Breast cancers that occur in young women up to 5 to 10 years' postpartum are associated with an increased risk for metastasis and death compared with breast cancers diagnosed in young, premenopausal women during or outside pregnancy. Given the trend to delay childbearing, this frequency is expected to increase. The (immuno)biology of postpartum breast cancer is poorly understood and, hence, it is unknown why postpartum breast cancer has an enhanced risk for metastasis or how it should be effectively targeted for improved survival. The poorer prognosis of women diagnosed within 10 years of a completed pregnancy is most often contributed to the effects of mammary gland involution. We will discuss the most recent data and mechanistic insights of the most important processes associated with involution and their role in the adverse effects of a postpartum diagnosis. We will also look into the effect of lactation on breast cancer outcome after diagnosis. In addition, we will discuss the available treatment strategies that are currently being used to treat postpartum breast cancer, keeping in mind the importance of fertility preservation in this group of young women. These additional insights might offer potential therapeutic options for the improved treatment of women with this specific condition. Breast cancer is the most frequently diagnosed cancer in women worldwide and remains the leading cause of cancer-related deaths, with the majority of deaths resulting from metastatic disease.Age at diagnosis, parity status, and breastfeeding history are among the most important risk factors for postpartum breast cancer. Older age at first birth correlates with an increased risk for postpartum breast cancer. Because of the trend to delay childbearing, incidence numbers are expected to increase. The increased incidence in young women (<45 years) matches the decrease in parity observed in this age group.Postpartum breast cancer that occurs 5 to 10 years' postpartum is associated with worse survival rates and an almost 2-fold increased risk for metastasis compared with breast cancers diagnosed in young, premenopausal women during and outside pregnancy.In this review we will explore whether postpartum breast cancer, defined as breast cancer diagnosed up to 5 to 10 years in women<45 years of age, can be seen as a distinct entity with a unique biology. We will focus on the mechanisms that underly the poor prognosis of postpartum breast cancer, especially those related to mammary gland involution (regression of the mammary gland to its pre-pregnant state). In addition, we will discuss the available treatment strategies that are currently being used to treat these young women, keeping in mind the importance of fertility preservation.Due to the sparsity of human breast tissue, studies of postpartum breast cancer in women are limited and often with very small patient numbers. In the next paragraphs we will further elaborate on current knowledge with regard to the influence of involution, lactation, and the tumor microenvironment on the tumor biology of this cancer. Most evidence to date is derived from rodent models .During pregnancy, the mammary gland epithelium undergoes extensive proliferation and differentiation in order to prepare for lactation. After parturition in the absence of lactation, or at weaning, the mammary gland remodels to a functional and morphological state similar to pre-pregnancy, a process called involution.During postpartum involution in both mice and humans, a minority of mammary epithelial cells survives cell death. Resistance to cell death plays an important role in tumor initiation, as it results in the propagation of potentially harmful mutations that allow unregulated growth and division.Furthermore, available evidence, mainly supported by multiple pre-clinical animal models, points to mammary gland involution as being a driver of metastasis. Extensive apoptosis of mammary secretory epithelium, extracellular matrix remodeling, and adipocyte repopulation were shown to occur in the initial phase of mammary gland involution  – part IAnother mechanism in the involuting gland that has been suggested to influence postpartum breast cancer prognosis is related to an increased peritumor lymphatic vessel density. Increased lymph node metastasis has been observed in postpartum involuting preclinical mouse models  is often associated with high risk, healthcare providers regularly consider more aggressive treatments for these young women. However, these breast cancer therapies might result in a decreased reproductive health, ovarian-insufficiency, delayed childbearing due to prolonged treatment, breastfeeding problems, and concerns regarding future fertility.Dependent on the biological subtype, modified radical mastectomy or systemic therapy are often seen as the first line of treatment in young patients. As no differences in outcome between mastectomy vs lumpectomy with radiation was found in more than 20 000 young women with breast cancer,As long as no other specific (targeted) therapies are identified for patients with postpartum breast cancer, treatment should, however, not differ from current guidelines advised for young women with breast cancer. As postpartum breast cancer can interrupt a woman’s life in many ways, it is important to address considerations regarding fertility and family planning with the young mother prior to initiation of treatment. Breast cancer treatment can reduce the probability of conceiving up to 70% as compared with healthy women of the same age.As postpartum breast cancer might be characterized with a distinct biology that accounts for its poor prognosis, future research could focus on novel therapeutic strategies that specifically address the biology of postpartum breast cancer  up to 5 to 10 years after delivery has been associated with an increased risk for metastasis and death. This poor prognosis has been correlated to the distinct biology of postpartum breast cancer, which arises from processes related to lactation (duration) and mammary gland involution. Despite accumulating evidence from preclinical animal models into the factors underlying the aggressive biology of postpartum breast cancer, the exact mechanisms that lead to the poor prognosis of postpartum breast cancer in humans remains largely unknown. Additional insight is needed to improve prognosis and quality of life in this important group of young women. A first potential mechanism underlying its aggressive biology might be the immunosuppressive state that has been observed during postpartum involution. Patterns of altered immune infiltration have been found to persist in the primary tumor microenvironment for several years after delivery.Future research should especially focus on finding evidence of a postpartum signature in women with a postpartum breast cancer diagnosis, which could be based on gene expression data in human tissue and/or blood. Improved understanding of the pathways underlying the increased metastatic rate and the identification of molecular and/or cellular biomarkers with prognostic and/or predictive value in humans is a prerequisite for exploring optimized therapeutic modalities for postpartum breast cancer.


Background: Atherosclerosis and cancer share multiple disease pathways. Yet, it is unclear if atherosclerosis is associated with a subsequent higher cancer risk. We determined the association of atherosclerotic calcification in the aortic arch, as proxy for systemic atherosclerosis, with the risk of cancer.Methods: Between 2003 and 2006, 2,404 participants  from the prospective population-based Rotterdam Study underwent computed tomography to quantify calcification in the aortic arch. Participants were followed for the onset of cancer, death, loss to follow-up, or January 1st, 2015, whichever came first. We computed sex-specific tertiles of aortic arch calcification volumes. Next, we examined the association between the volume and severity  of aortic arch calcification and the risk of cancer using Cox proportional hazard models.Results: During a median (interquartile range) follow-up of 9.6 years (8.9–10.5), 348 participants were diagnosed with cancer. Participants with the greatest severity of aortic arch calcification had a higher risk of cancer [hazard ratio for the third tertile compared to the first tertile of aortic arch calcification volume in the total population is 1.39 (95% CI = 1.04–1.86)].Conclusions: Individuals with the most severe aortic arch calcification had a higher risk of cancer. While this could reflect the impact of long-term exposure to shared risk factors, it might also point toward the co-occurrence of both conditions. Cardiovascular diseases and cancer remain the leading causes of morbidity and mortality worldwide , 2. SeveCommon risk factors such as age, smoking, obesity, and genetic susceptibility are known to contribute to the risk of both atherosclerosis and cancer. Specific molecular pathways leading to atherosclerosis, including inflammation, oxidative stress, and uncontrolled cell proliferation, are also involved in the pathogenesis of cancer , 10. As Due to the central anatomical location in the arterial system, the presence and amount of atherosclerosis in the aortic arch may provide an easy measurable proxy of the systemic burden of atherosclerosis within an individual. As such, aortic arch atherosclerosis has repeatedly been linked to mortality, in particular also of non-cardiovascular origin, of which cancer represents a substantial part , 13. HenThis study is embedded within the Rotterdam Study, a prospective population-based cohort study that investigates determinants and occurrence of chronic diseases in the middle-aged and elderly population. The design of the Rotterdam Study has been described in detail previously . At studn = 114), resulting in 2,404 participants for analysis. The follow-up for cancer took place continuously and was completed for this study until January 1st, 2015.For the present study, we used the follow-up visit between 2003 and 2006 as baseline, because during this period, participants who visited the research center were invited to undergo non-contrast multi-detector computed tomography (MDCT) scanning of the aortic arch as part of a project of visualizing arterial calcification . We scanwww.trialregister.nl) and into the WHO International Clinical Trials Registry Platform  under shared catalog number NTR6831. All participants provided written informed consent to participate in the study and to have their information obtained from treating physicians.The Rotterdam Study has been approved by the Medical Ethics Committee of the Erasmus MC (registration number MEC 02.1015) and by the Dutch Ministry of Health, Welfare and Sport . The Rotterdam Study has been entered into the Netherlands National Trial Register  to perform non-contrast CT scanning. We scanned the aortic arch using an extra-cardiac scan that reached from the aortic arch to the intracranial vasculature (1 cm above the sella turcica). Detailed information on both scans is provided elsewhere . As proxDiagnoses of cancer were based on medical records of general practitioners  and through linkage with Dutch Hospital Data, the Netherlands Cancer Registry, and histology and cytopathology registries in the region. Incident cancer was defined