | 29.65 (27.91, 31.40) | 1.80 |
| 2006 | 3075 | 39.12 (37.74, 40.50) | 50.59 (48.38, 52.79) | 28.14 (26.44, 29.84) | 1.80 |
| 2007 | 3048 | 39.00 (37.62, 40.38) | 48.72 (46.56, 50.88) | 29.77 (28.00, 31.54) | 1.64 |
| 2008 | 3033 | 38.24 (36.88, 39.60) | 49.82 (47.65, 51.99) | 27.10 (25.43, 28.76) | 1.84 |
| 2009 | 3206 | 39.76 (38.39, 41.14) | 49.78 (47.64, 51.91) | 29.94 (28.19, 31.69) | 1.66 |
| 2010 | 3153 | 38.66 (37.31, 40.01) | 47.26 (45.19, 49.32) | 30.42 (28.65, 32.18) | 1.55 |
| 2011 | 3130 | 38.00 (36.67, 39.34) | 46.65 (44.61, 48.69) | 29.38 (27.66, 31.10) | 1.59 |
| 2012 | 3128 | 37.55 (36.23, 38.87) | 46.41 (44.40, 48.42) | 28.30 (26.60, 29.99) | 1.64 |
| 2013 | 3246 | 38.58 (37.26, 39.91) | 47.54 (45.52, 49.56) | 29.32 (27.60, 31.04) | 1.62 |
| 2014 | 3343 | 39.21 (37.88, 40.54) | 47.58 (45.58, 49.58) | 30.71 (28.95, 32.47) | 1.55 |
| 2015 | 3438 | 39.94 (38.60, 41.27) | 49.17 (47.15, 51.18) | 30.11 (28.37, 31.84) | 1.63 |
| 2016 | 3462 | 39.73 (38.41, 41.05) | 48.03 (46.06, 50.00) | 30.64 (28.89, 32.38) | 1.57 |
| 2017 | 3500 | 40.10 (38.77, 41.43) | 48.31 (46.34, 50.28) | 31.19 (29.42, 32.95) | 1.55 |
| 2018 | 3497 | 39.48 (38.17, 40.79) | 48.35 (46.39, 50.30) | 29.59 (27.88, 31.30) | 1.63 |
| 2019 | 3375 | 37.73 (36.45, 39.00) | 45.78 (43.90, 47.66) | 28.57 (26.88, 30.25) | 1.60 |
| 2020 | 3486 | 38.35 (37.08, 39.62) | 46.24 (44.37, 48.12) | 29.37 (27.68, 31.07) | 1.57 |
| Overall | 67,339 | – | – | – | – |
| P for trend | 0.044 | < 0.001 | 0.180 |
In 2000, SE region displayed the greatest percent difference in age-standardized BC mortality rate between urban and rural areas, with rates 96.6% higher in urban areas than in rural areas (Fig. 3). In 2020, NW region displayed the greatest percent difference in age-standardized BC mortality rate between urban and rural areas, with rates 66.7% higher in urban areas than in rural areas (Fig. 3). In 2000, the lowest absolute percent difference in age-standardized BC mortality rates between urban and rural areas was in S region with a rate 53.6% higher in urban areas than in rural areas (Fig. 3). In 2020, the lowest absolute percent difference in age-standardized BC mortality rate between urban and rural areas was in W region, with a rate 29.4% higher in urban areas than in rural areas (Fig. 3). Notably, the combined urban/rural age-standardized BC mortality rate is nearly the same as the urban rate in BI region where most of the population lives in urban settings (Fig. 3). In 2020, 90.6% of people in BI region lived in urban settings [9]. In 2000, 89.4% of people in BI region lived in urban settings [9].
Trends in BC mortality over two decades at national and sub-national levels in Romania
Nationally, the age-standardized BC mortality rate in women decreased 3.2% in Romania between 2000 and 2020, from 39.60/100,000 women to 38.35/100,000 women (Fig. 2). Age-standardized BC mortality rates in women decreased in all regions except S and C regions (Fig. 3). The greatest overall decrease was in BI region, which saw age-standardized BC mortality rates in women decrease 10.2% between 2000 and 2020. The greatest increase of overall age-standardized BC mortality rate in women was in C region, which saw age-standardized BC mortality rates in women increase 8.16% between 2000 and 2020.
In urban areas, age-standardized BC mortality rates decreased 11.1% between 2000 and 2020, from 51.99/100,000 women to 46.24/100,000 women (Fig. 2, Table 1). Age-standardized BC mortality rates decreased in urban areas of all regions except for S region (Fig. 3). Among urban areas, the greatest decrease in age-standardized BC mortality rate in women was in NE, which saw a 14.9% decrease, while the greatest increase in age-standardized BC mortality rate in women was in the S region, which saw a 1.5% increase (Fig. 3).
