Sense of coherence (SoC) is the origin of health according to Antonovsky. The link between SoC and risk of cancer has however rarely been assessed. We performed a cohort study of 46,436 women from the Karolinska Mammography Project for Risk Prediction of Breast Cancer (Karma). Participants answered a SoC-13 questionnaire at recruitment to Karma and were subsequently followed up for incident breast cancer. Multivariate Cox models were used to assess the hazard ratios (HRs) of breast cancer in relation to SoC. We identified 771 incident cases of breast cancer during follow-up (median time: 5.2 years). No association was found between SoC, either as a categorical  or continuous  variable, and risk of breast cancer. In summary, we found little evidence to support an association between SoC and risk of breast cancer. Health, by definition of the World Health Organization (WHO), is a state of complete physical, mental and social well-being . The theSense of coherence (SoC) is the essence of the theory of salutogenesis, defined as “a global orientation that expresses the extent to which one has a pervasive, enduring though dynamic feeling of confidence that (1) the stimuli deriving from one’s internal and external environments in the course of living are structured, predictable, and explicable; (2) the resources are available to one to meet the demands posed by these stimuli; and (3) these demands are challenges, worthy of investment and engagement’ . AccordiThe theory of salutogenesis has been applied in different fields of health and medicine. For instance, a potential link has been suggested between SoC and different somatic diseases , includiIn total, we included 46,436 eligible women  in the present study. The median age at baseline was 54 years (range: 40–74). More than half of the women were post-menopausal, and had college education or above . Women w≤10 years vs. >12 years of education), previous or current smoking , and never or ≥10 g/d drinking  were all associated with a lower SoC score.In the linear regression, we found SoC to be positively associated with age , number of births , and a higher physical activity  . Higher We identified 771 incident cases of breast cancer during follow-up . We did not observe an association between SoC and risk of breast cancer, when comparing women with strong SoC to women with weak SoC , with or without multivariable adjustment . No statWe found little evidence to support an association between SoC and the risk of breast cancer in a population-based cohort study, including 46,436 women at 40–74 years who attended mammography screening in Sweden. Our study represents the first attempt to date to examine the association of SoC with the subsequent risk of breast cancer.The correlations noted between SoC and different characteristics of the women are consistent with results from previous studies, which found SoC to increase with age , and decTo our knowledge, few studies have examined the link between SoC and risk of cancer. The strength of the present study includes the large-scale population-based cohort design, the comprehensive information collected from questionnaires, and the complete follow-up through linkages to national registers, which reduce greatly the possibility of systematic and random errors. There are however also limitations in our study. In the SoC-13 questionnaire used in Karma, 12 out of the total 13 items were reversed as a result of restructuring answers. Reverse item bias may therefore exist in SoC scoring due to acquiescence, careless responding, or confirmation bias . HoweverIn summary, based on a large cohort of Swedish women, we found little evidence to support an association between SoC and the risk of breast cancer.karmastudy.org. In this study, we included participants who had no prevalent breast cancer, were at the age of 40 to 74 years, and had completed at least two-thirds of the items included in SoC-13 questionnaire at the baseline visit. The participants were then individually followed up from the date of baseline visit, through cross-linkages to various Swedish national registers, using the unique Swedish personal identity numbers. The personal identity numbers were replaced with study specific identity numbers at the Swedish National Board of Health and Welfare before data were received by the researchers. The follow-up ended at a diagnosis of breast cancer , emigration out of Sweden , death (through Causes of Death Register), or October 6th, 2017, whichever occurred first.The Karolinska Mammography Project for Risk Prediction of Breast Cancer (Karma) cohort recruited 70,872 women who attended a mammography screening or clinical mammography between October 2010 and March 2013 at any of the four mammography units  in Sweden . ParticiSoC was measured at baseline using the SoC-13 questionnaire , which wIn this study, we used information from the baseline questionnaire, including sociodemographic factors , lifestyle factors , and other known risk factors for breast cancer including reproductive and hormonal factors, family history of breast cancer, history of benign breast disorders or other malignancies. We also used breast density percent measured at baseline by previously reported STRATUS software . FinallyWe first described the baseline characteristics of women according to different categories of SoC . We assessed the correlations between sociodemographic and lifestyle factors and SoC using linear regression models. We then used Cox proportional hazards models to assess the association between SoC and the risk of breast cancer. We first fitted a model not adjusted for any other covariables (Model 1). In a full model (Model 2), we adjusted the analyses for sociodemographic factors  and lifestyle factors , and known risk factors for breast cancer including reproductive and hormonal factors , as well as family history of breast cancer, benign breast disorders, other malignancies, and breast density. We tested proportional hazard assumptions of the Cox models using Schoenfeld residuals and found no major deviation from the assumptions. To assess the potential temporal pattern of the association, we did a sensitivity analysis by fitting a flexible parametric model allowing for the effect of SoC on breast cancer risk to vary over time since study entry. We further performed a sub-analysis to assess whether the studied association would differ between subtypes of breast cancer using the full model. The statistical analyses were performed using Stata, version 16, StataCorp LP and R (version 4.0.2). We used a two-sided p<0.05 to indicate statistical significance. In the interests of transparency, eLife publishes the most substantive revision requests and the accompanying author responses.Acceptance summary:Sense of coherence refers to a person's psychological ability to properly adapt to stress and adversity during the life course. The scale was developed to measure how people view life and to identify how a person may use her/ his intrinsic resources to overcome difficulties while maintaining their health. It seeks to understand why some people remain healthy under stress while others become sick. Using the excellent database from the Karolinska Mammography Project for Risk of Breast Cancer, the current study did not show an association between sense of coherence and breast cancer.Decision letter after peer review:eLife. Your article has been reviewed by three peer reviewers, one of whom is a member of our Board of Reviewing Editors, and the evaluation has been overseen by a Senior Editor. The following individual involved in review of your submission has agreed to reveal their identity: Jitka Pikhartova (Reviewer #3).Thank you for submitting your article "Sense of coherence and risk of breast cancer" for consideration by eLife, the reviewers have discussed their critiques with one another. What follows below is the Reviewing Editor's edited compilation of the essential and ancillary points provided by reviewers in their critiques and in their interaction post-review. Please submit a revised version that addresses these concerns directly. Although we expect that you will address these comments in your response letter, we also need to see the corresponding revision in the text of the manuscript. Some of the reviewers' comments may seem to be simple queries or challenges that do not prompt revisions to the text. Please keep in mind, however, that readers may have the same perspective as the reviewers. Therefore, it is essential that you attempt to amend or expand the text to clarify the narrative accordingly.As is customary in eLife". Please let us know if you would like to pursue this option. Given the present situation, we will give authors as much time as they need to submit revised manuscripts. We are also offering, if you choose, to post the manuscript to bioRxiv  along with this decision letter and a formal designation that the manuscript is "in revision at Summary:Sense of coherence (SoC) refers to a person's psychological ability to properly adapt to stress and adversity during the life course. The scale was developed to measure how people view life and to identify how a person may use her/ his intrinsic resources to overcome difficulties while maintaining their health. It seeks to understand why some people remain healthy under stress while others become sick. The SoC concept has been widely used and there is evidence suggesting a link between SoC and several health outcomes including cardiovascular disease and diabetes. However, the association between SoC and cancer is less studied. In the current study, the authors examine the association between SoC and risk of breast cancer using data from a cohort study of 46,436 women recruited in the Karolinska Mammography Project for Risk of Breast Cancer (Karma). This well-conducted study did not show an association between SoC and breast cancer. This study represents a potentially valuable contribution to the literature on SoC and breast cancer. However, there are a few substantive concerns.Essential revisions:While the authors provide a brief explanation of the SoC, the theoretical framework is still underdeveloped, and the explanations and definitions are vague and unclear. The text would benefit from a more elaborated explanation of theory of salutogenesis and how it relates to breast cancer. In addition, the authors need to provide a more comprehensive definition of SoC and its three aspects of comprehensibility, manageability and meaningfulness, notably explaining more about the nature of the stimuli as mentioned in the paper. A clearer definition of Generalized Resistance Resources (GRRs) is also required.In summary, the manuscript fails to highlight the theoretical importance of examining the link between SoC and breast cancer, except that previous studies' results have been mixed or that no clear relationship has been established for this association. It is unclear to the reviewer which aspect of this current manuscript can resolve the issues of the existing mixed results on this topic.The analytical approach of the paper needs to be improved; we recommend that the authors run a sensitivity analysis without adjustment for life stressors, hours of sleep, and quality of life. This is for the following reasons:• "Sense of coherence (SOC) reflects a coping capacity of people to deal with everyday life stressors". Therefore, life stressors should not be adjusted for; the effects of SOC are likely washed away when stressful life events are included as confounders (over adjustment).