as any primary malignant tumor, excluding non-melanoma skin cancer. Only pathology-confirmed cancers were included in analysis to exclude the possibility of false-positive cancer diagnoses. Diagnoses were coded independently by two physicians according to the International Classification of Diseases, Tenth Revision (ICD-10). In case of discrepancy, consensus was sought through consultation with a physician specialized in internal medicine. Date of diagnosis was based on date of biopsy (solid tumors) and laboratory assessment (hematologic tumors), or—if unavailable—date of hospital admission or discharge letter. Follow-up of cancer registration was complete until January 1st, 2015.2) was computed. Furthermore, systolic and diastolic blood pressures were measured twice on the right arm with a random-zero sphygmomanometer of which the mean was used for analyses. Hypertension was defined as a systolic blood pressure of ≥140 mm Hg, a diastolic blood pressure of ≥90 mm Hg, or use of antihypertensive medication , intermediate education , or higher education . Smoking status was categorized as never, current, or former. At the research center, height and weight were measured from which the body mass index . First, we used Cox proportional hazard models to determine the association between aortic arch calcification [per 1-standard deviation (SD) increase] and the subsequent risk of cancer. Model 1 was adjusted for age at MDCT scan and sex. To investigate to which extent any association would be driven by shared risk factors, model 2 was additionally adjusted for shared risk factors including educational level, smoking status, BMI, hypertension .For all Cox proportional hazard models, follow-up time was used as timescale and started at date of MDCT scan until date of incident cancer, death, loss to follow-up, or January 1st, 2015, whichever came first. Censoring participants at date of death allowed us to compute cause-specific hazard ratios (HRs). The proportional hazards assumption was met for all analyses  by chained equations along with age, sex, calcification volumes, cardiovascular risk factors, and cancer incidence. Statistical analyses were performed using STATA v.15 (StataCorp).To account for missing data of covariables (maximum amount of missing data: 5.9%), we used multiple imputation . The effect estimates decreased with inclusion of longer follow-up duration .Regarding specific cancer types, we found that among women, aortic arch calcification was associated with a lower risk of breast cancer  and with a higher risk of lung cancer in the total population .No effect modification was observed by lipid-lowering and antithrombotic medication use and by median granulocyte count. All interactions were tested on the multiplicative scale and did not reach statistical significance . Although this indicates that severe atherosclerosis may be present before cancer diagnosis, it might also reflect reverse causation. It is possible that subclinical cancer development already influences the course of atherosclerosis. Since both atherosclerosis and cancer are conditions with a long preclinical phase, we cannot prove causality, nor can we rule out reverse causation.Overall, we found no prominent differences in the association between atherosclerosis and cancer before and after adjustment for cardiovascular risk factors. This suggests that overall, traditional cardiovascular risk factors do not fully explain potential co-occurrence of atherosclerosis and cancer. This could point toward other factors, such as genetic variation or exogenous factors, that may explain the differential susceptibility to either atherosclerosis or cancer. However, exposure to shared risk factors might explain the higher risk of cancer in those individuals with the most severe aortic arch calcification and the strong association with lung cancer. It is likely that individuals who have been exposed to shared risk factors for a long period, and in high amounts, have both the largest volumes of aortic arch calcification and the highest risk of cancer. This suggests that the co-occurring deterioration of atherosclerosis and development of cancer is due to long and severe exposure to risk factors. However, also in these individuals, the size of the effect estimates only slightly diminished after correction for shared risk factors.Sex differences—reflected by differences in hormonal levels—may also influence the apparent different impact of shared risk factors on the development of atherosclerosis and cancer. Aortic arch calcification was associated with a lower risk of breast cancer in women. It has previously been proposed that an inverse association between aortic atherosclerosis and cancer holds in particular for cancers that are hormone-dependent or highly affected by genetics rather than for those caused by exogenous factors . Also, aSeveral strengths of our study are worth mentioning. Our study is a large prospective population-based study and therefore less vulnerable to selection and information bias than retrospective ones. In addition, we have prospective and unbiased collection of many risk factors that are not available in healthcare databases. All cancers were pathology proven, which excludes the chance of misclassification. Also, we had an image-based assessment of calcification volumes and standardized ascertainment of cancer incidence.Yet, some potential limitations need to be addressed. First, despite sufficient power to detect a large effect size of 1.5 for all cancers , we acknowledge the lack of statistical power to elaborate on specific cancer types. Second, strong associations of atherosclerosis with the risk of cardiovascular events and mortality may have weakened any potential association of atherosclerosis with cancer. Nevertheless, our finding that the most severe aortic calcification is associated with a higher risk of cancer—while these persons have the highest risk of mortality—might indicate that the effect of survival is limited. Third, the burden of atherosclerosis may influence the prognosis and course of cancer rather than the development itself. Ideally, measures of atherosclerosis at multiple time points are needed to also assess changes in atherosclerotic burden before cancer diagnosis. Future studies are needed to unravel differences in the etiology between atherosclerosis and cancer explained by other factors such as genetic and exogenous factors. Lastly, calcification is only a part of the atherosclerotic plaque. Non-calcified parts of the plaques cannot be visualized with non-enhanced CT. Nevertheless, it has been shown that calcification volume is an adequate measure for the total underlying plaque burden .We found that only individuals with the most severe aortic arch calcification had a higher risk of cancer, potentially through long-term parallel exposure to shared risk factors. Other factors, such as genetic variation or exogenous factors, may further explain susceptibility to either atherosclerosis or cancer.Data can be obtained upon request. Requests shou towards the management team of the Rotterdam Study (secretariat.epi@erasmusmc.nl), which has a protocol for approving data requests. Because of restrictions based on privacy regulations and informed consent of the participants, data cannot be made freely available in a public repository.www.trialregister.nl) and into the WHO International Clinical Trials Registry Platform  under shared catalog number NTR6831. All participants provided written informed consent to participate in the study and to have their information obtained from treating physicians.The studies involving human participants were reviewed and approved by the Medical Ethics Committee of the Erasmus MC (registration number MEC 02.1015) and by the Dutch Ministry of Health, Welfare and Sport . The Rotterdam Study has been entered into the Netherlands National Trial Register (NTR; JT, KW, and DB contributed to conception and design of the research. JT, KW, RR, MV, BS, SS, MI, MK, and DB provided essential reagents or provided essential materials. JT and KW analyzed data. performed statistical analysis, and wrote the paper. JT, KW, and DB had primary responsibility for final content. JT, KW, RR, MV, BS, SS, MI, MK, and DB provided intellectual content to the paper. All authors have read and approved the final manuscript.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.


This study aimed to determine the factors affecting early diagnosis and screening behaviors of healthcare workers concerning breast cancer and the breast cancer risk levels using the risk identification model and to evaluate the relationship between breast cancer risk levels and early diagnosis and screening behaviors.Overall, 466 healthcare workers from Balikesir Province, Turkey participated in this cross-sectional study. Data were collected thanks to a questionnaire prepared by the researchers. Cuzick-Tyrer model was utilized to determine breast cancer risk levels.78.1% of the healthcare workers regularly perform breast self-examination (BSE), 11.6% had clinical breast examination (CBE), 7.7% had breast ultrasound scan and 4.5% had mammography. BSE behavior increased, as education level got higher. Mammography screening behavior increased in those aged 40 yr and older and those with breast or ovarian cancer history in their family. There was not any relationship between breast cancer risk levels and early diagnosis and screening behaviors.Early diagnosis and screening behaviors of healthcare workers were low concerning breast cancer. Age, education level and family history are the most prominent factors affecting early diagnosis and screening behaviors of healthcare workers. Informing healthcare workers on breast cancer risk factors and screening can make positive contributions to them and the public through them. Breast cancer is the most frequent type of cancer and the leading cause of mortality in women in Turkey as it is in the world , 2. BreaWHO suggests the implementation of community-based breast cancer screening programs in line with the countries' possibilities . Breast Determining the risk of breast cancer in women is very important in terms of intervention and prevention to reduce the risk of breast cancer . There aLifestyles of healthcare workers regarding the risk of breast cancer and their use of early diagnosis methods are indicators of their awareness on this matter. Because midwives and nurses are at higher risk of cancer due to working conditions –13. In aThis study aimed to determine the factors affecting early diagnosis and screening behaviors of healthcare workers concerning breast cancer and the breast cancer risk levels using the risk identification model and to evaluate the relationship between breast cancer risk levels and early diagnosis and screening behaviors.The population of this cross-sectional study consists of female midwives and nurses (N= 680) working in two different hospitals providing healthcare services in Balikesir Province, Turkey. These hospitals are the largest public hospitals that have the largest number of nurses and midwives in the province. It was aimed to reach to the entire population by not doing sample selection. Questionnaires were collected in sealed envelopes from the participant at the institutions where they work. Twelve healthcare