Population density, altitude, rate of higher education, smoking rate, obesity rate, parity, unemployment rate, breastfeeding rate, oral contraceptive usage rate, and Gross Regional Domestic Product per capita were considered as potential confounders. Ambient air pollutant concentrations were positively and significantly associated with the breast cancer incidence rate: per 100 ppb CO increase, Odds Ratio OR = 1.08 , per 10 ppb NO2, OR = 1.14 (95% CI = 1.12–1.16), per 1 ppb SO2, OR = 1.04 (95% CI = 1.02–1.05), per 10 µg/m3 PM10, OR = 1.13 (95% CI = 1.09–1.17). However, no significant association between the air pollutants and the breast cancer mortality rate was observed except for PM10: per 10 µg/m3 PM10, OR = 1.05 (95% CI = 1.01–1.09).Breast cancer is one of the major female health problems worldwide. Although there is growing evidence indicating that air pollution increases the risk of breast cancer, there is still inconsistency among previous studies. Unlike the previous studies those had case-control or cohort study designs, we performed a nationwide, whole-population census study. In all 252 administrative districts in South Korea, the associations between ambient NO In South Korea, breast cancer is the second most common after thyroid cancer and has annually increased by 6.1% from 1999 to 20143. Increased exposure to environmental female hormones is considered to affect the rise of breast cancer incidence. In addition, hormone-dependent cancer is increasing in industrialized countries4.Breast cancer is the most frequently diagnosed cancer among women worldwide2 and NOx)9, fine particulate matters (PM10 and PM2.5)11, and polycyclic aromatic hydrocarbons (PAHs)13 are reported to associate with breast cancer incidence. The physiological mechanisms by which air pollutants affect breast cancer are largely explained in two ways. First, air pollutants may directly cause genetic mutations, as they are carcinogenic15. Second, air pollutants may affect breast cancer incidence by increasing breast density, which is known to be a risk factor. Yaghjyan et al. reported an association between exposure to PM2.5, O3, and mammographic breast density16. Female hormones affect breast density, and some air pollutants are known to exhibit endocrine-disrupting properties, including xenoestrogens17. However, in the Danish Diet, Cancer and Health cohort (1993–1997) study, little evidence of association between traffic-related air pollution exposure and breast density was found18. Hung et al. reported a positive association between high levels of PM2.5 and breast cancer mortality rate, by considering PM2.5 as a marker for polycyclic aromatic hydrocarbons19.There is growing evidence indicating that air pollution is a risk factor for breast cancer. Nitrogen oxides  was 24,149,865. The total number of breast cancer incidence in 2004–2013 was 133,373, and the total number of deaths by breast cancer in 2005–2016 was 23,565.Characteristics of the observed districts throughout the study period are shown in Table 2 and O3 concentrations were colinear with a correlation coefficient of −0.862. O3 concentrations were excluded from the multivariable model due to its lesser correlation (0.659) with the breast cancer incidence rate than that of NO2 concentrations (0.774). Both NO2 and O3 concentrations poorly associated with the breast cancer mortality rates (<0.2 for both). Other air pollutants, CO, SO2, and PM10 showed little evidence of collinearity with <0.7 correlation coefficients. Among the confounding factors, higher education rate was collinear with population density, parity, unemployment rate, breastfeeding rate, and oral contraceptive usage rate with >0.7 correlation coefficients. Among those, only higher education rate was included in the model due to its strongest association with the breast cancer incidence rate (0.832). Altitude, smoking rate, obesity rate, gross regional domestic product (GRDP) per capita, and higher education rate were not significantly collinear among each other, so those five confounding factors were incorporated to the beta regression model in estimating the odds ratio (OR) of CO, NO2, SO2, PM10 concentrations for breast cancer incidence and mortality rates as covariates.In multicollinearity analysis among the air pollutants, the NO2, SO2, and PM10 were significantly associated with breast cancer incidence. For example, a district with 10 ppb higher NO2 concentration suffered from higher OR of breast cancer incidence by 1.14 . In multi-pollutant models, all of the four pollutants remained associated with the breast cancer incidence rate when additionally adjusted with the other three pollutants. On the other hand, air pollutants’ concentrations and the breast cancer mortality rates exhibited subtler associations. CO, NO2, and SO2 showed positive but not significant associations, both in single- and multi-pollutant models. Only PM10 exhibited significant associations with the breast cancer mortality rate both in single- and multi-pollutant models, but with smaller ORs than those with the breast cancer incidence rate.Table 2 and PM10 concentrations were significantly and positively associated with the breast cancer incidence rate in South Korean female population. This result is consistent with previous studies that reported significantly higher risk of breast cancer incidence11, and is partly consistent with studies that reported suggestive27 or null28 associations between air pollutants and breast cancer. Our study adds evidence of a significant positive association to the aforementioned studies. It is also important to note that our finding is based on region-based national census data that encompassed the entire female population of a country  for more than 10 years, including the complete set of diagnosed breast cancer incidences  and deaths  during that period. This region-based national census data could covary out possible confounders, including the data-collection method and any other unknown factors. This adds a new layer of evidence for the association between air pollution and breast cancer incidence rates to the previous studies that had case-control or cohort settings. Differences in the significance of the positive association in our study and aforementioned studies may be due to the relatively severer air pollution in South Korea . This weak association implies that there are some districts with higher mortality rates than expected with their incidence rates. Many of these districts are located in rural areas, supporting an idea that they are underserved by the healthcare system (including late-detection or late-diagnosis) but we did not find significant differences between these low-incidence-high-mortality districts and the other districts. After the breast cancer diagnosis, a patient may have various treatment and management options that considerably affect the mortality rate, and those are hard to parameterize in a census-based study setting. For instance, living in a polluted urban area may lead to a high incidence rate but not to a high mortality rate, by providing better access to healthcare resources than other parts of the country. Similarly, the higher-education rate is positively correlated with the incidence rate, but not with mortality rate. Higher education is usually associated with a Westernized diet pattern, fewer childbirths, prolonged time-to-first pregnancy, and less breastfeeding. These factors contribute to a higher risk of breast cancer incidence. On the other hand, higher education may lower the mortality rate by promoting patients to seek better means to fight the disease. There are studies reporting that different education groups have disparate treatment and mortality patterns in South Korea29 and China30.On the other hand, no significant association was found between air pollution and breast cancer mortality rates except PM32, and the average duration of living in the same district, according to the 2005 Census, was about 7.7 years32.Our breast cancer incidence and mortality statistics are based on a validated national census database, encompassing the whole female population in South Korea. Although this makes our study robust, a limitation also arises. Because the unit of analysis was a district, not an individual, some information considered to be important in breast cancer incidence could not be obtained, such as: histologic subtypes, stage at diagnosis, menopausal status, molecular subtypes, mammographic breast density, occupational history, and patient-specific exposure to air pollution. Further research is needed to unveil the interplay of breast cancer, air pollution, and these not-yet-studied risk factors. We did not perform a lag analysis due to the lack of temporal resolution in the breast cancer incidence that had been surveyed every 5 years . Because there was no predefined ‘duration of exposure’ nor a ‘lag-year’ value from an exposure to air pollution to lead to a breast cancer incidence or mortality case, the average of daily air pollutant concentrations throughout the study period in each district was considered to represent the level of air pollution. More frequent survey on the breast cancer incidence would enable time series analysis and may lead to richer implications to the field. Another limitation is the lack of migration history data. We contend that migrations would not significantly flaw the current study because only approximately 10% of the population moved between different districts in South Korea between 2003 and 2013Our study suggests a positive association between air pollution and breast cancer incidence, but less definitively with the mortality rate. This region-based, nationwide, whole-population study adds a new layer of evidence for the association.Ethical approval was not required because this study was performed using a publicly accessible, national epidemiology database.32 is a publicly accessible database that was used to extract the breast cancer incidence and mortality rate, which was classified by the Korean Standard Classification of Disease codes for “breast cancer”, C50, and corresponding with the same disease category in the 10th revision of International Statistical Classification of Diseases (ICD-10) and Related Health Problems codes. Mortality statistics were provided from 2005–2016, and incidence statistics were from 2004–2013 by the KOSIS database. There are currently 252 Si-Gun-Gus in South Korea. Si-Gun-Gu is a level in the Korean administrative-area system, similar to the county in the United States. All 252 districts were included in this study, except Ulleung-Gun—a group of islands 130 km away from the east coast, populated by fewer than 10,000 people. The incidence and mortality rates were age-adjusted per 100,000 by the standard populations as of July 1st, 2010 in South Korea. Breast cancer incidence or