BRCA1 or BRCA2 mutations face difficult choices about reducing their breast cancer risk. Understanding their treatment preferences could help us improve patient counseling and inform drug trials. The objective was to explore preferences for various risk-reducing options among women with germline BRCA1/2 mutations using a discrete-choice experiment survey and to compare expressed preferences with actual behaviors.Unaffected women who carry BRCA1/2 mutations who were unaffected with breast or ovarian cancer were recruited through research registries at five clinics and a patient advocacy group.A discrete-choice experiment survey was designed wherein women choose between hypothetical treatments to reduce breast cancer risk. The hypothetical treatments were characterized by the extent of breast cancer risk reduction, treatment duration, impact on fertility, hormone levels, risk of uterine cancer, and ease and mode of administration. Data were analyzed using a random-parameters logit model. Women were also asked to express their preference between surgical and chemoprevention options and to report on their actual risk-reduction actions. Women aged 25–55 years with germline Between January 2015 and March 2016, 622 women completed the survey. Breast cancer risk reduction was the most important consideration expressed, followed by maintaining fertility. Among the subset of women who wished to have children in future, the ability to maintain fertility was the most important factor, followed by the extent of risk reduction. Many more women said they would take a chemoprevention drug than had actually taken chemoprevention.BRCA1/2 mutations indicated strong preferences for breast cancer risk reduction and maintaining fertility. The expressed desire to have a safe chemoprevention drug available to them was not met by current chemoprevention options.Women with The online version of this article (doi:10.1007/s10549-017-4332-3) contains supplementary material, which is available to authorized users. BRCA1 or BRCA2 mutation carriers face high lifetime risks of breast and ovarian cancer. For BRCA1 carriers, the risk of breast cancer ranges from 56%  for the attribute descriptions in the survey). Risk-related attributes were presented using risk grids with 100 figures . The risThe attribute levels were used to create a set of medicine choice questions based on an experimental design with known statistical properties. The design was created using a SAS implementation of a commonly used D-optimal algorithm to construct a fractional factorial experimental design –40 folloRespondents were presented with three risk-reducing treatments  and screening Fig. . The twoDemographic information , risk perceptions, current level of distress , and through the research registries at Creighton University (US), Women’s College Hospital (Canada), Royal Melbourne Hospital , Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer (kConFab) at the Peter MacCallum Cancer Centre , and Manchester Centre for Genomic Medicine (UK). FORCE recruited respondents who provided a self-reported diagnosis of their BRCA1/2 status through its website, newsletters, and social media. The clinical sites identified respondents who met the inclusion criteria and mailed them invitation letters with the URL of the online survey and a unique password. Institutional review boards at RTI International and all participating sites approved the study. All patients provided informed consent prior to their inclusion in the study.Women aged 25–55 years with an inherited mutation in the The DCE data were estimated using the random-parameters logit model to calculate the preference weights for all attribute levels using NLOGIT software, version 5.0 . Random-P > 0.05), so the main-effects model was selected as the final model.Pretest interviews suggested that treatment duration may influence the preference for specific attributes, including ability to get pregnant, temporary menopause-like symptoms, and treatment-related risks. To test for interactions between duration and other attributes, an additional model was estimated, but the interaction terms were not statistically significant . The subgroup analyses included interaction terms in the main-effects model. A Chi squared test was estimated to test for the joint significance of the interaction terms.The preference weights from the random-parameters logit model were used to predict the share of the sample that would have selected hypothetical treatments in several scenarios. A hypothetical medicine with the characteristics of bilateral mastectomy or a bilateral oophorectomy was separately compared with two hypothetical medicines with characteristics like tamoxifen or an anti-RANKL monoclonal antibody.t test was used for comparison of means.The responses to questions that asked women whether they would have chosen mastectomy, oophorectomy, one of two medicines, or screening only were summarized by calculating the percentage of women who selected each option. A Chi squared test was used for comparison of percentages, and a BRCA1 mutation, 46% had a BRCA2 mutation, and 1% had both BRCA1 and BRCA2 mutations . Women who wanted to have children placed the most importance on preserving their fertility .The relative importance of the attributes depends on whether the woman wanted to have children at the time her genetic mutation status was identified, and the difference in preferences between the subgroups was statistically significant  (P = 0.02), whereas there was no significant difference in the percentage who had mastectomy by mutation (P > 0.05). Combining the women who had surgery with the women who had not had surgery but who said they would in the future brings the total to 70% for mastectomy and 83% for oophorectomy . When asked to select reasons for not having done so, the top reason was that their doctor had not recommended any of the medicines (52%), followed by concern about side effects (39%). Fourteen percent wished to get pregnant Table .In Fig. When women were asked to select all the measures they would have if they had their decisions to make again, 79% selected oophorectomy, 74% selected mastectomy, 31% selected Medicine 1 (similar to a RANKL inhibitor like denosumab), and 28% selected Medicine 2 (similar to tamoxifen)  and five months (denosumab) after discontinuing these agents before attempting to conceive in order to avoid potential harmful effects to the fetus , 50.BRCA1/2 generally. The DCE questions can only accommodate a limited number of attributes, so important attributes such as the risks associated with surgery and the level of ovarian cancer risk reduction were not included. Relative preferences for the attributes such as breast cancer risk reduction could be different if additional attributes had been included. Finally, past actions to reduce breast cancer risks were self-reported.Several limitations should be considered in the interpretation of our study results. The sample may not be representative of women with BRCA1/2 mutations regarding the attributes of different options to reduce their risk of breast cancer. The preferences expressed in the survey were compared with actual actions and questions about what the women would have done if there had been other chemoprevention options available. Preferences for high levels of risk reduction and the ability to maintain fertility were dominant and reflected the actual choices women made.DCE studies provide a systematic method for ranking preferences for treatment options. This is the first study to implement the DCE methodology to provide a clear picture of the preferences among women with BRCA1/2 mutation. Future research is warranted to determine the efficacy and safety of RANKL inhibitors in this population.Our survey indicated interest in chemoprevention, despite the low uptake of tamoxifen until now. Tamoxifen is not an acceptable option for chemoprevention for most women, in part due to its cancer-related stigma. A new chemoprevention option would be more acceptable to women who carry a Supplementary material 1 (DOCX 13 kb)Below is the link to the electronic supplementary material.