workers were excluded from the research because they did not complete the questionnaire fully. In total, 466 healthcare workers completed the questionnaire fully.Data were collected thanks to a questionnaire prepared by the researchers. The questionnaire included questions on participants' sociodemographic characteristics, lifestyle, early diagnosis and screening behaviors and breast cancer risk levels. Cuzick-Tyrer model was utilized to determine breast cancer risk levels . AccordiInstitutional approval was obtained from the Local Ethics Committee. The study was conducted in accordance with the Declaration of Helsinki. Informed consent was obtained from the participants in the study. The data collection stage of the research took place from Jan to Sep 2017.P<0.05.The data were analyzed through the SPSS for Windows 20.0 . Continuous variables were presented with their averages and standard deviations, categorical variables were presented with their number and percentage distributions. Odds Ratio (OR) and 95% confidence interval (CI) were calculated to assess the relationship between independent variables  and dependent variables . Pearson chi-square test, chi-square for trend test, Fisher's exact test and logistic regression analysis were used for statistical analysis. In an attempt to examine the factors affecting BSE behavior, a logistic regression model, which includes age, education level, presence of chronic diseases and family history of breast or ovarian cancer, was established. In an attempt to analyze the factors affecting mammography behavior, a logistic regression model, which includes age, education level and family history of breast or ovarian cancer, was established. Statistical significance level was considered to be Overall, 466 healthcare workers participated in this study. The average age of the participants was 33.3±7.4 . Out of all participants, 78.1% stated to have regular BSE, 11.6% to have CBE, 7.7% to have breast US and 4.5% to have mammography. Approximate breast cancer risks of participants were estimated based on the Cuzick-Tyrer model. 92.1% of the participants had low 10-year breast cancer risk, whereas 7.9% had high risk. Lifetime breast cancer risk was low for 91.0% of the participants and high for 9.0%.P<0.05). BSE behavior is reduced in the age group of ≥40 yr (Crude OR: 0.50 95% CI: 0.27–0.92). As the level of education increases, BSE behavior increases (P<0.05). Those who have a chronic illness tend to have BSE more often (P<0.05) (P<0.05) (P<0.05)  . In the (P<0.05) . Except (P<0.05) . Except P<0.05). Mammography behavior is 3.43 times more in those who have family history of breast or ovarian cancer (P<0.05)  . In the While mammography behavior remains the same in the age groups of 20–29 yr and 30–39 yr, the age group of ≥40 yr is found to have mammography 28.66 times  more often (not shown in the tables). Except for age and family history of breast or ovarian cancer, there was no relationship between other characteristics of healthcare workers and their behavior of having mammography.In matters of prevention from breast cancer and early diagnosis, the public needs to be informed about these notions. Healthcare workers play the principal role in raising the awareness of the public. Attitudes and behaviors of healthcare workers, who set an example for the public in respect to prevention from breast cancer and early diagnosis, towards cancer screening programs affect the success of national cancer screening programs , 8, 14. BSE is an easy, harmless, no-cost early diagnosis method that every woman can perform. Every woman should perform BSE regularly to be aware of any abnormal changes in their breasts . 78.1% oThe healthcare workers participating in this study are young, have higher education level and have history of chronic illnesses are related to their behaviors of having BSE. In studies conducted on healthcare workers, those, who were young and had higher education level, performed BSE more often, which conforms to our findings –20. In cCBE is the palpation of axilla and all breast tissues by a physician or other trained healthcare personnel and the assessment of breast cancer findings. Especially women, who are under 40 yr of age, should have CBE regularly . 11.6% o7.7% of the healthcare workers participating in our study have had breast US. In other countries, breast US rate in healthcare workers is 33.0% to 92.0% , 23, 25.Except for their age and history of breast or ovarian cancer, there was no relationship between other characteristics of healthcare workers and their behavior of having mammography. In the age group of ≥40 yr, mammography screening behavior is observed 28 times more often. This finding is consistent with the literature. Studies conducted in other countries ascertained that as age advanced, mammography behavior of healthcare workers increased , 28, 29.A study conducted on women living in four different cities in China concluded that women, who worked, were married and had higher education levels, performed more breast screening practices . AlthougThough there is not a proven genetic mutation, approximately 10%–20% of breast cancer patients have family history , 9. ThisThis study did not ascertain any relationship between breast cancer risk levels and early diagnosis and screening behaviors. Age, education level and family history are the most prominent factors affecting early diagnosis and screening behaviors of healthcare workers. Healthcare workers from all stages of the healthcare industry should be able to lead the public and provide consultation services with respect to breast cancer screening , 7. It iEthical issues  have been completely observed by the authors.


Circulating glycemic traits (GTs) have been considered a risk factor for breast cancer, but studies using GT-associated genetic variants as an instrumental variable are limited and inconclusive.Our Mendelian Randomization analysis used the most recent genome-wide datasets focusing on European women.Of 44 single-nucleotide polymorphisms (SNPs) with GTs, 38 fasting-glucose and 6 fasting-insulin SNPs showed heterogeneous associations with breast cancer, without significant directional pleiotropy observed.Our findings indicate a null association between genetically determined GTs and breast cancer risk among European women. Our findings may contribute to more complete characterizing of metabolic pathways in GTs and breast cancer. Previous studies for circulating glycemic traits (GTs), including fasting glucose (FG) and insulin (FI) concentrations, have shown inconsistent associations with breast cancer development . This is1. Detailed rationale and design of the studies have been described elsewhere (2): (i) OncoArray; the Atlas of GWAS Summary Statistics (ATLAS3): (ii) CGEMS Breast Cancer GWAS, (iii) GEE adjusted for age, and (iv) GEE for age and body mass index. Study participants from each dataset provided written informed consent. Genetic instruments for each dataset were single-nucleotide polymorphisms (SNPs) associated with the trait at the genome-wide level (p < 5E-08).For the GT instrumental variables, we used the recently updated publicly available data in 2019 from genome-wide association studies (GWASs) of the Meta-Analysis of Glucose and Insulin-related traits Consortium (MAGIC) in non-diabetic European womenlsewhere . For brek mean change in the risk factor per additional variant allele with standard error σXk and an observed Yk changes in the log-odds or the log-probability of an outcome per allele with standard error σYk. The inverse-variance weighted estimates combine the ratio estimates from each variant in a fixed-effect meta-analysis model:We performed MR analysis using the inverse-variance weighted method  which quThe approximate standard error of the estimate is:The results were reported as risk ratios and 95% confidence intervals for the change in breast cancer risk per unit increase in FG (mmol/L) or natural log-transformed FI (pmol/L). To determine the extent of pleiotropic signal, we applied Cochran’s Q test and the MR-Egger analysis. Given obesity and diabetes’s established role for breast cancer, we excluded those relevant SNPs from the analysis. R3.6.1 was used. The Institutional Review Board of the University of California, Los Angeles, approved this study.r2 < 0.1) were matched to either BCAC or ATLAS datasets  and unmeasured confounding factors that could have introduced bias. MR analysis might also be subject to non-linearity between exposure and outcome, but potential violation of the linearity assumption tends to bias MR estimates toward the null, rather than generating a spurious association . MoreoveOur findings indicate a null association between genetically determined GTs and breast cancer risk among European women. Our study may contribute to more complete characterizing of molecular pathways in GTs and breast cancer. It also highlights the need to conduct a more comprehensive and individual-level analysis using more detailed trait information, including risk causing confusion in this field of research.The datasets generated for this study are available on request to the corresponding author.SJ, NM, SH, and Z-FZ designed the study. SJ and SH performed the genomic data QC and statistical analysis and interpreted the data. NM and Z-FZ supervised the genomic data QC and analysis and participated in the study coordination and interpreted the data. SJ secured funding for this project. All authors participated in the manuscript writing and editing, read and approved the submission of the manuscript.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.


