Concerns have been raised that extensive use of personal care products that contain endocrine disrupting compounds increase the risk of hormone sensitive cancers.To assess the effect of skincare product use on the risk of pre- and postmenopausal breast cancer, estrogen receptor positive (ER+) and negative (ER-) breast cancer and cancer of the endometrium.We used data from 106,978 participants in the population-based Norwegian Women and Cancer cohort. Participants were categorized into non-, light, moderate, frequent and heavy users of skincare products based on self-reported use of hand and facial cream and body lotion. Cancer incidence information from the Cancer Registry of Norway was linked to individual data through the unique identity number of Norwegian citizens. Multivariable Cox proportional hazard regression was used to assess the effect of skincare product use on the risk of cancer of the breast and endometrium. We used multiple imputation by chained equations to evaluate the effect of missing data on observed associations.heterogeneity ≤ 0.99). The magnitude and direction of the effect estimates based on complete case analyses and multiple imputation were similar.We found no associations between use of skincare products and incidence of premenopausal breast cancer , postmenopausal breast cancer  or endometrial cancer . Use of skincare products did not increase the risk of ER+ or ER- breast cancer and there was no difference in effect across ER status (0.58 ≤ pHeavy use of skincare products, i.e. creaming the body up to two times per day during mid-life, did not increase the risk of cancer of the breast or endometrium. Use of skincare products such as body lotion, facial cream and hand cream is common among Norwegian women . SeveralAmong frequently used EDs in PCPs are phthalates, ultraviolet (UV) filters, triclosan and parabens . Phthala/in vitro experiments ) age at enrollment was 54.7 (4.8) years. During the mean follow-up time of 10.7 (2.6) years, 3408 women were diagnosed with breast cancer and 681 with endometrial cancer. Mean age at breast and endometrial cancer diagnosis were 60.1 (5.5) and 61.0 (5.2) years, respectively.Age at enrollment was similar in all categories of skincare product use. Compared to light users, a larger proportion of women with under−/normal weight and postmenopausal status were found among the heavy users. Further, heavy users were slightly younger when they had their first child and a larger proportions had < 3 children compared to the light users. Heavy users were also more frequent current and former users of OC, MHT and cigarettes, more physically active and reported higher intake of alcohol than the light users Table .Table 1trend ≤ 0.63) In fact, moderate use of skincare products was associated with 23% decreased risk of endometrial cancer   = 0.44).Frequent/heavy users of skincare products did not experience increased risk of premenopausal breast cancer , postmenopausal breast cancer  or endometrial cancer  compared to the non−/light users. Nor did the moderate users, and there was no linear trend across effect estimates  , although we did not find significantly reduced HRs for any of the categories    the exposure classification in large scale epidemiological studies is challenging, as exposure usually is estimated from questionnaires. This limits the individual exposure assessment as detailed plasma concentration of EDs for each participant is not available. The questionnaire based approach has however been used for decades in nutritional epidemiology and if a proper validation study is performed, as in the our pervious study [Use of PCPs is considered an important source of paraben exposure for humans , 12. Sevus study , the queus study . iii) Thus study . They alThe strengths of this study includes the large and national representative sample, the linkage to national registries that ensures complete information about death, emigration and cancer diagnosis and the detailed information about sociodemographic, reproductive and lifestyle variables that we included in our analyses. Our previous study of plasma concentrations of parabens in relation to reported use of skincare products confirmed that individuals classified as frequent or heavy users of skincare products experience elevated circulatory concentrations of methyl-, ethyl- and propyl parabens compared to the non-users . PhilippWe have previously assessed the change in use of skincare products over an eight year period. We found moderate agreement (weighted kappa: 0.52) and that almost 92% of women were classified into the same user group ±1 category [The NOWAC questionnaires did not include questions about which part of the body that was covered in body lotion; therefore we assumed that one application of body lotion covered nearly the whole body (91%). This may be seen upon as a limitation as many women only use body lotion on arms and legs, suggesting that our measure “% skin covered in cream per day” may overestimate the exposure. However, we have previously shown that “% skin covered in cream per day” was strongly associated with plasma concentrations of parabens within the NOWAC cohort , and we /in vitro findings regarding paraben exposure and the risk of breast cancer. Our finding that use of skincare products during mid-life was not associated with breast and endometrial cancer risk adds important knowledge to this research field.Our study was also unable to address whether the location of body lotion application was associated with breast or endometrial cancer risk. This may be important if dermal absorption of EDs on specific areas is more relevant for breast/endometrial carcinogenesis than continuously elevated systemic concentrations. Finally, we did not have information on antiperspirant and cosmetic use, which could be important sources of paraben exposure. Nevertheless, previous studies have called for epidemiological investigations in order to confirm or refute in vivoOur population-based prospective cohort study provides evidence that heavy use of skincare products, i.e. creaming the body up to two time per day during mid-life, does not increase the risk of pre- or postmenopausal breast cancer, ER+ or ER- breast cancer or endometrial cancer.Additional file 1. Hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between skincare product use and risk of cancer. Skincare product use modelled in continuous scale using restricted cubic spline transformations of “% skin covered in cream per day” with 4 knots.Additional file 2. Hazard ratios (HRs) and 95% confidence intervals (CIs) for the associations between skincare product use and risk of pre- and postmenopausal breast cancer and endometrial cancer after multiple imputation by chained equations of missing values of included covariates.Additional file 3. Hazard ratios (HRs) and 95% confidence intervals (CIs) for the associations between skincare product use and risk of estrogen receptor positive (ER+) and negative (ER-) breast cancer after multiple imputation by chained equations of missing values of included covariates.Additional file 4. Hazard ratios (HRs) and 95% confidence intervals (CIs) for the associations between usage frequencies of body lotion and risk of pre- and postmenopausal breast cancer, endometrial cancer, ER+ and ER- breast cancer.Additional file 5. Hazard ratios (HRs) and 95% confidence intervals (CIs) for the associations between usage frequencies of body lotion, hand cream and facial cream combined and risk of pre- and postmenopausal breast cancer, endometrial cancer, ER+ and ER- breast cancer.


Diet is a modifiable component of lifestyle that could influence breast cancer development. The Mediterranean dietary pattern is considered one of the healthiest of all dietary patterns. Adherence to the Mediterranean diet protects against diabetes, cardiovascular disease, and cancer. Reported consumption of a Mediterranean diet pattern was associated with lower breast cancer risk for women with all subtypes of breast cancer, and a Western diet pattern was associated with greater risk. In this review, we contrast the available epidemiological breast cancer data, comparing the impact of consuming a Mediterranean diet to the Western diet. Furthermore, we will review the preclinical data highlighting the anticancer molecular mechanism of Mediterranean diet consumption in both cancer prevention and therapeutic outcomes. Diet composition is a major constituent shaping the gut microbiome. Distinct patterns of gut microbiota composition are associated with the habitual consumption of animal fats, high-fiber diets, and vegetable-based diets. We will review the impact of Mediterranean diet on the gut microbiome and inflammation. Outside of the gut, we recently demonstrated that Mediterranean diet consumption led to distinct microbiota shifts in the mammary gland tissue, suggesting possible anticancer effects by diet on breast-specific microbiome. Taken together, these data support the anti-breast-cancer impact of Mediterranean diet consumption. It is predicted that there will be 15 million newly diagnosed cases of cancer and 12 million cancer patient deaths in 2020 . ObesityMore than 12% of US women will be diagnosed with breast cancer during their lifetime, and in 2019 an estimated 268,600 new cases will be diagnosed . Breast To lower the risk for cancer, diet-based recommendations include consuming a dietary pattern that consists largely of vegetables (including beans and legumes), fruits, and whole grains. In addition, recommendations include reducing exposure to the following dietary components: processed red meats, refined sugars, carbohydrates, fat, and excessive alcohol .The Western dietary pattern (WeD)  that is consumed by many in the United States is recognized for containing high amounts of refined starches, sugar, red and processed red meats, saturated fats, trans fats, and low amounts of fruit, vegetables, and whole grains. It was reported that more than half of the calories in the WeD come from highly processed foods. A cross-sectional study utilizing National Health and Nutrition Examination Survey 2009–2010 in 9317 participants who were at least 1 year of age and older revealed that nearly 58% of the energy intake, stated as almost three out of five of calories, was in the form of highly processed foods [n = 242 (27%)), compared to women with low adherence to the WeD (n = 169 (19%)) with a fully adjusted odds ratio (ORQ4 vs. Q1) of 1.25  1.03–1.52). It was reported that the association was specific to overweight and obese women (adjusted ORQ4 vs. Q1 (95% CI 1.41 (1.13–1.76)). There was no association between MeD and mammographic density [The WeD has been associated with elevated breast cancer risk. A study was conducted to evaluate the association between dietary patterns and risk of breast cancer in Spanish women. Researchers recruited 1017 women with incident breast cancer and 1017 matched healthy controls of similar age with no history of breast cancer. They utilized the Alternate Healthy Eating Index and the Alternate Mediterranean Diet score to assess diet adherence. The researchers