In rural areas, age-standardized BC mortality rates decreased 1.6% between 2000 and 2020, from 29.86/100,000 women to 29.37/100,000 women (Fig. 2, Table 1). Age-standardized BC mortality rates decreased in the rural areas of NE, SW, W and NW regions, and increased in SE, S, C and BI regions (Fig. 3). Among rural areas, the greatest decrease in age-standardized BC mortality rates in women was in SW region, which saw a 17.9% decrease in age-standardized BC mortality rate in women, while the greatest increase in age-standardized BC mortality rate in women was in C region, which saw a 15.2% increase in age-standardized BC mortality rate between 2000 and 2020.
Age-standardized urban–rural mortality rate ratios (MRRs) decreased from 1.74 to 1.57 over the study period (Table 1). Furthermore, the P-values for the trendline of overall mortality and urban mortality are significant at a 99.9% confidence level (Table 1). There is thus a significant decrease in overall BC age-standardized mortality from 2000 to 2020, and a significant decrease in urban age-standardized BC mortality over the same period (Table 1).
Table 2 illustrates the comparison of age-standardized BC mortality rate (2000–2020), crude BC incidence rate (2008–2020), and crude BC prevalence rate (2013–2020) in women by sub-national regions of the country. Six regions exhibit a decrease in age-standardized BC mortality rate and two regions exhibit an increase in age-standardized BC mortality rate during the study period (Table 2). Crude incidence and prevalence rates did not show any consistent patterns in relation to the mortality changes (Table 2). Interestingly, prevalence increased in all but one region over the 2013–2020 period (Table 2).
Table 2.
Comparison of age-standardized breast cancer mortality (2000–2020) and crude incidence (2008–2020) and prevalence rates among women in Romania by sub-national regions of the country
| Sub-National Area | Age-Standardized Mortality | Incidence | Prevalence | ||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| 2000 Age Standardized Mortality Rate (95% C.I.) | 2020 Age Standardized Mortality Rate (95% C.I.) | % Change 2000 to 2020 | Rank 2000 | Rank 2020 | % Change 2008 to 2020 | Rank 2008 | Rank 2020 | % Change 2013 to 2020 | Rank 2013 | Rank 2020 | |
| Romania | 39.60 (38.20, 4.00) | 38.35 (37.10, 39.60) | − 3.2 | − 14.1% | 30.2% | ||||||
| North-West | 43.67 (39.40, 48.00) | 40.65 (36.90, 44.40) | − 6.9 | 7 | 4 | − 12.3% | 4 | 4 | 38.7% | 6 | 8 |
| Center | 40.33 (36.00, 44.70) | 43.62 (39.60, 47.60) | 8.1 | 4 | 7 | − 35.2% | 8 | 2 | − 6.5% | 8 | 4 |
| North-East | 33.70 (30.40, 37.00) | 30.59 (27.80, 33.40) | − 9.2 | 3 | 2 | − 4.7% | 1 | 3 | 25.7% | 3 | 3 |
| South-East | 41.34 (37.30, 45.40) | 40.89 (37.20, 44.50) | − 1.1 | 5 | 6 | − 7.2% | 6 | 6 | 27.0% | 7 | 6 |
| South | 32.75 (29.50, 36.00) | 35.17 (32.10, 38.30) | 7.4 | 2 | 3 | 4.7% | 2 | 5 | 51.7% | 2 | 2 |
| Bucharest-Ilfov | 55.51 (50.40, 60.70) | 49.85 (45.70, 54.00) | − 10.2 | 8 | 8 | − 58.6% | 5 | 1 | 71.3% | 1 | 1 |
| South-West | 31.78 (28.00, 35.60) | 29.33 (25.90, 32.80) | − 7.7 | 1 | 1 | 0.9% | 3 | 7 | 42.5% | 4 | 7 |
| West | 43.43 (38.50, 48.30) | 40.08 (35.80, 44.40) | − 7.7 | 6 | 5 | 79.4 | 7 | 8 | 38.0% | 5 | 5 |
Discussion
This study revealed three interesting observations. First, the study revealed significantly higher age-standardized BC mortality rates in urban-dwelling women than their rural-dwelling counterparts in Romania, consistent across all regions of the country. Second, the study showed regional variation of age-standardized BC mortality rates among Romanian women. Third, the study found a lack of concordance between the changes in mortality and incidence rates by region.