Cardiovascular death (CVD) in breast cancer patients without chemotherapy (CT) or (and) radiotherapy (RT) has not been studied yet. This study evaluates the correlation between breast cancer and CVD risk independent of chemotherapy or (and) radiotherapy.Data of female breast cancer patients without receiving CT or RT were retrieved from the Surveillance, Epidemiology, and End Result (SEER) database (2004–2015). Data were divided into two cohorts: tumor resection cohort and no resection cohort. The CVD risk in patients was expressed as standardized mortality ratios (SMRs). A 1:1 propensity score matching (PSM) was applied to balance inter-group bias, and competing risk regressions were utilized to evaluate the impact of tumor resection on CVD.P<0.001) in breast cancer patients who did not receive CT or RT compared to the general population. Breast cancer patients without tumor resection showed higher CVD risk than patients who underwent tumour resection . After PSM, the CVD risk among patients without tumor resection indicated an increase of 1.165-fold compared to patients with tumor resection .The CVD risk was significantly higher (SMR = 2.196, 95% CI: 2.148–2.245, Female breast cancer patients are at higher risk of CVD despite unexposure to cardio-toxic CT or RT. However, female breast cancer patients subjected to tumor resection have decreased CVD risk. These results indicated that monitoring female breast cancer patients not receiving RT or CT might serve as a preventative measure against CVD. Breast cancer is a serious common threat for women’s health, accounting for 30% of new cancer cases in females, and is on a growing trend , 2. RapiAt the present, the mainstream belief among cardio-oncologists is that cardiotoxic therapies, including chemotherapy (CT) or radiotherapy (RT), are the main contributors to increase CVD risk in breast cancer survivors , 7. The Previous studies indicated that CVD risk might also be higher among breast cancer patients not exposed to CT or RT. A recent study revealed that breast cancer survivors suffered elevated CVD risk . FurtherOn the molecular level, breast cancer is a heterogeneous disease and the treatment selections for breast cancer patients are affected by the molecular subtypes, especially CT and hormonal therapy . Breast This study evaluates the CVD risk among breast cancer patients who opted out of the CT or (and) RT, no matter they received hormonal treatments or not. The analysis aims to achieve three objectives. Objective 1 is to evaluate CVD risk of breast cancer patients who never received CT or RT in comparison to the general population. Objective 2 is to evaluate CVD risk of breast cancer patients who never received CT or RT and were either subjected or not to tumor resection in comparison to the general population. Objective 3 is to conduct internal comparisons among breast cancer patients, aiming to reduce treatment selection bias and evaluate the independent effect of tumor removal on the CVD risk in breast cancer patients who never received CT or RT. The study aims at updating the guidelines of which breast cancer population requires prevention and monitoring for CVD risk.http://seer.cancer.gov/). The SEER database has been frequently used for cardio-oncology studies  database, an authoritative program providing data of 18 cancer registries and covering approximately 34.6% of the American population  or radiotherapy (RT) were included in this study. Targeted therapy is classified as one kind of CT in the SEER database. The inclusion criteria were as follows: (1) case selection  = “C50.x”; (2) pathological diagnosis between 2004 and 2015; (3) patients with only one primary tumor; (4) patients with active follow-up. The exclusion criteria were as follows: (1) history of CT or RT; (2) unknown causes of deaths; (3) male patients; (4) age at diagnosis under 45 years old; (5) unknown stage according to the American Joint Committee on Cancer (AJCC) staging system; (6) unknown surgery. Patients under 45 years old were excluded due to their very low numbers . After tFirstly, for Objective 1, CVD risk in 10-year age-stratum  of the overall cohort was compared to that of the age-matched U.S. female population, which was expressed as standardized mortality ratio (SMR). Secondly, for Objective 2, the overall cohort was categorized into two cohorts according to surgical resection: tumor resection cohort and no resection cohort. We compared the CVD risk between the tumor resection cohort and the no resection cohort by using SMR. Thirdly, for Objective 3, participants were further excluded from the overall patients if they had unknown or unspecific information regarding their marital status, race, grade, estrogen receptor (ER) status, and progesterone receptor (PR) status. Patients with paired tumor site or unspecific tumor site were also excluded owing to their very low number. Then resection selection cohort was extracted and further divided into two sub-cohorts: tumor resection sub-cohort and no resection sub-cohort (Patient variables included surgery (tumor resection and no resection), age at diagnosis , race , marital status , laterality , grade , ER status , PR status , human epidermal receptor 2 (HER2) status , and AJCC stage  , hypertension without heart disease , cerebrovascular disease (I60-I69), atherosclerosis (I70), aortic aneurysm and dissection (I71) and other diseases of arteries, arterioles and capillaries (I72-I78), according to the International Classification of Disease-10 (ICD-10) codes , 23. TheP value of SMRs were calculated by using the methods by Rothman-Boice  was applied. The PSM was performed using logistic regression and nearest neighbor method with caliper width of 0.01. PSM should match the confounding variables instead of all baseline variables . The pothan 0.05 .Further, the univariate and multivariate Fine and Gray’s competing risks regressions were used to evaluate the independent effect of tumor resection on the CVD risk among breast cancer patients without CT or RT. The Fine and Gray’s competing risks regression was performed to account for the two competing events: CVD deaths and non-CVD deaths.https://www.r-project.org), respectively. Fine and Gray’s competing risks regression was conducted using Stata version 15 . A two-tailed P value < 0.05 was considered statistically significant.Chi-square test and PSM were analyzed using SPSS version 25.0  and R software version 3.6.1  patients and the no resection cohort included 14,294 (10.9%) patients. After further selection, the resection cohort consisted of 106,326 breast cancer patients.Compared to patients without tumor resection, patients with resection were more likely to be younger, married, white, ER-positive, PR-positive, HER2-unknown, and have lower grade, left breast cancer and have lower AJCC stage (P<0.001) compared to the general population. In all age strata (≥45 years old), breast cancer patients without CT or RT had a higher CVD risk than the general population at the same age   and 5.425 folds  in breast cancer patients with tumor resection and without resection respectively, compared to the general population. In all age strata (≥45 years old), the increased extent of CVD-related SMRs were all higher in patients without resection compared to the patients with tumor resection  . After the 1:1 PSM, 17,478 patients were included in the matched cohort, and the confounding covariates became balanced between the two groups  received tumor resection and 8830 (8.3%) did not. Before PSM, the variables  showed imbalanced between the two groups . To eliminate the possibility of producing false positive results, regression analysis of multivariate competing risks was performed and the tumor resection was confirmed as an independent risk factor that influences CVD both before PSM and after PSM. Adjustment for cofounding covariates  indicated a robust adjusted hazard ratio (HR) of no resection after PSM . After further adjustment , adjusted HR did not change distinctively and the CVD risk among patients without tumor resection increased to 1.166-fold compared to patients with tumor resection  . In the multivariate analysis .In the univariate competing-risks regression analysis  had higher CVD risk compared to the general population . Many prIn accordance with the study by Pavo et al.  who founP<0.05). The changes in regression coefficients of tumor resection were not obvious after PSM, which indicated that PSM was reliable to balance the basic condition of patients . Nevertheless, the confounding covariates should be taken into account as they may affect the therapeutic approach of choice and the CVD risk, which may cause treatment selection bias and false positive results. To control for this bias, we further utilized PSM to balance the confounding factors and performed competing risk regressions to verify the independent effect of tumor resection on CVD. After PSM, we obtained a robust result, showing that the CVD risk among patients without tumor resection increased by 1.165-fold compared to patients with tumor resection . This may be attributable to the overlapping risk factors of cardiovascular diseases and breast cancer, such as chronic systemic low-grade inflammation  on CVD risk in breast cancer patients is concerned, our results showed that these three receptors had no effect on CVD risk in breast cancer patients. These results were partially consistent with the study by Weberpals, et al.  who founThe mechanisms underlying higher CVD risk among breast cancer survivors without CT or RT remain obscure, but the hypothetical explanations may lie in cancer-induced CVD. On the one hand, our PSM-adjusted results support the speculation that breast cancer-bearing patients are at higher CVD risk, whereas the risk could be remarkably reduced after tumor resection. On the other hand, further supporting evidence comes from basic research reporting that tumor-induced inflammation might increase CVD risk. Breast cancer could damage the cardiovascular system of breast cancer-bearing mice by initiating systemic inflammatory reactions named neutrophil extracellular traps (NETs) . Cancer-The strengths of the present study are noteworthy for its large-scale population, long-term follow-up and multicenter cases. To the best of our knowledge, this is the first study to report that breast cancer survivors without CT or RT are inflicted by increased CVD risk on the population level. Some limitations of the study should be taken into account. Firstly, this is a retrospective non-randomized study which may have selection bias for patients. Nevertheless, we used PSM to resolve this limitation as much as possible. Secondly, the data on cardiovascular risk factors, cardiovascular comorbidity, and performance status were not provided by the SEER, and we could not distinguish their effects on CVD risk in our SEER-based study. To address this issue, we used CVD-related SMR in comparing the general population with or without cardiovascular conditions and performance status. Thirdly, the SEER registries do not provide the information of hormonal treatments. Nevertheless, we adjusted the molecular subtype (ER and PR) in multivariate competing-risks analysis, which might partly reduce the effect of hormonal treatments on our results.This study found that breast cancer patients free of CT or RT were at higher CVD risk, and tumor resection might be a contributing factor to decreased CVD risk in breast cancer patients. Existing breast cancer might strongly correlate with higher CVD risk. Clinical practices highlight that breast cancer patients free of CT or RT should also be targets for monitoring of CVD risk and prevention of the disease. Clinicians should start to monitor CVD risk and prevent CVD once breast cancer is diagnosed. Further studies and prospective trials are needed to verify our conclusions and to explore the underlying mechanisms.https://seer.cancer.gov/.The datasets presented in this study can be found in online repositories. The names of the repository/repositories and accession number(s) can be found below: TG: Conception, study design, data collection, analysis, interpretation of results, figure design, article draft writing, article–review, and editing. HZ and JY: study design, data analysis, interpretation of results, article draft writing, article–review, and editing. WL and KW: interpretation of results and figure design. MS and WP: study design and article draft writing. YML, and YXL: article draft writing. CL: Funding acquisition, interpretation of results, project administration and supervision, article–review, and editing. All authors contributed to the article and approved the submitted version.This study was funded by the National Natural Science Foundation of China (81100235), the Guangzhou Science and Technology Project of China (201804010214), and the Special Funds for the Cultivation of Guangdong College Students’ Scientific and Technological Innovation .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.