• Having a high SOC means that one is able to cope better with stressors in the surrounding environment; therefore, how stressed one feels is an inherent part of SOC and should not be adjusted for.• Quality of life (QOL) is also typically assessed as an outcome of SOC, rather than as a confounder as this paper has done. The stronger the SOC, the better the quality of life (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2465600/). Please omit QOL from the confounder list in the sensitivity analysis.• The study by Poppius et al. cited in the Discussion section did find an association with cancer in the shorter follow-up period of 8 years. In contrast to this study on SOC and breast cancer, Poppius et al. only adjusted for age, occupation, smoking, and alcohol consumption. In line with the above comments, the authors of the current study are over adjusting. Also, the Poppius et al. study combined all cancers and measured their association with SOC, so the endpoint is different. Hence, the differences in results between studies.According to the SOC literature: "Generalized Resistance Resources (GRR) comprise the characteristics of a person, a group, or a community that facilitate the individuals' abilities to cope effectively with stressors and contribute to the development of the individual's level of (SOC)"Table 1 – GRRs are part of the SOC concept, they shouldn't be separated from it . Please change the title of Table 1 to "participant characteristics associated with SOC" or something along those lines. Better to show that you are assessing the relationship of SOC with sociodemographics, lifestyle factors, etc. , and dispense with GRR terminology. Essential revisions:While the authors provide a brief explanation of the SoC, the theoretical framework is still underdeveloped, and the explanations and definitions are vague and unclear. The text would benefit from a more elaborated explanation of theory of salutogenesis and how it relates to breast cancer. In addition, the authors need to provide a more comprehensive definition of SoC and its three aspects of comprehensibility, manageability and meaningfulness, notably explaining more about the nature of the stimuli as mentioned in the paper. A clearer definition of Generalized Resistance Resources (GRRs) is also required.Thank you for the comments. We have now (1) elaborated the explanation of the theory of salutogenesis and how it might relate to breast cancer, (2) provided a more comprehensive definition of SoC and its three components as well as explained more about the nature of the stimuli mentioned in the paper, and (3) provided a clearer definition of Generalized Resistance Resources.1)Explanation of the theory of salutogenesis and how it might relate to breast cancer.Modified text :health, stress, and coping. According to this theory, health is a lifelong and dynamic process of actively coping with a variety of stress factors one might encounter in life , and, although stress is ubiquitous, people experience different health outcomes in response to stress.”“The theory of salutogenesis was developed by Antonovsky  to study factors that support human health and well-being, in contrast to “pathogenesis” which studies factors that cause diseases, with a specific focus on understanding the relationship between Modified text :“The theory of salutogenesis has been applied in different fields of health and medicine. […] No study has addressed this research question among women and for female cancer.”2)Definition of SoC and its three components as well as explanation about the nature of the stimuli mentioned in the paper.Modified text :“According to this theory, health is a lifelong and dynamic process of actively coping with a variety of stress factors one might encounter in life , and, although stress is ubiquitous, people experience different health outcomes in response to stress.[…] Accordingly, SoC has three components, namely comprehensibility, manageability and meaningfulness, and salutogenesis is greatly dependent on a strong SoC."3)Definition of Generalized Resistance Resources.Modified text :“Generalized Resistance Resources are one of the key determinants for SoC, consisting all resources that help a person cope and are effective in avoiding or combating a range of stress factors, including socioeconomic standing and social support .”In summary, the manuscript fails to highlight the theoretical importance of examining the link between SoC and breast cancer, except that previous studies' results have been mixed or that no clear relationship has been established for this association. It is unclear to the reviewer which aspect of this current manuscript can resolve the issues of the existing mixed results on this topic.We have now highlighted the theoretical importance of examining the link between SoC and breast cancer, as well as the added value of our study to the existing results on this topic.Modified text :“The theory of salutogenesis has been applied in different fields of health and medicine. […] To this end, we took advantage of a mammography screening cohort in Sweden and assessed the association of SoC with the subsequent risk of breast cancer.”Modified text :“Poppius et al.  reported a 52% higher risk of any cancer during an 8-year follow-up of middle-aged men in Finland, when comparing men with a weak SoC to men with a strong SoC. […] The role of SoC in other cancer types among women, in populations outside the Nordic countries, or among other age groups needs to be further investigated.”The analytical approach of the paper needs to be improved; we recommend that the authors run a sensitivity analysis without adjustment for life stressors, hours of sleep, and quality of life. This is for the following reasons:• "Sense of coherence (SOC) reflects a coping capacity of people to deal with everyday life stressors". Therefore, life stressors should not be adjusted for; the effects of SOC are likely washed away when stressful life events are included as confounders (over adjustment).• Having a high SOC means that one is able to cope better with stressors in the surrounding environment; therefore, how stressed one feels is an inherent part of SOC and should not be adjusted for.• Quality of life (QOL) is also typically assessed as an outcome of SOC, rather than as a confounder as this paper has done. The stronger the SOC, the better the quality of life (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2465600/). Please omit QOL from the confounder list in the sensitivity analysis.• The study by Poppius et al. cited in the Discussion section did find an association with cancer in the shorter follow-up period of 8 years. In contrast to this study on SOC and breast cancer, Poppius et al. only adjusted for age, occupation, smoking, and alcohol consumption. In line with the above comments, the authors of the current study are over adjusting. Also, the Poppius et al. study combined all cancers and measured their association with SOC, so the endpoint is different. Hence, the differences in results between studies.We agree with the reviewer that our original model 3 with the adjustment of life stressors, hours of sleep, stressed feeling and quality of life is likely overly conservative. We have now deleted model 3 from Table 2 and used model 2 as the full model in the results presented in Figure 2 and Table 3. We have also modified the text of the manuscript to reflect such changes.Modified text :“In this study, we used information from the baseline questionnaire, including sociodemographic factors , lifestyle factors , and other known risk factors for breast cancer including reproductive and hormonal factors, family history of breast cancer, history of benign breast disorders or other malignancies. We also used breast density percent measured at baseline by previously reported STRATUS software .”Modified text :“We first fitted a model not adjusted for any other covariables (Model 1). In a full model (Model 2), we adjusted the analyses for sociodemographic factors , lifestyle factors , and known risk factors for breast cancer including reproductive and hormonal factors , as well as family history of breast cancer, benign breast disorders, other malignancies, and breast density.”“We further performed a sub-analysis to assess whether the studied association would differ between subtypes of breast cancer using the full model.”Modified text :“More than half of the women were post-menopausal, and had college education or above (Table 1). Women with strong SoC were slightly older, more educated, less likely to smoke, and more physically active.”Finally, we have also modified the text that are relevant to the Poppius et al. study in the Introduction and Discussion sections to illustrate the potential explanations for the different findings observed between the Poppius et al. study and the present study.Modified text :“In contrary, there is so far one study, to the best of our knowledge, that assessed the role of SoC on cancer development, and found an association between weak SoC and an increased risk of cancer during an 8-year follow-up, although not 12-year follow-up, of a population of middle-aged Finnish men . No study has addressed this research question among women and for female cancer.”Modified text :“To our knowledge, few studies have examined the link between SoC and risk of cancer. Poppius et al.  reported a 52% higher risk of any cancer during an 8-year follow-up of middle-aged men in Finland, when comparing men with a weak SoC to men with a strong SoC. […] The role of SoC in other cancer types among women, in populations outside the Nordic countries, or among other age groups needs to be further investigated.”According to the SOC literature: "Generalized Resistance Resources (GRR) comprise the characteristics of a person, a group, or a community that facilitate the individuals' abilities to cope effectively with stressors and contribute to the development of the individual's level of (SOC)"Table 1 – GRRs are part of the SOC concept, they shouldn't be separated from it . Please change the title of Table 1 to "participant characteristics associated with SOC" or something along those lines. Better to show that you are assessing the relationship of SOC with sociodemographics, lifestyle factors, etc. , and dispense with GRR terminology.We agree with the reviewer(s) and have removed results about life stressors, stressed feeling, hours of sleep, and quality of life from Figure 1 and changed the title of Figure 1 as “Linear associations between sociodemographic and lifestyle factors and sense of coherence”. We have also removed these items from Table 1 and changed the title of Table 1 as “Characteristics of study participants by sense of coherence at baseline”. We have also modified the text of the manuscript to reflect such changes.Modified text :“In this study, we used information from the baseline questionnaire, including sociodemographic factors , lifestyle factors , and other known risk factors for breast cancer including reproductive and hormonal factors, family history of breast cancer, history of benign breast disorders or other malignancies. We also used breast density percent measured at baseline by previously reported STRATUS software .”Modified text :“In the linear regression, we found SoC to be positively associated with age , number of births , and a higher physical activity  . Higher BMI , non-European ancestry , less education , previous or current smoking , and never or ≥ 10g/d drinking  were all associated with a lower SoC score.”