reported that adherence to the WeD was associated with increased risk (OR high versus low adherence (95% (CI) 1.46 (1.06–2.01)) and that adherence to the MeD was related to lower risk (OR high versus low adherence (95% CI) 0.56 (0.40–0.79)) [n-6 eicosanoids from refined vegetable oils increase the production of pro-inflammatory cytokines.The WeD has been reported to promote inflammation ,12. ExtrThe Mediterranean dietary (MeD) pattern has consistently been considered one of the healthiest dietary patterns because of its inclusion of an abundance of plant-based foods and the lack of processed foods . The MeDp for trend = 0.008). When the researchers excluded the alcohol component from the scoring it did not greatly modify the ORs .Turatui et al. (2018) investigated the association between adherence to the Mediterranean diet and breast cancer risk utilizing hospital-based case-controls, and found that adherence to the MeD was associated with a reduced breast cancer risk . The resp for trend  =  0.032). These researchers also conducted a meta-analyses of their results along with another published cohort study, and reported that hazard ratios for high versus low MeD adherence were 0.94 for total postmenopausal breast cancer, 0.98 for ER+, 0.73 for ER−, and 0.77 for ER − progesterone receptor negative breast cancer [n  =  4152). After a median follow-up of 4.8 years, 35 confirmed incident cases of breast cancer were reported. Observed rates (per 1000 person-years) were 1.1 for the MeD with EVOO group, 1.8 for the MeD with nuts group, and 2.9 for the control group. The multivariable-adjusted hazard ratios compared to the control group were 0.32  for the MeD with EVOO group and 0.59  for the MeD with nuts group.The MeD was reported to reduce the risk of estrogen receptor negative (ER–) breast cancer, although in the same study, a non-significant weak relation with ER positive (ER+) and total breast cancer risk was found. This was a cohort study that followed 62,573 women aged 55–69 in the Netherlands for over 20 years. Adherence to the MeD was assessed by the alternate Mediterranean Diet Score, which excluded alcohol. The analysis was conducted on 2321 incident breast cancer cases and 1665 sub-cohort participants. The researchers found an inverse association between MeD adherence and risk of ER− breast cancer, with a hazard ratio of 0.60  for high MeD adherence versus low MeD adherence  that serve to keep gut contents and antigens separate from the immune cells of the gut-associated lymphoid tissue (GALT) . The exiDendritic cells in the gut lining sample bacterial antigens in the gut by extending processes between tight junctions of gut epithelial cells. The dendritic cells are then able to present the antigens to T cells in the Peyer’s patches . This presentation can induce T cell differentiation toward an immunosuppressive Treg cell phenotype in response to molecular patterns associated with commensal bacteria, or into an inflammatory phenotype in response to pathogenic particles . In thisHelicobacter pylori and human papillomavirus being widely accepted for their tumorigenic roles. However, growing evidence suggests that this estimate is low, and general microbial dysbiosis may also be accountable for tumorigenesis [It is estimated that approximately 15%–20% of carcinogenesis is related to microbial infection, with igenesis . As previgenesis . In eachClostridiaceae, Faecalibacterium, and Ruminococcaceae, and reduction in Dorea and Lachnospiraceae compared to controls [Breast cancer pathogenesis is associated with major gut microbial shifts, and patients were shown to express enrichment in controls . The exiStreptococcus, Staphylococcus, Bifidobacterium, Propionibacterium, and Lactobacillus bacteria and assists in early colonization of the infant gut microbiome [The presence of microbes in the mammary gland was first examined in the milk of lactating mothers . Human bcrobiome ,60. Howecrobiome . The oricrobiome .Sphingomonas yanoikuyae bacterial species. Notably, S. yanoikuyae may contribute to an immunomodulatory response in the breast microenvironment through expression of glycosphingolipid ligands, which activate invariant natural killer T (iNKT) cells [S. yanoikuyae in the mammary gland tissue.A healthy mammary gland microbial population has been associated with enrichment of the T) cells . FurtherIn order for probiotic bacteria to instigate a beneficial response in the mammary gland, microbial response elements must be present on host tissue. Xuan et al. reported enriched expression of microbial sensors , downstream signaling molecules , and antimicrobial response effectors  in healthy breast tissue. Further investigation of these genes may provide evidence for the mechanisms by which the healthy mammary gland microbiome utilizes the host immune system to interact with host tissue .S. yanoikuyae [Breast cancer has been associated with dramatic changes in the mammary microenvironment and microbiome. While normal mammary tissue exhibits enrichment of microbial response element genes, Xuan et al. noted significant reduction in microbial response element expression of breast tumor tissue. This observation was paired with a reduced population of potentially probiotic noikuyae .Staphylococcus in their tumor-adjacent mammary gland tissue compared to women without cancer [Lactobacillus [Further examination of the cancer-associated mammary microbiome utilized tumor samples and healthy control tissue from breast reduction surgeries. Mammary gland samples obtained from women undergoing lumpectomies, mastectomies, or breast reduction surgeries living in Canada or Ireland showed distinct genus taxa differences. See t cancer . In anotbacillus , suggestLactobacillus abundance when compared with mammary tissue from WeD-fed monkeys [Diet is a main determinant of gut microbial diversity; however, the impact of diet on microbiota in organ sites other than the gut are underexplored. In a non-human primate model, our group demonstrated that consumption of a WeD or MeD modulated mammary gland microbiota and metabolite profiles. Consumption of MeD resulted in an approximate 10-fold increase in mammary gland  monkeys . Moreove monkeys .Lactobacillus contains bile salt hydrolase activity that modifies secondary bile acid metabolite generation. These secondary bile acid metabolites can then serve as agonists for farnesoid X receptors [Lactobacillus in the mammary glands of MeD-fed monkeys may then increase mammary-gland-specific bile acid metabolite-mediated activation of farnesoid X receptor signaling for potential anticancer properties. In the clinical setting, postmenopausal women with newly diagnosed breast cancer displayed increased plasma deoxycholate (DCA) when compared with control plasma samples taken from healthy, age-matched, and BMI-matched women [Literature indicates that treatment of MCF-7-estrogen-receptor-positive breast cancer cell line with either chenodeoxycholate (CDCA) or glycochenodeoxycholate (GCDCA) resulted in opposed effects on proliferation; GCDCA increased MCF7 proliferation, while treatment with CDCA reduced proliferation . We spececeptors . The enred women ,72. Preved women . No signed women .Literature demonstrates a clear association between MeD-derived phenolic and phytochemical components and important health benefits . Our stuBifidobacterium in the gut [Bifidobacterium is commonly administered in probiotics and has been associated with an anti-inflammatory response in the gut. These supplements encourage a shift toward homeostasis in the gut microbial environment, in which the maintained balance prevents accumulation of pathogenic bacterial species and encourages an immunosuppressive reaction in the GALT [As evidence for diet-mediated microbial mechanisms in tumorigenesis grows, targeting the gut microbial contents for cancer treatment has garnered interest. Prebiotic and probiotic supplements are common selections for this goal. Prebiotics consist of indigestible food ingredients, often fibers, which are used to specifically stimulate the growth or activity of commensal gut microbiota to benefit gut health . Inulin  the gut . Bifidobthe GALT .Lactobacillus and Bifidobacterium. While the possibility of direct correlation between probiotics and cancer reduction remains under investigation, several cancer risk factors have been successfully abridged by probiotic supplementation. Probiotics are linked to altered glycemic control, contributing to decreased fasting blood glucose and insulin levels [Lactobacillus-based probiotics exhibited a reduction of circulating pro-inflammatory cytokines and successfully maintained remission status [Bifidobacterium infantis, another common probiotic species, was attributed with reduction in both gut mucosal and systemic inflammation [Probiotics directly treat gut dysbiosis by supplementation with live commensal bacterial species, often consisting of n levels . Addition status ,79. Bifiammation . As showammation .Lactobacillus probiotics has been successful in mouse syngeneic 4T1 triple negative breast cancer models. Oral supplementation with Lactobacillus helveticus-fermented milk in this model has resulted in increased cancer cell apoptosis and reduced production of pro-inflammatory cytokines, while treatment with Lactobacillus acidophilus has been associated with tumor growth retardation and reduced systemic inflammation [Lactobacillus casei reduced 4T1 tumor growth, vascularization, invasion, and metastasis [The use of probiotics in the treatment of cancer remains a relatively new idea. However, evidence for the potential success of this method is accumulating. The use of ammation ,83. Milktastasis ,85. ThesClostridium perfringens, Clostridium difficile, and Bacteroides in animal models [Lactobacillus populations, possibly supporting a gut-mammary gland signaling axis or suggesting similar dietary regulation of Lactobacillus in both tissue types. The metabolomics analysis of paired breast tissue indicated MeD-consumption-modified mammary gland bile acid metabolites, microbial-processed bioactive compounds, and antioxidant metabolites that were observed only in the breast tissue and not seen regulated in circulating plasma, supporting the concept of a localized mammary microbiota niche [A third emerging option for targeting the gut microbiome is dietary intervention. In this category, polyphenols, such as those found in grapes, green tea, and pomegranate, are an area of interest. Dietary polyphenols act as antioxidants, and sometimes even as antibiotics. While their structure makes bioavailability through gut absorption limited, microbial hydrolysis of glycosides assists this process . Treatmel models . Ellagicl models . Furtherl models  and mamml models  Lactobacta niche . Taken tEpidemiological data supports the critical impact of dietary pattern on breast cancer risk; WeD consumption elevates breast cancer risk, while consumption of a MeD reduces breast cancer risk. These could be due to several possible key molecular mechanisms; however, we propose that the regulation of the gut and mammary microbiome may be a key influencer on the anticancer role of MeD. Current research detailing population shifts of the gut microbiome suggests a potential mechanism for dietary influence on cancer risk through inflammation. Understanding this mechanism allows for utilization of the gut microbial composition as a target for cancer prevention and treatment. In this way, restoration of balance to the gut microbiome may prove a viable option for reduction of diet-mediated cancer risks and prognosis factors.As the discussion of the gut microbiome in cancer progresses, the focus will likely shift to include the diet-mediated roles of other tissue microbiomes in tumorigenesis. This is of particular interest in breast cancer, as labeled oral probiotics were identified in the breast milk, suggesting that gut bacteria may be able to travel to the mammary gland . Our gro


