Evidence on historical trends extracted embedded in recent data can advance our understanding of the epidemiology of breast cancer for Chinese women. China is a country with significant political, socioeconomic, and cultural events since the 1900s; however, no such studies are reported in the literature.Age-specific mortality rates of breast cancer during 1990–2015 in China were analyzed using APC modeling (age-period-cohort modeling) method. Net effect from birth cohort was derived to measure cancer mortality risk during 1906–1990 when no mortality data were collected, and net effect from time period was derived to measure cancer mortality risk during 1990–2015 when data were collected. Model parameters were estimated using intrinsic estimator, a novel method to handle collinearity. The estimated effects were numerical differentiated to enhance presentations of time/age trend.Breast cancer mortality rate per 100,000 women increased from 6.83 in 1990 to 12.07 in 2015. After controlling for age and period, the risk of breast cancer mortality declined from 0.626 in 1906–10 to − 1.752 in 1991–95 (RR = 0.09). The decline consisted of 3 phases, a gradual phase during 1906–1940, a moderate phase with some fluctuations during 1941–1970, and a rapid phase with large fluctuations during 1971–1995. After controlling for age and cohort, the risk of breast cancer mortality increased from − 0.141 in 1990 to 0.258 in 2015 (RR = 1.49) with an acceleration after 2005. The time trends revealed by both the cohort effect and the period effect were in consistency with the significant political and socioeconomic events in China since the 1900s.With recent mortality data in 1990–2015, we detected the risk of breast cancer mortality for Chinese women over a long period from 1906 to 2015. The risk declined more than 90% from the highest level in 1906–10 to the lowest in 1990–95, followed by an increase of 49% from 1990 to 2015. Findings of this study connected historical evidence with recent data, supporting further research to exam the relationship between development and risk of breast cancer for medical and health decision-making at the population level and prevention and treatment at the individual level. Breast cancer is the most common malignant tumor in women around the world. According to vital statistics from the World Health Organization’s International Center for Cancer Research, each year approximately 1.7 million new breast cancer cases are diagnosed worldwide, accounting for 25% of total malignant tumors in women; and 521,900 breast cancer deaths, accounting for 15% of the total malignant tumor deaths . This long period can be divided into three phases by changes in γk: (1) the Gradual Decline Phase (1906–40); (2) the Moderate Decline Phase (1941–70) with two slowing downs (cohort 1941–45 and cohort 1956–60); and (3) the Rapid Decline Phase (1971–95) with a plunge in breast cancer risk for three consecutive cohorts .Consistent with Figure The Gradual Decline Phase was corresponding to the persistent domestic political disturbances and foreign invasions after the thousand-year of feudal system was replaced by the first Republic of China. The Moderate Decline Phase was corresponding to the period from the end of Anti-Japanese Invasion in 1945, to the establishment of the People’s Republic of China in 1949 with important public health movement initiatives during the early years, followed by the establishment of health care systems. The Rapid Decline Phase was corresponding to the early stages of the Open Policies with a large number of women, particularly rural women rushing to the cities to make money.βj (blue line) and changes in the effect (orange line). The estimated βj s were a net measure of breast cancer mortality risk over time after adjustment of chronological age and birth cohort. Opposite to the declining cohort effect showing by γk, the estimated βj indicated a progressive increase in breast cancer risk. During the 25-year period, βj increased − 0.141 to 0.258 with a net increase of 0.399 = [0.258-(− 0.141)], equivalent to RR = 1.49 [= exp.(0.399)].Likewise, Figure βj (orange line), breast cancer risk during this period can be divided into two phase: The Slow Increase Phase (1990–2000) and the Quick Increase Phase (2000–2015). During the 1990–2000, changes in βj increased from 0.027 in 1999 to 0.053 in 2000 with 0.0026 per year [=(0.053–0.027)/10 years]; during the 2000–2015 period, changes in βj increased from 0.053 in 2000 to 0.169 in 2015 with 0.0077 per year [=(0.169–0.053)/15 years]. This difference indicated a 2.96 folds increases in the speed of breast cancer risk over the 25-year period.According to changes in βj in Figure βj was highly consistent with the continuously rapid economic growth since 2000 in China.The increasing trend depicted by γk and βj by controlling the impact of age αi, which is substantial. The estimated αi (blue line) in Figure αi, the estimated changes (orange line) indicate that the started at the highest level for women aged 20–24 years old, followed by a progressive decline to the lowest level by age group 50–54, ended with a slightly increasing trend. The time trend presented in Figure The APC modeling makes it possible to obtain adjusted measure of cancer mortality risk over time using In this study, we successfully analyzed 25-year mortality data of breast cancer among Chinese women. With data collect over 25 years during 1990–2015, we obtained adjusted measures of the risk of breast cancer mortality over a period of 110 years since 1906 using APC modeling method. Findings of this study have filled in 85-year data gaps in breast cancer epidemiology for women in China during 1906–1990 when no cancer data were collected. Furthermore, the time trend measured by period and cohort effect are net effect with the estimated cohort effect not affected by age and period and the estimated period effect not affected by age and birth cohort.Findings of this study provide systematic data the first time regarding the risk of breast cancer mortality for women in China from 1906 to 2015, of which, 25 years (1990–2015) with recorded data and 90 years (1906–1995) with no data, and an overlap of 5 years (1990–1995). According to the observed levels of and changes in the estimated cohort and period effects, the megatrend of breast cancer mortality for women in China can be divided into two phases: (a) the Historical Decline Phase (1906–10 to 1990–95) and (b) the Recent Increase Phase (1990–2015). By connecting the historical trend with significant socioeconomic events in the history of China, we can conclude that the risk of breast cancer for women in China is positively associated with development at the population level. If findings of this study can be verified with individual level data, they also add historical data to inform policy and decision-making for breast cancer prevention and treatment at the individual patient level.The two-phase increases in breast cancer mortality risk among Chinese women since 1990 provide one piece of recent data supporting a positive relationship between economic growth and risk of breast cancer –5. Increhttps://data.worldbank.org/indicator/SP.DYN.LE00.FE.IN). Although not a modifiable factor for breast cancer prevention, increase in life expectancy means more women live to old ages when the risk of breast cancer increases rapidly as indicated by the age effect we reported in this study. While it is true that breast cancer is a disease of affluence at the population level as supported by the positive relationship between breast cancer risk and economic grow as we observed in China and other studies in different countries [Frist, the positive relation at the population could be due to increases in longevity. Along with rapid economic growth, life expectancy at birth for women in China increased from 63.12 years in 1960 to 73.61 in 1980, and further to 78.29 in 2015 (World Bank, life expectancy at birth, female, Second, development-related risk factors are important. Different from longevity, increased risk of breast cancer for women in more developed countries could be due to the adaptation of high risk lifestyle and behaviors, such as delay in age of marriage, decline in breast-feeding , increasLast, the impact of medical technology and healthcare systems must be considered. Caution is needed when interpreting the positive relation between breast cancer risk and economic growth. In theory, economic growth will lead to advancement in medical and health technologies for cancer prevention and treatment, reducing breast cancer mortality, which is contradictory to the positive relationship between economic development and breast cancer mortality. However, it takes time to translate economic growth into advancement in medical and health technologies. The economic growth in China started in a few locations four decades ago, and started to spread to the country only in recent 10–15 years. Medical and health care services remain very backward in rural and less developed areas in China . Second,The declining trend in the risk of breast cancer mortality from 1906 to 1990 provides another piece of data from the long history in the past supporting the positive association between levels of development and risks of breast cancer among women. Despite the challenge to interpreting the relationship in detail in this study given the long history with complex and numerous changes in China since 1906, the Historical Decline Phase in breast cancer risk during 1906–1948 was consistent with a long period of progressive breakdown and deteriorations in many aspects in China, including the family systems, the societal systems, the government systems, the culture and economy. Life expectancy for Chinese was as low as 35 years prior to 1949. During this long period, agriculture was the backbone of the economy of China and the traditional lifestyles dominated in China. Women married at young ages; almost all mothers practiced breastfeeding; the society stigmatized women who used alcohol or tobacco; women often worked on the farmland or took care of family at home; and vegetables were the main ingredients in daily meal. All of these factors are protective for breast cancer.The Recent Decline Phase from 1949 to 1990 is more complex to understand. There was a continuous increase in life expectancy from 35 year in 1948 to 73.6 in 1980. Therefore, one explanation for the decline of breast cancer death could be due to rapid improvement in medical and health care. Typical examples include the establishment of the Three-Tier Healthcare Systems, the Policy of Prevention First, and the Policy of Rural Health First . MeanwhiFindings of this study bear significant implications. First, findings of this study suggest that breast cancer among women in China will increase as the country continues its current trend of urbanization and industrialization. Further, the increase will be quicker than that indicated by the vital statistics rates, which is biased by age and year of birth. Decision-makers and strategists for women’s health at the national and local levels must pay high attention to this issue and take proactive measures to curb the trend, including massive population-based prevention programs and clinical based treatment.Second, findings of this study underscore the need for additional studies to investigate factors at the individual level that eventually alter the risk of morbidity and mortality of breast cancer for evidence-based prevention and treatment. Many factors are reported to be associated with breast cancer for women in other countries, such as early development, puberty, breast growth, marriage, childbearing, breastfeeding , alcoholLast, our study findings suggest the need to examine disparities in access to effective breast cancer prevention and quality care in reducing breast cancer morbidity and mortality among women in China. Although development may increase risk of breast cancer morbidity, advancement in medical and publish health technologies may help to prevent and treat the disease. Therefore, equal opportunity for all women to access high technologies for prevention and treatment would be a strategy to break the positive relation between development and risk of breast cancer .There are limitations to this study. First, there is a lack of incidence data, preventing us from separating the risk of breast cancer morbidity from mortality. Epidemiological evidence derived from morbidity is stronger than from mortality data to describe breast cancer risk since incidence is less likely to be affected by technologies for medical care, availability, accessibility and utilization of care. We will continue our research when morbidity data become available. Second, caution is needed in interpreting a few study findings. For example, mortality rates for women aged 80–84 in 1990 were the only source of information for estimating cohort effect during 1906–10; and so did the mortality rates for women aged 20–24 in 2015 to estimate cohort effect during 1991–95. These two cohort estimates thus would be less robust than those for other cohorts. Third, this study is ecological in nature. The whole study was based on aggregated population-level data, ecological bias  must be Despite the limitations, findings of this study provide useful data supporting in-depth research with individual participant-level data.With recent mortality data in 1990–2015, we detected the risk of breast cancer mortality for Chinese women over a long period from 1906 to 2015. The risk declined more than 90% from the highest level in 1906–10 to the lowest in 1990–95, followed by an increase of 49% from 1990 to 2015. Findings of this study provide historical data supporting further research to exam the relationship between development and risk of breast cancer for medical and health decision-making at the population level and prevention and treatment at the individual level.