Breast cancer survivors (BCS) may have increased risk of hypothyroidism, but risk according to treatment modality is unclear. We estimated the incidence of hypothyroidism in women with breast cancer, and according to cancer treatment.Using nationwide registries, we identified all Danish women aged ≥ 35 years diagnosed with non-metastatic breast cancer (1996–2009). We matched up to five cancer-free women (controls) for each BCS. We excluded women with prevalent thyroid disease. Cancer treatment was chemotherapy with or without radiotherapy (RT) targeting the breast/chest wall only, or also the lymph nodes (RTn). We identified hypothyroidism using diagnostic codes, and/or levothyroxine prescriptions. We calculated the cumulative incidence, incidence rates (IR) per 1000 person-years, and used Cox regression to estimate hazard ratios (HR) and associated 95% confidence intervals (CIs) of hypothyroidism, adjusting for comorbidities.We included 44,574 BCS and 203,306 matched controls with 2,631,488 person-years of follow-up. BCS had a slightly higher incidence of hypothyroidism than controls . The overall IR was 4.45 (95%CI = 4.25–4.67) and 3.81 (95%CI = 3.73–3.90), corresponding to an adjusted HR = 1.17 (95%CI = 1.11–1.24). BCS who received RTn with chemotherapy  or without chemotherapy  had an elevated risk of hypothyroidism compared with matched controls and compared with BCS who underwent surgery alone .BCS have an excess risk of hypothyroidism compared with age-matched controls. BCS and those working in cancer survivorship settings ought to be aware that this risk is highest in women treated with radiation therapy to the lymph nodes and chemotherapy. Over the past 30 years, breast cancer survival has improved substantially due to earlier detection and improved adjuvant therapies . Today, 4 levels in the serum. Hypothyroidism can be controlled with levothyroxine substitution therapy.Hypothyroidism affects approximately 3% of the European population. The prevalence of hypothyroidism is higher in women and risk increases with age . HypothyHypothyroidism is a well-documented late effect of radiation therapy (RT) to the lower neck in lymphoma and head and neck cancer patients , 6. ReseWe therefore evaluated the incidence of hypothyroidism in breast cancer survivors and determined if this risk is modified by treatment modalities, compared with age-matched cancer-free women from the general population.This study was approved by the Danish Medicines Agency and the Danish Breast Cancer Group (DBCG). The use of personal data for the project has been approved by Aarhus University in accordance with General Data Privacy Regulations and the Danish data protection legislation and does not require informed consent from the research subjects or approval from governmental or ethical bodies.This population-based matched cohort study used prospectively collected data from national medical registries covering the entire Danish population of 5.7 million inhabitants. All citizens have free access to health care because it is completely tax funded. At birth or immigration, citizens are assigned a unique civil personal registration number that enables accurate and unambiguous individual-level linkage across all public registries .From the DBCG, we assembled a cohort of all women diagnosed with a first-time hospital diagnosis of non-metastatic breast cancer aged ≥ 35 years between January 1, 1996, and December 31, 2009. The DBCG clinical database was established in 1977 to optimize breast cancer diagnosis and treatment across Denmark and to improve breast cancer prognosis . All patBy linking to various registries, we excluded women with prevalent hypothyroidism, hyperthyroidism, and/or previous cancers at breast cancer diagnosis (see codes below).We used the DBCG database for information on adjuvant treatment, including chemotherapy (yes or no) and RT .Using the Danish Civil Registration System, for each breast cancer survivor, we matched with replacement  up to fiHypothyroidism was defined as a diagnostic code of hypothyroidism  8th edition codes: 244.00-244.03, 244.08, and 244.09, and ICD-10 codes: E03.2-E03.9 and E89.0) and/or at least two redeemed levothyroxine prescriptions in the absence of concomitant anti-thyroid drugs  Classification code: H03A) during follow-up. Information on diagnostic codes was obtained from the Danish National Registry of Patients (DNRP) covering information on all discharge diagnoses for inpatient hospital admissions since 1977 and outpatient and emergency room hospital contacts since 1995 . We asceWe ascertained information on hyperthyroidism from the DNRP .Information on prior cancers was ascertained from the DNRP (ICD-8 codes: 140-209 and ICD-10 codes: C00-99).We collected information on comorbidities diagnosed up to 10 years before the index date from the DNRP. We evaluated comorbidity for each individual using a modified version of the Charlson comorbidity index (CCI) excluding cancer from the index score  and cateFor the breast cancer cohort, we retrieved information on clinical characteristics from the DBCG including menopausal status at diagnosis, tumour size, histological grade, lymph node status, tumour oestrogen receptor (ER) status, and human epidermal growth factor receptor 2 (HER-2) status. We derived cancer stage by combining information on tumour size and lymph node status.We present descriptive statistics as count and percentages for the breast cancer cohort and matched control cohort, and tumour and treatment characteristics for the breast cancer cohort. We summarized the data sources for identifying cases of hypothyroidism  in each cohort. We calculated the cumulative incidence, incidence rates (IRs) of hypothyroidism per 1000 person-years, and associated 95% confidence intervals (95%CIs), and stratified results by calendar period, age, and CCI. To explore the risk of hypothyroidism in strata of cancer treatment, we created a composite variable with six categories for the receipt of RT and chemotherapy (CT) . IRs of hypothyroidism with 95%CIs were computed for each category in the breast cancer cohort and the matched control cohort. We plotted the cumulative incidence of hypothyroidism in the breast cancer and matched control cohorts and stratified according to treatment modality.Using Cox proportional hazards regression models using time since diagnosis/index date as the underlying time scale, we estimated hazard ratios (HRs) with 95%CI comparing the breast cancer cohort with the matched cohort adjusting for age and the CCI at the diagnosis/index date. This approach was repeated in strata of treatment modalities. Within the breast cancer cohort, we estimated HRs using no treatment (RT−/CT−) as the reference group. The models accounted for competing risks of death, emigration, and hyperthyroidism. We checked the proportional hazard assumption by visual inspection of the log of the estimated survivor function in the model. Follow-up time began 6 months after breast cancer diagnosis/index date to ensure completion of primary treatment. Follow-up time continued from 6 months after diagnosis/index through 1 January 2016.We conducted several sensitivity analyses. We stratified our analyses by the CCI to clarify if individuals with high comorbidity had a higher IR of hypothyroidism than those with low comorbidity due to more regular contact with healthcare providers. We also stratified by age and calendar to assess if the association changed by age or over calendar time. In the analyses restricted to the breast cancer cohort, we additionally adjusted for cancer stage, grade, and ER status (in addition to age and comorbidity).All statistical analyses were performed using SAS version 9.4 .The study cohorts consisted of 44,574 breast cancer survivors and 203,306 matched controls with 384,401 and 2,082,014 person-years of follow-up, respectively , the cumulative incidence of hypothyroidism was 1.8% (95%CI = 1.7 to 1.9) and 1.6% (95%CI = 1.5 to 1.6) in the breast cancer and control cohorts, respectively. The cumulative incidence of hypothyroidism was higher up to approximately 12 years after diagnosis, from which point the incidence was higher in the matched control cohort  . The HRs were similar to the overall breast cancer cohort among women who did and did not receive endocrine therapy  , 14, 19.Breast cancer RT may cause incidental exposure to adjacent tissues and has been associated with an increased risk of ischemic heart disease . Given tYounger breast cancer patients tend to have poorer prognosis and generally receive more aggressive cancer-directed treatment than older patients –33. AccoPrimary strengths of our study are the large sample size and long-term complete follow-up, the use of comprehensive clinical data on breast cancer patients, and the treatment information on all subjects. Individual-level data linkage to the Danish population-based registries enabled inclusion of detailed information on comorbid and other thyroid diseases for all participants. In addition, we were also able to include information on redeemed prescriptions. We excluded patients with prevalent hyperthyroidism at breast cancer diagnosis/index date. We also censored patients who developed hyperthyroidism during follow-up, as some treatments for hyperthyroidism such as radioactive iodine and surgery may increase the risk of hypothyroidism .Among our study’s limitations are the risk of misclassification in relation to outcome status because hypothyroidism is underdiagnosed in the general population . Such diWe had no information on lifestyle factors, so our findings may be prone to unmeasured confounding from factors such as smoking, obesity, and physical activity , 35. HowIt is worth noting that cancer-directed treatments in our study were based on intention-to-treat data from DBCG, rather than received treatments. Furthermore, we did not incorporate information on breast cancer recurrence in this study or on treatments given for recurrent breast cancer. It is likely that patients diagnosed with recurrent breast cancer, or other new primary cancers, would be treated with radiation therapy and/or chemotherapy. This may have contributed to our observed elevated risk of hypothyroidism in the breast cancer compared with the comparison cohort.Our large prospective study suggests that women with breast cancer had a long-term elevated risk of hypothyroidism compared with matched cancer-free women from the general population. The risk of hypothyroidism was highest in breast cancer survivors treated with RT targeting the lymph nodes, especially among those who also received chemotherapy. The thyroid gland should be considered an organ at risk in breast cancer radiation therapy targeting the lymph nodes and the dose to the thyroid gland minimized when possible. Oncologists and health care professionals working in cancer survivorship settings, as well as breast cancer survivors themselves, ought to be vigilant to the signs and symptoms of hypothyroidism, particularly among survivors who received radiation therapy to the lymph nodes and chemotherapy.Additional file 1: Supplementary Figure 1. CONSORT diagram showing the of inclusion and exclusion criteria for the cohort of breast cancer survivors and the matched control cohort. Supplementary Table 1. Incidence rates (IRs) and hazard rates§ of hypothyroidism for survivors of non-metastatic breast cancer and matched controls in strata by calendar period, age and comorbidity at index date. Supplementary Figure 2. Cumulative person-time in the cohort of survivors of non-metastatic breast cancer and the matched control cohort, with that in the matched controls divided by 5 to account for the 1:5 matching. Supplementary Table 2. Incidence rates (IRs) and hazard ratios and associated 95% confidence intervals (95%CI) of hypothyroidism in the cohort of women diagnosed with non-metastatic breast cancer between 1996 and 2009, who were registered in the Danish Breast Cancer Group clinical database, stratified by the receipt of radiation therapy – to the chest wall only (RTc) or with the addition of the lymph nodes (RTn) – and chemotherapy. .