deaths in the male population were too scarce to be included in the study, so only the female population was analyzed.Korean Statistical Information Service (KOSIS)2, NO2, O3, PM10, and PM2.5 concentrations are measured by National Ambient Air Quality Monitoring Information System (NAMIS), and publicly accessible via the AirKorea website. In total, there are 332 measurement stations nationwide. PM2.5 was not assessed in the current study because of shortage in measurement stations in the early study period. The average of each pollutant, per day, for each station was collected.Air pollution data throughout the study period and places were acquired from a publicly accessible database. CO, SOAlthough the air pollution data are based on the measurement stations, the population, incidence, and death statistics are based on the Si-Gun-Gu district system, which is not directly matched to each other. To match and integrate the datasets, we obtained the latitudes and longitudes of each air pollution measurement station and administrative authorities office as a representative location for each district. Then we estimated the average air pollutant concentrations throughout the study period for each administrative office by linearly interpolating air pollutant measurements from the surrounding three stations. Python programming language version 2.7  was used in the procedure.Considering the nature of cancer incidence that depends on long-term, cumulative exposure to putative carcinogens, a clear-cut exposure timing may not be determined. Rather, we summarized the mean ambient pollutant concentrations throughout the whole study period (2004–2016).Altitude, population density, higher-education rate, smoking rate, obesity rate, parity, unemployment rate, breastfeeding rate, oral contraceptive usage rate as of the 2010 Census, and gross regional domestic product (GRDP) per capita as of 2011 were accessed for every districts via the KOSIS database and considered as potential confounding factors. The rates are defined as follows: higher education rate , smoking rate , obesity rate , parity (number of childbirth per married >15-years-old women), unemployment rate (rate of unemployed >15-years-old women), breastfeeding rate , oral contraceptive usage rate . Parity, unemployment rate, breastfeeding rate, and oral contraceptive usage rate were provided only per 17 provinces, that is coarser than other covariates provided per 252 districts. For parity, unemployment rate, breastfeeding rate, and oral contraceptive usage rate, districts in the same province were attributed with the same estimates.34 models for the breast cancer incidence rates and mortality rates were built, and odds ratio (OR) of each air pollutant to the incidence and mortality rates were estimated, adjusting for the confounding factors. To estimate the 95% confidence intervals for ORs, a basic bootstrap method was applied. To minimize the multicollinearity in the model, variable pairs with Pearson’s correlation coefficients higher than 0.7 were identified, and variables of lower correlation with the breast cancer incidence rate and mortality rates were excluded from the model. R statistics software version 3.6.2  was used in this study.Data are shown as median and interquartile range and the 95% confidence interval (95%CI) where applicable. Multivariable beta regression


Although the relationship between reproductive factors and breast cancer is internationally proved, reliable data on former USSR countries are scarce. This study examines the association of parity, age at the first childbirth, number of children, and breast cancer risk in Lithuanian women.The study that included women from 40 to 79 years old was based on a dataset that was made up linking all records from the 2001 census, all cancer incidence records from the Lithuanian Cancer Registry and all death records from Statistics Lithuania between 6th April 2001 and 31st December 2009. Cox’s proportional hazards regression models were used to estimate the hazard ratios (HRs) for parity, age at the first childbirth, and number of children.If compared to nulliparous women, parous women had a lower risk of breast cancer  and this risk further decreased with an increasing number of children. Women who gave birth after the age of 25 had a significantly higher risk of breast cancer. This disadvantage became statistically insignificant or decreased after controlling for total number of children.Parity and age at the first childbirth are strong predictors of breast cancer risk among Lithu-anian women.  Reproductive and hormonal factors play an important role in breast cancer ,2. ThereThe study was based on a census-linked dataset based on linkages between all records from the 2001 population Census, all cancer incidence records from the Lithuanian Cancer Registry, and all death and emigration records from Statistics Lithuania for the period between 6 April 2001 and 31 December 2009. Linkages between the census, emigration, death, and Cancer Registry records were implemented using personal identification numbers as unique identifiers of individuals. For individuals who died or emigrated, the exposure time was censored at the date of death or emigration. All of the linkage procedures were implemented by employees of Statistics Lithuania, who have permission to work with individual level data. Only aggregated data in a frequency table format that combines aggregated cancer cases, deaths, and population exposures for every possible combination of relevant socio-demographic and epidemiological variables were provided for this study. As this is a population-based study, members of the research team did not have access to the individual-level data containing identifiers. No special administrative permissions were required to access the aggregated anonymized census-linked dataset.  This study did not use any individual data containing personal identifiers.For the analysis, the frequency records representing two or more cases were split into individual records. The study population included all women aged 40–79 in the 2001 census. Information about parity, age at the first childbirth, and number of children was taken from the census. Women with missing information about parity and/or number of children were excluded from the study (1.5%). Data about diagnosed breast cancer was taken from the Cancer Registry records. Women were observed from 6th of April 2001 until the date of breast cancer diagnosis, death, emigration, or the end of follow up , whichever came first. The Cox proportional hazard regression model, with person-years of follow-up as the time scale, was used to estimate the hazard ratios (HRs) and corresponding 95% confidence intervals (CIs) of developing breast cancer. The final multivariate Cox model was adjusted for parity, age at the first childbirth, and number of children. Effects of parity were estimated using the data for all women, whereas the remaining analyses (including multivariate models) were restricted only for women with children. Age at the census date was treated as a continuous variable. STATA 11 statistical software was used to carry out the analyses.In total, the dataset includes 819 222 women, which were followed for breast cancer, deaths, and emigration for an average 8.6 years. During the period of observation, a total number of 9 711 new breast cancer cases were diagnosed, whereas the total number of women person-years of exposure to risk amounted to 6.6 million. The univariate results suggest that nulliparous status is strongly associated with breast cancer . If compared to nulliparous women, parous women had 16% lower risk of breast cancer  and the risk of breast cancer further decreased with increasing number of children. Age at the first childbirth shows a significant risk only for women who gave birth after age of 30 . However, in the multivariate analysis after adjustment for number of children, the disadvantage of women having a first child after the age of 30 notably decreased . With increasing number of children, the risk of breast cancer was decreasing even after adjustment for age at first childbirth.The differences of breast cancer incidence in Europe are likely due to variations in reproductive factors, such as postponed first childbirth and lower parity across populations, and these changes in the childbearing pattern during recent decades will probably affect cancer incidence in the future . Breast Despite very rapid changes in childbearing patterns during the last two decades, the results of our study generally correspond to those observed in other European countries. A French prospective cohort study using the data of 1718 breast cancer cases revealed the protective effect of high parity on breast cancers . A meta-Our results suggest that the risk of breast cancer decreased in parous women with an increasing number of children and this advantage persisted after adjustment for the age at the first childbirth. Meta-analysis of three large case-control studies of breast cancer with a total data set of 4 072 cases and 4,099 controls from several Italian regions, identified that the breast cancer risk after adjustment for age at first live birth, did not differ among women with one to four live births, but was significantly below unity (relative risk (RR) 0.6) for those with five or more live births . The larHaving the first childbirth at the age of 30 or older, was a significant risk factor for breast cancer in the present study. Meta-analysis of Negri et al. also ascertained that the breast cancer risk was directly related to age at the first live birth (RR 1.8 for ≥28 years versus < 22 years) . Ewertz An analysis of Finnish grand multiparous women data showed that an older age at the first childbirth (≥ 30 years versus <20 years) nearly doubled the breast cancer risk (from 0.40 to 0.73) . A SwediThe methodological strengths of this study include a cohort design based on the follow-up of the entire population of Lithuania, a large sample size, a substantial number of women with breast cancer and a reliable identification of the cases over the study period. During the period of observation, women were followed for breast cancer, deaths, and emigration for an average 8.6 years, whereas the total number of person-years of exposure amounted to 6.6 million. The main limitation of the study is the retrospective nature; therefore, we could not take into account exposure confounding from other hormonal and reproductive factors which may have influenced the results .Our findings suggest that parity, age at the first childbirth, and number of children are important risk factors of breast cancer among Lithuanian women, however, a further more in-depth research is needed to examine potentially important direct and confounding effects of socio-economic and biomedical variables.