Risk stratification using genetic and other types of personal information could improve current best available approaches to ovarian cancer risk reduction, improving identification of women at increased risk of ovarian cancer and reducing unnecessary interventions for women at lower risk. Amounts of information given to women may influence key informed decision-related outcomes, e.g. knowledge. The primary aim of this study was to compare informed decision-related outcomes between women given one of two versions (gist vs. extended) of a decision aid about stratified ovarian cancer risk-management.n = 512) or extended (n = 519) version of a website-based decision aid and completed an online survey. Primary outcomes were knowledge and intentions. Secondary outcomes included attitudes  and decisional conflict.This was an experimental survey study comparing the effects of brief (gist) information with lengthier, more detailed (extended) information on cognitions relevant to informed decision-making about participating in risk-stratified ovarian cancer screening. Women with no personal history of ovarian cancer were recruited through an online survey company and randomised to view the gist (p = 0.66) or intention to participate in ovarian cancer screening based on genetic risk assessment (t(1029) = 0.43, p = 0.67). There were also no between-groups differences in secondary outcomes. In the sample overall (n = 1031), knowledge about ovarian cancer increased from before to after exposure to the decision aid , and 74% of participants said that they would participate in ovarian cancer screening based on genetic risk assessment.There were no significant differences between the gist and extended conditions in knowledge about ovarian cancer  contains supplementary material, which is available to authorized users. Ovarian cancer remains the leading cause of gynaecological cancer death in the UK, with approximately 11 women dying from the disease each day  cancer in comparison with other women of the same age . This was based on a measure of perceived health risks [never’, ‘rarely’, ‘sometimes’, ‘often’, ‘most of the time’). This measure was adapted from the Health Information National Trends Survey [th risks . Worry as Survey .Genetic literacy was assessed with six statements used in previous research [true); 2) Genes are made up of DNA (true); 3) Most genetic disorders are caused by a single gene (not true); 4) If a person has a faulty gene that has been linked with a disorder, they will always get the disorder (not true); 5) On average, a person has half their genes in common with their biological siblings (true); 6) A mother and daughter who look alike have more genes in common than a mother and a daughter who do not look alike (not true). Response options for each question were ‘true’, ‘not true’, and ‘not sure’.research –24: 1) GKnowledge about ovarian cancer was assessed using four statements specifically developed for this study (bold font indicates response options coded as ‘correct’ and consistent with the information provided in the decision aid): 1) The average risk of a woman developing ovarian cancer in her lifetime is… ; 2) Ovarian cancer mainly affects older women ; 3) Ovarian cancer can easily be found early with an ultrasound scan ; 4) There are some factors that increase the risk of developing ovarian cancer: being overweight; being over 50 years old; smoking; family history; taking the pill; having children; breastfeeding; being inactive; using talcum powder; having IVF treatment . Participants also scored up to three points if they correctly identified that taking the pill, having children and breastfeeding were not risk factors for ovarian cancer, as these have clearly been shown to be protective factors. This gave a total possible score of 10. The questions were adapted from the ovarian cancer awareness measure toolkit [ toolkit .Knowledge about PROMISE was assessed using six statements: 1) Genetic testing for ovarian cancer involves giving a blood sample (true); 2) PROMISE uses genetic information to estimate the risk of developing ovarian cancer (true); 3) Learning about personal risk of ovarian cancer may affect other family members (true); 4) Most women who take part in PROMISE will learn that they are at high risk of ovarian cancer (not true); 5) Women at high risk can’t do anything to reduce their chance of getting ovarian cancer (not true); 6) Women who take part in PROMISE will get some information about their risk of breast cancer (true). Response options for all statements were ‘true’; ‘not true’; ‘not sure’.Attitudes towards taking part in PROMISE were measured using a validated scale by Hersch and colleagues . The sca’, with response options being ‘yes, definitely’; ‘yes, probably’; ‘probably not’; ‘definitely not’ .Intention to take part in risk-stratified ovarian cancer screening based on genetic risk was adapted from a question by Power and colleagues : ‘If youDecision-related outcomes were assessed using six items adapted from the decisional conflict scale : 1) I wo; ‘There was enough information on the website to make a decision about whether or not to take part in PROMISE , and ‘I would have preferred to speak to a health professional before making a decision about whether or not to take part in PROMISE .Website usage was assessed at follow-up using three questions: ‘I read all the information on the website’ Demographic and personal information, worry about breast and ovarian cancer, genetic literacy and health literacy were assessed before the decision aid intervention. Perceived risk of ovarian cancer and knowledge of ovarian cancer were measured pre and post exposure to the decision aid. Knowledge about PROMISE, attitudes, intentions, decisional conflict, anticipated decisional regret and website usage were assessed after the decision aid intervention only  as an independent variable, and the time*group interaction reported. Overall, 1031 women participated in the study. There were 512 participants in the ‘gist’ decision aid group and 519 in the ‘extended’ group. Women were well distributed across the age groups, and ranged from 18 years upwards, with 7% aged 65 and over. The majority of participants were White (79.6%), spoke English as their first language (90.9%), and 26% were educated to Degree level. None had had a previous diagnosis of ovarian cancer. Twenty-five percent of participants had a family history of breast cancer, and 8.1% had a family history of ovarian cancer. Two thirds (68.8%) of participants perceived their risk of getting ovarian cancer to be the same as other women of their age. Forty-four percent of women reported worrying ‘sometimes’ about breast cancer, and 33.8% reported worrying ‘sometimes’ about ovarian cancer. The full socio-demographic characteristics of the sample and each group are illustrated in Table Knowledge about ovarian cancer increased from pre- to post-intervention in the sample overall . There was no significant difference between the gist and extended conditions . The mean score for knowledge about PROMISE was 3.97 out of 6 after the decision aid; mean scores were not significantly different between the gist and extended conditions (4.02 vs. 3.92 respectively: t(1029) = 0.87, p = 0.39) (see Table p = 0.55) ; mean scores were not significantly different between the gist and extended conditions  = 0.60, p = 0.67) ; there was no difference between the gist and extended conditions (t(1029) = 0.43, Decisional conflict: Overall, the majority (94%) of participants agreed or strongly agreed that they would feel that they would be making an informed choice about taking part in PROMISE, and three quarters (77%) reported that they knew the risks of taking part in PROMISE. However, over half (54%) also felt unsure about what they would choose, and only two thirds (67%) felt that the decision about whether or not to take part in PROMISE would be easy for them. The mean score for decisional conflict was 2.09 (SD = 0.32) . Mean scores did not differ between the gist and extended information decision aid groups (t(1029) = 0.20, p = 0.84).Anticipated decisional regret: In the sample overall, 49% of participants agreed or strongly agreed that if they did not take part in PROMISE they would feel regret, and similarly 55% agreed or strongly agreed that if they did not take part, they would later wish