BRCA1 and BRCA2 when the affected individual is premenopausal, controversy surrounds the benefit in less understood risk-profile clinical scenarios. This comprehensive review explores the current evidence underpinning the role of contralateral prophylactic mastectomy and its impact on contralateral breast cancer risk and survival in three distinct at-risk groups affected by unilateral breast cancer: known genetic carriers, those with strong familial risk but no demonstrable genetic mutation and women who are of young age at presentation. The review supports the role of contralateral prophylactic mastectomy in “high risk” groups where the evidence suggests a reduction in contralateral breast cancer risk. However, this benefit is less evident in women who are just young at presentation or those who have strong family history but no demonstrable genetic mutation. A multidisciplinary and personalized approach to support individuals in a shared-decision making process is recommended.The uptake of contralateral prophylactic mastectomy is rising with increasing trends that are possibly highest in the USA. Whilst its role is generally accepted in carriers of recognized high-risk predisposition genes such as  A stuFactors that contribute to this decision include patient age, disease stage, previous breast biopsies, genetic predisposition or family history of breast cancer, fear of recurrence, concern with cosmetic symmetry and physician recommendation ,5,6,7,8.Patients tend to overestimate their risk of developing a contralateral breast cancer ,10 as weImprovements in modern multidisciplinary management have led to a reduction in the incidence of contralateral breast cancer from approximately 0.6% to 0.2–0.5%/year . ConsequThis comprehensive review explores the current evidence underpinning the role of contralateral prophylactic mastectomy and its impact on contralateral breast cancer risk and survival in three high-risk groups affected by breast cancer: (i) genetic carriers, (ii) strong family history with no demonstrable mutation, and (iii) young women.BRCA”, “TP53”, “PALB2”, “CHEK2”, “ATM”, “mutation carrier”, “family history”, “young women”, “non-genetic carriers”, “overall survival”, “disease-free survival”, “contralateral breast cancer” and “risk” were included. Relevant references from identified papers were also included.A comprehensive literature review was performed, assessing all studies published in the English literature from 1974 to March 2019 across Embase and Medline search engines. Search terms “contralateral prophylactic mastectomy”, “unilateral breast cancer”, “BRCA carriers with breast cancer carry a higher risk of contralateral breast cancer, 23.7% (95% CI 17.6–30.5), compared with non-carriers, 6.8% (95% CI 4.2–10), respectively, . This risk was higher in BRCA1 compared to BRCA2 carriers  [BRCA1/2 carriers at a median follow-up of 12.5 years was shown to be 2–3 times higher compared to non-carriers . The 10-year cumulative contralateral breast cancer risk following the initial breast cancer diagnosis was 21.1% for BRCA1, 10.8% for BRCA2 and 5.1% for non-carriers [BRCA1, 13.5% (95% CI 9.2–19.1) for BRCA2 and 3.6% (95% CI 2.2–5.7) for non-carriers [ = 0.04) . In a Ducarriers . These fcarriers .BRCA carriers [BRCA1/2 carriers combined  [BRCA1: 11–52%; BRCA2: 7–18%) [BRCA1: 25.5%; BRCA2: 17.2%) in patients <41 years, compared to 12.6% in the 41–49 year group  [The age of first breast cancer diagnosis is a significant predictor of contralateral breast cancer risk in carriers ,18,19. R 17–29%) ,22,23,24: 7–18%) ,22,24,25BRCA1/2 carriers with breast cancer, Graeser demonstrated that the 25-year cumulative contralateral breast cancer risk for BRCA1 carriers with the first breast cancer diagnosis at age <40years, 40–50 years and >50 years, was 62.9% (95% CI 50.4–75.4), 43.7% (95% CI 24.9–62.5) and 19.6% (95% CI 5.3–33.9) respectively. In BRCA2 carriers, the corresponding rates were 63% (95% CI 32.8–93.2), 48.8% (95% CI 22.7–74.9) and 16.7% (95% CI 1.0–32.4) for the respective age groups [In a retrospective study of 1042 BRCA mutation carriers [Contralateral prophylactic mastectomy reduces the risk of contralateral breast cancer in carriers ,26,27. TBRCA carriers with breast cancer [BRCA carriers with breast cancer, contralateral prophylactic mastectomy was associated with improved overall survival on multivariate analysis, having adjusted for risk-reducing salpingo-oophorectomy  [There is conflicting evidence on whether contralateral prophylactic mastectomy improves survival in t cancer ,29,30,3129–0.82) ,29,30,31p = 0.03). However, this difference was not significant once adjusted for prophylactic oophorectomy  [In a retrospective study by Van Sprundel, contralateral prophylactic mastectomy was associated with superior overall survival compared to active surveillance at 5-year follow up  . Notably = 0.14) .BRCA carriers who underwent contralateral prophylactic mastectomy against those who did not  [BRCA carriers and non-carriers with triple negative breast cancer [A meta-analysis by Valachis demonstrated no difference in breast-cancer-specific survival between  = 0.40) . However = 0.40) . To furtt cancer . The avaCHEK2, TP53, ATM, PALB2, PTEN, and CDH1 account for a small fraction of familial breast cancers. The available studies are sparse and primarily family-based, with potential ascertainment bias. It should be noted that the existing literature focusses mainly on relative rather than absolute risk estimates.Mutations in CHEK2* 1100delC carriers  [CHEK2 carriers may be more sensitive to ionizing radiation that may contribute to contralateral breast cancer rates in patients receiving adjuvant radiotherapy following breast conserving surgery [In a recent meta-analysis, Akdeniz demonstrated an increased contralateral breast cancer risk for 77–4.27) . This mu77–4.27) ,38,39,40 surgery . The tru surgery .TP53 carriers with breast cancer.There are no studies estimating contralateral breast cancer risk in ATM  were associated with a lower contralateral breast cancer risk  compared to those with rare, missense ATM mutations. The protective mechanisms may occur through an alteration in ATM activity as an initiator of DNA damage response or through its role in TP53 regulation [ATM variants may exert a protective effect and reduce contralateral breast cancer risk, while rare ATM missense, deleterious variants may act synergistically with radiation exposure to increase this risk [c.1899-55T>G , c.3161C>G , c.5558A>T , and c.6348-54T>C  were associated with significantly reduced risk. On the other hand, female carriers of any rare missense ATM variant, who received radiation therapy for their first breast cancer, had a significantly elevated contralateral breast cancer risk compared to unexposed women .In a multicentre, population-based, case-control study, Concannon suggested that four common variants of gulation . Bernstehis risk . In thisATM variants and the overall risk of contralateral breast cancer remains controversial, although the combination of radiotherapy and certain ATM missense variants appears to accelerate tumour development [The direct relationship between the presence of elopment .PALB2 carriers with breast cancer.There are no studies estimating contralateral breast cancer risk in CDH1 carriers.There are no studies on the risk of contralateral breast cancer in PTEN carriers with breast cancer.There are no studies estimating contralateral breast cancer risk in BRCA1/2 genes .No studies have investigated the role of contralateral prophylactic mastectomy in the risk reduction of contralateral breast cancer in patients with a diagnosis of breast cancer that harbor a genetic mutation in non-TP53, CDH1 and PTEN mutations because of the additional competing cancer risk. In view of the limited evidence, no further comment can be made, except to reinforce that contralateral prophylactic mastectomy should be considered on an individual basis for women with unilateral breast cancer in this group.There is no data to support any survival benefit from contralateral prophylactic mastectomy in this group of patients (“other” genetic carriers). This would be even more challenging in those with A positive family history remains a strong risk factor for contralateral breast cancer, even after excluding mutation carriers ,47,48. TBRCA1/2 mutation, Rhiem observed a cumulative contralateral breast cancer risk, 25 years after a first breast cancer diagnosis of 44.1% (95% CI 37.6–50.6) in BRCA1 positive families, 33.5% (95% CI 