Previous studies on the association between polyunsaturated fatty acids (PUFAs) and cancer have focused on n-3 PUFAs. To investigate the association between intake or blood levels of n-6 PUFAs and cancer, we searched the PubMed and Embase databases up to March 2020 and conducted a meta-analysis. A total of 70 articles were identified. High blood levels of n-6 PUFAs were associated with an 8% lower risk of all cancers (relative risk (RR) = 0.92; 95% confidence interval (CI): 0.86–0.98) compared to low blood levels of n-6 PUFAs. In the subgroup analyses by cancer site, type of n-6 PUFAs, and sex, the inverse associations were strong for breast cancer , linoleic acid (LA) , and women . In the dose-response analysis, a 2% and 3% decrease in the risk of cancer was observed with a 5% increase in blood levels of n-6 PUFAs and LA, respectively. Thus, there was no significant association between n-6 PUFA intake and the risk of cancer. The pooled RR of cancer for the highest versus lowest category of n-6 PUFA intake was 1.02 (95% CI: 0.99–1.05). Evidence from prospective studies indicated that intake of n-6 PUFAs was not significantly associated with risk of cancer, but blood levels of n-6 PUFAs were inversely associated with risk of cancer. Polyunsaturated fatty acids (PUFAs) are long-chain fatty acids which include more than one double bond in their backbone and are classified as n-3 PUFAs and n-6 PUFAs, according to the position of the first double bond in the carbon chain . GeneralSome studies have recommended reducing n-6 PUFA intake, pointing out that n-6 PUFAs, especially arachidonic acids (AAs), produce eicosanoids that can increase inflammatory disorders ,5. Most According to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement , two autWe searched for eligible articles published up to March 2020 in the PubMed and Embase databases. The search terms were as follows: “(fat OR fatty acids) AND (cancer) AND (risk OR incidence)”. To supplement the search, we reviewed the reference lists of previous reviews and the retrieved articles.To be included in this meta-analysis, articles had to meet the following criteria: (1) prospective design (cohort or nested case-control); (2) intake of n-6 PUFAs or blood levels of n-6 PUFAs as the exposure of interest; (3) cancer as the outcome of interest; and (4) reporting of relative risks (RRs) and 95% confidence intervals (CIs). If more than one article provided the RRs for risk of the same cancer site from the same cohort, the study including the largest population was selected for the meta-analysis.The following information was extracted: first author’s surname, publication year, region of study, cohort name, dates of study period, sex and baseline age of subjects, number of cases and subjects/controls or person-time, types of cancer, types of n-6 PUFAs, RRs with corresponding 95% CIs for all categories of n-6 PUFA intake or blood levels of n-6 PUFAs, and adjustment factors. We included the RRs that were maximally adjusted for potential confounders in the meta-analysis.The study quality was evaluated using the Newcastle-Ottawa quality assessment scale . This scThe pooled RRs and 95% CIs were calculated using the DerSimonian and Laird random-effects model . Any resP value for nonlinearity was obtained by testing the regression coefficient of the second spline equal to zero [A dose-response meta-analysis was carried out using the method described by Greenland and Longnecker ,15,16. T to zero .Q statistic [I2 statistic [p ≤ 0.05. All statistical analyses were conducted with STATA software version 14.2 .Heterogeneity across studies was assessed using the tatistic  and quantatistic . To expltatistic  and Eggetatistic  tests weA total of 70 publications were eligible for meta-analysis of the prospective association between intake or blood levels of n-6 PUFAs and the risk of cancer ,89,90,91versus lowest categories of n-6 PUFA intake was 1.02 (95% CI: 0.99–1.05) (p = 0.15) or Egger’s test (p = 0.24). We did not find any significant associations in the subgroup analyses by cancer site, type of n-6 PUFAs, or sex (p = 0.06) or nonlinear (p = 0.92) association between n-6 PUFA intake and the risk of cancer.Forty-six articles including 99,877 cancer cases investigated the association between n-6 PUFA intake and the risk of cancer ,87,90,9199–1.05) . No evid, or sex . In the versus lowest categories of blood n-6 PUFAs was 0.92 (95% CI: 0.86–0.98) with no significant heterogeneity  . Subgroup analysis by cancer site showed a significant inverse association between blood levels of n-6 PUFAs and breast cancer , and nonsignificant inverse associations were observed between blood levels of n-6 PUFAs and prostate , colorectal , and other cancers   . The res75–1.08) . For thep = 0.43). By type of n-6 PUFAs, blood levels of LA were also inversely associated with risk of cancer  without significant evidence of nonlinearity (p = 0.30)  A. There  = 0.30) B. For blIn the present study, we conducted a meta-analysis of prospective studies on the association between intake or blood levels of n-6 PUFAs and the risk of cancer. Our findings indicate that high blood n-6 PUFA levels are associated with a lower risk of cancer. Compared to people with the lowest blood levels of n-6 PUFAs, those with the highest blood levels of n-6 PUFAs had an 8% lower risk of cancer from any site. In the dose-response analysis, a 2% decreased risk of cancer was observed for a 5% increase in blood levels of n-6 PUFAs. When considering the site of cancer, breast cancer risk showed the strongest inverse association with blood levels of n-6 PUFAs. By type of n-6 PUFAs, the strongest inverse association was observed between blood levels of LA and risk of cancer. For sex, the inverse association was slightly stronger in women than in men. Regarding n-6 PUFA intake, no significant association was found in relation to the risk of cancer.A previous meta-analysis published in 1998 summarized the results from studies on LA intake and breast, colorectal, and prostate cancer . This stMost studies included in our meta-analysis of n-6 PUFA intake assessed dietary intake using food frequency questionnaires. The few studies using a food diary, food record, or 24-h dietary recall showed a nonsignificant inverse  or positThe results from the subgroup analysis by cancer site showed that the inverse association between blood levels of n-6 PUFAs and the risk of breast cancer was stronger than that of other sites. Breast cancer is a common cancer that has been studied a lot in relation to fat intake, and thus the largest number of studies were included in our meta-analysis. A large prospective study involving 2982 breast cancer cases found a 19% lower risk of breast cancer in women with the highest blood levels of total n-6 PUFAs, compared to those with the lowest blood levels of total n-6 PUFAs . When we2 (PGE2), which is derived from AA, has been found to increase tumor growth in previous studies [Although the evidence for the association between n-6 PUFAs and risk of disease was relatively limited compared to that of n-3 PUFAs, one meta-analysis including 310,602 individuals reported a low risk of CHD among people with high intake of LA . Another studies . Concern studies . However studies , and the studies .versus lowest) and dose-response meta-analyses. There was no significant heterogeneity, and the robustness of the results was identified through sensitivity analysis. In addition, there was no publication bias, which often could be of concern in meta-analysis. Despite these strengths, several limitations of this study should be noted. First, our meta-analysis of the association between n-6 PUFAs and the risk of cancer did not completely cover all cancer sites since previous studies have mostly focused on the risk of common cancers, such as breast, colorectal, or prostate cancer. Second, meta-analysis cannot solve problems of confounding that were inherent in the original studies. Although all studies included in the meta-analysis adjusted for age and most of the studies additionally controlled for major confounders such as BMI, smoking or alcohol, unknown or unmeasured factors might be a cause of confounding. Third, blood levels of n-6 PUFAs were measured at only at baseline, and thus, there is some possibility of change in blood levels of n-6 PUFAs during follow-up times. However, a previous study showed that a single measurement of blood levels of fatty acids reasonably reflected the blood levels over long periods [To the best of our knowledge, this is the first meta-analysis investigating the association between intakes or blood levels of n-6 PUFAs and risk of cancer from any site. As few studies have focused on n-6 PUFAs among the studies examining the association between fatty acids and the risk of cancer, our meta-analysis may provide useful information for future studies investigating the effect of n-6 PUFAs on the development of cancer. We tried to avoid recall bias by including only prospective studies in the meta-analysis. The inverse association between blood levels of n-6 PUFAs and risk of cancer was observed both in categorical  had a lower risk of cancer, compared to those with low levels of n-6 PUFAs in blood . The observed inverse association between blood levels of n-6 PUFAs and cancer risk was strong for breast cancer, LA, and women. We found no significant association between n-6 PUFA intake and the risk of cancer. Taken together our findings, n-6 PUFAs are unlikely to have an adverse effect on the development of cancer. Although it is not desirable to encourage people to eat high n-6 PUFAs, it might not be necessary to reduce n-6 PUFA intake excessively. Further well-designed prospective studies that use food records as a dietary assessment tool, consider blood levels of n-6 PUFAs as an exposure, or cover the risk of rare cancers are warranted to verify the effect of n-6 PUFAs on the risk of cancer.