The aim of the present study was to evaluate the knowledge, attitude, and practice of breast cancer screening methods among female patients attending five primary healthcare centers in Najran, Saudi Arabia. A cross-sectional survey was conducted on 500 female patients, and a direct interview questionnaire was used to collect data. Our results indicated a low knowledge about breast cancer, breast self-examination, mammogram and clinical breast examination was 54.4%, 56%, 90.4%, and 83.8%, respectively. Nineteen percent of patients demonstrated a high knowledge of breast self-examination. Breast self-examination was performed by 35% of patients, whereas 15% of patients received mammograms and 19.8% clinical breast examinations. The most common barrier for screening methods of breast cancer was that patients were unaware of half of the screening methods. A total of 20.6% of women did not perform breast self-examinations because they were not well trained, and 26.4% of women did not receive clinical breast examinations because there was no female doctor available. The main source of information among the women patients was social media (52.4%), whereas 8.8% received information through their healthcare provider. In summary, the majority of women demonstrated poor knowledge about breast cancer and screening methods. Additional effort should be put forth through women’s healthcare providers to increase the awareness of breast cancer screening. That means we need to continue emphasizing the importance of primary healthcare for early detection of breast cancer in the early stages.The online version of this article (10.1007/s13187-018-1423-8) contains supplementary material, which is available to authorized users. Breast cancer is the second most common cancer worldwide, and most frequent among females . The numIn Saudi Arabia, breast cancer usually presents at advanced stages and more frequently in young pre-menopausal age women compared with Western countries . AccordiThe Najran region is located in the south west corner of the Kingdom of Saudi Arabia. It is bordered in the north by Riyadh and Eastern Regions, in the east by the Eastern Region, in the south by Yemen, and in the west by the Aseer Region. The population census reported that Najran city has a population of 331,683 .Many studies were conducted in Saudi Arabia regarding knowledge and practice of breast cancer screening methods. In a study conducted, the Breast Cancer Screening in Saudi Arabia: Free but Almost No Takers, it was found that among 10,735 participants of study 89% of women reported not having a clinical breast exam and 92% reported never having a mammogram . Other sThe awareness of breast cancer plays an important role in early detection and prevention of the disease, and the primary healthcare center is the first basic level of contact between women and families within the health system. Therefore, our study aimed to evaluate the knowledge, attitude, and practice of breast cancer screening methods among female patients attending primary healthcare centers.Our study consisted of a cross-sectional, interviewer-administered, questionnaire-based survey method. The study took place at five primary healthcare centers in Najran City, Saudi Arabia. All female patients who attended and registered at the five primary healthcare centers in Najran city who agreed to participate in the study were included with 100% response rate; no exclusion criteria was performed. The medical condition of participants was stable either antenatal care visit for pregnant women or follow-up of chronic medical disease like diabetes mellitus or hypertension. The study was conducted from September 1, 2017 to December 31, 2017. A total of 500 participants were included, with a margin of error at 5% and a confidence interval of 95%. An ethical approval letter was obtained from the research committee at the College of Medicine, Najran University, before the start of the study.The researcher used a self-administered questionnaire consisting of the following: (1) sociodemographic data, including age, educational level, nationality, medical, and gynecology history; (2) knowledge of breast cancer, mammograms, clinical breast examinations, and breast self-examinations; (3) attitude, practice, and barrier for breast cancer screening; (4) source of information. The pilot study was conducted in 30 patients to evaluate the content of the questionnaire and the average time it took to complete. Then, corrections were made accordingly. These 30 pilot study cases were not included in the main study. Data was obtained by the research team who gave the questionnaire directly to the female patients. Each participant took 5 to 7 min to complete the questionnaire.P value less than or equal to 0.05 was considered to be statistically significant. Any correct answer was given a score of one point; otherwise, a score of zero was given. The discrete scores for the different knowledge domains were summed. Knowledge score was categorized into poor score for those who had a score of less than 50% of the maximum score, moderate knowledge if score was 50 to 75%, and good knowledge if score was above 75% of the maximum score. Descriptive statistics, including frequencies and percent, were used to describe the frequency of each response for the categorical data. Chi-square test/Monte Carlo exact test and Fisher’s exact test were used to test for associations between sample characteristics and knowledge level.Data were collected, revised, coded, and entered into a statistical software program (IBM SPSS version 21). All statistical analysis was performed using two-tailed tests, with an alpha error of 0.05. Five hundred 100%) women that participated in the study completed the interview questionnaire. The demographic and medical characteristics of the participants are shown in Online Resource 00% womenP = 0.001). The second predictor was education level (P = 0.006). In addition, women’s history of benign breast disease was a high predictor of breast cancer knowledge (P = 0.045).We calculated the distributions of predictors for the general knowledge of breast cancer Table . The higP = 0.001). The age of marriage (P = 0.003), age of menarche (P = 0.005), and age of participants (P = 0.012) was a predictor of breast cancer screening knowledge.The distributions of predictors of breast cancer screening methods are shown in Table A total of 35% of women that attended the primary healthcare center performed breast self-examinations; 15% underwent a mammogram. Moreover, 19.8% of women visited their physician for a clinical breast examination. The remaining 30.2% have not had a breast screening method.The barriers to breast cancer screening are shown in Table More than half of women (52.4%) received information about breast cancer and screening methods from social media, whereas 8.8% obtained information from their healthcare providers. A total of 19.8% of women received information from television through health programs, 6.2% from magazines/newspapers, and 13.0% from other sources.Breast cancer is the most common cancer in Saudi Arabia. Over the next 20 years, breast cancer cases are expected to soar four times higher in the Middle East. Breast cancer affects Saudi women at an early age compared with developed countries, imposing socio-economic burdens. Most cases are detected at later stages, leading to lower rates of recovery . The awaThe present study showed that a low percentage of women have not been trained to perform breast self-examinations. In a similar study, only a third of women had performed breast self-examinations , whereasOur findings were similar to previous studies that indicated a low percentage of women have had a mammogram , 14–16. In the present study, the main source of information about breast cancer was from social media, which was similar to a previous study . These fIn the present study, we observed that the majority of women in Najran City demonstrated a poor knowledge of breast cancer and breast cancer screening methods. Additional effort should be put forth through women’s healthcare providers, social media, schools, universities, shopping malls, famous people, and hospitals to increase the awareness of breast cancer screening through the importance of primary healthcare for early detection of breast cancer in the early stages.ESM 1(DOCX 15 kb)


Chronic inflammation may be involved in cancer development and progression. Using 28 inflammatory-related proteins collected from prospective blood samples from two case-control studies nested in the Italian component of the European Prospective Investigation into Cancer and nutrition (n = 261) and in the Northern Sweden Health and Disease Study (n = 402), we tested the hypothesis that an inflammatory score is associated with breast cancer (BC) and Β-cell Non-Hodgkin Lymphoma  onset. We modelled the relationship between this inflammatory score and the two cancers studied: (BC and B-cell NHL) using generalised linear models, and assessed, through adjustments the role of behaviours and lifestyle factors. Analyses were performed by cancer types pooling both populations, and stratified by cohorts, and time to diagnosis. Our results suggested a lower inflammatory score in B-cell NHL cases , and, to lesser, extent with BC  compared to controls, mainly driven by cancer cases diagnosed less than 6 years after enrolment. These associations were not affected by subsequent adjustments for potential intermediate confounders, notably behaviours. Sensitivity analyses indicated that our findings were not affected by the way the inflammatory score was calculated. These observations call for further studies involving larger populations, larger variety of cancer types and repeated measures of larger panel of inflammatory markers. More specifically inflammation is one of the enabling hallmarks of cancer3 and is thought to influence several phases of cancer development including initiation and progression4 through both intrinsic (genetic events) and extrinsic (soluble mediators) pathways5. Epidemiological, pharmacological and genetic research provide solid evidence that inflammation can increase cancer risk and promote tumour progression7. Epidemiological studies have already examined the link between