22.4–44.7) in BRCA2 positive families and 17.2% (95% CI 14.5–19.9) in BRCA1/2 negative families [In a retrospective study of 6230 women from high risk families, with or without a known families . This effamilies ,53.BRCA1 and BRCA2-positive family history, respectively. The corresponding risk was 28.4% in patients from non-BRCA families [The age at which the affected relative is diagnosed with their first breast cancer and the presence of bilateral disease impacts on contralateral breast cancer risk. Rhiem further observes that patients diagnosed with breast cancer at age <40 years had a cumulative risk 25 years from primary diagnosis of 55.1% and 38.4% for families .The highest risk lies with women who have relatives with early-onset, bilateral breast cancer ,53,54,57BRCA-positive families . However, only 4% (19/430) of the cohort were non-carriers, with the remaining 96% representing mutation carriers. Fayanju reported a significant reduction in pooled relative  and absolute risk –(−12.4)) of metachronous contralateral breast cancer amongst recipients of contralateral prophylactic mastectomy [p < 0.0001) of contralateral breast cancer following contralateral prophylactic mastectomy, at a median follow-up of 17.3 years, compared to a matched cohort of women who did not receive mastectomy. However, this cohort, with either an affected 1st or 2nd degree relative was not screened for mutation status [Contralateral prophylactic mastectomy may reduce the risk of contralateral breast cancer in women with an elevated genetic or familial risk . This mestectomy . This ann status .McDonnell also demonstrated a contralateral breast cancer risk reduction following contralateral prophylactic mastectomy in pre- and postmenopausal women with a strong family history of breast/ovarian cancer i.e., 94.4% (95% CI 87.7–97.9) and 96% (95% CI 85.6–99.5) respectively, at a median follow up of 10 years using the Anderson model  to prediThe evidence on the effect of contralateral prophylactic mastectomy on disease-free and overall survival is conflicting .p = 0.03) and disease-free survival  on multivariate analysis [BRCA1/2 carrier [A Cochrane review of 1708 women with variable familial risk, who underwent contralateral prophylactic mastectomy, concluded that although this decreased the incidence of contralateral breast cancer, there was no association with survival improvement . The metanalysis . In a reanalysis . Further carrier .BRCA mutation carriers, which may confound contralateral breast cancer risk and survival. Furthermore, they do not consider risk-reducing adjuvant therapies. In a retrospective study of 652 patients ≤35 years compared to 2608 women >35 years, the relative risk of contralateral breast cancer was 2.48 in the younger, compared to the older group [The definition of ‘young’ age group in the literature, varies from the “under-35”- to 50 years. Young age at first primary breast cancer diagnosis is associated with an increased contralateral breast cancer risk, poor prognosis and serves as an independent predictor of recurrence and breast-cancer-related death ,69,70,71er group . The conp = 0.07) in the contralateral prophylactic mastectomy vs. non-mastectomy group, and in ER-negative disease, 0.16% vs. 0.90% (p = 0.05) respectively [The younger age group is generally underrepresented in studies evaluating the role of contralateral prophylactic mastectomy. Using a Surveillance, Epidemiology, End Results database analysis of 107,106 women, of whom 8902 (8.3%) underwent contralateral prophylactic mastectomy, Bedrosian conducted a subgroup analysis of young women (<50 years) and the risk of contralateral breast cancer after contralateral prophylactic mastectomy, in both ER-negative and ER-positive, early-stage breast cancer. In ER-positive disease, the cumulative incidence of contralateral breast cancer during the 6-year study period was 0.13% vs. 0.46% . However, this did not translate to an improvement in breast cancer-specific survival [There is conflicting data on the impact of contralateral prophylactic mastectomy on survival in this patient group. In a population-based study of 614 women <35 years, 81 (13.2%) of whom were elected for contralateral prophylactic mastectomy, Bouchard-Fortier demonstrated that recurrences, defined as local, regional or distant, were significantly fewer for patients with contralateral prophylactic mastectomy than without , compared to the unilateral mastectomy group [p < 0.001) between these two groups [p = 0.046), although this effect was not demonstrable for 5-year overall survival [In an analysis of the National Cancer Database between 2004 and 2014, Lazow demonstrated that after controlling for patient demographics, tumor grade and use of adjuvant therapies, bilateral mastectomy in women < 40 years was associated with increased 10-year overall survival . This effect was not reproduced in young women with early-stage, ER-positive breast cancer [There is a suggestion that contralateral prophylactic mastectomy may confer benefit in young women with early-stage, ER-negative breast cancer. In a population-based study of 107,106 breast cancer patients, 3731 (3.48%) of whom were young (18–49 years), contralateral prophylactic mastectomy was associated with improved disease-specific mortality  [Other retrospective cohort or population-based studies refute the survival benefit of contralateral prophylactic mastectomy in young women ,73,75,77Overall, these findings should be interpreted with caution as the quality of the data does not allow for definitive conclusions to be drawn.Contralateral prophylactic mastectomy is increasingly being performed despite an ambiguity of evidence to support an oncological benefit. In 2007 and 2009, two studies reported that contralateral prophylactic mastectomy rate had increased 148% and 150% among all patients diagnosed with non-invasive and invasive breast cancer respectively ,80. CurrBRCA1/2 gene mutations [Although intuitively it is expected that contralateral prophylactic mastectomy would decrease the risk of contralateral breast cancer, the available data only support this in patients with utations ,26,27. IDespite the potential decrease in contralateral breast cancer, the effect of contralateral prophylactic mastectomy on oncological outcomes is debatable as studies suggest that this reduction is not translated into survival benefit. Moreover, the role of contralateral prophylactic mastectomy per se as a contributing factor for improved outcomes in women with unilateral breast cancer is difficult to accurately define, as the majority of the available data is of limited quality. Meta-analyses are only as strong as the independent studies they comprise. The majority of studies are retrospective cohorts and based on population/family studies. Therefore, the results should be interpreted with caution because of potential uncontrolled biases. The way to address these issues is with higher quality data but it is unlikely that the future will harbour randomized clinical trials investigating the impact of contralateral prophylactic mastectomy on contralateral breast cancer risk and survival due to patient preference and ethical considerations. One proposal is to set up robust prospective registries to help enhance our knowledge in the field. The majority of existing studies do not account for the significant role conferred by improved systemic therapies and its effect on contralateral breast cancer risk and improved oncological outcomes, factors that merit future research.BRCA1/2 mutations, patients with a history of mantle field radiation to the chest before age 30 years [Recently, and in order to aid clinicians approach this controversial topic, both the American Society of Breast Surgeons and Association of Breast Surgery published consensus statements on the utilization of contralateral prophylactic mastectomy. Both were aligned on supporting its use in women with significant contralateral breast cancer risk i.e., 30 years ,86. HoweIn conclusion, contralateral prophylactic mastectomy may be supported in ‘high-risk’ groups as evidence indicates a possible reduction in contralateral breast cancer risk and also potentially improved oncological outcomes. The evidence to demonstrate that this may confer benefit in the other risk groups or in older patients is less established. It is therefore imperative to follow a multidisciplinary, personalised approach, to educate women on the best available evidence and to support individuals in a shared-decision making process.