they had. The mean anticipated decisional regret score was 2.56 (SD = 0.66), on a scale where 1 = low anticipated regret, and 4 = high anticipated regret. Mean scores did not differ between the gist and extended information groups (t(1029) = 0.02, p = 0.98) (see Table p = 0.88). There was also no significant difference between the two groups in the proportions of participants who thought the website contained sufficient information to make a decision about whether or not to take part in PROMISE (t(1029) = −1.34, p = 0.18) (see Table There was no significant difference between the gist and extended groups in the amount of information on the website-based decision aid that participants reported reading (t(1029) = −0.15, This study examined the effects of a web-based decision aid on key components of informed decision-making about risk-stratified ovarian cancer management, and compared the effects between a gist and an extended version of the decision aid. We found that knowledge about ovarian cancer improved significantly overall, indicating that the decision aid was successful in increasing knowledge; an essential component of informed choice. This finding is consistent with a review which found that decision aids increased patients’ knowledge about treatment or screening options . AlthougTo our knowledge, this is the first study to assess the impact of a gist versus extended version of a decision aid about risk-stratified ovarian cancer screening on aspects of informed decision-making. Different components of informed decision-making were measured, including knowledge, intentions and attitudes, in an attempt to capture the multidimensional nature of informed choice . MoreoveOur findings also suggest that providing participants in the planned PROMISE feasibility study with a decision aid may valuably help increase potential participants’ understanding of some key concepts, and that either a gist or extended version could achieve this desired outcome. There were no differences in knowledge about ovarian cancer, knowledge about the PROMISE study or intentions to participate in the PROMISE programme between those who viewed the gist and those who viewed the extended version of the decision aid. Neither were there differences in attitudes towards PROMISE, anticipated regret or decisional conflict between the two groups. The absence of differences in components of informed decision-making between the two groups suggests that the amount of information provided in the decision aid had little impact on people’s knowledge acquisition, attitudes or intention. Contrary to the study hypotheses, we found no evidence that participants in the gist group were able to retain more information, nor that those in the extended group experienced information overload. These findings support previous research which found no difference in colorectal cancer screening interest between participants who received a brief decision aid with two screening options and those who were given a more detailed decision aid containing five options .An alternative explanation for the study’s results is that the two versions of the decision aid were not sufficiently different to elicit differences in informed decision-making outcomes. The gist version was five pages long, and the extended version was eight pages, so perhaps this was not enough of a difference to affect information-processing. In light of this it might be worthwhile for future research comparing different levels of information in decision aids to ensure that gist versions are limited to one or two pages, to establish a sufficient difference between experimental groups. Moreover, all participants were able to access as much or as little information as they desired, albeit within the confines of their version of the decision aid. Detail about which pages each participant accessed and for how long was not recorded, so it is not known how much information each participant actually read. It is therefore possible that the amount of information read by participants in the two groups did not differ.It is also possible that the modality of the decision aid (i.e. website) was not particularly well-suited to the type of decision that was being made. Wilson and Wolf  claim thDecision aids are an effective tool to increase patients’ knowledge of their options when faced with a healthcare decision, so are likely to be valuable tools to help people make informed decisions. It is therefore potentially important that healthcare professionals consider providing patients with decision aids, and that such decision aids are available to them. This will be particularly important if stratified ovarian cancer risk-management becomes implemented in clinical practice, because it is a novel approach to screening and thus most patients’ knowledge of this concept will be low. Decision aids may be pivotal in improving knowledge levels and helping women to clarify their values in order to make informed decisions. Future research could explore the effect of providing women with decision aids about stratified ovarian cancer risk-management that are more different to each other in terms of the amount of information that is provided. The format of decision aid could also be manipulated, for example by using mobile apps and printed materials as well as websites, to ascertain whether this affects informed decision making outcomes.This study found that a web-based decision aid about (genetic) risk-stratified ovarian cancer screening significantly increased women’s knowledge about ovarian cancer. No differences in knowledge or other components of informed decision-making between participants who viewed a gist version vs. an extended version of the decision aid were observed. Further research is needed to determine the ideal volume and type of content for decision aids about stratified ovarian cancer risk-management.Additional file 1:Decision aid text. The text that was included in the two versions of the Decision Aid used in the online experiment: 1. Gist version (pages 1 to 4); 2. Extended version (pages 5 to 10). (PDF 143 kb)Additional file 2: Table S1.Table S2. Participants’ knowledge about genetics (‘genetic literacy’); Table S3. Participants’ knowledge about ovarian cancer and the PROMISE study in the sample overall. (DOCX 16 kb)Factor loadings for decisional conflict and anticipated decisional regret items;


Pnon-linear = 0.012); compared with the reference hours (6 h or 7 h), with increasing sleep hours, the risk of breast cancer increased (Ptrend = 0.028). Moreover, a nonlinear relationship was found between sleep duration and estrogen receptor-positive breast cancer (Pnon-linear = 0.013); the risk of estrogen receptor-positive breast cancer increased with increasing sleep hours compared to the reference hours (Ptrend = 0.024). However, no nonlinear relationship was found between sleep duration and estrogen receptor-negative breast cancer; the risk of estrogen receptor-negative breast cancer was 1.035 for every additional sleep hour. Compared to women with the reference number of sleep hours, women with a longer sleep duration might have a significantly increased risk of breast cancer, especially estrogen receptor-positive breast cancer.Sleep patterns have been associated with the development of cancers, although the association between sleep duration and breast cancer remains controversial. The purpose of our study was to explore the relationship between sleep duration and breast cancer risk. The PubMed and Web of Science databases were searched, and restricted cubic splines were used to explore the dose-response relationship. Data from 415,865 participants were derived from 10 studies. A J-shaped nonlinear trend was found between sleep duration and breast cancer incidence ( Globally, breast cancer is the most frequently diagnosed cancer and the leading cause of cancer mortality among women. The incidence of breast cancer increases by 5 percent each year in low- and middle-income countries and thus represents an increasingly urgent public health problem , 2. ManyRecently, sleep patterns  and their relationships with related health outcomes have been studied, mostly regarding chronic diseases such as cardiovascular diseases, diabetes, obesity, and metabolic syndrome –7. As a This meta-analysis was conducted according to the meta-analysis of observational studies in