inflammation and risk of some cancers including bladder, oesophageal, ovarian, prostate or thyroid cancer6 but also colorectal cancer8 and others7.Inflammation is a key pathway in many diseases including cancer10, CRP13 and/or immune related factor9 and risk of BC in prospective settings and results were inconsistent15. Several prospective studies have also examined the association between B-cell Non-Hodgkin Lymphoma (B-cell NHL) and circulating levels of inflammatory markers providing strong evidence of a subtle role of inflammation in B cell NHL development and progression26. These studies have suggested an increased risk of B cell NHL and/or its subtypes with increased blood levels of interleukin25, chemokines25, immune activation markers22 and growth factor19. While other studies reported negative association of interleukin with risk of B cell NHL23.While breast cancer (BC) is the most commonly diagnosed cancer among women worldwide, B-cell lymphomas (BCLs) are the most common hematopoietic cancers in both men and women in the developed world. Few epidemiological studies have investigated the association between blood levels of cytokinesThe prevalence of these two cancers and the conflicting results regarding the role of inflammation underline that BC and B-cell NHL are particularly relevant to explore the role of inflammation in cancer initiation.28. In the present work, we investigate inflammatory scores to ascertain their link with cancers onset. We used data from the EnviroGenoMarkers (EGM) project designed as two nested case-control studies including breast cancer (BC) and Β-cell Non-Hodgkin Lymphoma  cases within two cohorts. Specifically, we constructed our inflammatory score using a large panel of cytokines, chemokines and growth factors measured in prospectively collected peripheral blood samples in 268 participants from the Italian component of the European Prospective Investigation into Cancer and Nutrition  and 492 participants from the Northern Sweden Health and Disease Study (NSHDS). Making the most of the EGM dataset, we examined participant’s inflammatory status through the inflammatory score  in relation to cancer onset as a common mechanism in disease initiation and progression. These associations were investigated for each type of cancer (breast cancer and B-cell NHL separately), and after stratification by time-to-diagnosis (TtD).Previous studies generally focus on the concentration levels of individual biomarkers, and since these biomarkers are systemic, associations between individual biomarkers and cancer may not be always apparent. The use of lower resolution summary scores may improve statistical power and reveal associations with cancer riskKey characteristics of the study population are reported in Table The breast cancer population includes a total of 167 women  with a slightly higher proportion of cases in both cohorts after excluding individuals with missing data  as an alternative inflammatory score showed that our conclusions were robust to our definition of the inflammatory score and we identified the same significant association indicating a lower inflammatory score in the BC cases diagnosed less than 6 years after enrolment  indicated a lower inflammatory score compared to controls  and future risk of colorectal, lung and BC during a median follow-up period of 4.8 years in a Danish general population27. To test the robustness of the definition of the inflammatory score, we defined, as an unsupervised alternative, a score using the first principal component obtained from the 28 inflammatory related proteins. Our results and conclusions remained stable with either score.Our study has a number of strengths. First, the prospective design limits both recall and reverse causation bias which can be induced by the disease itself, treatments or lifestyle changes after diagnosis. We also had access to a wide range of information about lifestyle factors and hormonal status which allowed us to adjust for important potential confounders. Additionally, the availability of two cohorts allowed for independent confirmation of the observed signals and comparison of the inflammatory score and cancer association results between two countries. Moreover, compared to most previous prospective studies, we measured and combined into a score a large panel of inflammatory proteins to capture the inflammatory load. We know of two studies which have examined several markers of inflammation both individually and jointly as an inflammatory score and have reported that the use of a score is a robust method to explore the association between inflammatory load and future risk of cancer30, heavy drinking31, physical inactivity32 and body mass index is related to higher chronic inflammation and adverse health outcomes33. In our study, after controlling for behavioural and education, no significant changes were observed in the associations indicating that these variables do not act as confounder in the observed association between inflammation and cancer, suggesting that inflammation may be causally linked to cancer risk.As a general pattern, behavioural factors and education did not seem to explain a substantial part of case-control differences in the inflammatory score. An unhealthy lifestyle, including smokingOur study remains however restricted to a limited set of potential confounders and mediators, hence hampering the generalisability of our conclusion.34. Our results may appear to be contradictory. This may be due to our approach which summarises the association of 28 inflammatory related proteins with disease risk using a score to better capture the inflammatory status and improve statistical power but also attributable to the timing in which blood samples were collected and cancer diagnosed, or to other factors or confounders. Several epidemiological studies have explored the link between circulating marker of adiposity and inflammation in relation to BC risk with the underlying idea that obesity associated inflammation may increase the risk of cancer36. The release of inflammatory mediators may then take place in the adipocytes and might not be apparent at the same level in the circulatory system37. The time from blood collection to cancer diagnosis may change according to studies and influence results. In our results a lower inflammatory score in BC cases compared to controls was only observed in those diagnosed less than 6 years after enrolment. Early BC cases may present inflammatory differences compared to those developing BC cancer later or may be already in a pre-disease stage caracterized by a lower inflammatory score suggesting that inflammatory status differs according to BC cancer evolution time.A vast majority of the studies looking at the association between inflammation and BC risk used the CRP and a recent meta-analysis concludes a modest statistically significant positive association between CRP concentration and breast cancer risk38. In a previous study in a subset of EPIC-Italy’s population, the authors reported association between lower levels of IL-2, INF-y and upper levels of ICAM and risk of NHL18. In another study, it has been shown that lower levels of leptin was associated with increased risk of NHL and upper levels of IL-10 increase risk of B-NHL; they also found no association between a composite score from a principal component and future risk of NHL20. A case control study in the PLCO trial reported an increased risk of NHL with elevated serum levels of TNF-R1 and sCD2717. Our results demonstrate that future cases of NHL had a lower inflammatory score compared to controls. This provides further support for the subtle status of deregulated immune response or failure to modulate the immune response appropriately in relation to NHL risk. It is also established that NHL is one of the most common malignancies occurring after immunosuppressive therapy use due to transplantation40.Numerous studies have investigated the association between pre-diagnostic inflammation and NHL using cytokines, chemokines and other immune markers independently. These studies showed a deregulation of these biomarkers with future risk of NHL suggesting subclinical dysfunction as a consistent risk factorInflammation has multifaceted role in cancer including initiation, promotion and progression. Deregulation of biological processes can lead towards chronic inflammation or play in immunosuppressive roles. Our results from a case-control study nested within 2 Europeans cohorts focusing on 2 specific cancers (BC and B-cell NHL) suggest an association between the presence of cancer and a lower inflammatory score and support the complex role of chronic inflammation in cancer development. The use of the PC1 aimed to measure the inflammation variability captured by the 28 proteins. These findings call for further studies to better understand how inflammatory changes evolve involving larger populations, larger variety of cancer types and repeated measures of larger panels of inflammatory markers.www.envirogenomarkers.net) was designed as two nested case-control studies and includes participants from the Italian component of the European Prospective Investigation into Cancer and nutrition41  and the Northern Sweden Health and Disease Study42 (NSHDS), which have been described previously44. The Envirogenomarkers project and its associated studies, experimental protocols and methods were approved by the Regional Ethical Review Board of the Umeå Division of Medical Research, for the Swedish cohort, and the Florence Health Unit Local Ethical Committee, for the Italian cohort. All methods were carried out in accordance with the approved guidelines.The Envirogenomarkers study . Standardized procedures were used to identify newly diagnosed cases of cancer based on automated linkages to cancer and mortality registries, municipal population offices and hospital discharge systems. In Naples follow-up information was collected through periodic personal contact. All participants signed a written informed consent and the ethical review boards of the International Agency for Research on Cancer, and of the collaborating institutions responsible for subject recruitment in each of the EPIC recruitment centers approved the study.NSHDS is a prospective cohort study that included 95,000 participants from the general population from 1990 up to January 2008. It includes three sub-cohorts, of which the largest is the Västerbotten Intervention Programme (VIP) that mainly recruits individuals aged 40, 50 or 60 years. At initial recruitment, subjects were asked to complete a self-administered questionnaire to collect demographic, medical and lifestyle information and a separate self-administered food frequency questionnaire. Informed consent was obtained from all participants and a medical examination was conducted during which a blood sample was taken. Incident cancers occurring during follow-up were identified by linkage with the Swedish Cancer Registry and the local Northern Sweden Cancer Registry. NSHDS study was approved by the Local Ethical Committee in Umeå, Sweden. The sample selection strategy