Currently, the Breast Cancer Risk Assessment Tool (BCRAT), also known as the Gail model (GM) has been widely recognized and adapted for to study disparity in racial and ethnic groups in America including Asian and Pacific Islander American females. However, its applicability outside America remains uncertain due to diversity in epidemiology and risk factors of breast cancer in populations especially in Asian females. We sought to evaluate the performance of the GM to predict breast cancer risk in Asian countries.cancer, mammary, carcinoma, tumor, neoplasm, risk assessment tool, BCRAT, breast cancer prediction, Gail model, Asia, and Asian.This study identified articles published from 2010 by searching PubMed, MEDLINE, Scopus, Web of Science, Google Scholar and gray literature. The initial search terms were breast The search yielded 20 articles, with 7 articles addressing the AUC and/or the expected (E) to observed (O) ratio of predicted breast cancer risk, representing the accuracy of the GM in the Asian population. One publication reported the sensitivity and specificity but no AUC. None of the studies were accepted as the standard for reporting prognostic models. Several studies reported good prognostic testing and likely developed a new model modifying the items in the instrument.The results are not strong enough to develop breast cancer risk in the setting of Asian countries. Involving the breast cancer risk of the Asian population in developing a prognostic model with good statistical understanding is particularly important and can reduce flawed or biased models. Identifying the best methods to achieve well-suited prognostic models in the Asian population should be a priority. Cancer Research; Health Sciences; Public Health; Epidemiology; Women's Health; Breast cancer risk; Gail model; systematic review. Both the incidence and mortality of breast cancer vary among populations throughout the world; it is estimated that over a half of new cancer cases diagnosed among women are in developing countries. In 2018, according to GLOBOCAN, newly diagnosed cases and breast cancer-associated deaths accounted for approximately 11.6% and 6.6% of all cancer types, respectively , 4. The http://www.cancer.gov/bcrisktool/), is the most commonly used to predict breast cancer risk and was originally developed for use in white females to estimate breast cancer risk [The Breast Cancer Risk Assessment Tool (BCRAT), also known as the Gail model (GM)  and Social Science Citation Index (SSCI)), and Google Scholar as well as gray literature sources were considered to identify breast cancer risk using the GM applied in the Asian population. The last electronic search was conducted on June 19, 2019. The main keywords were entered by a combination of Medical Subject Heading (MESH) terms and text words, including “breast cancer” OR “mammary” OR “carcinoma” OR “tumor” OR “neoplasm” AND “risk assessment tool” OR “BCRAT” OR “breast cancer prediction”, “Gail model”, and “Asia” OR “Asian”. Any publication of every design  were identified and searched from January and May 2019. Studies that met the following inclusion criteria were included: published in English; accessible in full-text; assessed breast cancer risk instruments using the GM applied in Asian populations; and provided sufficient data. Sufficient data assessed by the method of all articles involving in this study addressed the area under the curve (AUC) or the expected (E) to observed (O) ratio of predicting breast cancer risk or measuring a 5-years breast cancer risk and lifetime breast cancer risk. The exclusion criteria were articles that were not published in English, including proceedings, case reports, scientific conference articles, article reviews, publications that were not in the databases above, and studies that did not report sufficient data.3In total, 120,263 English language articles were retrieved starting from 2010 which was the year that the GM or BCRAT in the Asian population was available for testing, to 2018. There were 77 references found after a detailed screening of the titles and abstracts based on data related to the application of the breast cancer GM. Then, after full-text reviews and the removal of duplicated articles, as many as 25 articles were screened that further met the eligibility criteria. Five studies were discarded due to no available full-text report. Ultimately, only twenty relevant articles were used in this literature review .Figure 2Twenty articles were yielded from the initial search , 56, 57.Of the publications that employed the GM in Asian populations, one was a longitudinal cohort study, two were retrospectively designed, two had prospective longitudinal formats, and five were observational case-control studies. In this systematic review, we included ten cross-sectional studies, one cohort study, one case control study and one prospective study because they focused on the follow-up of invasive breast cancer from the instrument application used. Based on the GM, those articles reported that the mean breast cancer risk at the five years and over a lifetime were uncertain. The characteristics of each article are summarized in 4This review highlights the scarcity of studies that have investigated the prediction of breast cancer risk using instruments such as the GM, especially focusing on Asian populations, with a detailed appraisal of the characteristics of model performance, such as calibration, discrimination and accuracy. In particular, 6 studies provided an evaluation of how successful their prognostic models were, while most studies had no validation at all. However, none of the instruments in our literature review that have been validated were reported to be unsuitable with the standard of prediction models.Instruments that have good calibration show a good discriminative capacity of the model to separate patients who experience events from those who do not , 60, 61.A good performance was mostly reported for the GM as a prognostic model among Western populations, such as American , CanadiaSome limitations should also be acknowledged. First, several studies evaluated in this current study did not utilize the standard tools for assessing the methodological quality of the studies conducting prognostic testing. This is because a limited number of studies in Asian women and published in English have employed predicting breast cancer risk using the GM model Second, some randomized trials followed up patients with invasive breast cancer, whereas prospective studies involved in this literature review were rare. However, our literature review had some strengths. First, a total of 20 published studies were not limited to publications with cross-table data but extended to studies with AUCs and 95% CIs, the expected (E) to observed (O) ratio or the lifetime or 5-year follow-up of breast cancer risk. Second, the sample size conducted in the literature review was sufficient to estimate the reliability and enhance the statistical power of the data analysis. Third, the included studies were conducted in different countries, which made the results more generalizable. Therefore, we concluded that the results based on the current evidence are relatively convincing.5In general, the current study has provided evidence that the application of the GM in predicting breast cancer risk among the Asian population is scarce. The results are not strong enough to develop breast cancer risk in the setting of Asian countries. At present, there is a paucity of adequate performance of the GM in Asian countries for the model to be applicable across cultures or even outside the health care setting in which such instruments were developed. Involving the breast cancer risk of the Asian population in the development of a prognostic model with good statistical understanding is particularly important and can reduce flawed or biased models. Further research is necessary to identify the best methods to achieve well-suited prognostic models in the Asian population and should be a priority.All authors listed have significantly contributed to the development and the writing of this article.Ministry of Research, Technology and Higher Education of Republic Indonesia) No PD-016/SKPP.TJ/LPPM UAD/III/2019.This work was supported by Kemenristek Dikti (The authors declare no conflict of interest.No additional information is available for this paper.


This short version of the interdisciplinary S3 guideline “Peri- and Postmenopause—Diagnosis and Interventions” is intended as a decision-making instrument for physicians who counsel peri- and postmenopausal women. It is designed to assist daily practice. The present short version summarizes the full version of the guideline which contains detailed information on guideline methodology, particularly regarding the critical appraisal of the evidence and the assignment of evidence levels. The statements and recommendations of the full version of the guideline are quoted completely in the present short version including levels of evidence (LoE) and grades of recommendation. The classification system developed by the Centre for Evidence-based Medicine in Oxford was used in this guideline.The online version of this article (10.1007/s00404-020-05682-4) contains supplementary material, which is available to authorized users. Peri- and postmenopausal women often seek medical assistance because of climacteric symptoms (e.g. vasomotoric symptoms). They want information (a) about the physiological changes during the menopausal transition period and (b) ways to alleviate their symptoms to improve their quality of life. During peri- and postmenopause, symptoms may change. Dysfunctions and diseases may develop that may or may not depend on the changes of sex hormones. Perimenopausal women often ask for information about how to prevent diseases that are typically associated with the perimenopausal transition and the postmenopause. The current S3 guideline, Peri- and Postmenopause—Diagnosis and Interventions’ is based on the previous interdisciplinary S3 guideline, Hormone therapy in perimenopause and postmenopause’ [Perimenopause—women with irregular menstrual cycles and possibly vasomotor symptoms.Postmenopause—women without a menstrual bleeding for at least 1 year in the absence of interventions which may cause amenorrhea .Peri-/postmenopause—women after hysterectomy with vasomotor symptoms. In women who are using hormone replacement therapy (HRT), it may be difficult to define the menopausal status.The different phases of the menopausal transition can be mainly diagnosed by clinical criteria. Hormone measurements are usually not necessary , 2. The In women older than 45 years, measurements of anti-Müllerian hormone, inhibin A, inhibin B, antral follicle count or ovarian volume should not be used to diagnose peri- or postmenopause. Follicle stimulating hormone (FSH) measurement may be used in women between 40 and 45 years with climacteric symptoms or irregular menstrual cycles and in women younger than 40 years with suspected premature ovarian insufficiency , 2.Vasomotor symptoms such as hot flushes and night sweats are the most common symptoms of the climacteric syndrome in peri- and postmenopausal women. Other symptoms such as sleep disturbances, mood swings, anxiety, and sexual impairment may also be associated with the peri- and postmenopause. In contrast to the vasomotoric symptoms, it is not clear whether the other symptoms are caused by hormonal changes. Loss of estradiol is the main cause of the climacteric syndrome, but the exact role of serum and tissue level changes of estradiol and other hormones such as androgens and gonadotropins is unclear.Frequency and duration of all climacteric symptoms vary considerably and may be influenced by a number of factors such as general health and well-being, socioeconomic status, cultural influence, and other factors. The prevalence of hot flushes has been reported to be between 14 and 51% among premenopausal women, about 50% among perimenopausal women, and between 30 and 80% among postmenopausal women [Peri- and postmenopausal women should be informed about the phases of peri- and postmenopause, the diagnosis, typical symptoms . In addition, they should be informed about the benefits and risks of different treatments strategies and the long-term effects of peri- and postmenopause on female health. Peri- and postmenopausal women should also be informed about different treatment options such as hormonal interventions, non-hormonal interventions and non-pharmacologic interventions.Estradiol is the most efficient means of therapy of climacteric symptoms. Therefore, HRT should be offered all women with moderate to severe climacteric symptoms with significant impairment of their quality of life. For women with an intact uterus, EPT is the most efficient treatment of vasomotoric symptoms. Hysterectomized women should only receive ET. The progestin component of EPT can be applied cyclically or continuously. Potent progestins such as synthetic progestins should be used for at least 10–12 days per month. Shorter treatment periods, or the use of natural progesterone and