Bladder cancer is three to four times more common among men than women. The objectives of this study were to explore the association between reproductive and hormonal factors and risk of bladder cancer among women using data from the Prostate, Lung, Colorectal and Ovarian (PLCO) cohort, and to perform a meta-analysis based on cohort studies. After a median of 11.6 years of follow-up, 237 incident bladder cancer cases were identified in PLCO cohort. Compared with menopause at 50-54 years, earlier menopause (< 45 years) was positively but not significantly associated with bladder cancer risk . In the meta-analysis, parous women had significantly lower bladder cancer risk than nulliparous women . In addition, menopause at an earlier age was significantly associated with a higher risk of bladder cancer . In conclusion, this study indicated a greater risk in bladder cancer among nulliparous women and among women with early menopause. Further studies are needed to understand the underlying mechanisms. Incidence rates of bladder cancer differ notably between men and women. The estimated numbers of new bladder cancer cases in 2020 in the United States will be approximately 62,100 and 19,300 for men and women, respectively [Animal and human-cell preclinical studies have indicated that steroid hormone receptor signaling plays an important role in bladder cancer development and progression –5. EmergAfter a median of 11.6 years of follow-up, 237 incident bladder cancer cases were identified in PLCO cohort. In this meta-analysis based on the PLCO cohort and seven previously published prospective studies, we observed a higher risk of bladder cancer among nulliparous women compared with parous women and among women who experienced early menopause. No association was observed for any use of HRT, although a no significantly lower risk was found among women using EPT.Although the findings of PLCO cohort did not support an inverse association between parity and bladder cancer, parity has been shown to be negatively associated with bladder cancer risk in various observational studies –11. MostEarly age at menopause has been associated with a higher risk of bladder cancer in several previous cohort studies , 11, 16 Many prospective studies, including the PLCO cohort, have either found a null association or a positive association between bladder cancer and HRT , 11, 16.Strengths of the PLCO study included the large size, the population-based setting, a comprehensive list of potential confounders, and a virtually complete follow-up. Strengths of our meta-analysis included the strict inclusion criteria (restriction to prospective studies), the large sample size, and the homogeneity across eligible studies. Several limitations should also be mentioned. First, only baseline exposure data were used in the PLCO analysis and thus we were not able to take into account change in exposure status over time. Second, the results were still potentially biased by residual confounding after multi-adjustment. In the PLCO cohort, we could not adjust our results for exposures to chemicals and physical activity. Third, a meta-analysis is unable to solve problems with confounding variables that could be inherent in the original studies and inadequate control of all known confounders may bias the summary results. Finally, the PLCO and meta-analysis have some contradicting results. For example, menopause at an earlier age was significantly associated with a higher risk of bladder cancer in the meta-analysis. On the other hand, an earlier menopause was positively but not significantly associated with bladder cancer risk in the PLCO cohort, which may have limited sample size and statistical power compared with a meta-analysis.In conclusion, our study indicated an elevation in risk for bladder cancer among nulliparous women and among women who reported earlier age at menopause. The underlying mechanisms that may be responsible for these relationships remain to be determined.The design and methods of the PLCO screening trial have been published . BrieflyIn this study, participants were excluded if they were male ; had not returned a baseline questionnaire ; had reported a previous cancer at baseline ; had died of an unknown cause or had an undetermined case status (n = 36); or did not have follow-up time (n = 333). Thus, the cohort for analysis consisted of 70,584 women.Incident cases of primary carcinoma of the urinary bladder were updated annually using a self-reported questionnaire. Participants were asked whether they had been diagnosed with any cancer, cancer types, and diagnosis date in the previous year. State registries, death certificates and physician reports were examined as additional sources of cancer incidence data. Cancer diagnoses were verified through medical record abstraction. Participants were followed until cancer diagnosis or death, or end of follow-up .2 vs. ≥ 25 kg/m2), education (≤ high school vs. ≥ some college), and smoking status (never vs. former ≤ 15 years since quit vs. former > 15 years since quit vs. former year since quit unknown vs. current smoker ≤ 1 pack per day vs. current smoker > 1 pack per day vs. current smoker intensity unknown). Tests of multiplicative interaction were performed using likelihood-ratio tests compared models with and without the interaction term. The proportional hazards (PH) assumption was examined using the Schoenfeld residual test [A multivariate Cox proportional hazards model was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). Models were adjusted for potential confounders including age , race (non-Hispanic White vs. Other), body mass index .i) investigated the associations between hormonal and/or reproductive exposures and bladder cancer risk, (ii) risk estimates with their 95 % CIs were given or sufficient information was provided for calculation, and (iii) the study design was cohort, nested case-control, case-cohort or clinical trial. Seven previously published prospective studies [. A two-sided P-value <0.05 was considered significant.We analyzed the effects of ever versus never exposure to parity, age at menopause, use of any HRT, and use of EPT for HRT on bladder cancer risk using a meta-analysis approach, because these associations reported in published literature were inconsistent. If a single study reported results for different exposures  but did not report the overall results, we combined the corresponding estimates using the methods proposed by Hamling et al. , taking


Published studies on the risk of radiation-induced second primary malignancy (SPM) after radioiodine treatment (RAI) of differentiated thyroid cancer (DTC) refer mainly to patients treated as middle-aged or older adults and are not easily generalizable to those treated at a younger age. Here we review available literature on the risk of breast cancer as an SPM after RAI of DTC with a focus on females undergoing such treatment in childhood, adolescence, or young adulthood. Additionally, we report the results of a preliminary international survey of patient registries from academic tertiary referral centers specializing in pediatric DTC. The survey sought to evaluate the availability of sufficient patient data for a potential international multicenter observational case–control study of females with DTC given RAI at an early age. Our literature review identified a bi-directional association of DTC and breast cancer. The general breast cancer risk in adult DTC survivors is low, ~2%, slightly higher in females than in males, but presumably lower, not higher, in those diagnosed as children or adolescents than in those diagnosed at older ages. RAI presumably does not substantially influence breast cancer risk after DTC. However, data from patients given RAI at young ages are sparse and insufficient to make definitive conclusions regarding age dependence of the risk of breast cancer as a SPM after RAI of DTC. The preliminary analysis of data from 10 thyroid cancer registries worldwide, including altogether 6,449 patients given RAI for DTC and 1,116 controls, i.e., patients not given RAI, did not show a significant increase of breast cancer incidence after RAI. However, the numbers of cases and controls were insufficient to draw statistically reliable conclusions, and the proportion of those receiving RAI at the earliest ages was too low.In conclusion, a potential international multicenter study of female patients undergoing RAI of DTC as children, adolescents, or young adults, with a sufficient sample size, is feasible. However, breast cancer screening of a larger cohort of DTC patients is not unproblematic for ethical reasons, due to the likely, at most slightly, increased risk of breast cancer post-RAI and the expected ~10% false-positivity rate which potentially produced substantial “misdiagnosis.” Treatment of differentiated thyroid cancer (DTC) in childhood, adolescence, or early adulthood with surgery, radioiodine iodine-131, I-131) therapy (RAI), and thyroid hormone replacement achieves 10-year survival rates of 95%, with relatively low recurrence rates of 10–30%  review available literature on the risk of breast cancer as an SPM (A) independent of the type of treatment of RAI and (B) after RAI of DTC, with a focus on young females, and (2) report the results of our preliminary international multi-registry survey to evaluate the availability of patient data for a sufficiently powered multicenter international study of DTC patients given RAI as children, adolescents, or young adults. This research project was sponsored by the German Federal Office for Radiation Protection.The literature included in the analysis was identified by two independent reviewers (VD and RS), principally using an automated literature search for English language papers published from 1984 to 2018 regarding breast cancer after RAI of DTC. The search was carried out using the online Medline (PubMed), Cochrane, and Embase databases. The main search terms were “thyroid” OR “breast” OR “mamma” AND “cancer” OR “malignancy” OR “carcinoma” OR “tumor” AND “second primary malignancy” AND “radioiodine therapy.” Besides the automated search, a manual search for additional relevant publications was made of the bibliographies of the papers identified automatically.N < 500), narrative reviews of the literature, editorials, and letters to the editor were excluded. Also excluded were publications regarding studies not differentiating between synchronous and metachronous SPMs.Systematic reviews, meta-analyses, cohort studies, and case–control studies were included. Case reports, single-center studies with small databases or study samples  were extracted:First author, date, countrySetting , single-center or multicenter designDuration of the study and of the follow-up timeStudy sample characteristics , exclusion criteria in the studyDTC characteristics (histology and TNM stage)Surgery, RAI yes/no, cumulative I-131 activity as a surrogate for radiation doseSPM  before/after RAILatency period, age dependency, dose dependency of SPM, and breast cancer incidence (correlation with I-131 activity)◦ absolute number◦ excess absolute risk◦ excess relative risk◦ observed/expected incidence (O/E)◦ odds ratio◦ relative risk◦ standardized incidence ratio (SIR)◦ incidence rate ratio◦ hazard ratio (HR)Risk estimates for secondary breast cancer after DTC (independent of treatment) and for secondary breast cancer after RAI of DTC, expressed as one or more of the following:with corresponding 95% confidence interval (CI).Because of the heterogeneity and the variable design of the studies in the literature, only a qualitative and not a pooled analysis was performed.n = 12), case reports (n = 11), letters to the editor (n = 4), and unclear specification if the breast cancer was diagnosed before or after DTC (n = 32) (the papers could be excluded on more than one grounds).Using the search strategy described above, a total of 233 citations were found , 169 of Thus, altogether 40 publications were included in our analysis ; they arSpecifically, n = 28) were cohort studies of large population-based tumor registries , re, re46), n = 8) and the type of treatment  was not specified.The first cohort study describing an increased risk for breast cancer after DTC, that of Ron et al. , alreadyOn the contrary, two