epidemiology (MOOSE) checklist .Two authors (Chunyang Lu and Hao Sun) conducted a computerized search for published articles in the PubMed and Web of Science databases from inception to September 2nd, 2016, without language restrictions. Discrepancies were resolved through discussion with other authors (Jinyu Huang and Songcheng Yin). The following search terms were used: (1) breast cancer OR mammary cancer OR breast neoplasms OR mammary neoplasms; (2) sleep OR sleep duration OR sleep pattern. We also screened the reference lists of relevant review articles and included studies for additional information.Studies were included only if they met all the following criteria: (1) the study was an observational study (case-control study or cohort study); (2) the outcome was the first incidence of breast cancer; (3) the exposure was sleep duration with at least three categories; and (4) there were available effect estimates (risk ratios (RRs)) or odds ratios (ORs) and 95% confidence intervals and the corresponding number of cases and person-years or subjects for each category of sleep duration. Comments, reviews, letters, animal experiments, and studies involving other cancers were excluded. If multiple publications were available for a study, data from the most recent and complete publication were included.Two authors (Chunyang Lu and Hao Sun) evaluated study eligibility and conducted data extraction independently using a predefined standardized data extraction form. The variables in the form included the following: name of the first author, publication year, study country, study name, study design, follow-up year (if cohort study), investigation year (if case-control study), age at baseline, the proportion of postmenopausal participants, method of sleep data collection, the ascertainment of breast cancer, sample size (numbers of participants and incident cases) in each category, covariates adjusted in the multivariable analysis, and effect size (RRs or ORs) with a 95% CI for all categories of sleep duration.Quality assessment was performed according to the Newcastle-Ottawa Quality Assessment Scale (NOS) , which iP value for nonlinearity was calculated by testing the null hypothesis that the coefficient of the second and third spline was equal to 0. If the hypothesis did not hold, we conducted a linear dose-response meta-analysis to test the risk of breast cancer with each additional hour of sleep. Otherwise, the nonlinear dose-response meta-analysis was conducted to show each hour's risk of breast cancer (from 4 h to 10 h). We also performed subgroup analyses stratified by menopausal status  and estrogen receptor (ER) status (ER+ or ER−). All analyses were performed with STATA version 12.0 , and all tests were two-sided with a significance level of 0.05.First, we conducted restricted cubic splines with five knots at the 1st, 25th, 50th, 75th, and 99th percentiles of exposure distribution to fit the potential nonlinear trend between sleep duration and incidence of breast cancer. In this method, the distributions of cases and participants and the fully adjusted RRs or ORs and 95% CIs in each sleep duration category were required. For studies that did not report the numbers of breast cancer cases for each category of sleep duration, these numbers were inferred based on the total numbers of cases and the reported risk estimates. Additionally, for each of the included studies, we assigned the reported median or mean sleep duration of each category as the category sleep duration. When a study reported only the range of sleep duration for a category, we used the average value of the lower and upper bounds of that category. When the shortest or the longest category was open-ended, we assumed that the open-ended interval length had the same length as the adjacent interval. The reference category was set to 6 h (the lowest risk of breast cancer in our study based on the dose-response curve) or 7 h  . A P valA total of 10 studies –18 compoThe characteristics of the studies and participants included in this study were presented in Tables Pnon-linear = 0.012). For the overall analysis, we used a fixed-effects model because there was no significant within-study heterogeneity (Pheterogeneity = 0.064). Because there was a nonlinear trend, we conducted a nonlinear dose-response meta-analysis to evaluate each additional sleep hour's risk of breast cancer. As Ptrend = 0.028).A J-shaped nonlinear trend between sleep duration and breast cancer incidence was shown in Pnon-linear = 0.139; Pnon-linear = 0.298). Therefore, we conducted a linear dose-response meta-analysis. The results showed that the relative risk (RR) of breast cancer was 1.012 in the premenopausal population and 1.003 in the postmenopausal population for every additional sleep hour; however, neither showed statistical significance .Four studies , 14–16 aPnon-linear = 0.013) and a linear relationship between sleep duration and ER− breast cancer (Pnon-linear = 0.139). As shown in Ptrend = 0.024). Regarding ER− breast cancer, a linear dose-response meta-analysis showed that the RR of ER− breast cancer was 1.035 for every additional sleep hour (Ptrend = 0.352).Three studies , 11, 12 Our meta-analysis included 10 studies involving 415,865 participants to reliably quantify the association between sleep duration and breast cancer risk. An increased risk trend was found between sleep duration and breast cancer; our study also indicated that, compared to women with a normal sleep duration, women with a longer sleep duration might have a significantly increased risk of breast cancer; this was not observed among women with a shorter sleep duration. Subgroup analysis for breast cancer by ER status also showed a positive association between sleep duration and the risk of ER+ breast cancer, although this was not observed for ER− breast cancer.Before 2008, most published articles involving sleep duration and breast cancer risk reported null findings –18 or thPtrend = 0.018) [The positive association between sleep duration and risk of breast cancer and ER+ breast cancer in our study was unexpected, as the melatonin hypothesis suggests that a short sleep duration is associated with decreased levels of melatonin, and melatonin is known to regulate susceptibility to cancer and to have antiproliferative activity . However= 0.018) . In addi= 0.018) , and inc= 0.018) , 29, whi= 0.018) , 31. Fur= 0.018) , 33.There were several limitations of our study. First, misclassification bias might exist in our study because sleep duration was self-reported in the included studies. Compared with wrist actigraphy, which was an objective measure of sleep, self-reported sleep duration showed poor validation, and the sleep duration reported in questionnaires tended to be longer than the measured duration , 35. HowIn conclusion, our dose-response meta-analysis indicates that women with longer sleep durations might have a significantly increased risk of breast cancer, especially of ER+ breast cancer, compared to that of women with a normal sleep duration.


OR per natural log unit change in CRP for breast cancer was 1.16 (95% CI: 1.06-1.27). There was moderate heterogeneity among studies (I2 = 45.9%). The association was stronger in Asian population  compared to European  and American . Prediagnostic high-sensitivity CRP concentrations  was superior to common CRP  in predicting breast cancer risk. The meta-analysis indicated that elevated CRP levels was associated with increased risk of breast cancer. Further research effort should be performed to identify whether CRP, as a marker of inflammation, plays a direct role in breast carcinogenesis.Associations between elevated C-reactive protein (CRP) and breast cancer risk have been reported for many years, but the results remain controversial. To address this issue, a meta-analysis was therefore conducted. Eligible studies were identified by searching the PubMed and EMBASE up to December 2014. Study-specific risk estimates were combined using a random-effects model. Altogether fifteen cohort and case-control studies were included in this meta-analysis, involving a total of 5,286 breast cancer cases. The combined  Breast cancer is the second most common cancer worldwide and, by far, the most frequent cancer among women with an estimated 1.67 million new cancer cases diagnosed in 2012 3C-reactive protein (CRP) is a