is described in Supplementary Fig. Our study population includes breast cancer (BC) and B-cell non-Hodgkin lymphoma (B-cell NHL) cases who were healthy at blood collection and were clinically diagnosed from 2 (minimum chosen duration to avoid the inclusion of cancer cases at enrolment) to 15.5 years after inclusion. Only invasive breast cancer cases were included in the study. All eligible B-cell NHL cases, including multiple myeloma were included. For each case, one suitable control was selected among participants in each cohort who were alive and free of cancer and were matched by center, gender, date of blood collection (+/−6 months), and age at recruitment (+/−2.5 years). We considered all B-cell NHL subtype together and in the text B-cell NHL includes multiple myeloma.45. Four analytes were excluded from further statistical analyses due to high rates of non-detection (>75%). Finally, 12 cytokines, 10 chemokines and 6 growth and angiogenic factors were measured for all participants  including a random intercept depending on technical covariates (microtiter plate). In a second step, we subtracted from the measured protein levels the random effect estimates measuring the variation linked to technical covariates to obtain denoised data 48.For each participant, a blood sample was collected at enrolment and stored in citrate  or EDTA (Sweden). Within two hours, plasma was separated and placed in cold storage. Biosamples underwent inflammatory profiling in two distinct phases and 32 of inflammation-related proteins were measured using the milliplex HCYTOMAG-60K and HSCYTMAG-60SK kits , according to the manufacturer’s protocol48, and under the working hypothesis of a consistent contribution of each inflammatory marker to the overall inflammatory burden, we summarized the individual inflammatory status as a score derived from the 28 proteins assayed: for each protein, we defined a dichotomized indicator: “high concentration” = 1, and “low concentration” = 0 based on the highest quartile of the denoised protein concentrations, and summed across the 28 proteins these binary indicators48. Principal component analysis (PCA) is a mathematical algorithm that reduces the dimensionality of the data while retaining most of the variation in the data set49. PCA of these 28 inflammatory markers concentrations shows that 19 PCs explained more than 90% of the total variation seen in the dataset .Our inflammatory score and its continuous alternative (PC1) were regressed against the disease outcome  on the pooled population. We used the same model adjusting for potential confounders collected at enrolment for each type of cancer: age, gender, phase, cohort and center (Model 1). Potential confounders included behavioural factors: body mass index ; smoking status ; alcohol consumption ; physical activity ; and education  as a proxy for socioeconomic status. Based on model 1, we controlled separately for behavioural factors (hereafter referred to as model 1 + behaviours) and for participant’s educational level (hereafter referred to as model 1 + socioeconomic position). The fully adjusted model included behavioural and socioeconomic factors listed above and was additionally adjusted for the reproductive/hormonal variables for BC analyses only. The latter comprised menopausal status ; contraceptive usage ; age at menarche (binary: ≤12 years old or >12 years old); menopausal hormone use  and parity .We fitted our models on data for each cohort separately . To evaluate the impact of follow-up time and consider a potential effect of the preclinical phase of the disease, analyses were also stratified on the time to diagnosis as defined by the time elapsed between blood collection and clinical diagnosis: below or above the median time to diagnosis (6 years) across the entire population of cancer cases. We used the same time to diagnosis cut-off (below or above 6 years) for each type of cancer since the median time to diagnosis vary little across cancer type (5.84 years in BC and 6.09 years in B-cell NHL). In these analyses, cases were compared to all controls to preserve statistical power. Analyses were also performed by BC and B-cell NHL histological subtypes.50 using the RStudio environment v.0.99.484. All p-values with p < 0.05 were considered statistically significant.Statistical analyses were performed in R v3.2The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.Supplementary Information


Incidence of breast cancer in the Kingdom of Saudi Arabia (KSA) has increased in recent years. Screening helps in early detection of cancer and early diagnosis and timely treatment of breast cancer lead to a better prognosis. Women in the healthcare profession can have a positive impact on the attitudes, beliefs, and practices of general public. Therefore, it is important that the healthcare workers themselves have adequate knowledge and positive attitudes. We conducted a study to assess the knowledge, attitudes, and practices related to breast cancer screening among female healthcare professionals.A cross-sectional study was conducted on female health professional of KFMC . Data was collected using a pre-designed, tested, self-administered questionnaire. The questionnaire included specific sections to test the participants’ knowledge, attitude, and practices related to cervical cancer and its screening. Data analysis was done using descriptive statistics.n = 63, 16.0%), nurses , and allied health workers . Only 6 (1.5%) participants had a good level of knowledge of breast cancer and 104 (26.8%) participants demonstrated a fair level of knowledge. Overall, 370 (93.7%), 339 (85.8%), and 368 (93.2%) participants had heard of breast self-examination, clinical breast examination, and mammography, respectively. A total of 295 (74.7%) participants reported practicing breast self-examination, 95 (24.1%) had undergone clinical breast examination, and 74 (18.7%) had ever undergone mammography.A total of 395 health care workers participated in this study. The mean age of the participants was 34.7 years. Participants included physicians (The knowledge, attitudes, and practices related to breast cancer screening were found to be lower than expected. Active steps are required to develop educational programs for the health care staff, which might empower them to spread the knowledge and positively influence the attitudes of female patients in the hospital. Breast cancer is the most common cancer among women worldwide . In 2018Although there has been immense progress in the treatment of breast cancer, prognosis remains poor in developing countries including KSA . An impoBreast cancers in women from Arab populations have different characteristics and affected patients are at least a decade younger. Hence, the of Ministry of health in KSA guidelines in contrast to international guidelines recommend the use of screening strategies with mammography for the detection of breast cancer in women aged 40–49 years every 1 to 2 years. The indication that higher benefit on breast cancer mortality justifies a recommendation in favor of implementing breast cancer screening using mammography in this age group in this population.Based on local cancer registry data, the incidence of breast cancer in the KSA for the age group 50–69 years is similar to the ones reported in the literature in other countries. Hence the Ministry suggests screening with mammography in women aged 50–69 years every 2 years and no screening with mammography for women aged 70–74 years, however a nationalized large scale screening program is yet to take off .In KSA despite the healthcare facilities being free of cost, utilization of breast cancer screening methods, including mammography, is very low with one study reporting that out of women 50 years or older, 89% of them reported not having a clinical breast examination (CBE) and 92% of women reported never having a mammogram in the past year .For effective screening and early diagnosis, adequate knowledge and awareness are of utmost importance. Women healthcare workers can bring about a significant change in the overall perspective of their female patients, regarding screening practices and positively influence their attitudes and beliefs . They arSeveral studies have been conducted in other developing countries to assess the knowledge and practices of breast cancer screening both in the general population as well as specifically in healthcare professionals –18. In KA cross-sectional study was conducted on female healthcare workers  in 2018, including physicians, nurses, and allied health staff, at King Fahad Medical City (KFMC), Riyadh, Saudi Arabia.Data were collected using a pre-designed, pre-tested, and self-administered questionnaire. The questionnaire was developed from previous studies after an in depth literature review , 20–22. After an extensive literature search, the various survey questions were formulated and the questionnaire was divided into several sections. Some of the question were modified or deleted as per the recommendations of the expert committee since they were either off topic or not suitable for health care workers. The questionnaire included different parts.First part elicited socio-demographic data on age, clinical experience, education, designation, department, marital status, age at marriage, number of pregnancies, number of children, history of breast cancer, and family history of breast cancer of each study participant.Questions relating to knowledge of breast cancer were included in the second part. These questions were included under three categories: potential risk factors, signs and symptoms, and ways of screening/diagnosis of breast cancer including BSE, CBE, and mammography.The respondents were requested to record their answers by choosing one of the three options: ‘Yes’, ‘No’, or ‘Don’t Know’. The scale was then dichotomized (Yes = 1 and No/Don’t Know = 0) and the total knowledge score for each participant was computed by adding up (maximum score of 30). The total score was then categorized as poor knowledge (score of 0–4), fair knowledge (score of 5–14), and good knowledge (score of 15–30).Participants’ attitude regarding breast cancer was assessed in the third part by asking them to rate 10 specific statements on a 5-point Likert scale. Following 10 statements were included in the questionnaire: 1) Any woman is at risk for breast cancer; 2) Breast cancer can be prevented; 3) If I examine my breast myself, I cannot detect abnormalities in my breast; 4) There is no reason to examine my breasts; 5) If I knew the benefit of breast self-examination, I would have done it by now; 6) Women prefer female doctor for breast examination; 7) If there is no problem in the breasts, periodic breast examinations by a physician are not required; 8) Early detection methods have no effect on treatment; 9) Personal hygiene decreases breast cancer risk; 10) By early diagnosis of breast cancer, the person will have prolonged life. Participants were asked to choose one of the following options for each of the statements above: ‘strongly agree’, ‘agree’, ‘neither agree nor disagree’, ‘disagree’, or ‘strongly disagree’. For presenting results, ‘strongly agree’ and ‘agree’ were combined; similarly, ‘disagree’ and ‘strongly disagree’ were combined.Participants’ practices were assessed through the last section asking specific questions about BSE, CBE, and mammography. Participants were asked whether they had heard of BSE, CBE, and mammography and whether they believed these tests were useful for early detection of breast cancer. Other questions under BSE enquired whether they had been taught BSE, whether they practice BSE, what age should BSE be done, how frequently should BSE be done, what is the best time to do BSE, what action must be taken when any abnormality is found in BSE, and what, according to them, are the benefits of BSE. Similarly, questions under CBE sought information on whether they had undergone CBE, how CBE is done , and how often should CBE be done. Questions on mammography tested the participants’ knowledge on what age mammography should be started, how often should it be done, and whether they had undergone mammography.An informed consent was obtained from each participant before enrolment and no compensation or incentive was paid to the participants for this study. The study was approved by the ethics committee at KFMC.The study population was stratified according to their professions into three groups: physicians, nurses, and allied healthcare workers. To ensure appropriate representation from each group of healthcare professionals, the proportionate population sampling method in the form of 4:1:1 for nurses, physicians, and allied healthcare workers, respectively, was adopted. Hence, 260 nurses (out of 2400), 65 physicians (out of 600) and 65 allied health care workers (out of 700) were approached on a random basis from each department and the total sample size was determined to be 390.The statistical package for social science (IBM SPSS statistics 22. Ink) was used for data analysis. Descriptive statistics  were used to describe the demographic characteristics, knowledge, attitude, and practice of breast cancer screening.n = 239, 60.5%). Respondents included 261 (66.1%) nurses, 63 (16.0%) physicians, and 71 (18.0%) other healthcare workers including pharmacists, dieticians, technicians, health educators, physiotherapists, and therapists. Majority of the participants were bachelor’s degree holders  and 52 (13.2%) had a postgraduate qualification. Average work experience was 10 [A total of 420 questionnaires were distributed to the KFMC female employees of which 395 (94%) were returned and included in the analysis. The mean age (SD) of the participants was 34.7 (8.3) years. Majority of the participants were married n = 239, 0.5%. Resrses, 63 .0% physiThe knowledge score achieved in this study is very low; the median score of (range) = 10–5). When ranked in order, the 75th percentile is =5 . Therefore, in this study, we considered a score of . When ra as fair For other risk factors listed in the questionnaire, less than 14% responded ‘Yes’. Under the section of signs and symptoms of breast cancer, 49 (12.4%) participants agreed that scaling/dry skin in the nipple region could be a sign of breast cancer and 40 (10.1%) participants knew that weight loss could also be a sign of breast cancer. Less than 10% of the participants responded ‘Yes’ to rest of the signs/symptoms. Similarly, a lower rate (< 10%) was observed for the methods of diagnosis of breast cancer. The median (IQR) total score of knowledge about breast cancer was 1 (0–5), and only 5 (1.3%) participants appeared to have good level of knowledge (score: 15–30), while 104 (26.3%) scored fair level knowledge (score:5–14).p = 0.113). When compared, there was no statistically significant difference of proportions of the fair (score: 5–14) knowledge among female physicians working under different specialties at KFMC (p = 0.183).Slightly higher proportion of the fair (score: 5–14) knowledge was achieved by other allied health workers 27 (38.6%) comparing to 13 (21.7%) by the physician, and 64 (24.6%) by the nurses, however, this was not significant statistically  participants had heard about mammography. A total of 287 (72.7%) participants agreed that mammography should be started at 40 years of age and 183 (46.3%) participants believed that mammography should be done every year. Seventy-four (18.7%) participants had undergone mammography  participants responded that they were not old enough and 75 (24.0%) didn’t believe there was any reason to undergo mammography.Knowledge and awareness play a vital role in early detection and optimal treatment of breast cancer. The knowledge level of healthcare professionals and their attitudes towards screening methods for breast cancer are important determinants of the practice of these methods by their patients. This study was, therefore, conducted to evaluate the knowledge, attitudes, and practices of breast cancer screening in the female healthcare workers at KFMC. Our cohort demonstrated especially poor knowledge on risk factors, signs and symptoms, and methods of diagnosis. The knowledge related to breast cancer in our cohort appears to be lesser than that found in some other studies –22. Our With regard to BSE, the results appeared positive with most participants being aware of the importance of BSE. Their knowledge related to BSE was also satisfactory. Also, almost 75% of the participants reported practicing BSE. This is much higher than the rate for BSE seen in some other studies , 20, 23.As regards to the practice of screening methods, results from studies conducted in other developing countries have not been very encouraging either. An important barrier in other countries is financial constraints , 18, 28.N = 816) was conducted by Abdel-Aziz et al. in the Al Hassa region of KSA to evaluate the perceived barriers for breast cancer screening. They found personal fears such as fear of physicians, fear of results, and fear of hospitals as the main barriers for not practicing screening for breast cancer [Also, reservations that women may have about screening also need to be addressed. Recently, a study (t cancer . Being hN = 500) conducted in five primary healthcare centers in Najran, Saudi Arabia, 57% of the study participants were unaware of mammogram and BSE and 44% were unaware of CBE [In a study (e of CBE . Thus, le of CBE . Interese of CBE .One limitation of our study is that it was conducted at one center. Nevertheless, this study provides important insights on the current knowledge and practices of screening methods in female healthcare workers and emphasizes the need for educational programs for the healthcare staff at KFMC. The results also urge other hospitals in the KSA to conduct similar studies to evaluate gaps in the knowledge, attitudes, and practices in their staff. Moreover, we recommend further studies to validate the questionnaire through analysis as the questionnaire was compiled after in-depth review of several articles in the field of study and more extensive studies to be conducted to draw comparison between the differences in health care and non health care workers knowledge and attitude towards screening and practices.Overall, the knowledge, attitudes, and practices of the staff related to breast cancer at KFMC were found to be lower than expected. However, the study population had fairly good awareness of the availability and the usefulness of the screening methods. The results from this study, conducted on women healthcare professionals at KFMC, highlight the need for well-planned and comprehensive educational programs for the hospital staff.Although, the screening tools and resources are available and free of charge in KSA however there is lack of active educational programs and campaigns directed at healthcare workers. Hence, inadequate knowledge about methods of breast cancer screening and their benefits among them could be the reason for lower than expected results of the study. In addition, a nationalized education and screening program in the region, combined with considerations for social and cultural factors needs to be functional.


BRCA1 and BRCA2, for the purpose of identifying high-risk individuals who would benefit from earlier screening and more sensitive methods such as magnetic resonance imaging. We also consider risk-based screening in the general population, including whether every woman should be genetically tested for high-risk genes and the potential use of polygenic risk scores. In addition to enabling early detection, the results of genetic screens of breast cancer susceptibility genes can be utilized to guide decision-making about when to elect prophylactic surgeries that reduce cancer risk and the choice of therapeutic options. Variants of uncertain significance, especially missense variants, are being identified during panel testing for hereditary breast and ovarian cancer. A finding of a variant of uncertain significance does not provide a basis for increased cancer surveillance or prophylactic procedures. Given that variant classification is often challenging, we also consider the role of multifactorial statistical analyses by large consortia and functional tests for this purpose.Breast cancer screening modalities and guidelines continue to evolve and are increasingly based on risk factors, including genetic risk and a personal or family history of cancer. Here, we review genetic testing of high-penetrance hereditary breast and ovarian cancer genes, including  In the United States, approximately 1 in 8 women will develop breast cancer in their lifetime, and approximately 40,000 women and 460 men die of breast cancer each year ,3,4,5. IBreast cancer screening includes mammography, a low-dose X-ray of the breast, and for individuals at high-risk, breast magnetic resonance imaging (MRI). There is clear evidence that screening mammography decreases mortality due to breast cancer in women between the ages of 50 and 69 with an estimated risk reduction of mortality of 25–31% . Harms rWhile DNA damage induced by X-rays could potentially increase the risk of subsequently developing cancer , mammogrMammography works by using low dose X-rays to identify abnormalities in, and changes to, the breast. Mammograms can detect calcifications, which are small build-ups of calcium, and masses that can be tumors. Calcifications are typically classified as microcalcifications which can be associated with tumors and macrocalcifications which are not usually cancer-related . Cysts, In 1993, a system for reporting mammographic, ultrasound and MRI results, the Breast Imaging Reporting and Data System (BI-RADS), was first developed to increase standardization across providers for identification of suspicious lesions ; the mosCurrent recommended breast cancer screening guidelines vary slightly between agencies ,29. The Screening guidelines change for women with a lifetime risk of breast cancer of 20% or higher. For these high-risk women, an annual breast MRI and mammogram are recommended beginning at age 30 . MRI is BRCA1 or BRCA2 pathogenic variant (PV). Many prediction models have been developed to identify individuals at a