The province of Quebec (Canada) has implemented a breast cancer screening program to diagnose this cancer at an early stage. The strategy is to refer women 50 to 69 years old for a mammogram every two years by sending an invitation letter that acts as a prescription. Ninety per cent (90%) of deaths due to breast cancer occur in women aged 50 and over. Numerous studies have shown social inequalities in health for most diseases. With breast cancer, a significant paradox arises: its incidence is lower among disadvantaged women and yet, more of them die from this disease. The health care system might play a role in this inequality. The scientific literature documents the potential for creating such inequalities when prevention does not consider equity among social groups. Immigrant women are often disadvantaged. They die of breast cancer more than non-immigrants. Studies attribute this to late-stage diagnosis due to poor adherence to mammography screening programs.The main objective of our research is to assess how Haitian immigrant women in Montreal are reached by the Quebec Breast Cancer Screening Program, and specifically how they perceive the mammogram referral letter sent by the program.i) In-depth interviews with influential community workers to identify the most relevant issues; ii) Focus groups with disadvantaged women from Montreal’s Haitian community.The study uses a two-step qualitative method: A mammogram referral letter from the Breast Cancer Screening Program may be a barrier to compliance with mammography by underprivileged Haitian women in Montreal. This might be attributable to a low level of literacy, poor knowledge of the disease, and lack of financial resources.Barriers may be underestimated in underprivileged immigrant and non-immigrant communities. A preventive strategy must be adapted to different sub-groups and must also take into account lower literacy levels. To increase mammography uptake, it is crucial that the benefits of prevention be clearly identified and described in understandable terms. Finally, economic access to follow-up measures should be considered. In 2017, it was estimated that there were 26,500 new breast cancer cases in Canada and that 5000 women died of the disease . Indeed,To detect the disease early, the Quebec Breast Cancer Screening Program (QBCSP) provides free mammograms to women aged 50 to 69 years old. When they reach age 50, women receive a medical referral letter every two years inviting them to have a mammogram. The strategy is to facilitate medical referrals and monitor test uptake. Since the start of the program in the 1990s, a significant decrease in mortality from breast cancer has been observed .As explained in the introduction, the letter sent by the QBCSP acts as a referral for a mammogram. However, the participants did not think it looked like a referral form, as intended. They were confused about the contents of the letter. Their questions pointed out the importance of some details omitted from the letter and which need clarification:Occasionally, despite the fact that participants were addressed in Creole, their answers were off-topic. This suggests that the question was not properly understood.The researcher noted moments of silence, again implying lack of understanding. Sometimes, the researcher had to explain, restate, or guide the discussion to ensure that participants understood.The most misunderstood words were ‘mammogram’ and ‘screening’. However, participants said they understood the word ‘breast’, but would still prefer the Creole translation of the word.There were signs of social desirability when it came to commenting on the health system or the letter. Participants reported being quite satisfied with the letter and had almost no comments on its content and format, despite their lack of understanding. This contradiction will be further discussed below.This category included cultural characteristics specific to Haitians and socioeconomic characteristics attributable to any disadvantaged group.Women from the Haitian community perceive breasts as a very important part of the female body, representing beauty, pleasure, and maternity. These women are not uncomfortable or inhibited when it comes to breasts.Haitian women recognize the importance of going to a doctor and having confidence in him or her.The women said they fear death and feel vulnerable to the disease. We will see below that a minority of participants do not feel vulnerable and are not afraid, because of their fatalistic dispositions.“Researcher: Do you think that most Haitian women understand the letter?”“Participants: No. Those who don’t will ask someone to explain it.” [Translation]Participants expressed the importance of having support from the community, especially because they are illiterate:“I can’t be afraid of the disease since it’s chosen me.”“You can’t be afraid because it’s not you who put it in yourself.”“I have children; Jesus will not do this to me.” [Translation].As stated previously, some women said they were not afraid of breast cancer:Participants stated that their friends do not seem to participate in the program.Finally, a very important social characteristic of these women is using Creole as the language of communication. Participants expressed the need to have a translation of the letter’s key words, so they could understand the main issues presented.Participants were aware of the disease and had enough knowledge to understand that it is serious. Some referred to the hereditary nature of this disease, mentioning that they would feel more vulnerable if they had a family history of breast cancer. In addition, participants understood that the disease affects all groups, regardless of race, country of origin, or other factors.As for the causes of breast cancer, some participants said that lifestyle habits like smoking, drinking alcohol, malnutrition, and bad eating habits affected the likelihood of contracting the disease.Despite having somewhat limited knowledge, and though several women were aware of breast self-examination and knew how to perform it, very few participants were familiar with mammograms.One participant talked about the reliability of the test. She mentioned the false-positive and false-negative results as being the main reason why she does not get mammograms, along with the anxiety they provoke. This segment was also coded as a barrier.“My kids are not like me. They know.”“We know nothing about breast cancer.” [Translation].Some participants openly admitted that they know little about the disease:There were mistaken beliefs about breast cancer and mammograms. Participants believed that a blow to the breast systematically causes breast cancer. They also thought that mammograms could cause breast cancer because of the pressure on the breasts. Concerns were also raised regarding radiation exposure. There was a misconception about mastectomies as well: participants thought that one cannot function with a missing breast and that cancer will kill no matter what.Stress concerning the outcome and challenges posed by the disease was also a concern. Participants said they would rather not know they are sick, because knowing would make them sicker.“When I lived in Haiti, I didn’t know there was a disease like breast cancer. I saw several women die. When I got here, I understood they probably died from breast cancer. [ …] In my village, in the countryside, not everybody thinks about breast cancer”. [Translation].Participants said that breast cancer is not a prevalent disease in Haiti. In fact, the WHO reports that 6% of all deaths (men and women) in Haiti were attributed to cancer in 2010 . HoweverParticipants were unaware that breast cancer was inside the breast most of the time, and did not necessarily form a lump on the surface. They did not know that breast cancer was an insidious disease that one could not feel.We noted some confusion between breast and cervical examinations, hence the confusion about mammograms. Participants also did not know the difference between a mammogram and a simple X-ray.We observed that lack of knowledge was also due to a limited understanding of the French language. As we handed out the QBCSP letter, we observed that the women had difficulty reading and understanding it. It should be noted that in Haiti, French is used by the upper-middle class only.Another issue was the concept of mail. Many people do not have formal addresses in Haiti. Moreover, in many villages and neighbourhoods, postal service is poor. People in Haiti, particularly in low socioeconomic classes, very rarely receive letters by mail.Participants expressed a preference for Haitian doctors so they could communicate in their mother tongue and better express their concerns. They clearly stated their apprehension about not being able to explain their feelings well in French or English.Other health system barriers noted by participants were not having a family physician, the false positive and false negative controversy (as presented in the news), waiting times in hospitals and clinics, and the cost to avoid waiting lists. Indeed, in Montreal, if a mammogram result is of concern, further exams are prescribed, including ultrasounds. However, waiting lists for these tests can be very long and only patients who can afford it can skip the waiting period and pay to have it in a private clinic.The QBCSP sends a letter in French or English since Quebec is a bilingual province. To better understand at least the purpose of the letter, participants asked that the words ‘breast’, ‘mammogram’, and ‘cancer’ be translated into Creole.The letter is one page long and has five dense paragraphs. Participants suggested a shorter letter, which would look more like a traditional prescription, meaning a smaller and less elaborate piece of paper, clearly identified as a prescription referral.The QBCSP intended to give readers an idea of the size of tumours that can be detected by mammography by drawing a simple dot. Participants did not understand what it referred to at all, and suggested adding a drawing of breasts to illustrate the point and give a better idea of the size of the dot compared to the breast. They also suggested comparing it to the size of a fruit.Overall, participants felt that the content of the letter lacked appeal. They suggested using simpler, more accessible language and shorter sentences, so that readers are taken straight to the essential information.Finally, participants suggested promoting mammography and the breast cancer screening program on television and radio during the news because, they claim, all Haitians watch the news.Study results suggest that the referral letter is an important barrier to getting a mammogram, mainly because it is poorly understood by women with very low literacy levels. The scientific literature also identifies low levels of literacy as an obstacle to mammography –53. The Consistent with previous studies, results show that stress related to outcome is a significant barrier to getting a mammogram , 54. AccThe in-depth interviews allowed us to understand that women of the Haitian culture sometimes provide an explanation for illness that draws on religious beliefs; disease comes from the devil or from God. Participants seemed to perceive breast cancer as a disease given by God, for reasons beyond their comprehension. Several studies have found that other cultures also believe that the devil can cause a person to develop breast cancer , 56, 57.Findings differ from those of other studies on immigrant women and their adherence to mammography , 63, 64.Participants’ enthusiasm and their mostly positive comments about the letter were inconsistent and contradicted what is suggested in the literature—that women from disadvantaged backgrounds adhere less to breast cancer screening programs , 65–67. Our study addressed several specific points about the content of the letter. First, it indicates that women in the Haitian community are not shy about their breasts, a factor that is favorable for mammography. They requested that the word ‘breasts’ be translated into Creole in the letter so they can better relate to what is being asked. Second, women did not understand the dot used to illustrate the size of a possible tumour detected by a mammogram. To address the issue, it could be judicious to include more explicit drawings of a breast tumour to enhance understanding. Including such drawings would not be a problem, since Haitian women are not shy about their breasts. Third, the fact that most women in focus groups did not know the meaning of the word ‘mammogram’ indicated that there is a mismatch between the language used in the letter and the target community’s literacy levels. Although some women knew what an X-ray is, they did not know that breast X-rays existed, or that a mammogram is an X-ray. Therefore, it would be worthwhile to explain the technical jargon in the letter to make the letter clearer for the women.In terms of the format of the letter, no participant understood that it was a referral. It is important that it look like a referral for a test, which is usually on a smaller piece of paper, and/or be clearly entitled ‘PRESCRIPTION’. Secondly, it is imperative to be aware that the mail system in Haiti is not the same as in Canada. Women stated that they do not always pay attention to their mail since they are not used to this communication system. Social desirability was present in participants’ responses.In summary, research results show that there is significant lack of knowledge and understanding of breast cancer and mammograms. Some cultural characteristics can explain the attitudes and beliefs related to this matter. However, a lack of knowledge and understanding as well as negative attitudes and beliefs about mammograms could be countered by introducing better strategies in the health system, especially through the QBCSP referral letter. Moreover, there appears to be a problem with accessibility; the ‘Health System’ category indicates barriers in Quebec’s health care system that cause poor adherence to breast cancer screening and even low utilization of the system. Also, the format of the QBCSP letter and level of language used limit the women’s understanding, which supports our initial hypothesis.This research approach corresponds to an exploratory perspective. Although the scientific literature acknowledges several barriers to immigrant communities accessing preventive services, this aspect of the QBCSP has never been evaluated.An important strength of this project is that it was a two-step process: in-depth interviews, notably with leaders of the Haitian community, which permitted optimal preparation of the focus groups; and the focus groups themselves, which were designed in collaboration with the leaders.The originality of this research project is reflected in the proximity of the researcher to the participants. The fact that she is herself of Haitian descent and speaks Creole enabled her to conduct the focus groups in Creole, be more culturally sensitive, and provide a better interpretation of the results. This facilitated communication and expression of details and feelings that participants were ready to share.Social desirability was repeatedly observed in this study. The researcher asked the questions in such a way as to try to bypass some social desirability biases.Common limits of focus groups, such as the group effect, were detected. Participants occasionally waited for someone else to respond before contributing their own insights. Use of focus groups probably led to more homogenized results.The vast majority of participants in this study had problems with literacy. They were unable to understand the letter, which clearly created a barrier to the QBCSP’s objectives. To compensate for this limitation, the researcher read the letter to participants so they could express their lack of understanding. This may have raised additional issues regarding the letter that may not have come up otherwise.The main objective of this research project was to evaluate the QBCSP’s strategy of using a referral letter to invite eligible women to have a screening mammogram. The main conclusion is that the technical wording of the letter did not match participants’ literacy levels, which created a major obstacle to adherence to the program. There is an obvious need for simpler wording, as well as a letter in their native language. In addition, participants voiced a clear preference for Haitian physicians, which could enhance adherence to mammography.To promote a culture of prevention in immigrant communities, there must be a more appropriate communication plan that will make them feel confident and safe. In light of our results, a new referral letter should be prepared and adapted to the targeted community, based on the conclusions of the current study. Qualified Haitian doctors who are waiting to have the right to practice in Quebec could also be involved in promoting participation in the QBCSP. Given the good reputation of these doctors in their country, they could be trained as spokespersons for the breast cancer screening program in their community.Social inequality in breast cancer mortality could result from a failure of the health system. One might wonder if the referral letter is understood even by native French and English speakers from disadvantaged groups or with low literacy levels. This topic could be the subject of further research.