sensitive and widely used systemic marker of inflammation, which is mainly produced in the liver along with other acute-phase proteins in response to cytokines, such as Interleukin-6 (IL-6), IL-1, and Tumor Necrosis Factor-α (TNF-α)68RR] = 1.10, 95% confidence interval [CI]: 0.97–1.26). However, significant heterogeneity was also found (I2 = 51.0%), and the estimation was based on only 1,240 breast cancer cases. Several epidemiologic studies with large sample size or long-term follow-up was performed thereafter. Therefore, a meta-analysis of cohort studies and case-control studies was conducted to further clarify the association between the elevated levels of CRP and breast cancer risk.During the last decade, several epidemiologic studies have appraised the associations between CRP and breast cancer risk. Thereinto, a meta-analysis published in 2009 found that a natural log (ln) unit increase in CRP was not statistically significant associated with breast cancer risk  were summarised in 13151617218101218191114810131617111215181419810111718191113141581016201217ORs for each study and all studies combined for one unit change in ln(CRP) were shown in OR per natural log unit change in CRP for breast cancer was 1.16 (95% CI: 1.06-1.27). However, there was moderate heterogeneity observed across studies included .The multivariable-adjusted OR = 1.42, 95% CI: 1.08-1.85) than in cohort studies and nested case-control studies . The combined OR for breast cancer was 1.12 (95% CI: 1.02-1.23) for studies conducted in Europe, and 1.08 (95% CI: 1.01-1.16) in USA and 1.57 (95% CI: 1.25-1.96) in Asia. Elevated CRP levels significantly increased the risk of postmenopausal breast cancer , but not significantly for premenopausal breast cancer . Stratifying results by CRP markers showed that high-sensitivity CRP  had a stronger association than common CRP . And when stratified by CRP assay methodology, the combined OR was 1.25 (95% CI: 1.05-1.49) for CRP levels measured by ELISA assay, and 1.14 (95% CI: 1.03-1.27) by other assay. When cancer cases stratified by case diagnosis method, the association was significant for cases reported by cancer registry  and pathology reports , but not by medical records .To explore the heterogeneity among studies of one unit change in ln(CRP) and breast cancer, we performed subgroup analyses . The assOR again when omitting one study at a time. OR per natural log unit change in CRP ranged from 1.13 (95% CI: 1.05-1.22) to 1.19 (95% CI: 1.09-1.30). The meta-analysis result of the combined OR per natural log unit change in CRP for breast cancer was not significantly affected by omission of any of the 15 individual studies, which meaned that each single study didn’t influence the stability of combined OR estimate.To address the potential bias due to the quality of the included studies, we performed the sensitivity analysis by calculating combined P values for Begg’s (0.805) and Egger’s tests (0.172) and the near-symmetric funnel plot . In contrast to that study, our meta-analysis enlarged breast cancer cases to 5,286 and the summary risk estimate showed smaller heterogeneity (I2 = 45.9%).Our summary estimate of CRP and breast cancer risk in cohort studies was similar to that of another meta-analysis, which included 5 prospective studies with only 1,240 cases and reported a unit increase in ln(CRP) was associated with 10% increase in breast cancer risk. However, the result was not statistically significant and considerable heterogeneity was found . Moreover, more comparable dose-response relationship were created for each study, and subgroup analyses stratified by 7 different variants were conducted, thus the effect of potential confounders was minimized. In addition, the combined However, the present meta-analysis has several limitations. First, studies included in this meta-analysis were heterogeneous, which could be explained by differences in populations, CRP markers, and CRP detection method. To address this issue, the random-effects model meta-analysis was reported to combine data whenever significant heterogeneity was noted. We used appropriate well-motivated inclusion criteria to maximize homogeneity, and performed sensitivity and subgroup analyses to investigate potential sources of heterogeneity. Second, information was limited for the results stratified by menstrual status and BMI categories as not all studies involved here provided relevant information. Finally, a meta-analysis is not able to solve problems with confounding factors that may be inherent in the included studies. Although all the included studies presented here were carefully adjusted for potential confounders, including age, BMI, physical activity, smoking, alcohol consumption, HRT use, nonsteroidal anti-inflammatory drug (NSAID) use, it is possible that the associations of circulating CRP with breast cancer risk have been inflated by residual confounding or reverse causality. Insufficient control for confounding factors can skew the results in either direction, to exaggeration or underestimation of risk estimates. Besides, although it has been demonstrated that CRP levels are relatively stable over short periods of time and have little or no diurnal variation30In conclusion, the findings of this meta-analysis indicated that elevated CRP levels was associated with increased risk of breast cancer, especially among the Asian population. Although causality evidence was insufficient, these results seemed to support a role of chronic inflammation in breast carcinogenesis. Further studies, especially with high-quality and more breast cancer cases involved cohort studies, are needed to identify whether CRP, as a marker of inflammation, does play a direct role in breast carcinogenesis.A systematic search up to December of 2014 was conducted in MEDLINE (via PubMed) and Excerpta Medica database (EMBASE) to identify relevant articles. Search terms included “C-reactive protein” or “C reactive protein” or “CRP” combined with “breast cancer”. Additional relevant references cited in retrieved articles were also evaluated.RR (or odds ratio [OR] estimates in case-control studies) or hazard ratios (HR) estimates with their corresponding 95% CI . If the study was reported in duplication, the one published earlier or provided more detailed information was included. Review articles and editorials were included if they contained original data. Abstracts were excluded.All papers were reviewed by two authors independently. Uncertainties and discrepancies were resolved by consensus after discussing with a senior researcher. All studies included in the final meta-analysis satisfied the following criteria: (a) cohort or case-control study design; (b) report results on blood CRP levels; (c) breast cancer incidence as the outcome of interest; (d) report RR or OR estimates with corresponding 95% CIs for CRP as a continuous variable or at least 3 categories of CRP levels. For each study, we extracted the risk estimates that were adjusted for the greatest number of potential confounders.Two of the authors performed the data extraction from each article and discrepancies were resolved by consensus. For studies meeting inclusion criteria, a standardized data extraction form was used to extract the following data: the first author’s name, year of publication, country of origin, study design, cohort study name, participants enrolled criteria, period of enrollment, the length of follow-up for cohort study, the number of participants (or person-years) and cancer cases, participants characteristics , CRP measurement methods, and RR or OR per natural log unit change in CRP with 95% CI was used to compute the combined OR of elevated CRP levels and the risk of breast cancer. A fix-effect or random-effect model was used to combine the data, based on the Mantel–Haenszel methodRR) or (OR) for one unit increase in ln(CRP).The Q test  and I2  was used to assess the heterogeneity between eligible studies, which test total variation across studies that was attributable to heterogeneity rather than to chanceCochrane P < 0.05 was considered statistically significant.All statistical analyses were performed using STATA version 12 for Windows . A two-tailed How to cite this article: Guo, L. et al. C-reactive protein and risk of breast cancer: A systematic review and meta-analysis. Sci. Rep.5, 10508; doi: 10.1038/srep10508 (2015).