greater than population risk of developing breast cancer. Models combine many factors such as family history, hormonal and reproductive history, and other personal and environmental contributors to address one or both focuses  and 69% (95% CI 61–77%) by age 80 [PALB2, another high-risk gene, the estimated risk of breast cancer by age 70 is 35% (95% CI 26–46%) [The lifetime risk of breast cancer varies between genes. Current breast cancer risks for carriers of y age 80 . For PAL 26–46%) . PVs in  26–46%) . The lar 26–46%) ,105. BRCA1, some moderately penetrant variants have been identified, including p.Arg1699Gln (c.5096G>A), which has risk of breast cancer to age 70 of about 20% [ATM, one missense mutation, p.Val2424Gly (c.7271T>G) confers a higher risk of breast cancer than truncating ATM variants  and may do so by acting as a dominant negative [Even within a gene, distinct PVs can confer different risks. In bout 20% ,107. In negative ,109,110.BRCA PV, current NCCN recommendations are to receive a clinical breast exam every 6–12 months starting at age 25, an annual breast MRI with contrast beginning at age 25, and an annual breast MRI with contrast and mammogram at ages 30–75. As the lifetime risk of breast cancer is high, many women with PVs in BRCA1 or BRCA2 undergo risk-reducing mastectomy, which reduces the risk of breast cancer by 90–95% [TP53 PVs are similar to the BRCA genes, except that annual clinical breast exams and MRIs begin at age 20 instead of 25 years. For PALB2, CDH1 and NF1, the NCCN recommends an annual mammogram screen and annual MRI beginning at age 30 unless the age of cancer diagnosis within a family is earlier. For moderate risk genes with lifetime risk estimates of 20% or more, the NCCN recommends annual screening mammogram and annual MRI beginning at age 40 unless family history suggests beginning earlier.Breast cancer screening guidelines by the National Comprehensive Cancer Network (NCCN) differ according to the gene in which a woman has a PV. For women with a y 90–95% . Breast BRCA1 PVs and 7% for BRCA2 PVs [BRCA PV carriers, recommendations include monthly breast self-examinations with semi-annual clinical breast exams beginning at age 35 [As male breast cancer is quite rare in the general population, there are no breast cancer screening recommendations for men. However, for men who inherit a PV in a high-risk breast cancer gene, the risk of breast cancer is substantially elevated, with lifetime estimates of 4% for RCA2 PVs . For malt age 35 .An important aspect of genetic testing is that the results can impact multiple individuals beyond the person being tested. Because pathogenic variants can be inherited, one of the touted benefits of identification of an HBOC PV is that unaffected family members can also be tested for the PV and, if positive, can undergo risk-reducing surgeries and/or more intensive screening/surveillance. However, in practice, cascade testing (testing of relatives for known PVs) has not been as successful as anticipated. One of the difficulties is that the genetic counselor or physician providing results to a patient is not typically the care provider of other family members and, as such, cannot reach out directly to family members. Other barriers to cascade testing include family culture and communication, the impetus for the proband to contact family members and explain the genetic information, and interest/willingness of family members to test . In one BRCA1 and BRCA2, as well as other high-risk cancer genes [BRCA PV status has been shown to improve health outcomes. For example, all-cause mortality is estimated to be 60% lower in individuals who carry a BRCA PV and follow NCCN recommendations  [With the advent of next-generation sequencing-based panels and clinical exome and genome analyses, the ability to screen tens to thousands of genes for PVs is feasible. As costs have come down and the benefits of knowing one’s PV status are clear, there have been calls for population-based screening for er genes . Knowledrgeries) ,117. Desrgeries) . About 9BRCA1 and BRCA2 has been carried out in Ashkenazi Jewish individuals, in the United Kingdom, Israel and Canada, and has been shown to be feasible and affordable [BRCA1 and BRCA2 in the Ashkenazi Jewish population makes sense given that there are three major PVs found in that population  and they occur in 2-2.5% of unselected individuals [BRCA were reported from the MyCode Community Health Initiative research study in which unselected individuals in the Geisinger Health System underwent exome analyses [BRCA PV variant. Of these, three individuals were found to carry an early-stage cancer that was treatable. These data suggest that population-based screening has the potential to save lives and may be feasible within a healthcare system. From a financial perspective, screening everyone for HBOC high- and moderate-risk genes via genetic testing, versus using a family and personal history-based criteria for testing, has been estimated to be cost-effective. In one study, quality-adjusted life years and breast cancer prevention, respectively, were estimated at ~$54,770 and 2396 breast cancers per million women screened, when a panel of genes was included [BRCA PV should be tested, and then only after genetic counseling [Population-based screening for fordable ,120,121.ividuals ,123,124.analyses . Fifty-fincluded . Howeverunseling . StudiesBRCA1 and BRCA2 testing to all women diagnosed with ovarian cancer identified through pathology or tumor registries, along with follow-up testing and counseling of family members [One potential strategy that lies between full population-based testing, and testing individuals that have a strong family history or early-age of cancer diagnosis, is to offer HBOC testing to all individuals with a diagnosis of breast or ovarian cancer. One such initiative, Traceback Testing, which is funded by the National Cancer Institute, recommends offering at least  members . This apATM and CHEK2 [With the advent of genome-wide association studies (GWAS), sparked by the completion of the Human Genome Project in 2003, came the technological capability and funding to uncover thousands of genetic variants, mainly single nucleotide variants (SNVs), also known as single nucleotide polymorphisms, that correlated with disease predisposition in humans . These vnd CHEK2 . Women iBRCA1 and BRCA2 PV carriers, and PRS scores within this population have been able to better stratify risk [BRCA1 or BRCA2 PV carriers by Kuchenbaecker et al. (2017) [BRCA1 PV carriers, the PRS model that predicted ER-negative breast cancers was more predictive than the overall breast cancer model that was more predictive in BRCA2 PV carriers. Overall, however, they concluded that incorporating PRS and other clinical risk factors, like family history, into a PV carrier’s risk may lead to better care and decision making due to further refinement of breast cancer risk estimates [BRCA1 or BRCA2 PVs, as Lecarpentier et al. (2017) found that polygenic risk score models created for breast cancer were also indicative of breast cancer risk in men with BRCA1 or BRCA2 PVs [BRCA1 or BRCA2 PVs [As breast cancer risk is neither genetic alone nor due exclusively to environmental, reproductive or other lifestyle factors, creating predictive models that combine the multitude of non-genetic risk factors along with polygenic risk scores is of critical importance. Several groups have begun to assess this . One stuify risk ,132,133.stimates . This waRCA2 PVs . They alRCA2 PVs .Clinical trials have started to evaluate the utility of PRS for breast cancer screening decision-making. In 2016, the WISDOM trial (Women Informed to Screen Depending on Measures of Risk)—a randomized controlled trial with the goal of evaluating annual mammographic screening versus personalized, risk-based screening with respect to the number of late-stage cancers detected, was started. The study has a target goal of 100,000 women, who will be stratified into different screening schedules  ,136. TheMultiple companies have begun to offer PRS on their breast cancer panels or as a stand-alone test. Myriad Genetics offers a breast cancer risk prediction tool in their commercially available myRisk® Hereditary Cancer test , which pBRCA1 and BRCA2 have key domains near their C-termini, nearly all nonsense or frameshift mutations that lead to protein truncations are classified as deleterious [As discussed above, variants identified in genetic screens that cannot be classified as benign, likely benign, likely pathogenic or pathogenic are designated VUS . Since beterious . Varianteterious . In contBRCA1 and BRCA2, respectively, listed in ClinVar, both within and outside exons/introns. Importantly, 37% (~2600) and 46% (~4600) of the BRCA1 and BRCA2 germline variants, respectively, listed in ClinVar are VUS. This is most certainly an underestimate of the number of VUS presently identified, since findings may be reported to databases other than ClinVar or may not be reported at all. The fact that >97% and 99% of the VUS listed in ClinVar that affect the coding sequence of BRCA1 and BRCA2, respectively, are missense, underscores the challenges of classifying this category of variants.Novel variants in breast cancer susceptibility genes, many of which are VUS, are frequently identified in genetic screens. As an example, at present, there are approximately 7100 and 9900 distinct germline variants in BRCA1 and BRCA2 VUS identified in genetic screens do not inform such decisions. The result is that many women who would benefit may not receive the breast cancer screening they need. Thus, risk-stratified breast cancer screening can be enhanced by better classification of variants identified in BRCA1, BRCA2, and other breast cancer genes.It should be noted that findings of VUS limit the power of genetic screens to guide decision making about when to increase breast cancer screening. Although family and personal history are also utilized as part of decisions of when to recommend elevated cancer surveillance, BRCA2. One promising alternative for classifying VUS are functional tests, based upon expression of a protein which contains the variant in cells with a deficiency for the particular gene. Given the known functions of BRCA1 and BRCA2, such functional tests may be related to homology-directed DNA repair (HDR), cellular resistance to DNA damaging agents, or cellular survival/proliferation in the absence of exogenous DNA damage ,142. SinBRCA1 and BRCA2 [At present functional characterization cannot stand alone to determine the pathogenicity of variants in genes such as nd BRCA2 . The Evind BRCA2 . Membersnd BRCA2 ,156,157.BRCA1, BRCA2 and other breast cancer genes. Cascade genetic testing of unaffected family members can identify individuals that may benefit from heightened surveillance for breast cancer, but uptake needs to be improved. While the identification of VUS in genetic screens is prevalent and limits the ability of these screens to guide recommendations for breast cancer screening, extensive efforts are underway to increase the number of variants that are being classified. Notably, in the future, population screens of all women for HBOC high- and moderate risk genes could lead to increased breast cancer surveillance in women that would benefit from this [Here, we have reviewed how genetic testing can be employed to guide risk-stratified breast cancer screens. While earlier detection has reduced the mortality rate for breast cancer , there arom this ,124. Fin