BRCA1 or BRCA2 gene mutation have up to an 80% lifetime risk of breast cancer unless their breasts are surgically removed, but many decline or defer surgery and choose screening, hoping that if cancer occurs, it will be detected at a curable stage. In this study 489 women with a BRCA1 or BRCA2 mutation aged from 25 to 65 years, who had never had breast or ovarian cancer, were screened annually with breast magnetic resonance imaging (MRI) in addition to mammography and were followed for an average of 13 years (range: 9 to 23 years). Ninety-five of the 489 women enrolled in the study had a bilateral preventive mastectomy in the follow-up period. Of the 91 women diagnosed with breast cancer, four died of breast cancer. The most common cause of death was ovarian cancer. For women with BRCA mutations who choose annual screening with MRI and mammography, the probability of dying of breast cancer within 20 years is 2%.Women with a BRCA1/2 mutations. However, long-term breast cancer-related mortality with screening is unknown. Between 1997 and June 2011, 489 previously unaffected BRCA1/2 mutation carriers aged 25 to 65 years were screened with annual MRI plus mammography on our study. Thereafter, participants were eligible to continue MRI screening through the high-risk Ontario Breast Screening Program. In 2019, our data were linked to the Ontario Cancer Registry of Cancer Care Ontario to identify all incident cancers, vital status and causes of death. Observed breast cancer mortality was compared to expected mortality for age-matched women in the general population. There were 91 women diagnosed with breast cancer ) with median follow-up 7.4 (range: 0.1 to 19.2) years. Four deaths from breast cancer were observed, compared to 2.0 deaths expected  2.0, p = 0.14). For the 489 women in the study, the probability of not dying of breast cancer at 20 years from the date of the first MRI was 98.2%. Annual screening with MRI plus mammography is a reasonable option for women who decline or defer risk-reducing mastectomy.Annual breast magnetic resonance imaging (MRI) plus mammography is the standard of care for screening women with inherited  BRCA1 or BRCA2. For these women, the estimated risk of developing breast cancer by age 70 ranges from 45% to 88% [BRCA2 mutation carriers [One in 400 women in the general population carry a germline mutation in % to 88% . Bilatercarriers . Some wocarriers ,7.BRCA mutation carriers make informed decisions about management of their risk.Annual screening with contrast-enhanced magnetic resonance imaging (MRI) in addition to mammography, starting at age 25 or 30, is now the standard of care for female mutation carriers who decline or defer bilateral risk-reducing mastectomy ,9,10,11.BRCA mutation carriers who were screened annually with MRI and mammography. Women had not been diagnosed with breast or ovarian cancer prior to enrollment. We report the long-term breast cancer-specific survival and causes of death for the 489 women in the cohort.In 1997, we began a prospective observational study of BRCA1 mutation and 241 had a BRCA2 mutation. The characteristics of the study population are presented in Of the 502 unaffected women enrolled in the study, 13 were excluded because they did not complete the first MRI. Of the remaining 489 women, 248 had a The median duration of follow-up from the first MRI examination for the cohort was 12.7 years (range: 8.5–22.5 years). Of the 489 women, 71.2% had ten or more years of follow-up. Ninety-five of the 489 women underwent a preventive bilateral mastectomy in the follow-up period. The mean age of preventive mastectomy was 43.4 years (range: 28 to 58 years). The mean time from first MRI to preventive mastectomy was 4.3 years (range: 0.01 to 20.1 years). There were four cases of breast cancer diagnosed at preventive mastectomy. All four of these women are currently alive. Among the 95 women who had preventive mastectomy, there were no cases of breast cancer diagnosed after the surgery.A total of 91 breast cancers were diagnosed, including 72 invasive cancers and 19 cases of ductal carcinoma in situ (DCIS). Among the 91 women, 60 cases of breast cancer were diagnosed prior to December 2011 and 31 were diagnosed from 2012 to 2016. The characteristics of the breast cancers are presented in Of the 60 cancers diagnosed during the study period, 28 were detected by MRI alone, 19 were detected by MRI and another screening method, one was detected by mammography alone, one was detected by ultrasound alone, three were palpable, one was an interval cancer and four were discovered at prophylactic mastectomy . For the 31 cancers detected in the follow-up period, the mode of detection is unknown. Given that most women would have enrolled in the provincial high-risk screening program, most would likely have been detected by MRI .BRCA1 mutation carriers and 2.6% for BRCA2 mutation carriers. The ten-year cumulative incidence of breast cancer for the entire cohort was 20.6% and the 15-year cumulative incidence of breast cancer was 24.1%  was a BRCA1 mutation carrier, who delivered a baby 13 months after her last screening MRI. Twenty-four months post-delivery at age 33 she was diagnosed with a (self-detected) invasive ductal carcinoma, with 28 of 31 lymph nodes positive. She died of distant metastases at age 37.Patient #2 (424) was a BRCA1 mutation carrier diagnosed with breast cancer on her first screening with MRI at age 48. The cancer was 3-cm, ER-positive and node-positive. She received adjuvant chemotherapy and hormonal therapy. She developed diffuse distant metastases six years later and died at age 55. Patient #3 (455) was a BRCA1 mutation carrier diagnosed in 2010 at age 45 at her fifth round of screening with MRI screen-detected cancer. This 1.1-mm, grade I, triple-negative, node-negative invasive ductal carcinoma of the breast was treated with breast conserving therapy. In July 2015, she had targeted radiation to a solitary liver metastasis with a different molecular profile than the breast primary . In December 2016, there was liver progression and spread to the peritoneum and lung was noted. Following one cycle of carboplatin, paclitaxel +/− veliparib, she had a lower GI bleed, which led to the diagnosis of a cancer of likely intestinal origin (GATA-3-negative). Whether this was a primary or metastatic lesion could not be determined. The peritoneal disease responded to the single-course chemotherapy but there was liver progression. A second liver biopsy then showed GATA-3-positive disease. The patient died in July 2018 at age 53. Patient #4 (566) was a For the 72 women with invasive breast cancer, the median follow-up was 7.4 (range: 0.1 to 19.2) years. The ten-year actuarial survival was 94.0% and the twenty-year actuarial survival was 90.1% . Overallp = 0.14). .There were four deaths from breast cancers observed in the cohort. Based on SEER rates of breast cancer incidence and breast cancer survival, there were 2.0 deaths expected  2.0) and this difference was not statistically significant  and four deaths from other causes.BRCA mutation, who were annually screened with MRI and mammography for a median of 12.7 years. The incidence of breast cancer was 2% per year. There were 19 cases of DCIS diagnosed and none of these women died of breast cancer. There were 72 cases of invasive cancer diagnosed, with four breast cancer-related deaths, and for these 72 women, the estimated 20-year survival was 90%, while for the entire cohort of 491 women, the 20-year probability of breast cancer-free survival was 98.2%. The standardized mortality ratio from breast cancer was not significantly different from that of the general population.In this study, we followed 491 women with a germline These results will be very reassuring to women who are reluctant to undergo risk-reducing mastectomy. Other women will still choose to undergo risk-reducing mastectomy to avoid the inconvenience and stress of annual scans (and sometimes biopsies) and the possibility of a breast cancer diagnosis and treatment  with its side effects and complications. A recent concern is the finding of long-term retention of gadolinium in the brain after repeated contrast-enhanced MRI scans, although no neurologic consequences have been reported . HoweverBRCA mutations identified at eight Dutch academic centers, 2857 previously unaffected female mutation carriers were identified, of whom 1128 opted for risk-reducing mastectomy and 1729 opted for breast surveillance, which consisted of annual MRI and mammography for women aged 25 to 60 years. Median follow-up from enrollment in the registry was 10.3 years. Median follow-up from breast cancer diagnosis was not stated explicitly but was approximately 6.5 years. In the BRCA1 mutation group, there were 268 breast cancers and 20 breast cancer-related deaths among the 990 women in the surveillance cohort (2.0%) and eight breast cancers and one death among the 722 women in the mastectomy cohort (0.1%). In the BRCA2 mutation group, there were 144 breast cancers and seven breast cancer-related deaths among the 739 women in the surveillance cohort (0.1%) and no breast cancers in the mastectomy cohort (n = 406). The authors concluded that breast surveillance may be more effective for BRCA2 than for BRCA1 mutation carriers. There are several possible explanations for the higher death rate among the BRCA1 mutation carriers diagnosed with breast cancer in this study compared to ours. Our patients were older at the time of diagnosis than those in the HEBON study  and the tumor growth rate of BRCA-related cancers has been shown to slow progressively with age [In a recent report from the Hereditary Breast and Ovarian Cancer Netherlands (HEBON) study , from a with age . In our BRCA mutation carriers (10%) with breast cancer developed distant recurrences at a median follow-up of nine years [BRCA1 mutation carriers) after a median follow-up of 12 years [BRCA mutation carriers who opted for annual breast screening with MRI and mammography and were subsequently diagnosed with breast cancer, the 5-year survival after breast cancer was 94% [There are survival data from other breast MRI surveillance studies. In the Dutch MRI screening (MRISC) study, five of the 51 ne years . In the 12 years . In a re was 94% .BRCA2 mutation carriers died 10 or more years after diagnosis [There are several limitations to our study. Distant breast cancer recurrence was not a measurable outcome for our entire cohort because this is not available in the Ontario Cancer Registry. Nevertheless, through the annual questionnaires completed by all patients diagnosed with breast cancer prior to 2012, none of whom were lost to follow-up, we identified two patients who developed distant metastases and are currently alive. We were unable to document the exact number of MRI and/or mammography examinations that occurred after our active surveillance period was completed in 2011; however, the great majority of participants would have been eligible for the province’s high-risk screening program. It is also possible that some women had a bilateral mastectomy or were diagnosed with breast cancer outside Ontario after the active surveillance was stopped. Finally, our follow-up of the 58% of women who had ER+ breast cancers may not have been long enough, as late distant recurrences of