While many risk factors for breast cancer, such as family history, are not modifiable, some, however, can be modified. The study used formative qualitative research to learn about the physical activity intervention preferences and needs of first-degree female relatives (FDFRs) of breast cancer patients; that information was then used to develop a targeted physical activity intervention.Twenty FDFRs first completed a 12-week physical activity intervention and then attended two sequential focus groups . In the first set of focus groups participants provided feedback on the intervention. In the follow-up focus groups, proposed changes based on collected responses from the first groups were presented and participants provided feedback to further refine the intervention.Overall, we found strong interest for an intervention using breast cancer-related health concerns to promote positive behavior change. A theme underlying all of the feedback was the desire for a personalized intervention that was directly relevant to their lives. Participants wanted this personalization achieved through individually tailored content and incorporation of stories from other FDFRs. In order to successfully use concerns about breast cancer to motivate behavior change, participants also wanted a discussion about their individual risk factors for breast cancer including, but not limited to, lack of physical activity.This study demonstrates women’s interest in receiving personalized information and highlights specific ways to individualize an intervention that increases motivation and engagement. Using a sequential qualitative approach was effective for formative intervention development.NCT03115658 (Retrospectively registered 4/13/17). Breast cancer is the second leading cause of cancer death among women, and women with a family history are at increased risk for developing breast cancer . AccordiData from numerous studies has consistently found an inverse relationship between participation in regular physical activity and breast cancer risk with, on average, a 20% risk reduction –9. ReseaWhile physical activity interventions have been developed for a variety of populations including healthy adults and cancer survivors, no interventions have been developed with a focus on first-degree relatives of cancer patients. While these individuals may be healthy themselves, they may also have different health concerns and motivations for exercising. Research suggests that changes in a health behavior are more likely when the intervention is tailored to motivators that are personally relevant to the target group –21. FDFRWomen with at least one FDFR  diagnosed with breast cancer were recruited for this study. Eligible women had to be engaging in less than 90 min per week of moderate intensity physical activity as the intent was to develop an intervention for underactive FDFRs. Exclusion criteria included: personal diagnosis of any type of cancer except basal cell carcinoma; currently pregnant or intention to get pregnant in the next 3 months; presence of a known medical condition that would make it difficult/dangerous to exercise ; severe psychiatric illness; plans to move from the area in the next 6 months; or unable to read and speak English. Web and radio advertisements and a local news story were used to recruit participants. Written informed consent was obtained, and the protocol was approved by the institutional review board of The Miriam Hospital, RI.Participants first completed a 12-week physical activity intervention, which had previously been developed for healthy men and women, and then attended two sequential focus groups. In the first set of focus groups participants provided feedback on the 12-week physical activity intervention. In the second focus groups participants returned to provide feedback on proposed changes to the invention that were made based on collected responses from the first groups.The intervention was a 12-week theory-based and individually-tailored physical activity intervention shown to be efficacious with sedentary men and women –25. At tA total of 7 focus groups were conducted with the women after the end of the intervention period, four in the first round, and three in the second round. Twenty women (4–6 per group) attended the first round of focus groups, in which we sought to understand their experience in the physical activity intervention and response to the new materials. We also asked how the intervention could be modified to better address the needs of FDFRs like themselves. An open-ended qualitative data collection guide was used to provide consistency across groups. The questions were designed to elicit specific feedback about current intervention and proposed changes in the future. The focus group guide questions and prompts were used as facilitative tools, rather than a rigid script, allowing emergent ideas to be raised.Women who attended the first round of focus groups were invited back to attend the second round. Eighteen of the 20 women attended the second round focus groups (4–8 per group). In these groups we sought feedback on proposed modifications to the intervention that were developed based on the information learned through the first round of focus groups. A slide presentation was used to present the proposed modifications in comparison to the original intervention, and to show mocked up examples of new intervention components.Focus groups were audio recorded, and field notes were taken at each focus group. The focus group guides were developed by PhD-level staff experienced in physical activity interventions, breast cancer research, and qualitative methods (S.J.H. and R.K.R.). Due to practical limitations of participants being limited to those who were enrolled in the physical activity intervention it was decided to hold the focus groups as long as no fewer than 4 participants attended. The facilitator (S.J.H.) was known to the participants because she did exercise goal setting with them in the intervention portion of their study participation. In each focus group the facilitator addressed this familiarity, explaining that she had not developed the intervention but had used protocols from a previous study on which she sought participant feedback. Participants were candid in their feedback and we believe that participants understood that they were asking to partner with the facilitator to respond to and help modify the PA intervention in which they participated. Debriefing was done after each focus group with the facilitator (S.J.H.) and note-taker to allow for iterative modification of the agenda and to assess data saturation.Audio recordings were transcribed and each transcription reviewed by the facilitator (S.J.H.) to ensure accuracy. Transcripts were reviewed by two independent coders (S.J.H. and R.K.R.) using a coding guide developed from the focus group agendas to reflect key content areas and themes that emerged from the discussions. Separate coding guides were used for the first and second round of focus groups. Any discrepancies between the two coders were discussed and resolved. The agreed upon codes were entered in NVivo 10  to aid in = 20) were a mean age of 40 years old  predominantly identified as non-Hispanic White (85%) had college or graduate level education (60%) and had an annual income greater than $40,000 US dollars (66%). Seventeen reported that their mother had been diagnosed with breast cancer, two had sisters with breast cancer, and one woman had both a mother and sister diagnosed with breast cancer. Participants reported engaging in a mean of 30.25 min/week (SD = 33.07) of moderate to vigorous physical activity at baseline, that increased to an average of 180.25 min/week (SD = 137.80) of moderate to vigorous physical activity at the end of the 12 week intervention. Fifty-five percent of participants reported engaging in at least 150 min of moderate intensity exercise a week . Many participants, however, told us that this information was not motivating in the study, because the only connection between physical activity and breast cancer was in information sheets mailed out to them; that is the information could have been better integrated into the existing intervention materials and discussions. One woman stated: “We got these things but we never talked about them when we met with you either time so I think it didn’t connect at all because of that, because you didn’t talk about it” .Overall the women said knowing that physical activity was a way to reduce breast cancer risk provided them with a motivation to exercise. ““I think it’ll bring it together. When I first did it I didn’t get the feeling that breast cancer or anything about cancer was a part of the program much, so I think that’ll bring it nice and up to the front” .To address this feedback we proposed in the second round of focus groups to change the baseline in-person meeting, which previously focused only on physical activity, to also include a discussion about the relationship of breast cancer risk to physical activity. The women were very supportive of this idea: Discussion of personalize breast cancer risk factorsAfter you get our information you could be like, ‘well you’re 26, your mother had breast cancer at this age. This is what you should think about doing in 5 years. This is what you should do now’” . They wanted a personalized discussion in order to understand their own level of breast cancer risk. One woman said: “Just how worried really should I be? That was one of the questions on your form: ‘How much does this affect you?” And um, not a lot, but maybe it should” . In response, another woman said: “It affects me a lot and maybe it shouldn’t” .Almost all participants were interested in having a discussion at the start of the study about their personal risk factors for breast cancer. They were interested in a discussion that covered not only physical activity, but other modifiable and non-modifiable breast cancer risk factors as well. For example one woman stated: “To address this issue, we proposed incorporating a discussion about breast cancer risk factors tailored to participants’ individual risk factors including current weight, physical activity level, and menopausal status into the baseline session. Participants in the second set of focus groups were enthusiastic about this addition.Add personal stories from other FDFRsbring life to it [the print materials]” . They also said: “paper takes the emotion of it” , and that print “tends to sink in more when you can put a face or a name [to it]” . Another woman stated: “It might be good to hear some other people’s stories like that. It might help someone just to hear the personal stories…it might even encourage us to actually read the stuff” . Another suggestion from the women was to also allow the participants to be able to share their personal stories with one another. For example, one woman said “If there was like a website that people could put their personal stories on the website and you could go there and do them” .Many of the women thought incorporating personal stories throughout the intervention would increase motivation. They wanted to hear from women like themselves, other women whose family member had breast cancer, about increasing physical activity. They also wanted to hear about those women’s experiences with their family member’s cancer diagnosis and treatment. The women felt that seeing women like themselves be successful in increasing their physical activity could be motivational to their own success. The women suggested this could be accomplished by adding personal stories to the