P’s for trend ≤ 0.02). In conclusion, T2DM is associated with an increased risk of new-onset cancer in China, particularly cancers of the liver, pancreas, and female breast.Using data from the China Kadoorie Biobank Study, we conducted a prospective investigation on the association between type 2 diabetes mellitus (T2DM) and cancer risk in Chinese adults. A total of 508,892 participants  years) without prior cancer diagnosis at baseline (2004–2008) were included. We documented 17,463 incident cancer cases during follow-up through December 31, 2013. Participants with T2DM had increased risks of total and certain site-specific cancers; hazard ratios were 1.13 : 1.07, 1.19) for total cancer, 1.51  for liver cancer, 1.86  for pancreatic cancer, and 1.21  for female breast cancer. The associations were largely consistent when physician-diagnosed and screen-detected T2DM were analyzed separately, except for colorectal cancer , and for screen-detected T2DM, HR = 1.44 ). In participants without a prior diagnosis of T2DM, higher random blood glucose levels were positively associated with risks of total cancer, liver cancer, and female breast cancer (all  Diabetes and cancer are major public health threats in China. In a recent national survey, Wang et al.  reportedThe link between diabetes and different cancers has been studied extensively in different populations –7. In a Meanwhile, no consensus has been reached regarding the association between diabetes and cancer risk in the Chinese population. In a recent pooled-analysis of 19 Asian cohort studies (including 7 in Chinese populations), Chen et al.  reportedTherefore, we comprehensively examined the associations between baseline T2DM and risk of incident cancer in the Chinese population using the CKB data. The association between baseline random blood glucose (RBG) concentration and cancer risk was also assessed among participants without a prior T2DM diagnosis. We assessed such associations for all cancers combined and for major site-specific cancers.Details on the CKB Study design, methods, and procedures have been provided elsewhere , 13. BriTrained staff interviewed participants at baseline using a standardized electronic questionnaire requesting information on demographic and socioeconomic characteristics, lifestyle and behaviors , general health (such as disease history and current medication use), family history of disease (such as diabetes and cancer), mental disorders, and reproductive history (for women). Physical activity was estimated in terms of metabolic equivalent of task hours per day spent on work, transportation, housework, and nonsedentary recreation. Study staff took anthropometric measurements, such as weight and height, and basic physical measurements, such as blood pressure, using calibrated instruments according to standardized protocols. Ten-milliliter nonfasting venous blood samples (with a record of the time since the participant last ate) were collected from participants using ethylenediaminetetraacetic acid Vacutainers . Blood spot tests for measurement of blood glucose level were conducted on-site using a SureStep Plus meter  that was regularly calibrated with the manufacturer’s quality control solution. Participants who did not report physician-diagnosed diabetes but had an RBG level of 7.8–11.0 mmol/L were invited to undergo a fasting glucose test the next day at the project site. Prior physician-diagnosed diabetes was defined by a “yes” answer to the question, “Has a physician ever told you that you had diabetes?”. For reported diabetes, persons diagnosed at an age below 30 years and being treated with insulin at baseline enrollment were excluded as probable cases of type 1 diabetes . Screen-International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10), by trained staff blinded to baseline information. Morbidity information was collected through linkage with established disease registries for major diseases, such as cancer and diabetes, and the national health insurance system, which records the ICD-10 codes of hospitalizations.Study participants were followed up for morbidity and mortality information, mainly through existing disease monitoring systems . MortaliPrimary outcomes for the current study were total incident cancers (ICD-10 codes C00–C97), as well as site-specific cancers according to ICD-10 codes. Since there were few incident cases (<50) of some rare types of cancer among participants with T2DM, we focused on several major cancer types, including cancers of the esophagus, stomach, colon and rectum, liver, pancreas, lung, and female breast, which were also the most prevalent cancers in China (2) and 44 women without data on menopausal status. Thirty-five participants were excluded because they were judged highly likely to be type 1 diabetes cases. Finally, a total of 508,892 persons ) were included for the main analyses.We excluded 2,578 participants with a baseline history of physician-diagnosed cancer and 1,340 participants without information on parental history of cancer. In addition, we excluded 2 participants without data on body mass index (weight (kg)/height (m)Person-years were calculated as duration of time from baseline enrollment to the onset of cancer, death, loss to follow-up, or December 31, 2013, whichever came first. Cox proportional hazards regression models were used to analyze associations and generate hazard ratios and 95% confidence intervals. The proportional hazards assumption was tested by dividing the follow-up period into 3 intervals that held similar numbers of incident cancer cases and comparing effect sizes of T2DM for risk of incident cancer; no evidence of departure from the assumption was found. Incidence rates of cancers were estimated through direct standardization by sex, age , and study area, with the total study population as the standard.2 tests for trend or heterogeneity were applied to the log hazard ratios and their standard errors , and study area in the first model, and additionally controlled for educational level, parental history of cancer, and 4 modifiable risk factors  in the second model. Menopausal status was included for association analyses for female breast cancer. Data on all variables were taken from the baseline surveys. Adjusted hazard ratios were also calculated across strata of other risk factors , and χd errors , 15.Moreover, we conducted separate analyses for physician-diagnosed T2DM and screen-detected T2DM, with a common reference group of participants without T2DM. We also conducted sensitivity analyses by 1) excluding participants who had cancer diagnosed, died, or were lost to follow-up within the first 3 years of follow-up; 2) treating T2DM as a time-varying variable during follow-up ; 3) excluding persons with major prior noncancer diseases ; and 4) additionally adjusting for frequency of consumption of fresh fruit, vegetables, and meat in the model. The association between time since T2DM diagnosis (from the first diagnosis date to the baseline) and the risk of incident cancer was assessed after excluding screen-detected T2DM. In addition, we analyzed the association between baseline RBG and risk of incident cancer among participants without a history of physician-diagnosed T2DM. Because the association between diabetes and pancreatic cancer has already been reported in the CKB Study , we did P values were 2-sided, and statistical significance was defined as P < 0.05.All analyses were conducted using Stata 14 . All Among the 508,892 study participants without a prior cancer diagnosis, the mean age at baseline was 51.5  years. A total of 29,835 participants (5.9%) had T2DM at baseline, of whom 15,881  reported physician-diagnosed T2DM and 13,954  had screen-detected T2DM (Table https://academic.oup.com/aje), although associations of T2DM with liver cancer and female breast cancer differed statistically as regards age and cigarette smoking, respectively , including 1,457 cancers among participants with T2DM and 16,006 among those without T2DM  and female breast cancer (P for trend = 0.02) among participants with longer time from diabetes diagnosis to baseline.Among the participants with a diagnosis of T2DM, the association with liver cancer was stronger in those whose T2DM was diagnosed less than or equal to 5 years prior to baseline  than in those whose T2DM was diagnosed over 5 years prior to diagnosis  compared with persons without T2DM. The findings were consistent with those from a report by the American Diabetes Association and the American Cancer Society , as wellOur study found that T2DM was associated with a 13% increased risk of total cancer, which was slightly lower than the results from a recent pooled analysis of 19 prospective cohort studies in Asians   also repThe pooled analysis of Asian cohort studies showed an approximately 2-fold increased risk of mortality from liver cancer in persons with diabetes . Our estOur study showed a positive association between T2DM and risk of female breast cancer, which is consistent with the summary relative risk from a meta-analysis of 39 observational studies conducted primarily in Western countries . The effIn our study, higher RBG levels were associated with increased risk of total cancer and cancers of stomach, colon and rectum, liver, and female breast among persons without prior physician-diagnosed T2DM. Some of the positive associations existed even in the normal range of blood glucose values, which was consistent with findings from a prospective cohort study in South Korea . BesidesThe study had major strengths, including its prospective nature, a large sample size, geographic diversity, completeness of data collection, stringent case ascertainment and follow-up mechanisms, and a high retention rate. The findings are thus reliable and generalizable to the general population in China. However, there are certain limitations that need to be addressed. First, since new T2DM cases (previously undiagnosed diabetes) found at baseline were detected only on the basis of RBG level, case misclassification might have been possible. This was partially reflected by the discrepancies between the prevalence of newly diagnosed T2DM in our study (2.7%) and counterpart estimates based on several glycemic indicators, such as fasting plasma glucose, 2-hour plasma glucose, and glycated hemoglobin, in 3 nationally representative studies  , 32. SecIn conclusion, our study provides evidence of associations between T2DM and incident cancer, particularly cancers of the liver, pancreas, and female breast, among Chinese adults. Diabetes is undiagnosed among many Chinese adults, and many diagnosed cases are not properly treated . Since bWeb MaterialClick here for additional data file.