meta-analyses and one large pooled cohort study  comparinThe absence of an association between RAI of DTC and breast cancer was confirmed by all seven studies on the risk of breast cancer after such treatment upon examining the US SEER Registry  3, 18–22, 24. Thper se. Most importantly, in patients receiving cumulative activities of >4.4 GBq in comparison to patients receiving <4.4 GBq, the risk for breast cancer was not increased.In detail, Ahn et al.  noted thBrown et al.  did not Adly et al.  also anaThe second part of this report addresses a survey of patient registries from institutions known by the authors to specialize in treating children and adolescents with DTC. This preliminary study evaluated the availability of sufficient patient data to conduct an adequately powered international multicenter observational case–control study regarding breast cancer risk in female DTC survivors who were treated with RAI at a young age. Altogether eight academic tertiary referral centers from Germany, Ukraine, Poland, Italy, Brazil, Serbia, and Portugal agreed to participate. In addition, the German-Belarusian Foundation “ARNICA” contributed two separate datasets, one from their registry and the other from a dedicated smaller database which was set up for a “pilot study” that sought to test the feasibility of a multicenter international study on breast cancer risk in DTC survivors . The nine institutions participating in the registry survey were:Foundation “ARNICA,” Minsk, Belarus (feasibility study sample and routine registry)Institute of Endocrinology and Metabolism, Kiev, UkraineInstituto Nacional do Cancer—INCA, Rio de Janeiro, BrazilInstitute of Oncology Vojvodina, Department of Nuclear Medicine, Sremska Kamenica, SerbiaDepartment of Nuclear Medicine, University Hospital, Coimbra, PortugalDepartment of Nuclear Medicine, University Hospital, Münster, GermanyDepartment of Endocrinology, University Hospital, Pisa, ItalyClinic of Nuclear Medicine and Endocrine Tumors, M. Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Gliwice, PolandDepartment of Nuclear Medicine, University Hospital, Würzburg, GermanyIn the registry survey, in 2014–2015, the participating centers answered questionnaires requesting the most relevant information regarding breast cancer in female survivors of DTC, particularly those receiving RAI at an early age. These queries included the database's total number of female DTC survivors diagnosed during childhood or adolescence with or without a history of RAI, the percentage of DTC survivors who were ages <18 or <40 years of age at the time of the primary treatment, the cumulative activity of I-131 administered for RAI, and the follow-up regimen after RAI. Queries were also made regarding the incidence of SPM, specifically breast cancer, both before and after the DTC diagnosis. The registry study was performed with anonymous, aggregated patient data.The pilot observational cohort study alluded to above was performed in collaboration with the Foundation “ARNICA” and other organizations in Belarus and Germany in 2016–2017 . In this feasibility study, selected female patients given RAI for their DTC in childhood or adolescence and control patients not given RAI underwent clinical, imaging, and laboratory examinations as part of a screening program for breast cancer. As noted previously, the dedicated database that was created for the pilot study also was analyzed in the present study. To avoid duplicate publication, any patients in the dedicated database who also were in the Foundation “ARNICA” Registry were excluded from all analyses of the latter.n = 6,449) or not given RAI . The number of RAI patients per institution varied considerably from 15 to 1,644 and the number of controls from 0 to 419.The three largest groups of RAI patients, with more than 1,000 cases each, were contributed by the participating centers in Münster, Kiev, and Pisa. By contrast, by far the largest “no RAI” control group was provided by the Foundation “ARNICA,” Minsk, with a total of more than 500 controls (pilot study database plus registry). It is apparent from The data in The cohorts from the four other centers , which tExcept for the cohort from Kiev, all centers reported their cumulative activity of I-131 (in GBq) administered for RAI , 3B. TheEight of the nine centers , 3B provn = 909) and controls (n = 419) of the Minsk registry included a low number of breast cancer cases, eight and five, respectively, before the diagnosis of DTC. After the DTC diagnosis, there was one additional case of breast cancer and three additional cases of other SPM in the RAI patient group as compared to no case of breast cancer and one case of another SPM in the control group.Again, eight of the nine centers provided data about SPM and breast cancer before and after the diagnosis of DTC , 3B. TheThe rates of SPM and breast cancer were higher in the much older cohorts from Würzburg, Münster, Gliwice, and Pisa. The rates before and after the diagnosis of DTC reported by the latter three centers were very similar, ranging between 0.5 and 2.5%  for breast cancer and 0.6–4.5%  for SPM other than breast cancer. The exceptionally high rate of other malignancies before DTC in the Würzburg cohort may be explained, at least partially, by detection bias due to the existence of a comprehensive local clinical cancer registry and a follow-up program. In that cohort, systematic differences in the cumulative incidences of breast cancer and other SPM between RAI patients and controls were not recognizable.vice versa.In a comprehensive systematic review and meta-analysis, Nielsen et al.  investigThe majority of studies addressing this issue that are referenced here (22/34) indicate that there is a generally increased risk for breast cancer after diagnosis of DTC, independent of therapy. This observation was reflected in five of six systematic reviews, meta-analyses, and pooled studies . The obsIn the general population of the USA, breast cancer risk in women below age 45 years corresponds to approximately one case in 87, or 1.2% . To giveHowever, the only study specifically focusing on children and adolescents younger than 20 years old does not suggest an increased breast cancer risk in patients with DTC . There iBeyond the generally increased risk for breast cancer in DTC survivors independent of treatment, a history of RAI seems not to have any additional influence on this risk , 2A, 2C,Assessing the hypothesis of a generally increased risk for SPMs other than breast cancer in DTC patients/survivors was not an objective of the present study. However, in young (as well as adult) DTC patients after RAI, a generally increased risk for SPM seems to exist, specifically in organs and tissues relatively highly irradiated by RAI, e.g., salivary glands, gums, and other parts of the mouth, the stomach, and the kidneys .Concerning the risk of breast cancer in DTC survivors given RAI at a young age—the original focus of this review—data are inconclusive for many reasons. A general problem of critically reviewing publications from, e.g., tumor registries is that non-independent data sets from identical registries are analyzed and published repeatedly. This plays an important role in the context of our review because 11 of 40 studies utilized the SEER registry and, similarly, three studies from Korea, two studies from Taiwan, three studies from Israel, and two studies from Sweden all refer to the same respective databases from those countries , 2C. As Generally, the risk for breast cancer in DTC patients independent of therapy may be overestimated since the samples in 36 studies on the general risk of breast cancer in DTC patients included a large proportion of patients who were treated with RAI. Therefore, the studies' estimates of breast cancer risk in “all DTC survivors” might be conservatively high—because any increased risk due to RAI would materially elevate risk in the overall group.Detection bias is possibly the most relevant limitation for most of the studies published since patients with a cancer diagnosis tend to participate more strictly in cancer screening programs, e.g., for breast cancer. Detection bias, by the way, may be the cause for the surprisingly high rate, 14.7%, of SPM other than breast cancer before the diagnosis of DTC in the Würzburg registry. Another limitation of the literature is that the published studies often did not differentiate between synchronous and metachronous SPMs; indeed that is one reason why more than 30 papers were excluded from this literature review.In addition, when comparing DTC patients after RAI with DTC controls without a history of that treatment, selection may have introduced a relevant bias. That is because the indication for RAI depends on tumor stage, and RAI usually is not performed in patients with the frequently favorable stage pT1N0M0 . Conversin situ vs. invasive breast cancer in DTC patients, separately describing such an increased risk for carcinoma in situ only  and less often long follow-up times of 10–20 years . According to the American Thyroid Association's “Management Guidelines for Children with Thyroid Nodules and Differentiated Thyroid Cancer,” the minimum follow-up time for studies on outcomes and long-term side effects of DTC therapy in children and adolescents should be at least 10 years  are mostly not reported. Moreover, this activity is merely a surrogate for the radiation dose to breast tissue (in Gy), which only can be determined by individual measurements of uptake and effective half-time of I-131 in the body and the breast specifically. Regarding radiation exposure in general, a history of frequent diagnostic radiological examinations or accidental irradiation  may play an important role, confounding the interpretation of the impact of RAI.in vitro and animal studies have been published, but only a few studies in humans . Since dedicated registries of children and adolescents with DTC are rare and tend to contain only low numbers of cases, it might not to be possible to restrict the limit of “young age” at the time of RAI to 18 years. To ensure the recruitment of a sample size enabling sufficient statistical power, the age limit at the time of RAI probably should be increased to 40 years, which would cover about 35% of patients with DTC.Based on the maximum breast cancer rates in our registry survey (see Section Cumulative I-131 Activity) and on published data , it is aTaking into account that about 3,200 of the patients in this registry study already met the age <40 years criterion, it seems to be feasible to recruit 30% more cases by including additional patients from other DTC specialist centers in Germany and abroad. Regarding the controls not receiving RAI, this survey already identified 650 of the 660 necessary patients for a subsequent study.To summarize today's state of knowledge, independent of DTC treatment, there appears to be a bi-directional association of DTC itself and breast cancer. Nonetheless, the risk of breast cancer in adult DTC survivors is low, about 2%, slightly higher in females than in males, but based on the literature, presumably lower in children and adolescents than in older age groups. RAI is assumed not to substantially influence the lifetime risk of breast cancer after DTC, but data from those given such treatment as children or adolescents are sparse.The literature review and multicenter registry survey reported here lead to the following recommendation: an international multicenter study with a sufficiently high number of female DTC survivors is feasible; that study should have a case–control design and include female patients <40 years of age with DTC diagnosed 20–30 years earlier. For reasons of compliance and practicability, such a design should be preferred over a longitudinal study lasting several decades.However, especially given the likely at most slightly increased risk for breast cancer after RAI, breast cancer screening of a large cohort of female DTC survivors who received breast doses between 0.2 and 2 Gy from cumulative RAI activities of 1–15 GBq I-131  is not uCR contributed to concept development, study management, critical review of the literature, and editing of the final manuscript. RS contributed to study management, literature search, critical review of the literature, and language editing. TP contributed to the management and the analysis of thyroid cancer database in Minsk. MF contributed to the histology review of thyroid cancer database in Minsk. UMä contributed to the supply of registry data from Würzburg. UMa contributed to the statistical analysis and writing the statistics section of the manuscript. AV contributed to the supply of registry data from Münster. TB contributed to the supply of registry data from Kiev. JK contributed to the supply of registry data from Gliwice. RE contributed to the supply of registry data from Pisa. FV contributed to the supply of registry data from Rio de Janeiro. JM contributed to the supply of registry data from Sremska Kamenica. GC contributed to the supply of registry data from Coimbra. VD contributed to the study management, literature search, critical review of the literature, supply of feasibility study data from Minsk, and drafting of the manuscript. All authors contributed to the critical review. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Identifying breast cancer patients with pathogenic mutations that run in their families may improve the follow-up care they receive and breast cancer screening of their close relatives. In this study we identified breast cancer patients with high chances of having a pathogenic mutation and their close female relatives. We developed and tested two different kinds of letters and booklets that presented either personalized or generic information about screening and breast cancer that runs in families, and we encouraged participants to seek genetic evaluation. We found that both types of letters worked equally well for breast cancer patients and for relatives, regardless of their racial background. The personalized letters had slightly better outcomes. Some breast cancer patients and their relatives used genetic services and improved their screening practices. Black patients and their relatives were more satisfied with the booklets than other participants.n = 637) or the targeted (n = 595) intervention. Approximately 40% of participants were Black. Based on intention-to-treat analyses, YBCS in the tailored arm reported higher self-efficacy for genetic services (p = 0.0205) at 8-months follow-up. Genetic testing increased approximately 5% for YBCS in the tailored and the targeted arm  and for Black and White/Other YBCS . CBEs and mammograms increased significantly in both arms, 5% for YBCS and 10% for relatives and were similar for Blacks and White/Others. YBCS and relatives needing less support from providers reported significantly higher self-efficacy and intention for genetic testing and surveillance. Black participants reported significantly higher satisfaction and acceptability. Effects of these two low-resource interventions were comparable to previous studies. Materials are suitable for Black women at risk for hereditary breast/ovarian cancer (HBOC).We compared a tailored and a targeted intervention designed to increase genetic testing, clinical breast exam (CBE), and mammography in young breast cancer survivors (YBCS) (diagnosed <45 years old) and their blood relatives. A two-arm cluster randomized trial recruited a random sample of YBCS from the Michigan cancer registry and up to two of their blood relatives. Participants were stratified according to race and randomly assigned as family units to the tailored ( Women diagnosed with breast cancer younger than 45 years old (young breast cancer survivors-YBCS) constitute approximately 25% of new breast cancer cases in the US, and are more likely to carry germline pathogenic variants associated with hereditary breast and ovarian cancer (HBOC) syndrome ,2. NatioPaired with physician recommendations, theory-based and tailored interventions promote repeat screening, especially among racially diverse women ,23,24,25The present RCT builds on this prior work by oversampling for Black participants and by comparing the efficacy of two low-resource interventions delivered via postal mail, which included a targeted (more generic) versus a tailored (person-specific) intervention. The outcomes presented in this paper are initiation of genetic testing for YBCS, cascade genetic testing for relatives, and surveillance (CBE and mammography screening) consistent with national guidelines for YBCS and relatives. Satisfaction, acceptance, and perceived usefulness of the interventions were also assessed.The Theory of Planned Behavior (TPB)  guided tThe tailored intervention included the same booklet as above and a second booklet presenting basic principles of open communication and family support. The purpose of this second booklet was to enhance the tailored messages by encouraging participants to maintain open communication for family challenges associated with early cancer onset, and mobilize family support for obtaining genetic services and surveillance. Based on participants’ responses to the baseline survey, a computer algorithm generated a letter, which provided tailored feedback about the need to have genetic evaluation and surveillance/screening. Two messages were generated for dichotomous tailoring variables, i.e., had genetic testing (yes/no) and frequency of surveillance consistent with guidelines (yes/no). Two messages were also generated for continuous variables. Self-efficacy and intention for genetic testing and surveillance were scored from 1 to 7 and a cut-off score of ≤3.5 was used to identify participants with low versus high self-efficacy and intention. A score of “3.5” is between “Somewhat not confident/Somewhat unlikely” and “Neutral” indicating preference for a negative consciousness . Barriers for cancer surveillance, i.e., lack of physician referral, cost-related lack of access, fear of finding cancer, and perception that mammograms are unnecessary were also scored from 1 to 7 and a cut-off score of ≤5.5 was used to identify participants who reported low versus high barriers. A score of “5.5” is between “Neutral” and “Agree” and indicates the presence of a barrier. Personalized probabilities of developing cancer i.e., Gail and Claus scores were presented to relatives based on information provided in their baseline survey. Messages and tailored letters were reviewed for appropriateness and accuracy.n = 853 relatives (up to two relatives per YBCS); n = 442 (51.5%) accepted participation and n = 431 relatives were allocated to study arms. Overall, 11.9% YBCS and 27.4% relatives resided in 23 and 27 different U.S. states, respectively.Recruitment, enrollment, randomization and retention are shown in a consort diagram . ResponsAfter randomization, YBCS and relatives in both study arms did not differ at baseline . YBCS wep = 0.0205). Participants needing less support from providers were consistently more likely to report significant changes in outcomes related to use of genetic services, i.e., higher self-efficacy and higher intention for YBCS ; p = 0.002 and Beta = 0.490; CI: (0.334–0.645); p < 0.001), and higher self-efficacy for relatives . YBCS who were older ; p < 0.001), Black  p < 0.001), with cost-related barriers ; p < 0.001), and living further from genetic services ; p < 0.001) reported higher intention for genetic testing. ; p < 0.002). Older relatives were more likely to report a mammogram compared with younger relatives ; p < 0.002). From multiple linear regression analyses, YBCS without health insurance reported significantly higher self-efficacy for CBE and self-efficacy for mammography ; p < 0.001; Beta = 0.830; CI: (0.406–1.254); p < 0.001). Intention to have a mammogram increased for YBCS with a routine source of care ; p < 0.001)  of YBCS and 75.41% of relatives  reported CBE consistent with NCCN guidelines . In the < 0.001) Table A1As shown in n = 131; 74 YBCS and 57 Relatives) and the main findings remained consistent. Two out of three participants reported discussing intervention materials primarily with first-degree and with non-biological relatives, most often females and/or from the maternal side of the family. We compared acceptability and perceived usefulness for YBCS versus relatives; tailored versus targeted arm; and Black versus White/Other participants. Black participants reported significantly higher satisfaction, acceptability, and usefulness of the interventions, and getting information that helped them discuss ways to lower their breast cancer risk with their provider. Relatives requested significantly more information for breast cancer risk factors and screening.As shown in Uptake of genetic testing in both arms of our RCT increased approximately 5%, which is similar to a previous RCT reporting the efficacy of a booklet on rates of genetic testing . This chThere was no difference in participant satisfaction between the two interventions. Since rates of genetic testing at baseline were low and there was little variation among study arms for this key outcome, it would be interesting to study if our targeted booklet yields better rates of genetic testing when integrated in the healthcare system and the message were reinforced by provider referrals. Future studies should also perform a cost-effectiveness analysis of tailored versus targeted interventions for genetic testing , since tAn important finding of the RCT was that there was 5% to 10% increase from baseline to follow-up in CBE and mammography rates among YBCS and relatives in both study arms. Since they have already been diagnosed with the disease, YBCS are more likely to have an established relationship with the healthcare system and have cancer surveillance according to guidelines. In contrast, cancer-free relatives may not have a routine source of care and an established relationship with a provider who would guide their screening practices. Self-efficacy and intention for surveillance, which are important predictors of subsequent behavior , increasThis study included a large sample of Black YBCS. Black YBCS were more likely to report higher self-efficacy and higher intention for genetic testing, higher satisfaction with their participation in the study and intervention materials, and needing additional information about genetic services and breast cancer screening compared to White/Other participants. Taken together these findings suggest that intervention booklets and letters achieved higher acceptability and perceived usefulness among Black participants, which can increase effectiveness in special populations ,39,40. BStrengths of the study are the study design and the partnership between a state health department and a leading academic institution. Advantages of recruiting from a state cancer registry are the ability to identify retrospectively a large number of potentially eligible subjects, from diverse geographical areas and racial/ethnic backgrounds, enroll them in prospective trials, and produce results that are more representative. A disadvantage was the lower participation rate compared to recruitment from clinical sites ,46. HoweThis two-arm cluster RCT was conducted in the state of Michigan (NCT01612338); the protocol and study methodology have been previously published . InstituYBCS were eligible to participate if they were 20 to 45 years old when diagnosed with invasive breast cancer or ductal carcinoma in situ; 25 to 64 years old at the time of the study; Michigan residents at the time of diagnosis; and able to read English and provide informed consent. Female relatives had to be cancer-free and 25 to 64 years old; able to read English and provide informed consent; and YBCS would be willing to contact them. Up to two relatives per YBCS were included. Priority was given to younger and first-degree relatives . YBCS ann = 58 YBCS who reported that they or one of their relatives had a pathogenic variant in BRCA or other gene associated with hereditary breast cancer, or had another hereditary cancer syndrome . These YBCS were provided appropriate information and were excluded from the RCT because intervention materials were not applicable. There was n = 163 YBCS who reported a negative genetic test result. These YBCS and their relatives (n = 103) were included. None was a “true negative” and we could not exclude the possibility that there might be updated information to justify a new genetic evaluation. We could also not exclude the possibility of a pathogenic