endocrine-sensitive breast cancers are not uncommon . Among tiagnosis , so mostBRCA mutation carriers who choose to breastfeed for more than 6 months now recommend that regular annual screening with MRI and mammography be continued, despite the known reduction in imaging sensitivity in the lactating breast [Two of the four patients diagnosed with breast cancer on our screening study who died of metastatic breast cancer (#1 and #2) likely would have not developed breast cancer if they had undergone risk-reducing mastectomy at the time of their first MRI. However, patient #2 had a 3-year delay of MRI screening due to pregnancy and prolonged lactation, which likely contributed to the poor outcome. Screening guidelines for g breast . BRCA mutation carriers were screened with MRI every 6 months, plus annual mammography. Fourteen cancers were diagnosed, all node-negative, with no interval cancers. Mammography did not detect any cancers missed by MRI. The number of recalls and biopsies needed to detect one cancer by biannual MRI were 2.8 and 1.7, respectively, in BRCA1 mutation carriers and 12.0 and 8.0, respectively, in BRCA2 mutation carriers [Because with annual MRI and mammography, there is still an interval cancer rate of 5% and about 15% of cancers have axillary nodal involvement at diagnosis , some cecarriers . BRCA mutation carriers will likely improve as well. The results of a recently completed randomized trial of a PARP inhibitor vs. placebo in addition to standard adjuvant therapy for BRCA-related breast cancer are awaited with great interest [Breast cancer treatment outcomes for interest .BRCA1 mutation carriers and by the age of 45 for BRCA2 mutation carriers [BRCA1 mutation carriers, nor in BRCA2 mutation carriers who had undergone this surgery within the previous five years in [In our study, and in the HEBON study , the moscarriers . Meticulcarriers . This sucarriers ,27, althyears in . Even wiyears in . The incyears in . Detailed results of the study population and protocol have been published previously ,32 and aBRCA1 or BRCA2 mutation, no history of breast or ovarian cancer and two intact breasts were enrolled in a prospective breast screening study. Women with a prior history of other cancers were eligible for inclusion, providing the diagnosis was five or more years in the past. From 1997 until 30 June 2009, screening was performed at the Sunnybrook Health Sciences Centre and then at four additional academic tertiary centers in the province of Ontario, Canada  and The Ottawa Hospital) until 2011. Research ethics board approval was obtained from each institution and all participants provided informed consent (project identification number: 003-2000). Women who became pregnant discontinued screening until four to six months after delivery or weaning. Women diagnosed with breast cancer continued screening unless they underwent bilateral prophylactic mastectomy. For each patient diagnosed with breast cancer in study, method(s) of detection, tumor stage, ER, PR, HER2 and treatments were recorded. For women diagnosed with a second ipsilateral or contralateral breast cancer, only details of the first cancer were recorded for this study. Study subjects were included in the current analysis if they completed at least one successful screening MRI. All study subjects diagnosed with breast cancer prior to 2012  completed an annual mailed questionnaire that recorded new diagnoses of breast or other cancers, cancer recurrences and prophylactic mastectomies. Between 1 November 1997 and 30 June 2011, 504 women aged 25 to 65 years with a documented germline Study participants were screened annually with dynamic gadolinium contrast-enhanced MRI screening during the second week of the menstrual cycle as well as four-view mammography, generally done on the same day as the MRI. Film-screen mammography was performed until 31 December 2007, and digital mammography was performed thereafter. Annual ultrasound screening was also performed initially but was discontinued in 2005. In July 2011, MRI became an established screening test in Ontario supported by the Ministry of Health and was administered through the high-risk program of the Ontario Breast Screening Program (OBSP). At that time, MRI screening on a research basis was discontinued. All of the women in this study who did not have preventive surgery were eligible for annual MRI and mammography screening through the OBSP program from 2011 until the present day or until the age of 70. We do not have details of the MRI and/or mammography examinations (date of study or result) for MRI scans done from 2012 onwards, but the results of this program have been published [In 2019, a record linkage was conducted by linking the identifying information in our study database with that of the Ontario Cancer Registry of Cancer Care Ontario (CCO). For each subject, CCO provided the date of cancer diagnosis, the site of cancer diagnosis, the vital status and the cause of death. CCO recorded incident cases of breast cancer until 31 December 2016 and deaths from cancer until 31 December 2018. It was assumed that subjects who were not listed in the cancer registry as deceased were alive and were residents of Ontario on 31 December 2018. For breast cancer incidence, subjects were followed from the date of their first MRI screening until the first of the following: date of diagnosis of breast cancer, date of bilateral preventive mastectomy, date of death or 31 December 2016. The 10- and 15-year actuarial cumulative incidence rates were estimated using the Kaplan–Meir method. For breast cancer-specific mortality, subjects were followed from the date of their first MRI until the first of the following: death from breast cancer, date of bilateral risk-reducing mastectomy, death from another cause, date of last follow-up or December 2018. The 20-year cumulative risk of dying of breast cancer was estimated using the Kaplan–Meier method.We also estimated 10- and 20-year breast cancer-specific survival rates for women who developed invasive breast cancer; patients were followed from the date of diagnosis until the date of death from breast cancer, death from another cause or 31 December 2018.To estimate the expected number of deaths from breast cancer in the cohort if they were an average-risk population, we calculated the expected probability of death for each of the study subjects under the assumption that they did not have breast cancer at the time of the first MRI screening. To calculate the expected probability of death within a given interval for women who were initially cancer-free, we estimated the risk of breast cancer incidence in the cohort and then applied breast cancer case-fatality rates based on SEER data from the year of diagnosis until the end of the interval. Patients were censored from follow-up at the date of bilateral preventive mastectomy. For example, if a woman had a first MRI screening at age 50 and was followed until age 70, we asked: what is the probability that a cancer-free women at age 50 would develop and die of breast cancer before age 70? Accordingly, we calculated the expected probability of death from breast cancer for each study subject, according to the age at first MRI and the age at last follow up. To estimate the total expected number of deaths in the cohort, we summed the individual probabilities of death for each woman in the cohort as described above. To calculate the SMR, we compared the observed number of deaths to the expected number of deaths.BRCA1/2 mutation carriers enrolled in our study of annual breast screening with MRI and mammography, after a median follow-up of 13 years, there were only four cases of breast cancer-related death. Annual screening with MRI plus mammography is associated with a 20-year probability of not dying of breast cancer of 98%. Future studies will likely demonstrate even better breast cancer-specific survival due to improved screening technology and more effective treatments.Among 491 previously unaffected


Accumulated evidence suggests that reproductive factors are related to different breast cancer subtypes, but most studies on these relationships are mainly focused on middle-aged and older patients, and it remains unclear how reproductive factors impact different subtypes of breast cancer in young women.  We assessed the relationships between fertility factors and luminal A, luminal B, human epidermal growth factor receptor 2 (HER2)-enriched, and triple-negative breast cancer (TNBC) subtypes in 3792 patients and 4182 controls aged 20–70 years. Data on the reproductive history of the study participants were acquired through face-to-face interviews and questionnaires. We conducted case-control comparisons among tumor subtypes based on estrogen receptor (ER), progesterone receptor (PR), and HER2 statuses using unconditional polychotomous multivariate logistic regression models to compute odds ratios (ORs) and 95% confidence intervals (CIs). Ptrend < 0.05). Later age at first full-term birth was inversely related to the luminal A subtype (Ptrend < 0.05) in young women but correlated with an increased risk of the luminal A subtype (Ptrend < 0.05) in older women. Parous Chinese women 40 years old or younger who breastfed for 12 months or longer had a lower risk of luminal B and TNBC subtypes than women who never breastfed .  Parity was inversely related to both luminal A and luminal B subtypes in young women and older women (all  Our results implied that parity exerted a strong protective effect against luminal A and luminal B subtype breast cancer in young Chinese women, and long-term breastfeeding obviously decreased the risk of luminal B and TNBC subtypes in this population. Breast cancer is universally accepted as a heterogeneous disease with different molecular subtypes. Molecular subtypes of breast cancer are defined by the expression of hormone receptors and human epidermal growth factor receptor 2 (HER2). Many studies have shown that different subtypes of breast cancer have diverse clinicopathological features and prognoses –3. The rvs. >40 years).Several studies have shown that the proportions of luminal B and triple-negative breast cancer (TNBC) subtypes are significantly higher in young patients than in older patients , 20. SixFrom Mar 2012 to Dec 2017, 3912 incident female patients without history of any previous cancer at the People's Hospital of Shanxi Medical University were confirmed by surgery and pathology as having invasive breast cancer. Ultimately, 3792 patients were enrolled in the analysis, excluding 74 for whom molecular subtype confirmation was difficult  and 46 for whom reproductive history information was missing. Controls were selected from among healthy women who had not any malignant tumor and had routine breast mammography screening during the same period. For 4312 women, the mammographic and breast ultrasound screening report was negative during the same period of time, followed by a negative mammographic and breast ultrasound examination one year later. In total, 4182 healthy women who agreed to participate in the study were randomly assigned to the control group, with matching for age (within five years), excluding 130 women who were unwilling to provide to relevant information. Our study was approved by the Ethics Review Board of the People's Hospital