Regarding the first observation of higher mortality in urban than rural areas, as far as we know, this is the first study to examine urban–rural differences in age-standardized BC mortality rate in Romania. Studies in the United States have had mixed findings regarding BC mortality in urban and rural areas. Our findings are consistent with higher BC mortality rates in urban areas in some studies from the United States [16], while other studies in the United States have found that rural inhabitants tend to exhibit higher mortality than urban residents [17]. Studies in the United States have also found increased BC incidence in urban areas than rural areas [18]. Other United States-based studies indicate a disproportionate total mortality rate in rural areas but these studies did not stratify by cause of death [19, 20]. In the United States, prior to 1990, urban areas had higher rates of cancer mortality than rural areas, possibly for reasons related to standards of care, rates of insurance, and changes in health behaviors [21].
While other studies have compared BC mortality between European regions [22] and countries of the E.U. [23], few studies have compared BC mortality in urban and rural areas of the E.U. One study found that age-standardized BC mortality rates were higher in urban than rural areas of Lithuania during 1993–2004, and that age-standardized BC mortality rates decreased in the country in both urban and rural populations over the study period [24]. Conversely, a study found that the age-standardized BC mortality rate was higher in a rural region of Greece than an urban area from 1999 to 2008, but the difference was statistically nonsignificant [25]. Studies from other E.U. countries, including Ireland, France, and Poland, have found that risk of BC increases with urbanicity [26–28]. Women residing in urban settings in the UK and Netherlands have been shown to have higher breast density, which is associated with BC risk, suggesting that environmental or genetic factors may play a role in increased BC risk [29, 30].
In contrast to several studies that have found decreasing BC mortality rates in women aged 50–69 in European countries, studies have also found that age-standardized BC mortality rates among the same cohort in transitional countries––described as Central and Eastern European countries undergoing social, political, and economic changes––have remained stable [31]. At the same time, mortality rates among women aged 70–79 in such transitional countries have been found to be increasing [31]. Further studies of age- and country-specific influences on mortality would help to shed light on these differences.
A global meta-analysis of urban–rural disparities in BC diagnosis and outcomes found that women living in rural areas are more likely to be diagnosed with late-stage BC than their urban-dwelling peers [32]. Studies in Egypt, India and China have found that risk of BC increased with urbanicity [26–28, 33–35]. During the period 1987–99 in China, BC mortality rates were lower in rural areas than in urban areas, though rates increased more in rural areas than in urban areas [36]. Another study found that age-standardized BC mortality rates were higher in urban areas than rural areas of Trivandrum, South India during 2012–2014 [37]. Previous studies in the United States and United Kingdom have hypothesized higher BC mortality rates in rural areas due to health insurance inequities resulting in late-stage BC case presentation [38, 39].
Regarding the second observation of regional variation in age-standardized BC mortality rates, again, as far as we know, this is the first study to have examined intra-country variation in age-standardized BC mortality rates in Romania. However, previous studies have found that cervical cancer mortality also exhibits significant regional variation in Romania [14]. Another study also found variation between age-standardized BC mortality rates in 2018 across European Union countries, from a high of 43.2/100,000 women in Croatia to a low of 22.7/100,000 women in Spain [22].
In the United States, a study found that 2008–2019 age-standardized cancer mortality rates varied significantly between counties, from a high of 418.4/100,000 to a low of 66.1/100,000 [40]. Moreover, the same study found that the most influential risk factors for cancer varied across regions of the United States, with obesity being the strongest indicator of cancer risk in the Northeast and West, receipt of supplemental nutrition assistance program (SNAP) benefits being the strongest indicator in the Midwest, and smoking being the strongest indicator in the South [40].
Only 5–10% of BC risk is determined by hereditary factors, while non-hereditary, or environmental, factors represent a significant amount of BC risk [41–44]. Currently, known risk factors of BC, including environmental risk factors that influence a woman’s exposure to endogenous estrogens, such as age of menarche, age of first full-term pregnancy, number of children, duration of breastfeeding, and age of menopause, explain slightly more than 50% of BC risk [45, 46]. Thus, we may conclude that there are other exogenous estrogenic factors that may influence BC risk, as BC is associated with estrogenic exposures, and endogenous estrogens are not wholly responsible for non-hereditary risk [45, 46].
Environmental carcinogens may play a significant role in higher age-standardized BC mortality rates in urban areas of Romania. As Romania claimed the highest yearly per capita social cost caused by air pollution in the EU in 2018, there may be a relationship between high levels of air pollution and high rates of BC mortality in Romanian cities [47]. Other studies have hypothesized causal effects of higher concentrations of xenoestrogens in urban areas on BC incidence and mortality [33]. Evidence regarding the exposures of rural and urban women to environmental carcinogens may help to determine differences in total mortality, including BC mortality between urban and rural areas of Romania.