variant in relatives.The Michigan Cancer Surveillance Program inquired with the reporting facility and physician of record whether there was any reason that an YBCS should not be contacted. If a response was not received within 30 days, a recruitment package was mailed to the YBCS. Eligible YBCS received up to three mailed invitations over a period of four months. YBCS who accepted participation were asked in the baseline survey if they were willing to invite their first- and second-degree female relatives to take part in the study. In order to alleviate ethical concerns in contacting relatives without their explicit consent, recruitment materials were mailed to YBCS, who passed them on to relatives. When YBCS reported they already had genetic testing, a certified genetic counselor contacted them by phone to double-check that their response was accurate. There was YBCS and relatives had to return a signed informed consent before receiving the baseline survey. Recruitment of YBCS and relatives took place over six months from the date of mailing the first invitation letter to reduce bias due to sample “maturation”. Research staff at the cancer registry used a computer-generated algorithm to randomize (1:1) YBCS and relatives as stratified (Black vs. White/Other) family units  and allocate them to one of the two study arms. Research staff at the cancer registry were not involved in data analyses examining efficacy of the two interventions. YBCS and relatives were randomized as stratified (Black vs. White/Other) family units  to one of the two study arms (1:1) using a computer-generated allocation algorithm. All members of a family unit received intervention materials at the same time by postal mail and participants were unaware of the intervention materials delivered to the other study arm. Participants received $10 gift cards for completing the baseline survey and $20 gift cards for the follow-up survey, respectively. The study employed two research staff at 40% Full Time Equivalent (FTE) for six months for recruitment, mailing, and generating intervention materials. A certified genetic counsellor (10% FTE for three months) conducted risk assessments, and verified YBCS’ self-reports of being a mutation carrier and the content of intervention materials.Eligible YBCS were mailed a baseline survey (Time 1). Following assessment of their baseline information, their relatives were recruited, and family units were randomized to the targeted or tailored intervention. The follow-up survey (Time 2) was mailed to participants approximately 8 months after the intervention to allow sufficient time for pursuing the primary outcomes within the timeframe of the study. Research staff made two attempts via phone, mail, or email to contact YBCS and relatives if they did not return the follow-up survey within six weeks.Using data from previous mammography RCTs ,25, we chttps://www.r-project.org/). Descriptive analyses compared means and proportions in demographic and clinical factors between and within intervention groups across time (baseline and 8-month follow-up). Differences between intervention arms were tested at baseline and follow-up with two proportions z-test for proportions and with t-test for means. We performed separate analyses for YBCS and relatives for genetic testing, CBE, and mammography. Statistical analyses were performed using R 3.4.4.  excluding whoever had genetic testing at baseline but keeping dropouts (ITT); (2) excluding both whoever had genetic testing and whoever dropped out. Both analyses had shown similar results as presented in We conducted multiple linear regressions to explored associations between outcomes  and predictor variables for YBCS and relatives including intervention grouping, antecedents, and barriers. Changes in frequencies for outcomes were demonstrated after using Intention-To-Treat (ITT), defined as “once randomized, always analyzed” . Similarn = 270, 21.92%) from the follow-up survey. No special patterns of missing values were identified. We used demographic variables to examine if there was a clear pattern of lost-to-follow-up across subgroups using machine-learning approaches [p-values were pooled across the three models built using the three imputed datasets and adjusted for multiple testing using Bonferroni corrections.We examined core features of missing data  and cases who dropped out (proaches ,65,66. TThis RCT is aligned with evidence-based recommendations for public health action relevant to cancer predisposition cascade genetic screening ,68. Adop


Breast cancer, the most frequently occurring cancer in women, is a major public health problem, with over 1 million estimated new cases worldwide and nearly 459,000 related deaths every year [In particular, ductal carcinoma in situ shows overlapping epidemiology with invasive ductal carcinoma of the breast, sharing similar risk factors such as age, mammographic density, family history and hormonal therapy, as well as genetic factors such as BRCA1/BRCA2, histotypes and molecular subtypes, such as luminal A and B, HER2-enriched, and basal-type [BRCA1 and BRCA2 genes are involved in DNA double-strand break repair and relate to breast cancer. Shift work is associated with biological clock alterations and with a higher risk of breast cancer. Bracci et al. [BRCA genes throughout the day in healthy subjects, and measured BRCA expression levels in shift workers. Moreover, they measured the expression of these genes in lymphocytes from a group of shift and daytime workers. The change in 24-hour expression levels of BRCA1 and BRCA2 genes was statistically significant, decreasing from the peak at midday to the lowest level at midnight. Lower levels for both genes were found in shift workers compared to daytime workers. The diurnal variability of BRCA1 and BRCA2 expression suggests the relation of the DNA double-strand break repair system with the biological clock. The lower levels of BRCA1 and BRCA2 found in shift workers may be one of the potential factors related to a higher risk of breast cancer [i et al.  investigt cancer .However, some breast cancer risk factors may be preventable. Traditional risk factors for breast cancer include reproductive status, genetic mutations, family history and lifestyle. However, increasing evidence has identified an association between breast cancer and occupational/environmental factors.Breast cancers include a heterogeneous group of diseases with clinical behaviors that may vary according to the hormonal receptor status. However, limited knowledge is available on the role of breast cancer environmental and occupational risk factors, as regards the onset of specific molecular disease phenotypes. In a systematic review, Leso et al.  found thFurthermore, in occupational medicine, a significant advance in medical practice is the incorporation of the Clinical Decision Support Systems to assist and support healthcare staff in clinical decision-making, thus improving the quality of decisions and overall patient care while minimizing costs . Occupational physicians, therefore, need to face the return to work and the fitness for work of workers previously diagnosed with breast cancer with a sufficient cultural and technical background. In addition to individual characteristics preceding the diagnosis, clinical outcome, lifestyles and occupational variables are the most impactful factors on return to work, which need to be considered . Scienti


Brominated flame retardants (BFRs) are lipophilic substances with endocrine-disrupting properties. To date, only few investigations, mainly retrospective case-control studies, have explored the link between internal levels of BFRs and the risk of breast cancer, leading to conflicting results. We investigated the associations between plasma concentrations of two main groups of BFRs, PBDEs (pentabromodiphenyl ethers) and PBBs (polybrominated biphenyls), and the risk of breast cancer in a nested case-control study.A total of 197 incident breast cancer cases and 197 controls with a blood sample collected in 1994–1999 were included. Plasma levels of PBDE congeners  and of PBB-153 were measured by gas chromatography coupled to high-resolution mass spectrometry. Conditional logistic regression models, adjusted for potential confounders, were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs).Women were aged 56 years on average at blood draw. All cases, except for one, were diagnosed after menopause, with an average age at diagnosis of 68 years. Overall, we found no evidence of an association between plasma levels of PBDEs and PBB-153 and postmenopausal breast cancer risk . The analysis showed a non-linear inverse association for BDE-100 and BDE-153 and postmenopausal breast cancer risk; nevertheless, these findings were statistically significant only when the exposure was modeled as ng/L plasma  and not when modeled as ng/gr of lipids . These results were unchanged in stratified analyses by tumor hormone receptor expression or body mass index.Our results suggest no clear association between internal levels of PBDEs and PBB-153 and the risk of breast cancer in postmenopausal women. However, these findings need to be carefully interpreted, taking into account limitations due to the limited number of women included in the study, the lack of information concerning genetic susceptibility of cases, and the unavailability of exposure assessment during critical windows of susceptibility for breast cancer. More studies are warranted to further investigate the relationships between PBDE and PBB exposure and breast cancer risk. BRCA1 and BRCA2 genes) - and modifiable risk factors - such as use of hormonal treatments, alcohol consumption, tobacco smoking, overweight, and lack of physical activity, [Despite a large body of research, the etiology of breast cancer has not yet been fully delineated, as established risk factors cannot solely explain the increased incidence reported worldwide. In Europe, breast cancer is the most common cancer in women with an incidence of 60 to 155 cases per 100,000 [ctivity, , 4. TherBrominated flame retardants (BFRs) are lipophilic substances present as a mixture of congeners in several consumer products to make them less flammable. Produced since the early 1960s, their use has been progressively limited and banned in Europe during the 90s when the production reached the levels of 33,000 metric tonnes in 1994 . CommercThere is increasing interest in understanding the contribution of BFRs to breast cancer incidence; nevertheless, evidence of an association between environmental exposure to these chemicals and breast cancer risk is still inadequate to draw firm conclusions , 13. To Our objective was to prospectively investigate the associations between plasma concentrations of two main groups included in the family of BFRs, PBDEs and PBBs, and the risk of postmenopausal breast cancer in women in a case-control study nested in the French E3N cohort.Etude Epidémiologique auprès de femmes de l’Education Nationale) is a prospective cohort study involving 98,995 French women, aged 40–65 years at inclusion in 1990 and insured by a national health insurance covering workers from the French National Education System  [E3N  . ParticiBetween 1994 and 1999, E3N participants were invited to donate blood, resulting in the collection of blood samples from approximately 25,000 participants. Each sample was separated into 28 aliquots  that were stored in plastic straws in liquid nitrogen containers (− 196 °C) in a biobank.Breast cancer cases were identified through self-report in the questionnaires, from the MGEN files, or through information from death certificates. Deaths were reported by family members and by searches in the MGEN files, and causes of death were obtained from the National Death Index. Pathology reports were obtained for 93% of incident cases. We also considered cases for which pathology reports have not been obtained, because the proportion of false-positive self-reports was low in our study population (< 5%). Cases were identified up to 2013, which was therefore used as the date of end of follow-up in statistical analyses.n = 27) or who were diagnosed before blood sampling and/or before returning the dietary questionnaire were excluded (n = 11). Cases of Paget’s disease and benign