materials. They indicated that such stories would help “I would at least read it, and if I saw something on there that was interesting maybe I would respond” .To address these issues, at the second round of focus groups we proposed incorporating personal stories throughout the materials. The participants were very supportive of this plan. We also proposed a message board where participants could share their personal stories with the other participants. The overall feedback about providing a message board was positive, but the response about actual anticipated use of it was mixed. About half were interested in using a message board and about half said they would not use one. However, the women who were not interested in posting on a message board still indicated that they would be interested in reading other people’s posts. For example, “Add general breast cancer information“I almost think that maybe more information about breast cancer to go with it would have been helpful. Because in my situation, my mother currently does have breast cancer…. I know basically that it puts me at a higher risk to get it, but that’s pretty much where my knowledge stops” . Another woman had outdated information: “My mother died from breast cancer, so I had a lot of information. But it’s dated, because she died in 1996. So it would have been great for me to learn what they’ve learned since 1996” .Many of the women were also interested in information about breast cancer that was not related to physical activity. Some of the women reported having little information about breast cancer. “So when she was diagnosed I started collecting all sorts of information and actually my sister had it in 2001. So it was kind of like, I, oh for 10 years now it’s been circulating around my family. So for me I already knew more than I really wanted to know about breast cancer. And I kind of like, for me, it wasn’t going to be helpful for me personally. So perhaps an assessment of one’s like level of knowledge and understanding prior to enrollment in the study, might help to guide what materials are actually disseminated to people” .One woman was not interested in general breast cancer information. She reporting having a high level of knowledge and suggested a personalized approach where information was provided based on an individual’s need: Through the focus groups some of the women learned that the information they had was not accurate, which led to an interest in learning more about facts and myths about breast cancer and breast cancer risk. Several women also expressed an interest in receiving breast cancer related resources. This varied from books and suggested readings to local support groups for breast cancer survivors and their family members.Based on this feedback we proposed adding several types of breast cancer related information into the study and used the second set of focus groups to identify the specific topics they wanted covered in the new materials. Participants were interested in learning about genetic testing for breast cancer, information on free and low-cost mammograms, local breast cancer related talks , questions to ask their doctor, breast cancer support groups and family member support groups, breast cancer related charity walks, mental health resources, and reputable breast cancer related websites.Timing of being in an exercise program relative to cancer diagnosis“So I think it’s whenever we’re ready to sign up for the program. If it’s being offered and we feel we’re strong enough to do it, go for it. And if you can provide us with information if we signed-up we’d know that this is what we are getting into, but I don’t think there would be a specific time because everybody’s situation’s different” . Some women felt there was no optimal period of time. For example: “it’s been two years since my sister [was diagnosed], she just got her final full year clearance and I can’t think of a time when it would be more helpful or less helpful” . Several women stated that during a relative’s active treatment would not be optimal, since their priority at that time was helping their family. For example one woman said: “It would have done no good while my mother was going through treatments because while it probably wasn’t the best, pretty much all of my energy was focused on her” . However another felt that being in a program could provide support for someone whose family member was just diagnosed. One woman expressed that it was not the time since diagnosed that mattered to her, but rather her FDFR’s age at diagnosis. She was currently the same age that her mother was when she was diagnosed with breast cancer. Although two other women whose mothers were diagnosed over 10 years ago felt some “detachment”, they thought it would have been more motivating had they enrolled closer to the time of diagnosis. Due to the wide range of opinions about when to enroll in an exercise program, we did not explore limiting enrollment by time since diagnosis, and did not discuss this topic further in focus group 2.Participants varied greatly regarding when their relative was diagnosed. This ranged from very recently diagnosed and currently in treatment to being diagnosed over 30 years ago. We therefore explored whether there was an optimal time to capitalize on concerns about breast cancer risk to motivate behavior change. Overall the feedback was mixed, with the general sense that it was a personal decision. Participants provided feedback on the intervention including what motivated or did not motivate them to increase physical activity. They were also asked for ways the intervention could be improved to make it more relevant to women with a family history of breast cancer. Five key themes developed from the coding and analysis. Two of these areas, The current study sought to identify physical activity intervention preferences and needs of FDFRs. We found a strong interest for an intervention that used breast cancer related health concerns to promote positive behavior change. However, for this to be motivational the women wanted a personalized discussion at the beginning of the intervention to covered physical activity and other breast cancer risk factors. The women also wanted stories from other women like themselves to be incorporated into the materials to increase the interest and saliency of the information and to be able to share their own personal stories with other participants. In addition some of the women were interested in receiving general breast cancer information as they did not have current or accurate information; while those with up to date information were not interested in general breast cancer information. There was no consensus on the optimal time of when, in relation to their relatives breast cancer diagnosis, they would be most motivated to increase their physical activity; instead the women felt their readiness to change was a personal decision that would vary for each of them.The concern underlying all of these findings is the desire for a personalized intervention that provides information on individual risk factors. The women wanted to feel that the intervention was directly relevant to them and their lives. In order to successfully use concerns about breast cancer to motivate increasing physical activity the women said they needed a personalized discussion about how physical activity could benefit them. They also wanted a discussion about other personally relevant breast cancer risk factors. In addition, the woman suggested greater overall personalization of the content of the intervention materials. This personalization took two forms: one, through the addition of stories from women like themselves or by contributing their own stories to the material, and two, by providing information on topics based on the women’s current knowledge base or interest. Not only did they feel that a more personalized approach would be more motivational, but that it would increase their engagement in the intervention itself.This desire for personalization is not unique to FDFRs, but it highlights that tailoring an intervention to a concern that is personal to the participant, such as breast cancer risk was to these participants, may increase the participants’ motivation, increase the dose of the intervention they receive, and ultimately help motivate the desired behavior change. This is supported by other literature indicating that personalized interventions are more effective than standard interventions for producing behavior change , 31, 32.Prior to the focus groups, participants were enrolled in a physical activity intervention, suggesting that they were at least somewhat interested in increasing their physical activity; therefore, the feedback may not generalize to a less motivated group. We purposely chose to obtain feedback from women who had experienced the intervention themselves, and who could provide specific feedback on what actually worked well and what could have been done more effectively. We felt this would give us more accurate and informative feedback than asking people to conceptualize what they would want in an intervention. Having the experience of a physical activity intervention, including receiving intervention materials and trying to change their own physical activity behavior allowed participants to provide rich and informative feedback on how to modify a physical activity intervention to better address the needs of our target population.Although conducting sequential focus groups to gain in-depth feedback on developing a tailored physical activity intervention was a strength of this formative study, several limitations should be noted. The study had a small sample size which may limit the amount and range of feedback we received; however, it was appropriate for an exploratory study and during coding and analysis we found most topics to have rich data and felt that those data were saturated. The numbers attending some groups were relatively small, ranging from 4 to 6 overall. The facilitator was known to the participants; this was addressed at the outset of each group, to invite collaboration from the participants in the study aim of adapting an existing intervention. The sample consisted of mostly non-Hispanic White women, most were college educated, the majority of participants’ FDFR was their mother, and overall the sample was relatively young. These factors may limit the applicability of the results to more diverse populations. Future research should examine if intervention preferences found here are similar for sisters of breast cancer patients and for older women, whose concerns about breast cancer and risk for developing breast cancer may be more immediate than the current sample.This study supports personalization of materials to enhance motivation for behavior change. It also highlights specific areas and ways that personalization could be incorporated into interventions to increase motivation and engagement. While the details are specific to FDFRs the overall themes are likely generalizable to other groups. With the increase of technology being incorporated into interventions, future studies could be personalized to address the specific health concerns of that individual potentially using the feedback identified in the current study. Next steps are to test an intervention that incorporates personalization of content surrounding breast cancer and breast cancer risk to establish if these changes are effective at increasing adherence to physical activity guideline, provide physical and psychological benefits associated with being physically active and reduce cancer risk.