of Shanxi Medical University and was carried out according to the guidelines of the Declaration of Helsinki. All participants signed informed consent forms prior to their participation in this study.All information from the participants in the study was acquired by a trained staff using face-to-face interviews and a standardized questionnaire, including reproductive risk factors and other relevant risk factors. Reproductive risk factors included age at menarche, number of full-term births, age at first full-term birth, and breastfeeding duration. Ever breastfeeding was defined as lactation for more than one month. Other relevant risk factors included age at admission, family history of breast cancer in first-degree relatives, body mass index (BMI), history of smoking and drinking, and history of oral contraceptive use. For variables with missing data , we supplemented these data using the average value for the variable among controls in the same age group.The estrogen receptor (ER), progesterone receptor (PR), and HER2 statuses of all patients were evaluated by pathologists using rabbit monoclonal antibody for immunohistochemical (IHC) assays. We adopted high-pressure cooking for antigen retrieval. Data on all tumor biomarkers were retrieved from medical records. All invasive tumors were reevaluated by pathologists to confirm their aggressiveness. Subtypes and biomarkers of breast cancer were defined in accordance with the consensus at the 2013 St. Gallen meeting . ER/PR s2), history of oral contraceptive use (ever/never), and family history of breast cancer (yes/no).An unconditional polychotomous logistic model was used to assess the influence of fertility factors on the risk of different subtypes of breast cancer, and odds ratios (ORs) and corresponding 95% confidence intervals (CIs) were used as an assessment of the relative risk adjusted for potential confounders . We consP values were less than 0.05. SPSS version 22.0  was used for all statistical analyses.The number of completed pregnancies  was considered potential confounders when we assessed the influence of breastfeeding on the risk of different tumor subtypes. For trend analysis, categorical variables were treated as ordered discrete variables, e.g., 0, 1, and 2. The multivariate polytomous logit model was applied to assess heterogeneity between different subtypes, with luminal A breast cancer as the reference. We also examined multiplicative interaction terms generated by age at diagnosis between reproductive factors and tumor subtypes using logistic regression models  and models stratified by age (≤40/>40 years of age). We considered the analysis results to be statistically significant when n = 86, 12.0%), luminal B , HER2-enriched , and TNBC  in the young group and luminal A , luminal B , HER2-enriched , and TNBC  in the older group. Young women had a lower mean age at menarche than did older women. The mean number of live births was lower, and the mean age at first full-term birth was higher for young women than for older women. Similarly, the proportion of women who had ever breastfed was lower, and the mean duration of breastfeeding was shorter for young women than for older women. The distribution of other risk factors, including oral contraceptive use, BMI, and family history, is presented in The 3792 case participants comprised 3075 patients older than 40 years and 717 patients 40 years old or younger. According to age, tumor subtypes in the 3792 patients were classified as follows: luminal A (P > 0.05). The number of live births was not related to the risk of HER2-enriched or TNBC subtypes (both Ptrend > 0.05) but was significantly inversely associated with the risk of the other two subtypes (both Ptrend < 0.05). There was no significant difference between each subtype and the luminal A subtype in relation to the number of live births . Compared to nulliparous women, parous women had a lower risk of either the luminal A or luminal B subtype among older women, with odds ratios of 0.48  and 0.57 , respectively. Moreover, among these women, two or more live births were correlated with a lower risk of the luminal A subtype compared to only one birth . Older age at first full-term birth was correlated only with an increased risk of the luminal A subtype in parous women older than 40 years (Ptrend < 0.05). Furthermore, a significant difference existed between each subtype and the luminal A subtype regarding the age at first full-term birth in older women . In older women, a longer duration of breastfeeding was inversely correlated with the luminal A subtype (Ptrend < 0.05) but not correlated with the other three subtypes . Finally, no significant difference existed between each subtype and the luminal A subtype in terms of breastfeeding .As shown in Ptrend > 0.05; Ptrend < 0.05) in young women but was not correlated with the risk of the HER2-enriched or TNBC subtype (both Ptrend > 0.05). However, relative to women who had never given birth, parous women had a lower risk of either the luminal A or luminal B subtype among young women, with odds ratios of 0.41  and 0.40 , respectively. There was a significant difference between the HER2-enriched and luminal A subtypes in relation to parity in young women (P < 0.05). Two or more live births were not correlated with the risks of any subtype compared to only one birth among young women, while older age at first full-term birth was inversely correlated with the luminal A subtype (Ptrend < 0.05). In addition, a longer breastfeeding duration was correlated with a reduced risk of luminal B and TNBC subtypes in these women (both Ptrend < 0.05), but no significant correlation was observed between breastfeeding and either the luminal A or HER2-enriched subtype (both Ptrend > 0.05).No significant correlation was found between age at menarche and the risk of any tumor subtype in young women .Additionally, in the test of heterogeneity, there was no significant difference between each subtype and the luminal A subtype for age at first live birth and breastfeeding , but this association did not vary significantly by age (P for interaction > 0.05). Compared to luminal A tumors, we did not observe a significant association between breastfeeding and luminal B and HER2-enriched subtypes across ≤40 ages and >40 ages . For the TNBC subtype, there was no significant association with breastfeeding across all ages (both P > 0.05). However, we did observe a weak but significant interaction between breastfeeding and >40 ages (P for interaction = 0.04).Subsequently, we assessed associations between parity/breastfeeding and breast cancer subtypes according to age at diagnosis .A meta-analysis by Lambertini et al. showed that parity correlated with a 25% decrease in the risk of developing luminal breast cancer in parous women . The hypThe results of four previous studies showed that associations between parity and the risk of TNBC were inconsistent in young parous women < 45 years. Li et al. observed that parity was associated with a reduced risk of developing TNBC in parous women < 45 years , whereasA prior study found parity to be a strong protector against breast cancer in women when the first full-term birth occurred between 20 and 35 years of age . The assSeveral meta-analyses have shown that breastfeeding exerts a protective effect against luminal and TNBC subtypes, especially TNBC, with a stronger protective effect than for other subtypes –7. Two sLi et al. demonstrated that breastfeeding for 12 months or longer correlates with a 50% reduction in the risk of TNBC in young parous women compared to women who never breastfed . Two stuP > 0.05). Seemingly pregnancy produces a protective effect against HER2-enriched tumor. In parous women (>40 years), breastfeeding was not associated with TNBC tumor subtype when using luminal A tumor as the reference. However, we did observe that this association differed significantly by age (P = 0.04), which was related to parous women (>40 years) with TNBC tumors having different lactation ratios.In this case-case study, we observed that parity is related to a lower possibility of being developed with HER2-enriched breast tumors compared to luminal A tumors for women ≤ 40 years, and this relationship did not differ significantly according to age  had a strong protective effect against luminal A and luminal B tumor subtypes in young women, and breastfeeding for 12 months or longer (vs. never breastfeeding) largely reduced the risk of luminal B and TNBC subtypes in young women.In conclusion, the results of our study indicated that parity (


Whether an unfavorable lifestyle not only affects breast cancer risk, but also influences age at onset of breast cancer and survival, is under debate.In a population-based cohort, the Energy Balance and Breast Cancer Aspects throughout life (EBBA-Life) study, a total of 17,145 women were included. During follow-up, 574 women developed invasive breast cancer. Breast cancer cases were followed for an additional 9.1 years. Detailed medical records were obtained. Cox’s proportional hazard regression models were used to study the association between pre-diagnostic lifestyle factors , breast cancer risk, age at diagnosis, and survival.P = 0.032). Breast cancer patients with an unfavorable lifestyle, compared with patients with a favorable lifestyle, had almost a two times higher overall mortality risk .At study entry, 34.3% of the participating women were overweight and 30.7% were physically inactive. Mean age at breast cancer diagnosis was 58.0 years, and 78.9% of the tumors were estrogen receptor positive. Among menopausal women who did not use hormone therapy and had an unfavorable lifestyle (3–5 unfavorable factors), compared with women who had a favorable lifestyle, we observed a twofold higher risk for postmenopausal breast cancer , and they were 3.4 years younger at diagnosis  contains supplementary material, which is available to authorized users. A global increase in breast cancer incidence has been observed, with incidence rates being almost fourfold higher in the developed than in the less-developed countries, emphasizing that large differences in lifestyle may have an important role to play . Of noteThe association between body composition, including body weight and breast cancer risk, is well known. High Body Mass Index (BMI) has been positively associated with postmenopausal breast cancer , 5, but Possible biological mechanisms operating for most of these lifestyle factors may be mediated by adipose tissue, with low-grade chronic inflammation creating an environment that promotes breast cancer development and growth –22. AnotThe main aim of the present study was, therefore, based on a population-based cohort study, with a high attendance rate and detailed medical and histopathological information, to explore the joint effect of lifestyle factors on breast cancer risk, age at onset, and survival.This population-based cohort, the Energy Balance and Breast Cancer Aspects throughout life (EBBA-Life) study , 27, is The questionnaires were filled in at home and brought to the study site, where they were checked for completeness and inconsistency. Questionnaires included items about medical history, specific symptoms, dietary habits, lifestyle factors, reproductive factors, and use of medication including antihypertensive