dydrogesterone instead of synthetic progestins may increase the risk of endometrial hyperplasia and endometrial cancer. One must consider that different HRT preparations or routes of application have different risk profiles. Transdermal application may have a better risk–benefit ratio and should be preferred over oral preparations. Women who desire phytotherapy should be informed that numerous preparations exist, and that the safety of these preparations is often unclear. In addition, combinations of different phytotherapy compounds may have different effects and may interact with concurrent medications [Peri- and postmenopausal women may observe changes in sexual function. They should be asked about signs of vaginal atrophy such as dyspareunia. Loss of libido is common in ageing women. Low levels of estrogen and testosterone may be associated with loss of libido. However, there is no strict association between sex hormone levels and libido as reasons for loss of libido are complex. A psychotherapeutic intervention may be beneficial. Treatment with testosterone may be considered when HRT was not efficient for improving libido. Moisturizers and lubricants may be used alone or in addition to vaginal estrogen preparations. All these interventions are usually sufficient to reduce vaginal symptoms such as dryness, pain on intercourse or vaginal discharge. When estrogens are used for the treatment of vaginal dryness, estriol (E3)-containing preparations should be preferred. E3 may be used efficiently in low or ultra-low doses. The dosage may be increased if symptoms are not relieved. When treatment is terminated, symptoms typically re-occur. Side effects of vaginal ET are rare , 2.After starting HRT, women should consult their gynaecologist regularly  to monitor treatment effectiveness and tolerability of the therapy. Women should be advised to consult their gynaecologist in case of atypical bleeding. Modification of HRT has to be considered for several reasons during different phases of peri- and postmenopause. When treatment is well tolerated and no pathological symptoms occur, yearly gynecologic consultations are appropriate. Vaginal ultrasound examinations and endometrial thickness measurements should not be used routinely during HRT .If it is determined that HRT should be stopped, two options can be offered: gradually reducing HRT or ceasing immediately. Gradually reducing may limit recurrence of symptoms in the short term. Whichever method is chosen, it has no influence on the recurrence rate of symptoms in the longer term.Randomised controlled trials have shown that in women with urinary incontinence, vaginal ET leads to significant improvements compared to placebo. However, a significantly higher prevalence of incontinence was documented when ET was applied systemically. Specifically, prevalence of urinary incontinence was doubled compared to placebo. EPT also leads to increases of urinary incontinence. However, the effect was smaller than in ET users , 11.Two small studies have demonstrated that vaginal ET reduced the frequency of urinary tract infections. Oral ET did not lead to a reduction of recurrent urinary tract infections , 12, 16.Because of the various limitations of the trials, mainly the WHI, statements and recommendations on the effects of HRT on cardiovascular diseases are based on a moderate level of evidence. Large randomized intervention trials have shown no general protection against cardiovascular diseases by HRT but indicate a neutral or even negative effect of HRT in postmenopausal women . The anaThe highest vascular risks of oral HRT are venous thrombosis and thromboembolism , 19, 21.Ischemic strokes are the second most common and because of possible persistent disabilities very serious risk of oral HRT , 19, 26.Neither ET nor EPT have significant influences on the risks for coronary heart disease in primary and secondary prevention , 23, 25.Excessive weight reduction leads to an increased risk for atraumatic fractures. A body mass index below 20 should be avoided. Consequently, weight gain is associated with reduced risk of atraumatic fractures. Weight gain above a body mass index of 35 should be avoided. Exercise and sufficient intake of calcium and vitamin D is recommended , 32.A number of therapies are licensed for the treatment of osteoporosis: estrogen (in combination with progestin in non-hysterectomised women), bisphosphonates, selective estrogen receptor modulators (SERMs), and a human monoclonal antibody against the RANK ligand (Denosumab) and parathyroid hormone (teriparatid). The efficiency of EPT or ET for primary prevention of osteoporotic factors has been demonstrated in observational studies and randomized controlled trials. The current version of the S3 Guideline of the German Association of Osteology (DVO) recommends that prevention or treatment of osteoporosis by HRT is feasible when women have concurrent climacteric symptoms or do not tolerate or have contraindications against licensed treatments for the prevention or treatment of osteoporosis , 29, 32.The reduction of fractures by HRT is independent of the duration of HRT and the age at treatment initiation. In addition, the risk reducing effect of HRT seems to persist at a lower level after its termination. Since osteoporosis is a chronic disease, treatment is usually performed for longer durations depending on the assumed baseline risk for fractures. The mean duration is 3–4 years. In accordance to the results of the WHI, the following risk reducing effects can be expected: − 23 fractures per 1000 HRT users , − 20 non-vertebral fractures per 1000 HRT users (CI 6–30), − 8 vertebral fractures per 1000 HRT users (CI − 18 to + 9), − 0 hip fractures per 1000 HRT users (CI − 10 to + 4), − 36 wrist fractures per 1000 HRT users (CI 19–43) [There are no data with strong evidence for an increase for the risk or a beneficial effect on dementia in women using HRT before the age of 65 years . In the There is no convincing data for the efficacy of HRT in prevention or treatment for depression in peri- und postmenopausal women. Women with depression should be treated according to current treatment guidelines , 34.EPT may increase breast cancer risk. This was shown in a number of meta-analyses that included observational studies as well as randomized controlled trials (RCTs). In the randomized Women´s Health Initiative (WHI) trial, EPT led to an increased relative risk of breast cancer of 1.26 with 8 additional cases per 10,000 women per year , 35. CohHowever, this risk is reduced after stopping HRT. When HRT was initiated at or around the age of menopause, breast cancer risk increases were higher than in women who initiated HRT more than 5 years after menopause. EPT-containing progesterone leads to smaller increases of breast cancer risk compared to EPT-containing synthetic progestins . HoweverIn contrast to a large number of observational studies, the WHI trial demonstrated a significant risk reduction for breast cancer in ET versus placebo users . The meaIn summary, HRT may be associated with increased breast cancer risk. The elevation is relatively small and has to be included in the individual risk–benefit calculation before initiating HRT for climacteric symptoms.Vaginal ET may lead to increases of systematic estrogen levels. It is not known whether it may also lead to increases of breast cancer risk. Ultra-low doses of vaginal ET  lead to good clinical effects on vaginal symptoms. It is unlikely that such an ultra-low-dose vaginal ET has a causal influence on breast cancer risk even when the therapy is used chronically .Meta-analyses including observational studies and RCTs could not demonstrate an increased risk of relapse of breast cancer after using HRT , 46. HowWomen who have been or are being treated for breast cancer may complain about vaginal symptoms such as dryness, dyspareunia, and pain. They use vaginal ET six times more often than systemic HRT. Vaginal ET may lead to increases in serum estrogen levels. Vaginal ETs are different in type, dosage, and frequency of application. In Germany, estriol is frequently used for vaginal ET. Ultra-low-dose estriol in combination with lactobacillus acidophilus was tested in a small study on its safety and efficacy. In this study, vaginal atrophy was significantly improved and serum levels of estriol were only increased during the initial period of ET. After 4 weeks of treatment, levels of estriol were slightly elevated in 50% of users while not at all in the remaining 50%. It can be concluded that ultra-low-dose vaginal estriol therapy  may be used in breast cancer survivors if non-hormonal alternatives had insufficient results .ET may lead to an increased risk of endometrial cancer in postmenopausal, non-hysterectomized women. This effect is dependent on duration and dose of ET . StandarClinical studies did not show increased rates of endometrial hyperplasia after vaginal ET. Therefore, it is not recommended to add a progestin to vaginal ET. However, there are no data on endometrial safety of vaginal ET when used for more than 1 year .A recent meta-analysis has included only one randomized trial and five observational studies assessing the safety of HRT in women who have been treated for endometrial cancer. Of note, the risk of endometrial cancer relapse was reduced in HRT users. However, most studies included in this meta-analysis were retrospective observational studies. Therefore, the evidence regarding the oncological safety of HRT among endometrial cancer survivors is limited. It can only be concluded that HRT after early stage endometrial cancer may not lead to a relevant increase of the risk of relapse , 57, 59.Patients who have been treated for endometrial cancer may complain vaginal dryness, pain, dyspareunia, vaginal bleeding, and urinary incontinence. This may lead to sexual dysfunction and reduction of quality of life. Since it cannot be excluded that vaginal ET may lead to increase the risk of relapse, endometrial cancer survivors should be treated with non-hormonal moisturizers or lubricants . Ph-stabThe Collaborative Group on Epidemiological Studies of Ovarian Cancer performed a meta-analysis of 52 studies. This included data from 21 488 postmenopausal women with ovarian cancer. Data from prospective trials showed that HRT users had increased risk for ovarian cancer after HRT durations of less than 5 years (RR 1.43). The absolute increase of risk is 1 in 1000 after 5 years and 1 in 1600 women using HRT .After treatment, ovarian cancer patients may experience natural or therapy-induced menopause. These patients may suffer from climacteric symptoms. Younger women may develop estrogen-associated diseases such as coronary heart disease and osteoporosis , 70. TheReproductive factors may influence the risk of colorectal cancer. Studies have shown that HRT has no effect or reduces the risk for colorectal cancer , 73. In Premature ovarian insufficiency (POI) or premature ovarian failure (POF) is defined as loss of ovarian function before the age of 40 and affects 1% of women . EtiologAll types of menstrual disturbances and various climacteric symptoms can be found. Women with POI/POF have a higher risk for estrogen-dependent diseases. However, there is no prospective study which shows lower mortality by hormonal substitution. It might make sense to continue hormonal treatment in women with POF until the average age of menopause.There seems to be no difference between a hormonal substitution with HRT or contraceptive pills, although two studies reported a small difference in blood pressure in favour of HRT compared to contraceptive pills , 77. BotHRT might have a positive effect on blood pressure compared to contraceptive pills.HRT and contraceptive pills have a positive effect on bone health.HRT does not offer protection from pregnancies.Women with POI and contraindications for HRT should be advised about cardiovascular risks, bone health and alternative treatments of climacteric symptoms.Women with POI should be generously transferred to specialized centres.Women with POI/POF should be informed about the following facts:Women should be informed about risks and benefits of medical interventions. The communication should include the probabilities of expected benefits and possible risks of harm with the patient and possibly with an accompanying person. For an individual assessment and evaluation of the probability of benefit and the risk of harm of HRT individual factors such as the woman´s general state of health, age at menopause, previous HRT, duration and use, doses and type of HRT and diseases while using HRT should be taken into consideration. To give adequate information about the risks to the woman seeking advice, the doctor must be familiar with the principles of risk calculation. He or she should also be able to communicate the probabilities in such a way that the patient can make her own individual decision for or against the initiation of HT. The figures necessary for this communication can be found in the long version and in Table Supplementary file1 (DOCX 24 kb)Below is the link to the electronic supplementary material.