We believe that the possible reasons for the third observation of the apparently inconsistent trends of mortality compared to incidence rates in different regions in Romania over the 20-year study are one or more of the following: 1) differences in age structure of the female population in different regions of Romania. We have standardized mortality rates by age but we have not standardized the incidence rates by age because of the aggregate nature of the incidence data and absence of age of individual incidence cases; 2) differences in prevalence of environmental exposures and other BC risk factors that may have influenced incidence by regions; 3) differences in access to early detection facilities and BC diagnostic and treatment facilities that may have influenced stage diagnosis and consequently mortality but not incidence; and 4) differences in quality of data collection in different regions of the country that have resulted in potential biases in incidence but not morality. It is important to note that mortality data in Romania is of high quality and homogeneity. However, new cases that are the core for incidence data could be underreported. The fragmentary reporting could be due to different patient access to family physicians and specialists who are responsible for reporting new cases.
This is the first study to characterize urban–rural and regional age-standardized BC mortality in women in Romania. The study showed clear trends and significant differences between age-standardized BC mortality in women in urban and rural regions. The study also provides preliminary results for future investigations to elucidate factors contributing to mortality in different regions. Another strength of the study includes the spanning of the study data over a 21-year period, allowing for examination of age-standardized BC mortality rates before and after Romanian accession to the EU. Despite these strengths, our study had also some limitations. The lack of a population-based cancer registry data and data regarding the stage of BC at diagnosis significantly hindered our ability to determine the role of BC stage on mortality rates, as stage at diagnosis is a key indicator of survival. We were also unable to draw comparisons between BC mortality in Romania and the EU after 2017 due to a lack of standardized EU data. Furthermore, it is likely that access to BC screening, diagnosis, and treatment services changed after the onset of the COVID- 19 pandemic in January 2020, impacting BC mortality rates in Romania. Finally, reliable BC incidence data from Romania would have helped to contextualize mortality rates in urban–rural areas and different regions of the country, but the quality of the available cancer incidence data in Romania has been deemed as poor.
Conclusions
Rural/urban residence in Romania may be associated with higher age-standardized BC mortality rates in women in urban areas but is likely to indict other related social and structural factors. It is important to determine the possible factors that are related to the higher mortality rates in urban areas than rural areas of Romania. It is also important to consider that urban morality rates are decreasing at a faster rate than rates in rural areas. Reducing BC mortality rates may have potentials to improve Romanian health indicators. Furthermore, disparities between urban and rural areas of Romania may have analogs in other countries, and interventions addressing urban BC mortality in Romania may be applicable in these settings.
Future studies need to elucidate patient and system factors related to the regional variation of BC mortality rates. Development and implementation of quality population-based cancer registries will also be essential for obtaining reliable incidence rates [48]. Etiologic studies of BC in different regions of the country may help validate the BC incidence data of the country. Understanding factors related to the variable mortality rates described in this study may have implications for reducing BC mortality rates in Romania, other similar European countries, and middle-income countries globally.
Acknowledgements
The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute, the National Institutes of Health or the Romanian National Institute of Public Health.
Authors’ contributions
J.W.C. contributed to conceptualization, data curation, formal analysis, investigation, methodology, project administration, software, supervision, validation, visualization, writing—original draft and writing—review and editing, S.R. contributed to conceptualization, data curation, methodology, resources, validation, visualization and writing – review and editing, C.U., C.C., and F.F. contributed to data curation, methodology, resources, validation, and writing—review and editing, and A.S. contributed to conceptualization, funding acquisition, methodology, project administration, supervision, and writing – review and editing.
Funding
John Carew was supported by the Cancer Epidemiology Education in Special Populations (CEESP) Program from the National Cancer Institute, R25 CA112383.
Data availability
The datasets analyzed during the current study are available in the Romanian National Center for Statistics in Public Health, National Institute of Public Health (https://insse.ro/cms/) and Eurostat (https://ec.europa.eu/eurostat/statistics-explained/index.php?title=Mortality_and_life_expectancy_statistics) repositories.
Declarations
Ethics approval and consent to participate
This study used data stripped of all personal identifiers and was approved by the University of Vermont Institutional Review Board and the Romanian National Institute of Public Health Ethics Committee.
Consent for publication
Not applicable.
Competing interests
The authors declare no competing interests.
Footnotes
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
John W. Carew, Silviu Calin Radulescu and Li Zhang contributed equally to this work.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The datasets analyzed during the current study are available in the Romanian National Center for Statistics in Public Health, National Institute of Public Health (https://insse.ro/cms/) and Eurostat (https://ec.europa.eu/eurostat/statistics-explained/index.php?title=Mortality_and_life_expectancy_statistics) repositories.