Obesity is associated with an increased risk of estrogen receptor-positive breast cancer in postmenopausal women and a worse prognosis for all major breast cancer subtypes regardless of menopausal status. While the link between obesity and the pathogenesis of breast cancer is clear, the molecular mechanism of this association is not completely understood due to the complexity of both obesity and breast cancer. The aim of this review is to highlight the association between obesity and breast cancer and discuss the literature, which indicates that this association is due to chronic adipose tissue inflammation. We will discuss the epidemiological data for the association between breast cancer incidence and progression as well as the potential molecular mechanisms for this association. We will focus on the role of inflammation within the adipose tissue during the pathogenesis of breast cancer. A better understanding of how obesity and adipose tissue inflammation affects the pathogenesis of breast cancer will lead to new strategies to reduce breast cancer risk and improve patient outcomes for obese patients. Obesity is a condition of having excess body fat that poses a health risk. It is generally defined as having a body mass index (BMI)—an indicator of body fatness determined by dividing the weight of an individual by the square of their height—of ≥30, whereas BMIs from 18.5 to 24.9 are normal weight and BMIs within the range of ≥25 to <30 are considered overweight [Obesity is particularly prevalent in western countries, with the American and European regions having the highest prevalence of obesity. In the U.S. and Europe, 28.3% and 22.9% of adults were obese in 2015, a 2.2 and 1.6 fold increase, respectively, since 1980 ,8. ObesiThe health risk associated with obesity leads to increased health care costs. This, along with lost productivity due to these chronic health problems, contributes to the economic impact of obesity ,38. In 2There have been numerous epidemiological studies and meta-analyses to demonstrate that obesity is associated with both an increased risk of estrogen-receptor (ER)-positive breast cancer in post-menopausal women and worse clinical outcomes independent of menopause status relative to their normal-weight counterparts. Here, we will briefly cover this association, as it has been extensively reviewed ,41,42. SApart from the increased risk of developing breast cancer, several studies have shown that obesity is associated with worse outcomes for breast cancer patients irrelevant of subtypes. Several meta-analyses have been performed and provide strong evidence for the association between obesity and increased breast cancer mortality. One analysis of 43 studies found a 33% increased rate of death in obese patients . AnotherObesity also affects other aspects of breast cancer, including diagnosis, treatment, and metastasis. A few studies have shown a correlation between obesity and higher Tumor Node Metastastis (TNM) stage with increased lymph node involvement at time of diagnosis ,64. HoweA summary of some of these studies can be found in While the epidemiological link between obesity and breast cancer incidence and outcome is well established, the molecular mechanism explaining how obesity promotes breast cancer development and progression is less clear. Various mechanisms have been proposed to explain the correlation between obesity and breast cancer ,42. ThesAdipocytes are a major component of the breast, ranging from 7–56% of the total volume . It is rApart from an expansion of adipose tissue during obesity, obesity modifies the behavior and secretome of adipose tissue. Studies have discovered that obese postmenopausal women have an increased expression of aromatase in adipocytes, which leads to increased circulating levels of estrogens. This increase in circulating estrogens may contribute to the risk of ER-positive breast cancer in obese postmenopausal women . HoweverObesity leads to an increase in the adipokine leptin and a decrease in adiponectin. Numerous studies have been conducted on the role of these adipokines in breast cancer. A meta-analysis of 23 studies found that high leptin levels are positively correlated with the increased risk of breast cancer . Other sInflammation is a common factor between many obesity-associated comorbidities, including cancer, suggesting that obesity-associated inflammation may be a common factor in the pathophysiology of several obesity-related health risks ,115,116.Excess energy is stored as triglycerides in adipocytes, which—if it is too much—leads to the expansion of adipocytes via both hypertrophy, an increase in size, and hyperplasia, an increase in number . HoweverThere is strong evidence that obesity-associated inflammation is driving both the increased risk of breast cancer and poor breast cancer prognosis in obese women. In obese postmenopausal women, there is a positive correlation between circulating C-reactive protein (CRP)—a marker of inflammation—and breast cancer risk . CRP levMany inflammatory cytokines that are upregulated in inflamed adipose tissue under the obese condition are associated with breast cancer risk and progression. TNFα, IL-6, and IL-1β are all elevated in obese breast cancer patients and are associated with breast cancer progression and outcomes ,153,154.A summary of the proposed mechanistic links between obesity and breast cancer are presented in The evidence suggests that obesity-associated chronic inflammation in adipose tissue is, at least in part, driving the correlation between obesity and breast cancer. Given that adipocytes are an important component of the breast cancer tumor microenvironment , it is rIn order to study the association between adipose tissue inflammation and breast cancer, markers for inflamed adipose tissue need to be identified. As stated previously, obesity leads to adipocyte hypertrophy, cell death, the recruitment of macrophages, and the formation of CLS . The appThere are a few studies showing that the presence of CLS in mammary adipose tissue may increase the risk of breast cancer independently of obesity. One study looked for CLS in mammary adipose tissue from benign biopsies and found that a high CLS count was associated with an increased risk of developing breast cancer after adjusting for BMI, indicating that a high CLS count may be an independent marker of breast cancer risk . In anotThere is sufficient evidence to support the idea that obesity is a risk factor for the development of breast cancer and is associated with increased mortality. The association between obesity and breast cancer outcomes may be because obese patients tend to have a higher TNM stage when diagnosed, though some studies have shown that the correlation between obesity and mortality is independent of stage ,64,80. TGiven the evidence that adipose tissue and in particular adipose tissue inflammation is a major driver of the association between obesity and breast cancer, targeting adipocyte-secreted factors may be a viable therapeutic approach for improving outcomes for obese patients. Several agents targeting the chemokines and cytokines secreted by adipocytes which are elevated by obesity have been used in clinical and preclinical studies. These include Cenicriviroc, an inhibitor of C-C motif Chemokine Receptor 2 (CCR2), the receptor for C-C motif Chemokine Ligand 2 (CCL2), which is important in the recruitment of macrophages to obese adipose tissue ,172; TocAnother possibility is to treat the obesity itself, and there are a few clinical studies looking at the effect of weight loss on breast cancer, including the Breast Cancer WEight Loss (BWEL) study (NCT0270826). The effect of weight loss as a method for lowering breast cancer risk is supported by a few studies, including a large prospective study that found that sustained weight loss in women over 50 is associated with a reduced risk of developing breast cancer . Other sMany studies support that obesity-associated inflammation—particularly in mammary adipose tissue—is a major contributor to this association. Interestingly, some studies suggest that mammary adipose tissue inflammation may be a risk factor for breast cancer in normal weight individuals ,164,165.


P = 0.004), but not with acini counts (P = 0.808), in histologically normal tissue samples from donors and diagnostic BBD biopsies. Mediation analysis indicated that TDLU counts may explain a modest proportion (≤10%) of the association of the 313-variant PRS with breast cancer risk. These findings suggest that TDLU involution might be an intermediate step in the association between common genetic variation and breast cancer risk.Terminal duct lobular units (TDLUs) are the predominant anatomical structures where breast cancers originate. Having lesser degrees of age-related TDLU involution, measured as higher TDLUs counts or more epithelial TDLU substructures (acini), is related to increased breast cancer risk among women with benign breast disease (BBD). We evaluated whether a recently developed polygenic risk score (PRS) based on 313-common variants for breast cancer prediction is related to TDLU involution in the background, normal breast tissue, as this could provide mechanistic clues on the genetic predisposition to breast cancer. Among 1398 women without breast cancer, higher values of the PRS were significantly associated with higher TDLU counts ( Higher number of TDLUs and higher number of acini  indicate lesser TDLU involution. Among benign breast disease (BBD) patients, having reduced levels of TDLU involution is associated with increased risk of subsequent breast cancer3. Measures of TDLU involution are thought to reflect a global process occurring throughout the breast5. Two studies from European and Asian populations have also found greater TDLU involution surrounding ER-positive compared with triple negative breast cancers, primarily for acini measures7. While several hormonal and lifestyle breast cancer risk factors are known to affect TDLU involution8, how genetic risk factors relate to TDLU involution is not well understood.Terminal duct lobular units (TDLUs) are the milk-producing structures of the breast and the predominant anatomical structures from which breast cancers originate9. Recently, a polygenic risk score (PRS) for the prediction of breast cancer has been derived using 313 common variants from the largest available international genome-wide association dataset10. Any observed relationships between the 313-variant PRS and TDLU involution may provide mechanistic clues on the genetic predisposition to breast cancer. ER-specific PRS have also been recently developed10. Investigating whether ER-specific PRS are related to measures of TDLU involution could inform whether lobular involution shows differential relationships for genetic susceptibility predisposition to breast cancer subtypes.We previously examined whether 62 established breast cancer susceptibility loci were associated with TDLU involution and found limited evidence for an associationn = 1,089)11 and in the background, normal tissue of biopsies among participants diagnosed with BBD in the NCI Breast Radiology Evaluation and Study of Tissues (BREAST) Stamp Project (n = 309)12.Here, we assessed the relation between the 313-variant breast cancer PRS and TDLU involution in 1,398 women with histologically normal donated tissues in the Susan G. Komen Tissue Bank (KTB) at the Indiana University Simon Cancer Center . With respect to the 313 loci that formed the PRS, we found limited evidence for their individual associations with TDLU involution measures . Analyses stratified by study population suggested a stronger association in the tissue donors (KTB) compared to those diagnosed with BBD (BREAST Stamp) (data not shown). ER-positive and ER-negative PRS were both positively associated with TDLU count (P = 0.005 for ER-positive and negative) but not with acini count/TDLU .Greater values of the PRS were statistically significantly associated with higher TDLU counts  