Background: Previous studies suggest that education and income affect Brazilian women's breast cancer prevention behavior. The present study focused on the impact of perceived and estimated risk on mammography screening (MS) behavior.Materials and Methods: Information regarding socioeconomic variables and risk perception was obtained from 396 healthy women aged 40–79 years. Perceived comparative risk was measured on a seven-point Likert scale. A Breast Cancer Risk Assessment Tool of 5-year risk to develop breast cancer was used to determine objective risk. Estimated comparative risk was determined as categories of perceived risk relative to the objective risk. Regression analysis was applied to determine odds ratios (ORs) and confidence intervals (95% CIs) of variables.Results: Asked about the potential of MS to lower risk of death because of breast cancer, 215 (54.29%) responded that it does not lower risk. Women with low perceived comparative risk had a twofold  decreased chance to participate in MS annually, compared with women with high-perceived comparative risk (p = 0.020). Women without family history had a 7.6-fold  decreased chance of having a high-perceived comparative risk (p = 0.000). If compared with underestimation, the overestimation and accurate estimation of comparative risk tended to be associated with a decreased chance of MS attendance (p = 0.017). Regression modeling indicated that low educational level, no occupation, and no family history decreased the chance of women having MS .Conclusions: Risk perception depended on family history. Present data did not indicate that overestimation, or accurate estimation of comparative risk, increased chance of MS attendance. Educational level, occupation status, and family history, instead, determined MS performance. This is an opportunistic, not an organized, screening program, and women are not invited to participate. Furthermore, in Brazil, there are conflicting recommendations regarding the age threshold and interval for screening: the Ministry of Health recommends biannual mammography for women aged 50–69 years, whereas the Brazilian Society of Mastology recommends annual mammography screening (MS) starting at 40 years.5–7 Brazilian studies identified high income as the most important predictor of adherence.9 Two studies also identified higher educational level as predictor of adherence to the MS program.8 Furthermore, women with first- or second-degree relatives who had any type of cancer underwent regular MS more often than did women without any cancer in their families.9In Northeast Brazil, women often present at advanced stages of disease (Stage III and IV). High breast cancer mortality rates were attributed to nonadherence to the MS program.10–12 Estimated comparative risk, generally is determined as the relationship between perceived and objective risk. The latter can be measured with various models.13 Several previous studies focused on women's risk estimates of breast cancer.13–15 Other studies focused on possible associations between risk estimates and women's MS behavior.16–20Perception of risk comprehension may be another variable that affects women's MS behavior. The literature distinguishes between absolute, comparative, and numeric perceived risk.To the best of our knowledge, there are no Brazilian studies aimed at elucidation of the possible association between risk estimates and women's MS behavior. Increasing incidence and mortality rates in Northeast Brazil highlight the importance of identifying variables that affect adherence to the MS program. We asked whether overestimation and accurate estimation of comparative risk are positively associated with women's participation on the MS program. Risk perception and estimation were analyzed in the context of other important sociodemographic variables.The data sampling protocol was reviewed and approved by the Brazilian National Ethics Research Committee (CAAE Plataforma Brasil: 63089416.0.0000.5187). Written informed consent was obtained from each participant of the study. Consent to publish data anonymously was obtained from each participant of the study.21 Interviews were performed between March and October 2017. Socioeconomic variables and perception, respectively, estimation of breast cancer risk, were not different between women of both health service centers.Participating women were interviewed in waiting rooms for outpatient treatment of the health service center “Dr. Francisco Pinto” and the “Hospital Municipal Dr. Edgley,” both in Campina Grande, Northeast Brazil. Both are public institutions that do not offer MS and attend mainly to low-income persons without health insurance. In contrast to the “Hospital Municipal Dr. Edgley,” the health service center “Dr. Francisco Pinto” has no inpatient treatment. No differences were found among women of both institutions. Situated in the interior, about 120 km west of the state capital João Pessoa on the Atlantic coast, Campina Grande has a population of 385,276 (2010), making it the second largest city in the state of Paraíba.Interview of participants was always performed by one of the authors. Women were directly asked to participate. After explanation of the project and ethical considerations, the face-to-face interview started with a questionnaire filled out by one of the authors. To avoid selection bias, it was tried to interview all women present in the waiting room in the morning (8 o'clock a.m.–12 o'clock p.m.) and/or in the afternoon (2 o'clock p.m.–6 o'clock p.m.) of a defined day. Altogether, 430 women were asked to participate in the study, and 396 (92.10%) agreed in participation. Of these 396 women, 195 and 201 were from the “Hospital Municipal Dr. Edgley” and the health service center “Dr. Francisco Pinto,” respectively. Interviews normally were performed one to three times per week.Women were eligible for the study if they were 40 years or older and had not had any type of breast or ovarian cancer. Most of the interviewed women accompanied children, mainly because of vaccination. Other ones had viral infections causing cough and sneeze, or gastrointestinal problems. Furthermore, of each group of related persons, only one woman was interviewed to avoid possible repetitive information from family members.22 The questionnaire was subdivided into the following sections: (1) socioeconomic characteristics; (2) reproductive and health characteristics, including information regarding previous biopsies, and breast or ovarian cancer of the participant and first-degree relatives; (3) adherence to the MS program; and (4) perception of breast cancer risk.Interviews were based on a modified structured questionnaire developed in previous studies.Educational level was defined as follows. (1) Fundamental school with duration of 8 years was defined as “low.” (2) Middle school with duration of 11 years was defined as “middle.” (3) Higher educational levels were defined as “high.” Income was defined as minimum wage and multiple values of the minimum. The minimum wage in 2017 was R$937.00/month . Ethnic origin was based on self-reporting by interviewed women. Women were asked about their actual adherence to recommendations by the MS program. If asked about mammography utilization, the following options were distinguished: never, sometimes, every year, and every 2 years.23 Following data were used to calculate the 5-year risk with the tool. (1) Medical history of any breast cancer or ductal carcinoma in situ; this was for all 396 women. (2) Mutation in either the BRCA1 or BRCA2 gene; this was unknown in the case of all 396 women. (3) Age. (4) Race/ethnicity; this was in all 396 cases, Hispanic/Latinas born outside the United States. (5) Information about breast biopsies with benign diagnosis and their number. (6) Information about atypical hyperplasia; this was unknown in the case of all 396 women. (7) Women's age at the time of first menstrual period. (8) Women's age when they gave birth to the first child. (9) Number of first-degree relatives who had breast cancer.We used the Breast Cancer Risk Assessment Tool of the National Institute of Health (NIH) to calculate participants' 5-year risk of developing invasive breast cancer. The tool is based on the Gail model.p = 0.000).The risk of all 396 women to develop invasive breast cancer within the next 5 years was on average 0.86% (standard deviation [SD] = 0.31). The 5-year risk of 167 women, aged from 40 to 49 years, varied from 0.40% to 1.30% and was on average 0.56% (SD = 0.14), whereas in the group of 229 women aged ≥50 years, it varied from 0.80% to 1.40% and was on average 1.08%  test was applied to compare categorized variables. t-test, Mann–Whitney test (U-test) and analysis of variance (ANOVA) were applied to compare continuous variables. Results of multinomial logistic regression were presented as adjusted odds ratios (ORs), 95% confidence interval (95% CI), and p-value. p-Values of regression analyses were calculated using likelihood ratio tests for each variable. The four outcomes of regression analysis were defined by the performance of MS: never, sometimes, each year, and each second year. No performance of MS served as reference group. Significant variables of univariate regression analysis were used for regression modeling. Variables with significance level <0.2 in the univariate analysis were entered into the model. Then, variables with significance level <0.05 were kept in the model. Backward selection was used when significant variables were selected. The final model was tested for fitness using the likelihood ratio test. Statistical analysis was performed using SPSS STATISTICS™ software .Pearson's chi-square . Of 108 and 168 women who never underwent MS and underwent it every year, 13 (12.04%) and 41 (24.40%), respectively, had a family history .During the interviews, women were also asked about limitations and benefits of MS. When women were asked if MS can prevent breast cancer, 357 (90.15%) responded correctly that it does not prevent the disease. Asked about the potential of MS to lower risk of death because of breast cancer, 215 (54.29%) responded that it does not lower risk of death. Of these 215 women who believed that MS cannot lower risk of death, 75 (34.88%) never performed MS and 140 (65.12%) performed it , whereas heterogeneous data distribution of marital status, income, and ethnic origin was insignificant  and 23 (10.04%) overestimated the comparative risk (p = 0.000; p = 0.000; Perceived comparative risk was dependent on family history and this effect was stronger in women aged ≥50 years compared with those aged between 40 and 49 years . Women wp = 0.040; p = 0.010; p = 0.022; Sociodemographic variables and risk estimates of univariate analysis both were used for models of regression analysis . Risk esBrazilian women