drugs and hormone therapy .2) was calculated. Physical activity was reported according to type of physical activity over the last 12 months , duration, and hours of intensity exercise per week. Categories of physical activity were classified as follows: (1) sedentary physical activity: reading/sitting with no participation in recreational sport activities or competitions over the last 12 months; (2) moderate physical activity: walking/cycling at least 4 h a week and/or minimum of 1 h of strenuous physical activity per week (sweating/out of breath); and (3) hard physical activity: participating in strenuous training or sports competitions regularly/several times a week and/or exercise approximately every day. Alcohol intake was reported according to the number of days a month when alcohol was drunk, and has been validated [Height and weight were measured , and thealidated . Smokingalidated . MHT usen = 709). All women with missing information on BMI, physical activity, alcohol use, smoking, blood pressure, or MHT use were excluded (n = 2 765). Thus, 17,145 women were included in the final sample. The participants were followed from the date of entry into the study until the date of breast cancer diagnosis, date of emigration, date of death, or end of follow-up , whichever event occurred first.All breast cancer cases were identified through linkage to the Cancer Registry of Norway by using the unique, national, 11-digit identification number . We obtaThe breast cancer patients’ medical charts were reviewed to obtain detailed clinical data, including breast cancer histological type, grade (1–3), tumor stage (1–4) according to the TNM  classification, and breast cancer treatment. A total of 574 women were diagnosed with incident invasive breast cancer during follow-up (Online Resource 1). Follow-up after breast cancer diagnosis was calculated from the date of the diagnosis to the date of death, emigration, or end of follow-up.n = 407) of the tissue samples were analyzed on tissue microarrays (TMAs) at the University of Bergen, Norway (Centre for Cancer Biomarkers) [n = 167) were evaluated using immunohistochemistry for hormone receptor status and Ki-67, and immunohistochemistry and fluorescence in situ hybridization for human epidermal growth factor receptor-2 (HER2). A subset of the breast cancer cases (n = 522) with complete information on receptor status were categorized into three molecularly defined subgroups: (1) ER positive—patients with ER-positive (with or without progesterone (PgR)-positive) and HER2-negative status; (2) HER2 positive—all patients with HER2 overexpression; and (3) triple-negative breast cancer (TNBC)—HER2−, ER-−, and PgR-negative status.All breast tumor samples were fixed in 4% buffered formaldehyde before processing and embedding in paraffin. To obtain more complete and updated information on tumor characteristics, most (markers) , 35. BreTo characterize the change in incidence rates during follow-up, crude incidence rates were calculated as new breast cancer cases per 1000 person-years at risk for disease for the total cohort (30–90 years) and within the age groups: ≤ 55 years and > 55 years. Non-linearity in incidence trends was considered and an estimate calculated using a fractional polynomial in Poisson’s regression models. A total of 44 models were estimated to find the best-fitting model to describe trends in breast cancer incidence.Body composition favorable—BMI < 25 kg/m2 versus unfavorable—BMI ≥ 25 kg/m2.Physical activity favorable—moderate or more physical activity versus unfavorable—sedentary physical activity.Alcohol use favorable—no alcohol or ≤ 1 day a month drinking alcohol versus unfavorable— > 1 day a month drinking alcohol.Smoking favorable—no current smoking versus unfavorable—current smoker.Hypertension favorable—systolic blood pressure < 140 mmHg, diastolic blood pressure < 90 mmHg, and no antihypertensive medication versus unfavorable—systolic blood pressure ≥ 140 mmHg and/or diastolic blood pressure ≥ 90 mmHg, and/or use of antihypertensive medication.Multivariable Cox’s proportional hazard regression models were used to study whether a pre-diagnostic unfavorable lifestyle, assessed at baseline, was associated with breast cancer risk and mortality. To study the importance of the variation in lifestyle factors independently and in combination, we identified five different modifiable lifestyle-related factors associated with breast cancer development, and categorized each of them into favorable versus unfavorable based on international categorization  , 37:BodyThe participants scored 0 for each favorable lifestyle factor and 1 for each unfavorable one, resulting in a score range of 0–5. We then split these modifiable lifestyle factors into four categories according to the sum of unfavorable lifestyle factors: category 1 (reference): score 0; category 2, score 1; category 3, score 2; category 4, score 3–5. We constructed three separate regression models for each exposure to evaluate overall, premenopausal, and postmenopausal breast cancer as model-specific outcomes. Based on previous studies among women from the same cohort , premenoκ = 0.76). All the tests were two sided and the statistical significance was defined by P < 0.05. Statistical analyses calculating crude incidence of new breast cancer cases were conducted using STATA 14 . All other statistical analyses were conducted using SPSS 21.0 .Based on suggested biological mechanisms influencing these modifiable lifestyle factors and/or breast cancer risk and prognosis, several variables were studied as potential confounders: age (continuous), age at menarche (continuous), and number of live births (continuous). In the final analysis of survival, only age was included as a potential confounder. Breast cancer stage  did not influence our results, and was not included. A total of 111 breast cancer cases were checked for agreement between subtyping based on immunohistochemistry and TMA. We observed an agreement between these two methods in 93% of the breast cancer cases (n = 362), HER2 positive , and TNBC  (Online Resource 2).Among the 17,145 women included at study entry, 34.3% were overweight, 30.7% physically inactive, and 58% consumed alcohol > 1 day/month. We observed a 93% increase in overall age-adjusted breast cancer incidence through the period from 1995 to 2017  . Current smoking versus no/previous smoking was associated with a 30% decreased premenopausal breast cancer risk  Table .Table 2AAmong women who were MHT non-users, those with three to five unfavorable lifestyle factors versus those with no unfavorable lifestyle factors had more than a twofold increased risk of developing postmenopausal breast cancer  (Table Ptrend = 0.096). Among postmenopausal women who were MHT non-users, those with three to five unfavorable lifestyle factors versus no unfavorable lifestyle factors had a 142% increased risk for ER-positive postmenopausal breast cancer  (Online Resource 3). No association was observed between clustering of unfavorable lifestyle factors and HER2-positive cancer and TNBC overall (Online Resource 2).After stratification by breast cancer molecular subtype, women with three to five unfavorable lifestyle factors versus no unfavorable lifestyle factors had a 43% increased ER-positive breast cancer risk  (Table P = 0.023). Other tumor characteristics were not statistically differently distributed throughout the four categories of unfavorable lifestyle factors (Online Resource 4).Among MHT non-users who developed postmenopausal breast cancer, women with three to five unfavorable lifestyle factors were 3.4 years younger at diagnosis than those with no unfavorable lifestyle factors  (Table Ptrend = 0.050)  Table , Fig. 2.0) Table . Among p0) Table .Table 4AIn this population-based cohort we observed, over 20 years of follow-up, a 93% increased breast cancer incidence. Furthermore, among women who had a clustering of pre-diagnostic unfavorable lifestyle factors, compared with women who had a favorable lifestyle, we demonstrated a twofold increase in postmenopausal breast cancer risk. This increased breast cancer risk was restricted to MHT non-users, and confined to the most common breast cancer subtype: ER-positive breast tumors. Moreover, postmenopausal women with a pre-diagnostic unfavorable lifestyle were 3.4 years younger at breast cancer diagnosis compared with women who had a favorable lifestyle. Our study also demonstrated that a pre-diagnostic unfavorable lifestyle was associated with almost a two times higher overall mortality risk among women with breast cancer.Our observed results extend previous studies, but are also in part supported by others , 39. TheOur findings of a dose–response association between a joint combination of lifestyle factors and breast cancer risk with a twofold increase in postmenopausal breast cancer risk among women with an unfavorable lifestyle are supported –44. In aBRCA1/BRCA2 mutations carriers, physical exercise and healthy weight were associated with delayed age at breast cancer onset [To our knowledge, our results showing an association between an unfavorable lifestyle and earlier age at diagnosis of sporadic breast cancer have not previously been reported in a population-based cohort study. However, in a recent study weight gain was associated with earlier age at diagnosis . Moreoveer onset . Hence, In our study, we observed that a pre-diagnostic unfavorable lifestyle was associated with an almost two times higher overall mortality. An association between obesity and more advanced stage and higher grade at diagnosis among postmenopausal breast cancer patients has been found . We obseThe exact biological mechanisms explaining the association between lifestyle and breast cancer development have yet to be established, but an unfavorable lifestyle may accelerate aging and increase tumor growth, and result in chronic inflammation, metabolic dysfunction, and DNA methylation –68. TeloOur study had several strengths, which include its population-based approach, high attendance rate, the use of a standardized protocol for data collection, and measured height and weight. The study had high completeness rates of identification of breast cancer cases (Cancer Registry of Norway), and identification of death and emigration (Cause of death Registry). In an evaluation of the data quality of the Cancer Registry of Norway, completeness of reporting was estimated to be very high, 98.8% , limitinIn conclusion, our study supports a dose–response association between lifestyle behavior and sporadic breast cancer. An unfavorable lifestyle may alter biological pathways, accelerating tumor growth, and thereby increase breast cancer risk, lower the age at onset of sporadic breast cancer, and shorten the life expectancy among breast cancer patients. Consequently, our results not only support a key role of a healthy lifestyle to improve breast cancer prevention, but also suggest that tailored personal lifestyle advice should be included in daily clinical practice of potential importance for treatment outcomes and life expectancy for women diagnosed with breast cancer.Supplementary file1 (PDF 308 kb)Supplementary file2 (PDF 152 kb)Supplementary file3 (PDF 153 kb)Supplementary file4 (PDF 142 kb)Below is the link to the electronic supplementary material.