and breast cancer risk were based on previous results from the Mayo Benign Breast Disease Cohort13; and the present analysis provided the relationship between the PRS and TDLU counts. Using this approach, we estimated that ~4 to 7.4% of the relationship between the PRS and breast cancer risk would be explained by TDLU counts, if the odds ratio for the association between TDLU counts and breast cancer risk was between 1.25 and 1.45 based on previous results from the Mayo Benign Breast Disease Cohort.Mediation analysis was used to estimate the percent of the association between the PRS and breast cancer risk that might be explained by TDLU count Fig. , Table 314), TDLU involution is the first breast cancer risk factor found to be significantly associated with the 313-variant PRS. Lack of TDLU involution and elevated mammographic breast density are positively correlated histologic and radiologic measures, respectively, of breast tissue composition that are thought to provide independent information about breast cancer risk in women with BBD15. Mammographic density was not readily available in the KTB participants, and therefore, we did not have enough statistical power to evaluate the relationship between the 313-PRS and mammographic density in our study. If future studies identify a relation of the 313-PRS with mammographic density, then one could investigate inter-relationships between the PRS, TDLU involution and mammographic density in relationship to breast cancer risk.In this study, we assessed the relation between the 313-variant breast cancer PRS and measures of TDLU involution and found that higher values of the PRS were significantly associated with higher TDLU counts in histologically normal/benign breast biopsies. Although individual single nucleotide polymorphisms (SNPs) in the PRS have been associated with some breast cancer risk factors .Our result relating the 313-PRS with TDLU counts corroborates previous findings showing that family history of breast cancer is associated with increased TDLU counts8, computational pathology approaches may offer future opportunities to advance etiologic studies examining complex relationships between genetic susceptibility, breast tissue composition, and breast cancer risk. In addition, we focused our assessment of involution in the background normal tissue, excluding any observed BBD lobules. Even so, prior work suggests that TDLU involution in histologically normal breast tissue may reflect a global process occurring throughout the breast5. Finally, despite doubling the sample size from our previous analysis9, additional samples may be required to detect associations between individual genetic variants and TDLU metrics.Strengths of this study include the well-characterized epidemiologic and genetic data for study participants with standardized, reproducible measures of lobular involution in non-malignant breast tissues. We also applied an innovative analytical approach to estimate the percent of the association between PRS and breast cancer risk potentially explained by TDLU counts. A limitation of the current study is the lack of replication of our findings. Our study is based on observational assessment of TDLU involution. Although we have demonstrated strong within- and between-rater reliability for these TDLU metricsIn conclusion, we observed a statistically significant association between a recently developed 313-variant PRS for the prediction of breast cancer and TDLU counts, suggesting that TDLU involution may mediate relationships underlying common genetic susceptibility and breast cancer risk. Future studies may further investigate the use of the PRS for the prediction of TDLU involution, with potential applications in studies that lack measures of lobular involution.9. Briefly, the KTB is an annotated biobank, which has recruited healthy women who provided demographic, lifestyle, and cancer-related information via self-administered questionnaire, blood samples and normal breast tissues. Up to four breast tissue cores were obtained from the upper outer quadrant of the breast using a standardized technique with a 10-gauge vacuum-assisted biopsy. One sample was formalin-fixed and paraffin-embedded and stained with hematoxylin and eosin (H&E). Whole blood samples were collected using Vacuette® EDTA tubes. For this study, a 50 µl aliquot of samples were reconstituted at the Cancer Genomics Research laboratory  for genotyping. Details of the KTB have been described elsewhere (http://komentissuebank.iu.edu/)11. The current analysis was restricted to 1507 participants recruited from January 10, 2009 through September 14, 2012, aged 18–91 years, that were eligible for genotyping. Informed consent was obtained from all participants to use of their specimens and questionnaire data for research. Approval for this study was obtained from the Indiana University Institutional Review Board (IRB) and the National Institutes of Health Office of Human Subjects Research (NIH OHSR #4508).The study population has been previously described16. Blood and mouthwash samples were processed at the University of Vermont General Clinical Research Center. Leukocyte DNA was extracted from blood clots using phenol chloroform, and DNA was isolated from buccal cells using Gentra Puregene Buccal Cell Kits (Qiagen). The current analysis was restricted to 450 women who had eligible samples for genotyping. All women provided written informed consent and the study was approved by the IRBs at the University of Vermont and the NCI.The NCI BREAST Stamp Project is a cross-sectional study of mammographic density conducted among women, aged 40–65 years, who were referred for diagnostic image-guided breast biopsy from 2007 through 2010 at the University of Vermont College of Medicine and University of Vermont Medical Center. Demographic, lifestyle, and breast cancer risk factor information were collected via a self-administered questionnaire and a supplementary telephone interview. Participants underwent clinically-indicated breast biopsies, which were formalin-fixed paraffin-embedded blocks and H&E stained. Whole blood samples and mouthwash samples were collected as previously described2) on the slides was outlined using the lasso tool in Digital Image Hub and measured. The study pathologist measured the number of TDLUs (“TDLU count”). Acini count per TDLU was quantified using the TDLU analyzer software18 as previously described9. A high intra-observer agreement (Spearman’s r > 0.90) for the TDLU measures was previously reported8.H&E slides were scanned for image analysis on Digital Image Hub software . The total tissue area . Genotypes were generated using a cluster file provided by the Genetic Associations and Mechanisms in Oncology Consortium. Details of the OncoArray SNP selection and genotyping calling have been described elsewhere19,20. Briefly, ~50% of the SNPs for the OncoArray were selected to provide high coverage for imputation of common variants. The other 50% of SNPs were selected from lists supplied by investigators based on consortia decisions for different diseases. Of the 568,712 variants selected for genotyping on the OncoArray, 533,631 were successfully manufactured on the array (including 778 duplicate probes). Of these 533,631 variants, 38,868 were defined as problematic SNPs by the Consortium QC guideline, thus were excluded from the current analyses.DNA samples from 1957 women in the two studies (1507 from the KTB and 450 BREAST Stamp project) and 23 quality control samples were genotyped on the Illumina OncoArray chip20 and the 1000 Genome phase 3 data, we identified 98 subjects of non-European descent whom we excluded from the analyses.We further excluded samples and SNPs based on the criteria defined by the consortium QC guideline. Through a stepwise filtration, we excluded SNPs and samples with a call rate <95% and samples with extreme heterozygosity (>0.4 or <0.05) within each study. We also excluded 9 unexpected duplicates with genotype concordance rate >99%, excluded one nonfemale subject with X chromosome heterozygosity close to zero and 66 first-degree relatives based on identity by descent analysis. Using a set of population informative SNPsAfter genotyping, subjects were further excluded if they had a personal history of in situ or invasive breast cancer, has missing tissue area, pregnant at the time of blood draw, were previous donors (in the KTB), and/or currently taking hormone therapy, leaving an analytic population of 1398 women.21 and IMPUTE22 version 2, as in Michailidou et al.23, run on the NIH High-Performance Computing Biowulf cluster computing (http://hpc.nih.gov). The imputation was done in 5-MB around intervals around each of the 313 loci in the PRS10. Imputation quality as assessed by IMPUTE version 2 quality score was >0.80 and r2 > 0.3 for all loci.All samples were imputed using the October 2014 (version 3) release of the 1000 Genomes Project dataset as the reference panel and using a two-stage imputation approach using SHAPEIT210 and the log of effects sizes as weights. We standardized the PRS to have units of standard deviation (SD). With respect to the subtype-specific PRS, we used the weights from the hybrid method in Mavaddat et al., as this method was found to have the best performance.Analyses were conducted combining data from the KTB study and BREAST Stamp Project. The PRS for overall and ER-specific disease was computed using the 313 loci as described in Mavaddat et al.9, we used Poisson regression models with robust variance to compute per-SD relative risks and 95% confidence intervals for the association of TDLU measures  with the PRS. The PRS was modeled as a continuous variable and as a categorical variable based on quartiles computed in the entire study population. An offset variable was included in the model to account for the tissue area on the slide. We used the Wald test to assess whether a linear trend between the PRS and morphometric TDLU measures was present. Similar analyses were used to compute per-allele RR  and age. Sensitivity analysis were also carried out by adjusting for family history and visually assessed proportion of fibroglandular tissue. No significant differences were observed. We also conducted stratified analyses by study and by family history (data not shown).Similar to our previous analyses24 and the 95% CI were obtained by the bootstrap procedure with 10,000 resamples. For this procedure, we assumed that the relationship between the PRS and TDLU could be described by Poisson regression (see above) and that the parameters could be estimated using data from this study. Furthermore, we assumed that the joint effect between PRS and TDLU count on breast cancer could be described by logistic regression Eq.  agreed with the assumed value from Figueroa et al.13, and f(TDLU | PRS) agreed with results from our study). The constrained model was fit using approaches recently developed by Chatterjee et al.25.The estimation of the mediating effect was done using the procedure described by Imai et al.P values < 0.05 were considered statistically significant. Analyses were conducted using R 3.5.2 on a Mac platform.All statistical tests were two-sided and Further information on research design is available in the Nature Research Reporting Summary linked to this article.Legend Supplemental Data 1Supplemental Data 1Reporting Summary Checklist FLAT