aged 40–49 years are exposed to conflicting public recommendations regarding the benefit of MS. As the Ministry of Health recommends an age threshold of 50 years, it was not surprising that women aged 40–49 generally had lower participation rates of MS, compared with older women. Notably, more than 90% of interviewed women knew that MS cannot prevent breast cancer, however, more than half of all 396 women denied that it can lower the risk of dying from breast cancer. This indicated that most women also did not consider MS to be beneficial. Of the 215 women who believed that MS does not lower risk of death, most performed it nevertheless. One factor could be that many women rely on recommendations of their physician independent of their own opinion. Another factor could be that women, even those who believe that MS does not lower chance of death, perform it to know if they are healthy.24 However, when the perceived risk was associated with the objective risk of women, then the resulting estimated comparative risk tended to be inversely associated with MS participation. In univariate analysis, overestimation and accurate estimation of comparative risk were negatively associated with MS participation. This was surprising, as most previous studies did not reveal any positive or negative association of comparative risk estimation with participation in MS.20 Labrie et al.24 suggested that fear of breast cancer increased the perception of personal risk among women aged 30–49 years. A recent study performed in Malta suggested that nonadherence to organized MS programs was associated with fear.25 Similarly, women in the present study who feared the disease might have tended to overestimate risk had an accurate risk estimation. In addition, regular participation in MS could also lead to underestimation of risk.To the best of our knowledge, this is the first Brazilian study to analyze women's perception of estimation of comparative risk and its impact on MS behavior. Low perceived comparative risk was associated with a decreased chance of MS participation during each year. Similarly, a recent study associated perceived low risk with decreased participation in MS.14 By contrast, similar to our results, other studies performed in Turkey, Canada, and the United States revealed a positive association between family history of breast cancer and comparative risk perception.26Present data suggest that the perception of comparative risk was dependent on family history of breast cancer. In women aged ≥50 years, this effect was more prominent than for women aged 40–49 years. In a Turkish study, perception of risk did not depend on family history.27 Similarly, studies from Iran and the United States reported a positive association between family history of breast cancer and adherence to MS programs.20After adjustment of data, risk estimates did not contribute to heterogeneous distribution of MS categories in models of regression analysis. Education level, occupation status, and family history instead were identified as independent variables. Women without family history had a reduced chance of participation in regular MS. This result is in agreement with previous Brazilian studies that reported decreased MS attendance among women without family history of cancer.28–31 In agreement with our results, several Brazilian studies reported a greater chance of adherence to MS among women with higher educational levels.33 In contrast, a recent study also performed in the Northeast region of Brazil, among women who had predominantly a low educational level, high income instead of education was associated with MS participation.9 The nationwide adherence study by Narayan et al. in the United States identified both high income and educational level as important predictors of adherence to MS.29Data suggest that women with lower educational levels tended to undergo MS less often. In recent studies from various countries, high educational level was one of the most important predictors of adherence to MS.35 A recent Australian study, in contrast, revealed that among women with home duties, the chance to perform ever a mammogram was higher, compared with women with professional or technical occupation.36 The relationship between occupation and MS performance may be highly dependent on the social context.Data of the present study also indicated that occupied women performed MS more often compared with those who were not occupied. A positive association between performance of MS and occupation was also found in previous studies.Our study had several limitations: Participants were randomly selected. However, a selection bias that favored a certain socioeconomic background and a defined risk estimation of breast cancer cannot be excluded. Data sampling in a health service center may have caused a selection bias toward women with health seeking behavior. As only women with breast and ovarian cancer were excluded from the study, sampling may have caused a bias toward individuals with chronic diseases. Estimated risk was determined as a categorical rather than as a continuous variable. This may have obscured the power of the study to detect more detailed associations with MS behavior. Results of our study cannot necessarily be extrapolated to other regions of the country, particularly as income was an important variable in several previous Brazilian studies. Low resolution of data may have been linked to small sample size. Finally, the study did not elucidate why women who overestimated comparative risk, respectively, estimated it accurately and participated less often in MS, compared with women who underestimated it.Neither perception nor estimation of comparative risk was independent variables that explained women's MS behavior. Educational level, occupation status, and family history instead were the most important variables explaining heterogeneity of women's MS behavior. Perception of high comparative risk was associated with family history. Overestimation and accurate estimation of breast cancer risk did not lead to an increase of MS performance. Fear could be an important psychological variable that determines both overestimation and avoidance behavior. It might be desirable for health authorities to provide more detail regarding the benefits and limits of MS. More than half the women did not understand that MS is capable of reducing the risk of death from breast cancer. Conflicting opinions regarding its benefit are probably confusing women aged 40–49 years. Prospective Brazilian studies regarding the benefit of MS are lacking, and it is to date unclear whether MS can decrease the mortality rate of breast cancer among Brazilian women.


In the Human Epidermal Growth Factor Receptor-2 (HER2) rs1136201 variant, the presence of the G allele may promote cellular alterations and increase breast cancer risk, in addition to enhanced cellular proliferation, tumor aggressiveness, and metastases. The aim of this study was to investigate the presence of the single-nucleotide polymorphism (SNP) variant, rs1136201, within the HER2 gene in women from the Northeastern region of Brazil and breast cancer risk.The study included 140 women who were divided into two groups, case (breast cancer) and control (without breast cancer), with 70 women in each group. Peripheral blood of each woman was drawn for the study of genomic Deoxyribonucleic acid (DNA) extracted from leukocytes using the genotyping technique by real-time polymerase chain reaction.p=0.32), while the AG genotype occurred in 19 (27.2%) and 13 (18.6%) women in the case and control (p=1.00) groups, respectively. No statistically significant difference in GG and AG genotypes was observed between the case and control groups in premenopausal women (p=1.00). Furthermore, no significant difference in genotypes was observed between the groups, among postmenopausal women (p=0.14).The GG genotype occurred in 1 woman in both groups (1.4%) (In this study, the HER2 rs1136201 polymorphism did not show any statistically significant association with breast cancer, both in premenopausal and postmenopausal women. Nevertheless, further studies with a larger sample size should be performed to assess the association of HER2 polymorphism with breast cancer risk in women from the Northeastern region of Brazil. Breast cancer is a neoplasm that most commonly affects women worldwide, with an estimate of 2,088,849 new cases and 626,679 deaths in 2018 based on GLOBOCAN 2018 . In BrazBreast cancer is a disease of unknown etiology that involves multiple risk factors of which genetic alterations are the major ones . AlteratSNP in the HER2 gene is one of the most important genetic alterations in breast cancer . Variousp1=0.32 and p2=0.2, the sample sizes would be n1=n2=70, with a 5% level of significance. The power of the two-sided test would be only 37% and a on-sided test would have a statistical power of 49%. The low power is the main caveat of this study. Patients with histologically confirmed breast cancer and healthy patients (controls) that were negative for malignancy were included in the sutdy, as confirmed by physical examination and imaging tests. Women older than 80 years and patients suffering from liver, metabolic, cardiovascular, kidney disease or those reporting other types of malignancies were excluded from the study. A volume of 3 mL of blood was drawn using disposable syringes and needles by a specialized technician, after the patient received medical consultation. Whole blood was stored in proper vials containing anticoagulant (EDTA) and stored in a freezer at −20 °C. All women in the study were instructed not to use anti-inflammatory drugs during the 72 h before blood sample collection.The Internal Review Board of the Federal University of Piaui approved the study under number 43447015.8.0000.5214 and all patients signed an informed consent form prior to admission. This is a controlled cross-sectional study, involving patients managed in the Breast Disorders Outpatient Clinic of the Getulio Vargas (HGV) Hospital and Laboratory of Molecular Biology of the Natan Portella Hospital, Federal University of Piaui, Brazil, from March 2016 to December 2018. The study included 140 women, divided into two groups of 70 women each: case group (with breast cancer) and control group (without breast cancer). In fact, considering the asymptotic test to compare two sample proportions if the true proportions were ® DNA Mini Kit (Life Technologies) was used, following manufacturer’s instructions.For DNA extraction of sample leukocytes, the PureLink Genomic® dye and a probe labeled with FAMTM dye. TaqMan® probes incorporate minor groove (MGB) binder technology, where the VIC® probe detects allele 1 and the FAMTM probe detects allele 2. The reactions were conducted in final volumes of 20 μL per