breast disease were also excluded (n = 3). Finally, 240 incident breast cancer cases were available. Due to budget constraints, among those, 197 incident breast cancer cases (174 invasive and 23 in situ) were randomly selected and included in the study.As previously described , 281 bre2), all at blood collection, and year of blood collection.For each case, one control was sampled from women who were free of breast cancer at the time of diagnosis of the corresponding case (density sampling method). Controls were matched to cases by age (±2 years), menopausal status , body mass index (BMI) , being the trueness within the range between 3% (BDE-99) and 37% (BDE-28), and the precision ranged between 13% (BDE-47) and 28% (PBB153). The analytical performance was considered acceptable for all congeners; however, it should be noted the analytical uncertainty associated to lower concentrations for BDE28. Moreover, cleaned laboratory glassware was rinsed with dichloromethane prior to use and the analyses were carried out in an over-pressurized room to minimize environmental contamination followed by a continuous monitoring of the analytical procedure implemented through procedural blanks [The methodologies applied to isolate, detect, and quantify the PBDE congeners  and PBB-153 have been published elsewhere , 24. Bril blanks .In all statistical analyses, values below the limit of detection (LOD) were substituted with the equivalent of ½LOD. Kruskal–Wallis tests were performed to compare concentrations of PBDEs and PBB-153 between cases and controls. Spearman rank correlation tests were performed to determine correlation structures between plasma concentrations of PBDEs and PBB-153.Conditional logistic regression models were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) of breast cancer in relation to plasma concentration levels of PBDEs and PBB-153 expressed as ng/L plasma. We also used conditional logistic regression models using both the exposure variable as a continuous variable, after log-transformation, and as a categorical variable, dividing it into quintile groups based on plasma concentrations of PBDEs and PBB-153 in controls. When considering the exposure as a categorical variable, tests for linear trend were performed by assigning the median value to each quintile group and by modeling these values as continuous variables. For all adjustment variables, we considered the value collected in the last questionnaire available before the date of diagnosis in cases. All analyses were performed for each substance separately and for the sum of concentrations of PBDEs. An unadjusted model (Model 0) was fitted, as well as three adjusted models with an increasing number of covariates. Model 1 was adjusted for total plasma lipid content by the addition of a separate term in the model , as recommended by Schisterman et al. . Model 1Using multinomial regression, stratified analyses were performed based on tumor expression of estrogen (ER– vs. ER+) and progesterone (PR– vs. PR+) receptors including all variables used in Model 2. Since multinomial regression models do not consider the case-control matching, multinomial models were additionally adjusted for the matching criteria: age at blood draw (continuous), BMI at blood draw (continuous), and year of blood draw (continuous), except for menopausal status at blood draw, in order to avoid over-adjustment considering the a priori inclusion of age at menopause in the model . All subjects for whom the information on hormone receptors was not available were grouped as one “missing” category and inserted in the model.In order to better understand the underlying association between lipids, BFRs and breast cancer, all analyses were repeated using concentrations of PBDEs and PBB expressed as ng/gr of lipids in the plasma.Finally, the analyses were repeated excluding the case diagnosed before menopause and her matched control.Other authors highlighted that the evolution of body size over lifetime may have an impact of the risk of developing breast cancer . On the Then, Model 2 was adjusted for BMI variation over the 5 years preceding blood sampling .2.We conducted a stratified analysis based on BMI, considering groups with BMI < 25 and  ≥25 kg/mIn our study population, missing values were < 5% for all variables and were imputed to the median (continuous variables) or modal value .Statistical analyses were performed using the SAS software . The threshold for statistical significance was set at 5%. All statistical tests were two-sided.The main characteristics of the study population are presented in Table Quantifiable levels of PBDE-47, 99, 100, 153, and PBB-153 were detected in all samples. BDE-28 was detected in all samples except for one control with a concentration below the LOD, while BDE-154 was below the LOD in 99 samples (46 cases and 53 controls), representing 25% of the study population. The highest concentration of BFR in the overall population was observed for BDE-47 , while the lowest was observed for BDE-154  (Table Mean age at breast cancer diagnosis was 68.4 years (range 54.3–84.9 years). All cases were diagnosed after menopause except for one. Information on tumor hormone receptor expression was available in 161 cases (82%) for ER, and in 157 cases (80%) for PR. In total, 135 tumors were ER+ and 100 were PR+.Tables Sand SWhen considering concentrations of PBDEs and PBB in ng/L plasma as continuous variables, we did not find any statistically significant association between levels of PBDEs and PBB-153 and breast cancer risk. When considering these concentrations modeled in quintiles, we found no statistically significant association between the sum of PBDEs, BDE-28, 47, 99, 154, or PBB-153 and breast cancer risk in any of the models. In Models 1 and 2, women in the 3rd quintile group of BDE-100 were at lower risk of breast cancer when compared with those in the 1st quintile group . Similarly, when considering BDE-153, we observed a statistically significant inverse association with breast cancer risk for women in the 3rd quintile group when compared with those in the 1st quintile group in Models 1 and 2  . In addition, compared to the main analyses, the results remained virtually unchanged in terms of magnitude and statistical significance in sensitivity analyses adjusting for the evolution of women’s body size or BMI variation over the 5 years preceding blood sampling (data not shown).2) and considering PBDE and PBB concentrations in ng/L plasma, women in the 3rd quintile group of BDE-100 with a BMI < 25 kg/m2 were at lower risk of breast cancer . Among women with a BMI ≥25 kg/m2, we found an inverse association with breast cancer risk among women in the 3rd quintile group of BDE-153  and among those in the 3rd quintile group of PBB-153 . On the other hand, when considering concentrations of PBDEs and PBB in ng/gr of lipids in the plasma, we observed a statistically significant inverse relationship only for the 2nd and 3rd quintile groups of BDE-153 and only in women with a BMI ≥25 kg/m2   and women with diagnoses of benign breast conditions as controls (n = 95), failed to find any statistically significant association between serum levels of BDE-47 and breast cancer risk [n = 78) and women with benign histological changes as controls (n = 56), provided no evidence of an association between adipose tissue concentrations of BDE-47, − 99, − 100, − 153, and − 154 and breast cancer risk [A hospital-based study conducted among native Alaskan women, including invasive and in situ breast cancer as cases  in comparison to Europe between late 70s and 90s . For insOverall, we interpret the results from our study as null findings. However, it should be noted that when running the analyses with the exposure expressed as ng/L of plasma, we observed a non-linear inverse association between levels of PBDE-100 and -153 and breast cancer risk; nevertheless, this association was not statistically significant when considering concentrations in ng/gr of lipids in the plasma. With few exceptions, stratification by tumor hormone receptor expression and BMI categories yielded similar results as the main analyses. Therefore, given the relatively small number of cases upon which these estimates are based, the inconsistency in the results obtained for other PBDEs included in the study, and the numerous statistical analyses that were conducted, it is probable that these findings are due to chance.When interpreting these results, a limitation of our study that should be taken into consideration is that only a single measurement of PBDE and PBB-153 concentrations was available; we thus had no information on the true trajectories of exposure or on exposure levels during sensitive periods of breast development. The present study was conducted with a population exposed to low background levels of PBDEs and PBBs limiting the conclusion to the low end of the population dose-response curve. Moreover, previous studies have suggested that certain genetic factors may modify the associations between exposure to EDCs and risk of breast cancer , but no Nevertheless, our study presents several strengths. Thanks to the long follow-up duration of the E3N cohort, we were able to prospectively investigate the long-term health effects of plasma concentrations of PBDEs and PBB-153. Extensive information on the main breast cancer risk factors, such as reproductive history, use of hormonal treatments, anthropometric characteristics, and lifestyle-related risk factors, was collected prospectively in the cohort and thus at the same time for cases and controls. Finally, the availability of information on breast cancer expression of estrogen and progesterone receptors allowed us to better characterize the tumors and to perform stratified analyses.Our results suggest no clear association between internal levels of PBDEs and PBB-153 and risk of breast cancer in postmenopausal women. Although our results are similar to those found in previous research, they need to be carefully interpreted, taking into account study limitations due to the limited number of women included in the study, the lack of information concerning genetic susceptibility, and the unavailability of exposure assessment during critical windows of susceptibility for breast cancer. More studies are warranted to further investigate the relationships between PBDE and PBB exposure and breast cancer risk, in particular through deeper investigation related to the link between those markers and lipids, and documenting exposure levels for potentially active PBDE metabolites.Additional file 1 Table S1. Multinomial regression models to estimate the association between quintiles of PBDEs and PBB-153 plasma level expressed as ng/L and breast cancer risk stratified according to hormone estrogen receptor status: adjusted odds ratios (ORs) and 95% confidence intervals (CIs). Table S2. Multinomial regression models to estimate the association between quintiles of PBDEs and PBB-153 plasma level expressed as ng/L and breast cancer risk stratified according to hormone progesteron receptor status: adjusted odds ratios (ORs) and 95% confidence intervals (CIs). Table S3. Multinomial regression models to estimate the association between quintiles of PBDEs and PBB-153 plasma level expressed as ng/gr of lipids and breast cancer risk stratified according to hormone estrogen receptor status: adjusted odds ratios (ORs) and 95% confidence intervals (CIs). Table S4. Multinomial regression models to estimate the association between quintiles of PBDEs and PBB-153 plasma level expressed as ng/gr of lipids and breast cancer risk stratified according to hormone progesteron receptor status: adjusted odds ratios (ORs) and 95% confidence intervals (CIs). Table S5. Conditional logistic regression models to estimate the association between quintiles of PBDEs and PBB-153 plasma levels expressed as ng/L and breast cancer risk stratified according to the body mass index (BMI): adjusted odds ratios (ORs) and 95% confidence intervals (CIs) Table S6. Conditional logistic regression models to estimate the association between quintiles of PBDEs and PBB-153 plasma levels expressed as ng/gr of lipids and breast cancer risk stratified according to the body mass index (BMI): adjusted odds ratios (ORs) and 95% confidence intervals (CIs)