BsmI and ApaI VDR polymorphisms among patients with non-melanoma cancers and controls. An observational case-control study was conducted in a sample of 154 subjects. We observed no significant effects between these polymorphisms and skin cancer risk. When stratified for gender, GG and AG BsmI polymorphisms significantly increased the risk of basal cell carcinomas in males. In relation to ApaI, all three polymorphisms significantly increased the risk of basal cell carcinoma in males. When stratified for age, we found that being 70 years of age or younger was a protective factor against both skin cancers. Being a female and 70 years old or younger was a protective factor for basal cell carcinoma. A comparison of the frequencies of the VDR genotypes in patients older than 70 years vs. 70 years or younger also revealed age-dependent variations in patients with non-melanoma skin cancer. Our study suggests a role for VDR polymorphisms in non-melanoma skin cancer development.Exposure to sunlight is the major source of vitamin D and the main environmental cause of non-melanocytic skin cancers. Vitamin D, partly mediated through the vitamin D receptor (VDR), has potential therapeutic applications in skin cancer. The aim of this study was to investigate the association of  The likelihood ratio test (LRT) was calculated to evaluate the heterogeneity in the effects of the genotypes on the different types of skin cancer.Univariate and multivariate logistic regression analyses were performed to evaluate the association between independent variables (factors) and the occurrence of non-melanoma skin cancer (dependent variable). Multivariate and multinomial logistic regression was employed to calculate the odds ratios (OR) and 95% confidence intervals (IC) to assess the risk of skin cancer for genotypes, age and gender among the subjects.2 test or Fisher’s exact test. The significance cut-off value was p ≤ 0.05. The continuous variables are expressed as the mean ± standard deviation, and the categorical variables are expressed as percentages.The frequencies of the polymorphisms between the different groups were compared with the χAll statistical analyses were performed using SPSS for Windows, version 24.0 .A total of 154 subjects were included in our study. The patient group consisted of 81 subjects with non-melanoma skin cancer, and 73 healthy individuals were enrolled to serve as controls. A total of 72 (46.75%) were males, and 82 (53.24%) were females.Our subjects were between 38 and 94 years old with a mean age of 68.22 ± 14.53 years . The mean age of the control subjects was 60.58 ± 12.90 years and that of the BCC and SCC cases were 74.03 ± 12.19 and 78.40 ± 12.66 years, respectively.BsmI and ApaI polymorphism) of the analysed sample met HWE, both in the total sample (HWE BsmI p = 0.85 and HWE ApaI p = 0.51), in cases (HWE BsmI p = 0.48 and HWE ApaI p = 0.58) and in controls (HWE BsmI p = 0.29 and HWE ApaI p = 0.11). It is observed that the most frequent genotype for BsmI  was the AG , however, the least frequent was the AA genotype . The most frequent genotype for ApaI  was the GT , while the least frequent was the GG genotype .The distribution of the percentages of the genotypes . The multivariate logistic regression model carried out was significant, taking [BsmI polymorphism] * [Gender] as factors (p = 0.00), and [ApaI polymorphism] * [Gender] (p = 0.00). In relation to ApaI, we observed that the three polymorphisms  significantly increased the risk of BCC in males . Although all three polymorphisms increased the risk of BCC in males, they did so in different amounts depending on which polymorphism was involved. The GG ApaI polymorphism could increase the risk for BCC nearly 12 times. No significant main effects were observed for SCC in the analyses of the ApaI or BsmI polymorphisms  but not with SCC risk, compared to controls. It was also observed that being 70 years of age or younger was a protective factor against both BCC and SCC risk . There was no significant association between BCC or SCC risk related to VDR SNPs, age or gender .p = 0.00). . The multivariate logistic regression model carried out was significant, taking [Age] * [Gender] as factors (= 0.00). .GT ApaI polymorphism, all the other polymorphisms were protective against BCC in the patients who were 70 years old or younger. Similarly, the AG BsmI and GT ApaI polymorphisms were protective against SCC risk in the patients who were 70 years old or younger. The multivariate logistic regression model carried out was significant, taking [BsmI polymorphism] * [Age] as factors (p = 0.00), and [ApaI polymorphism] * [Age] (p = 0.00)  .AGGT, GGGG and AATT combined polymorphisms in our population , but we did not find any interactions between these nine combined polymorphisms and cancer risk.We studied the combined As far as we are aware, no previous studies have involved a Spanish population to assess the possible associations between VDR polymorphisms and non-melanoma skin cancer.BsmI or ApaI polymorphisms were studied alone, but there were significant and interesting results when adjusted for stratum age and gender. These results are conflicting when compared to those of a few similar published studies.It is already known that non-melanoma skin cancer is related to age ,17,18 anSkin cancers are the most common cancer type in most white-skinned populations and are an important health concern because they impose a substantial burden on health care systems ,22.2D3 has anti-proliferation and pro-differentiation effects in both melanocytes and cutaneous melanoma cells, mediated through the VDR [In relation to skin cancer, it is known that ultraviolet radiation (UVR) has strong carcinogenic effects on skin tissue, which makes it a strong risk factor for melanoma and non-melanoma skin cancer ,24. Alth the VDR .2D3, could inhibit the proliferation of melanoma cells [2D3 have been demonstrated in a wide variety of cancer cell lines, including breast or prostate cancer lines [As early as the 1980s, it was shown that the active form of vitamin D, 1α25(OH)ma cells . Followier lines .It has been shown that vitamin D inhibits hedgehog signalling and proliferation in murine BCCs . It has VDR is a crucial mediator of the cellular effects of vitamin D. A vast amount of information has been collected over the years regarding the association of VDR polymorphisms with the susceptibility of individuals to suffer from different diseases, such as cancer ,28.Associations of some of the VDR genotypes with skin cancer risk have been studied, both for melanoma ,30,31,32BsmI BB genotype was significantly associated with an increased risk of SCC  but not with BCC risk. An interaction was also observed between the BsmI polymorphism and the SCC risk among women with a high constitutional susceptibility, namely, lighter hair, fair skin colour, greater tendency to burn and more moles . Moreover, they observed an interaction between the BsmI polymorphism and the total vitamin D intake on the SCC risk, suggesting that women with the BB genotype and high vitamin D intake have the highest risk of SCC.In 2007, Han et al.  observedTaqI polymorphisms between affected and unaffected populations. The TT/tt genotype group was associated with a twofold increase in the odds of being affected by one or more solar keratoses. They did not observe an association between the ApaI polymorphism and solar keratosis prevalence when the genotypes were analysed alone. However, they did find a significant association when both polymorphisms were analysed in relation to other variables, such as skin colour or propensity to burn and/or tan. The fair-skinned people with the ApaI AA/aa genotypes had an approximately eightfold increase in the odds of being affected by solar keratoses compared with a fivefold increase in individuals with the Aa genotype and fair skin.If we consider solar keratoses as in situ SCC , we needApaI, TaqI or BsmI and BCC. They found an association between the presence of the TT genotype in the FokI VDR polymorphism, resulting in a >10-fold higher risk of BCC development.Later, in 2011, Lesiak et al.  studied ApaI, BglI and TaqI and BCC or SCC. There was a trend towards a higher distribution of homozygous genotypes for all three polymorphisms in the controls than in the BCC patients, but these differences were not statistically significant. No significant differences in the frequency of the individual genotypes between the SCC patients and the controls were found either. When the combined ApaI/TaqI/BglI genotype was analysed, an association of the genotype AaTtBb with BCC risk was found. They also found that the aaTTbb genotype was more frequent in the BCC and SCC groups compared to that of the controls.Köstner et al.  studied ApaI (rs7975232) GG + GT dominant genotypes were associated with a decreased occurrence of BCC when compared with the TT genotype . Nevertheless, the associations were no longer statistically significant in the adjusted model and after correction for multiple testing within each gene. Additionally, the SCC risk was decreased in participants with the FokI (rs2228570) TT vs. CC + CT genotypes, and this remained statistically significant after adjusting for confounders and correcting for multiple testing .Von Schuckmann et al.  found thBsmI SNP were twice as likely to develop non-melanoma skin cancer than participants with no mutation. Moreover, individuals with the A genotypes were only about half as likely to develop non-melanoma skin cancer. However, after adjusting for age and gender in the model, they did not find statistically significant results.Burns et al.  found thVery recent studies have followed this long-standing yet innovative line of research, as promising results are being found ,41.BsmI or ApaI polymorphism genotypes and skin cancer risk.In our observational case-control study, no significant main effects were observed between the BsmI polymorphisms significantly increased the risk of BCC in males . All the BsmI polymorphisms were protective against BCC in patients who were 70 years of age or younger. The AG BsmI polymorphism was also protective against SCC for the same age range.When stratified for gender and skin cancer risk, we found that GG and AG BsmI polymorphism genotypes and cancer risk. Han and colleagues observed that the BsmI dominant-BB (-GG) genotype was significantly associated with an increased risk of SCC, but our study did not support their findings.Like Lesiak and colleagues and Von Schuckmann and colleagues, our findings showed no statistically significant associations between the ApaI (rs7975232) GG and GT genotypes were associated with a decreased occurrence of BCC, but these associations were no longer statistically significant in the adjusted model. The same happened to Burns et al. [On the other hand, Von Schuckmann and colleagues found that s et al.  who founApaI polymorphisms observed any association between this polymorphism and non-melanoma skin cancer. As mentioned before, we found an association between the ApaI polymorphisms, BCC and SCC when analyses were adjusted for stratum gender and age. Similarly, Carless and colleagues found an association when they analysed their results in relation to other variables, such as skin colour or propensity to burn and/or tan.Like our findings, none of the other authors that had previously studied the We found no significant association between the combined genotypes and skin cancer, most likely due to the relatively low case numbers.It should be noted that individual VDR polymorphisms cannot be regarded as independent prognostic factors . We did Within the limited published data, there is no evidence that any polymorphism is clearly involved in the risk of having BCC or SCC. The inconsistent results may be due to high heterogeneity between studies and populations. This present study, to our knowledge, is the first report on BCC, SCC and VDR polymorphisms in the Spanish population.Our data and samples were drawn from a well-established observational case-control study in which all skin cancers were histologically confirmed. The polymorphisms were analysed by one laboratory with high validity and repeatability. In fact, the total correlation was demonstrated by measuring the samples in duplicate.BsmI and ApaI polymorphisms.Our results suggest that BCC and SCC are related to age and gender and that, at the same time, these variables may be influenced as well by Further studies with a larger number of participants, namely a cohort study, and more information about possible confounding factors and vitamin D status is needed to confirm or reject our results.