patient, containing: 10 μL TaqMan® Genotyping Master Mix; 0.5 μL of TaqMan® probe customized for SNP genotyping of HER2 human gene (SNP ID rs1136201.Cod.C___7452451_1_Context sequence VIC/FAM (5' fluorescent reporter dye):CGCCCCCAGCCCTCTGACGTCCATC[A/G]TCTCTGCGGTGGTTGGCATTCTGCT) . Genotyping was performed by real-time polymerase chain reaction (qPCR). Absolute DNA quantification of a sample is performed with the use of a standard curve, obtained by amplification of known quantities of the same DNA. SNP genotyping assays contain a probe labeled with VICTTCTGCT) ; 5.5 µL p<0.05.The Chi-square test was used to determine whether genotype distribution conformed to Hardy-Weinberg equilibrium. Genotype frequency was compared between women with breast cancer and women without the disease from a control group, using Fisher’s exact test. The odds ratio (OR) and 95% confidence interval (CI) were calculated using Fisher’s exact test due to low frequencies in lines. Statistical significance was set at p=0.32), while the AG genotype occurred in 19 (27.2%) women from the case group and in 23 (32.9%) women from the control group (p=1.00) (p=1.00). In addition, no significant difference was found between postmenopausal women from the case and control groups (p=0.14) (The study included 140 women (70 cases and 70 controls). Mean patient age and standard deviation was 49.1 ± 11.1 years for cases and 45.4 ± 12.8 for controls. Genotype frequencies of the rs1136201 variant of the HER2 gene conformed to Hardy-Weinberg equilibrium. The GG genotype was present in one woman (1.4%) in the case and control groups ((p=1.00) . After s(p=0.14) .The Brazilian population is constituted by a rich racial miscegenation, mainly composed of European descendants, African and indigenous populations. Therefore, as in other countries with a different racial pattern, the distributions of genetic variants in the Brazilian population commonly do not show a consistent genetic pattern . HER2 geIn cancer, HER2 may be deregulated by a variety of mechanisms, including mutations, HER2 polymorphism, HER2 overexpression, and overproduction of ligands for HER2 activation . AnalyseA case-control study of HER2 Ile655Val including Chinese women suggested that the GG homozygote was associated with an increased risk for breast cancer . Lee et Thus, some authors hypothesized that the HER2 Ile655Val polymorphism may be considered a genetic biomarker of susceptibility to breast cancer risk, although it is not reliable for the estimation of tumor aggressiveness. However, the association between the HER2 Ile655Val (rs1136201) SNP and breast cancer risk has still not been fully elucidated . Furrer Several authors have shown conflicting results regarding the association between the HER2 and breast cancer; HER2 has somatic variations in different ethnicities . Our resTherefore, in this study, there was no significant association observed between the SNP rs1136201 variant of the HER2 gene and breast cancer risk in both premenopausal and postmenopausal women from the Northeastern region of Brazil. Nevertheless, owing to the high degree of racial miscegenation in Brazil, further studies with a higher statistical power and a larger sample size are warranted.Escórcio-Dourado CS, Alves-Ribeiro FA, Lima-Dourado JC, da Silva BB conceived the study idea, interpreted the data, wrote and revised the manuscript. dos Santos AR, de Oliveira Pereira R, Tavares CB participated in the design, coordination of the study, interpreted the data, wrote and revised the manuscript. Silva VC, Costa PV collected the materials and conducted data extraction. Soares-Júnior JM, da Silva BB analyzed, interpreted the data and revised the manuscript. All authors have read and approved the manuscript.


The aim of this study was to examine if exposures to chemicals at the workplace were associated with an increased risk of postmenopausal breast cancer, using improved exposure estimates.The design is a case–control study, nested within a cohort of women from the Malmö Diet and Cancer Study. The study comprised 2400 women, 731 cases and 1669 matched controls, born 1923–1950 and living in Malmö, Sweden between 1991 and 1996. An occupational hygienist reclassified the probability for exposure given by a job-exposure matrix, using individual data on work tasks. First-time diagnoses of invasive breast cancer were identified through the Swedish Cancer Registry.Women exposed to chemicals in their occupational environment had a statistically significantly increased risk  of breast cancer, and the risk correlated positively with duration of exposure but not with exposure intensity. Women exposed to chlorinated hydrocarbon solvents for more than 10 years had a significant higher risk of breast cancer  as well as women exposed to oil mist for more than 10 years .This study gives some support to the hypothesis that exposure to organic solvents as well as oil mist is associated with increased risk of breast cancer. With 1 million new cases diagnosed in the world each year, breast cancer is the most common cancer among women globally   genotoxic action, (ii) alteration of mammary gland development or hormone responsiveness, and (iii) hormonal tumour promotion.. The EDCs can alter the breast development or promote tumour growth  which is described in detail elsewhere , diagnosis of breast cancer before baseline (n = 50), and premenopausal status until end of follow-up (n = 55). Since risk factors for pre- and postmenopausal breast cancer differ in some aspects, all premenopausal breast cancer cases were excluded  and a prevalence of exposure (P) for 300 occupations. The occupational hygienist reviewed and adjusted the prevalence estimate (P) for each woman’s exposure based on the description in the questionnaire. If a woman was considered as unexposed the prevalence was set to 0%, and if exposure was likely or certain it was set to 100%. The original prevalence was retained if the case-by-case evaluation did not indicate otherwise. The prevalence set by the occupational hygienist substantially increased the accuracy of the exposure estimates. Exposure estimates used in this paper were “ever exposed” (p > 0),” mean intensity”  and duration of exposure (years worked in the exposed occupation). Chemicals of interest for our study that were available in NOCCA was; 1,1,1-trichloroethane, benzene, benzo(a)pyrene, bitumen fumes, diesel exhaust, gasoline exhaust, methylene chloride, perchloroethylene, toluene, and trichloroethylene. Chemicals used from FINJEM were aliphatic and alicyclic hydrocarbon solvents, aromatic hydrocarbon solvents, chlorinated hydrocarbon solvents, other organic solvents , fungicides, herbicides, insecticides, polycyclic aromatic hydrocarbons (PAH), gasoline exhaust, and oil mist. Ever exposed to chemicals in our study was defined as having worked in an occupation where at least 5% of the employees were, according to the matrices, exposed to any of these chemicals. Exposure from participants’ three latest occupations was added and calculated up until the women were enrolled in the study. The age range of inclusion was 45–74 years of age with a mean age of 58 years, resulting in an almost complete working history for each woman.Exposure to chemicals was assessed through a combination of the Scandinavian job-exposure matrices NOCCA and FINJEM and an occupational hygienists estimation of every woman’s probability of exposure according to the specific work task specified in the baseline questionnaire  for breast cancer in women exposed to chemicals/never exposed women and in duration analysis of 1–10 years and > 10 years. Since there was no significant difference between the results, we used unconditional logistic regression for improved power. Crude estimates were adjusted for age only and the adjusted model included age, parity, age at first-term pregnancy, months of breastfeeding/child, HRT, physical activity, alcohol consumption, height, and BMI. Mean intensity was divided dichotomously at the median and analysed using logistic regression. Trend tests in Tables The MDCS study was approved by Lund ethical review board (LU 51-90) and the present study was approved by the Stockholm ethical review board (Dnr 2014/233-31/4).The nested case–control study comprised 2400 women, 731 cases and 1669 controls. Table p = 0.01).Table p = 0.03). Also, women exposed to oil mist > 10 years had a statistically increased risk of breast cancer  with a statistical significant trend of increasing duration of exposure to oil mist and risk of breast cancer (p = 0.04).In the ever/never analysis in Table When investigating the risk by mean intensity for each chemical in Table r = 0.01–0.38). However, when analysing individual chemical agents, the correlation was high for diesel and gasoline engine exhaust (r = 0.61), methylene chloride and 1,1,1-trichloroethane (r = 0.87), and fungicides and insecticides (r = 0.87).The correlation was low between the main chemical groups organic solvents, fumes, pesticides, and oil mist  of increasing time of exposure with increasing risk of breast cancer and women exposed to chemicals more than 10 years had an increased odds ratio of 1.88 (95% CI 1.20–2.96). These findings are in line with our previous finding investigating the entire cohort using a job-exposure matrix for exposure assessment  of developing breast cancer compared to unexposed women. These findings support previous studies on exposure to organic solvents and increased risk of breast cancer (Goldberg and Labreche 3 had an OR of 2.70 (95% CI 1.09–6.68) compared to unexposed women with a statistically significant trend (p = 0.04). This is notable, since the occupational exposure limit for oil mist today in Sweden is 1.00 mg/m3 . Exposure to oil mist among females in Sweden occurs mainly in textile work and could be an exposure from spinners’ oil in spinning machines or dyeing processes. Women exposed to a high intensity of oil mist with a mean average intensity of 0.46 mg/mThis study is based on the same cohort as our previous study of occupational chemical exposures and the risk of postmenopausal breast cancer  at recruitment and many were close to retirement, leaving an almost complete occupational exposure history for most participants. Another weakness in this study is the power. Only two controls per case for this study were feasible to examine for the occupational hygienist, where more controls would have been optimal to get the best power Woodward . The expIn conclusion, this study gives some support to the hypothesis that exposure to organic solvents as well as oil mist are associated with increased risk of breast cancer. The exposure assessment based on a case-by-case review of exposure gave slightly higher risk estimates for some exposures than a previous analysis based on a job-exposure matrix.