In Brazil, the population in general has little knowledge about genetic risks, as well as regarding the role and importance of the Cancer Genetic Counseling (CGC). The goal of this study was to evaluate cancer-related worry and cancer risk perception during CGC sessions in Brazilian women at-risk for hereditary breast cancer. This study was performed in 264 individuals seeking CGC for hereditary breast cancer. Both cancer-affected and unaffected individuals were included. As results, individuals with and without cancer reported different motivations for seeking CGC and undergoing genetic testing. A correlation was observed between age at the first CGC session and age at which the closest relative was diagnosed with cancer. Multivariate analysis showed that educational level, cancer risk discussion within the family, and number of deaths by cancer among first-degree relatives influenced positively the cancer risk perception. In conclusion, the results of this study indicate that cancer-related worry and cancer risk perception are significant aspects of morbidity in individuals seeking CGC, whether they are cancer-affected or unaffected. CGC has an important role in health education and cancer prevention for its potential of promoting an accurate perception of the risk. The development and rapid improvement in molecular diagnosis of inherited genetic diseases during the last decades resulted in an increasing need for genetic counselling (GC), since it is a process that provides information and support for at-risk individuals and their families. This is also applicable to individuals at-risk for a specific group of genetic disorders, the hereditary cancer syndromes. As cancer is usually diagnosed during adult life and can be prevented or diagnosed in very early stages, GC may be particularly important, since predictive testing of at-risk individuals may guide effective cancer prevention strategies .BRCA1 and BRCA2 were identified  criteria for a hereditary breast cancer syndrome through local, national and/or international collaborative research studies (Cancer Genetic Counselling (CGC) services have been established in many countries. They have developed quickly, mainly from the beginning of the decade of 1990, when several high-penetrance cancer predisposition genes, such as During CGC, the individual cancer risk perception, defined as the “subjective estimation of the likelihood that one might be diagnosed with cancer in the future”(Hardly any data exist on cancer-related worry and cancer risk perception in South American patients seeking GC for hereditary breast cancer (HBC) risk. This is a particularly interesting population because genetic testing for cancer predisposition is not easily and readily available to most people that rely upon the public health care system and the population, sometimes, do not have enough knowledge concerning hereditary cancer , São Paulo (SP) and Rio de Janeiro (RJ). Ethical approval was obtained from the respective institutional ethics and research committees. At inclusion, informed consent was obtained from all individual participants included in the study. Participants were assigned to two groups: (1) cancer-affected individuals with a family history suggestive of HBC, or (2) asymptomatic individuals with a family history suggestive of an HBC syndrome. All participants were asked to complete a cancer-related worry and perceived risk questionnaire before the first GC consultation, and had their pedigree and previous/present medical history recorded. Breast cancer screening procedures (adherence and periodicity) were recorded for all women. Using standard breast cancer screening guidelines . Additional information obtained included: patients’ understanding about breast cancer etiology, knowledge about genetic testing for HBC, habit of discussing cancer-related issues with relatives, presence of a relative during CGC sessions and motivation for GC and genetic testing. Detailed information on personal breast (and other) cancer history, breast cancer screening (performance and periodicity), and family history of cancer were also recorded.et al., 2003) as follows:Perceived lifetime risk of cancer (for self and other relatives) was assessed by four questions adapted from  developing cancer again”] for the affected individuals and scored by a visual analogic scale rating risk from 0-10 (expressed in %).Verbal risk of developing cancer was measured by the question “What do you feel is your lifetime risk of developing cancer” [or “(...) developing cancer again”] for the affected individuals and answers were scored from 1 to 4 .Relative lifetime risk of developing cancer was measured with two questions: “What do you feel is your lifetime risk of developing cancer compared to other persons of your age” and “How would you rate the lifetime risk of your close relatives developing cancer” [or “(...) developing cancer again” ] for the affected individuals. Answers to the first question were scored from 1 to 5 . Answers to the second question were evaluated by a visual analogic scale rating risk from 0-10 (expressed in %). Since this is a descriptive study, results are preliminary and no validation was performed at the time of recruitment or before. The instruments used were posteriorly valeted for the Portuguese language with no major modifications in relation to the original version in English.Cancer-related worry and its impact on daily life were assessed by the same instrument using two questions adapted from (BRCA gene). For analytical statistics, Student’s t-test for independent samples or ANOVA for more than two groups were used to compare symmetric variables. Mann-Whitney and Kruskal-Wallis tests were used when comparing asymmetric variables in two or more groups, respectively . Categorical variables were examined by Chi-square and multiple comparisons or Fisher’s exact test and the correlation coefficient of Spearman was used whenever analysis included two quantitative variables. Crohnbachs coefficient was used to verify internal consistency among questions of the instrument used to measure risk perception. In addition, multivariate analysis was performed to identify variables that may influence cancer risk perception and cancer-related worry. The variables included in the analysis were: previous diagnosis of cancer, educational level, discussion within the family about cancer-risk, presence of relatives during the GC session, number of deaths by cancer among first-degree relatives and perceived risk of cancer for other relatives.SPSS version 19.0 was used for data handling and statistical analyses. For descriptive analysis, categorical variables were described by their absolute and/or relative frequencies and quantitative variables were expressed as mean ± SD or median and range   .(p < 0.001) was observed between age at the first CGC session and age at which the closest relative was diagnosed with cancer  they had reached the age at which a close relative had been diagnosed with cancer (33.0%) and (b) they had a high number (3 or more) of cancer diagnoses in the family (31.5%). A correlation h cancer . A signiThe proportion of women reporting regular breast self-examination, mammography screening and breast examination by a health care professional was 52.2%, 92.0%, and 76.3%, respectively (data available for 253 women). In the group of women older than 40 years (information available for 147 women), the majority  were classified as hypovigilant, 15.7% (n=23) were classified as normovigilant, and 23.1% (n=34) as hypervigilant. No correlation was observed between educational level and adherence to screening procedures (p=0.269). The occurrence of familial cases of cancer was ascribed to “genetic factors” by 45.6% of the patients, common exposure to environmental factors by 22.6% and other factors (i.e. “Gods will” or “Bad luck”) by 31.7%.(p < 0.001). Reasons for undergoing genetic testing (in case HBC criteria were met) were evaluated for patients with and without cancer and results are presented in Patients showed some familiarity with the existence of cancer predisposition testing: 74.8% mentioned they had heard about such test. Educational level and knowledge about the availability of genetic testing were significantly correlated The analysis of pedigrees revealed that 87.1% of the probands had at least one deceased relative affected with cancer and 50.4% reported at least one first-degree relative affected by and deceased with cancer.BRCA gene was estimated with mutation prevalence tables  (Prior probability of carrying a mutation in a enetics) .Perceived numerical lifetime risk of developing cancer  was in average 44.5% with a median of 50.0%. It was perceived as < 10% by 21.2% of the patients, between 11-29% by 8.0%, and 330% by 70.8% of the individuals. Perceived verbal risk of developing cancer  was described as very high or high by 64.0%, moderate by 24.6% and low by 11.4% of the individuals.(p < 0.001). Furthermore, internal consistencies of answers to all four questions related to perceived risk of cancer was determined and found to be acceptable (Cronbachs µ 0.856).Perceived relative lifetime risk of developing cancer in comparison to other persons of the same age was described as higher or much higher by 68.6% of the individuals. Relative lifetime risk of developing cancer in comparison to other family members  was in average 45.5% with a median of 50.0%. It was perceived as < 10% by 19.3% of the patients, between 11-29% by 7.6%, and 3 30% by 73.1% of the individuals. A statistically significant correlation was observed between perceived lifetime risks of cancer for self and other relatives (p < 0.001). Comparisons of perceived numerical lifetime risk of developing cancer and cancer-related worry were performed for cancer-affected and unaffected individuals and are summarized in Regarding cancer-related worry, all individuals included in the study indicated that they have this concern at least sometimes, 47.0% worry half of the time or more and 24.2% worry all the time. When asked about the frequency with which this worry interferes with daily activities, most individuals (56.4%) indicated that interference occurred in 20.0% or less of the time. However, when analysing only those individuals that worry all the time about cancer, in approximately one third of those (34.4%) worry interfered in daily activities more than 80% of the time. Statistically significant correlations were observed between perceived risk of cancer and both, cancer-related worry and frequency of interference of this worry with daily activities p=0.002). Interestingly, there was no correlation between perceived chance of cure and the number of patients affected with and the number of deaths by cancer (p=0.547) in the family. However, when only first-degree relatives were considered in the analysis a trend towards a positive correlation was observed (p=0.134).Perceived chance of cure of cancer in general was considered very high by 6.8% (n=18) of the patients, high by 29.2% (n=77), and low by 37.5% (n=99) of the patients. Sixty-three patients (23.9%) considered cancer an incurable disease, and 7 (2.6%) did not answer. There was a poorly significant negative correlation between perceived risk of cancer and perceived chance of cure  composed mainly by women, and more educated than the average patient in the public Brazilian health care system . Cancer-It is noticeable that a significant number of individuals were accompanied by relatives not only in their first consultation but during the entire GC process, supporting the concept that cancer has an impact upon the entire family , through strong identification with an affected or deceased mother or sister” . In a siet al. (2002) an unaffected woman may be more concerned about her own risk and may feel that, since she is unaffected, her childrens risk are to some degree a lower priority  and therefore knowledge of these variables during the process of CGC is important to determine which risk communication strategy is more effective in a given situation (Work published by Finally, the way of dealing with risk is not only influenced by the individuals perception but also by his/her culture. In Brazil, the population in general has little knowledge about their genetic risks, as well as available opportunities of risk reduction through preventive measures. In addition, cultural aspects indicate that it is a society that has a high propensity to avoid risk and uncertainty results of this study indicate that cancer risk perception and cancer-related worry are a significant aspect of morbidity in individuals seeking CGC, whether they are cancer-affected or unaffected, and reinforce that the counselor must be aware of the influence of these factors upon the patient, his/her family and the counseling process itself. CGC may have an important role in health education and cancer prevention for its potential of promoting a more accurate perception of the risk. Genetic counseling may be instrumental to reinforce routine guidelines of breast cancer prevention, such as periodic mammographic examinations in women of different risk categories. For women such as those studied here, most of whom did not comply as expected for their age with screening guidelines, this aspect of counseling could be particularly important.The periodic analysis of the motivation, clinical features and risk profile of patients that are evaluated in cancer genetic clinics, as well as identification and understanding of the barriers to reach such individuals is essential to enable proper communication strategies in order to effectively achieve cancer risk reduction in genetically predisposed individuals.In this study was possible to indicate that cancerrelated worry and cancer risk perception are significant aspects of morbidity in individuals seeking CGC, whether they are cancer-affected or unaffected, and should always be addressed during counseling.It is important to considering the CGC setting including the culture and socioeconomics aspects to execute a coherent CGC, since this process has an important role in health education and cancer prevention for its potential of promoting a more accurate perception of the risk.