Breast cancer is one of the most common cancers and the second most responsible for cancer mortality worldwide. In 2014, in Portugal approximately 27,200 people died of cancer, of which 1,791 were women with breast cancer. Flaxseed has been one of the most studied foods, regarding possible relations to breast cancer, though mainly in experimental studies in animals, yet in few clinical trials. It is rich in omega-3 fatty acids, α-linolenic acid, lignan, and fibers. One of the main components of flaxseed is the lignans, of which 95% are made of the predominant secoisolariciresinol diglucoside (SDG). SDG is converted into enterolactone and enterodiol, both with antiestrogen activity and structurally similar to estrogen; they can bind to cell receptors, decreasing cell growth. Some studies have shown that the intake of omega-3 fatty acids is related to the reduction of breast cancer risk. In animal studies, α-linolenic acids have been shown to be able to suppress growth, size, and proliferation of cancer cells and also to promote breast cancer cell death. Other animal studies found that the intake of flaxseed combined with tamoxifen can reduce tumor size to a greater extent than taking tamoxifen alone. Additionally, some clinical trials showed that flaxseed can have an important role in decreasing breast cancer risk, mainly in postmenopausal women. Further studies are needed, specifically clinical trials that may demonstrate the potential benefits of flaxseed in breast cancer. Cancer is one of the most serious health problems in Public Health given its high and increasing prevalence worldwide, being one of the main causes of morbidity and mortality and also responsible for a significant decrease in life quality. According to the World Health Organization (WHO), in 2012, 14 million new cases of cancer were diagnosed, which were responsible for 8.2 million deaths worldwide, with 521,000 of them being attributed to breast cancer .In 2012, it was estimated that approximately 32.5 million people were cancer survivors, 5 years after being diagnosed with the disease. In 2030, it is expected that approximately 23.6 million new cases of cancer will be diagnosed each year .In 2014, in Portugal approximately 27,200 people died of cancer, of which 16,600 were men and 10,600 were women  –9.These less-conventional treatments may include diets with food that has proper nutritional characteristics to help fight the disease. Flaxseed has been one of the most studied foods regarding the possible relation to breast cancer. Some experimental studies in animals have been done but few progressed to clinical trials.PubMed, and websites of institutions like Cancer Research UK and the WHO. The keywords used in the research were as follows: cancer, flaxseed, lignan, breast cancer, and nutrition.To review the effect flaxseed may have in breast cancer, we conducted a bibliography research using sources from Breast cancer is considered as one of the most common cancers with the highest number of deaths worldwide. According to the WHO, it was estimated that in 2012, more than 1.68 million of women were diagnosed with breast cancer worldwide. Of these, approximately 521,000 died and in Europe, during the same year, more than 464,000 new cases were diagnosed and approximately 131,000 women died , 11.In 2014, in the United Kingdom, there were approximately 55,200 new cases of breast cancer , of which approximately 150 were diagnosed daily with approximately 11,400 deaths due to this kind of cancer. It is considered that one in eight women will be diagnosed with breast cancer during their lifetime , also known as linseed, belongs to the Linaceae family which originates from Europe, Asia, and the Mediterranean region. Flaxseed can be divided in two species: brown and golden. Golden flax develops in very cold climates, while brown flax develops in warmer and more humid climates. The latter must be ground to be better digested and absorbed by the body, thus increasing the bioavailability of the nutrients. It is considered a functional food that has nutrients with specific properties (antioxidant and/or antitumorigenic functions), such as omega-3 fatty acids, α-linolenic acid (LA), lignan, or fibers that are beneficial to one’s health, preventing some diseases, such as cancer and cardiovascular diseases, among others , making up around 95% of the seed’s lignan content. The remaining 5% consist of lariciresinol, pinoresinol, and matairesinol. After SDG lignan ingestion, bacteria in the colon act by converting the lignan into mammalian lignans, enterolactone, and enterodiol. These are structurally similar to estrogen, and have antioxidant activity and a weak estrogenic action Figure . It alsoBreast tumors that contain estrogen receptors are called estrogen receptor positive (ER+) and tumors that lack estrogen receptors are estrogen receptor negative (ER−). Women who have ER+ tumors are more likely to respond to hormonal treatments than women with ER− tumors .In our body, the biological active form of estrogen is estradiol, which is oxidized mainly in the liver to estrone. Estrone can be converted to two metabolites with different biological effects: 2-hydroxyestrone (2OHE1) and 16α-hydroxyestrone (16OHE1). While the first one has a small biological activity, the latter will increase the estrogen’s activity, promoting cell proliferation (growth of cancer cells) Figure , 26. WomTwo clinical trials concluded that 28 postmenopausal women, who followed a diet including 10 or 25 g of ground flaxseed for 7 or 16 weeks, witnessed an increased level of excretion of 2OHE1 in their urine, without an increase in the excretion of 16OHE1. These studies imply that flaxseed can have some protective effects in postmenopausal women (Polyunsaturated fatty acids (PUFAs) can be composed of omega-3 and omega-6. Linolenic acid and arachidonic acid (AA) are the main components of omega-6. The α-linolenic acid (ALA) is the precursor of the PUFA omega-3 family which forms eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) , 30.Omega-3 and ALA are also constituents of flaxseed. Flaxseed is considered as the best plant source of the essential omega-3 fatty acid. Studies suggest that the omega-3 fatty acid may have anticancer properties while omega-6 fatty acid can contribute to the development of cancer. Currently, in a regular diet, there is a higher amount of omega-3, than omega-6 , 30. StuTamoxifen is a drug used in the treatment of breast cancer, mainly in women with ER+. It can be used as an adjuvant therapy for breast cancer or metastatic breast cancer. It is a type of hormone therapy that is done during 5–10 years with several side effects –37.This drug works as an antiestrogen since, as it is an ER+ type of cancer, the tamoxifen acts throughout the whole body, blocking the action of estrogen on tumor cells, thus preventing their growth , 35.According to experimental studies, flaxseed does not have any type of interaction with drugs used in breast cancer treatments and can provide an additional protective effect when consumed along with the treatment. In animal studies, it was also verified that flaxseed, flax oil, or lignan SDG ingestion, in combination with tamoxifen, reduced the tumor’s size to a greater extent than tamoxifen treatment alone. Until now, there are no clinical trials that can prove the benefits that flaxseed ingestion can have in women with breast cancer during tamoxifen therapy .A study undertaken at the University of Toronto evaluated the effect of flaxseed and tamoxifen, alone and in combination, on the growth of ER+ human breast tumor cells in mice. These mice were injected with MCF-7 tumors and fed with different diets. The diets had 20–25 g of ground flaxseed, a tamoxifen pill (5 mg) or both. Tumor growth was monitored weekly. As a result, the flaxseed diet fed to the mice was the one that inhibited the growth of the ER+ human breast tumor cells. At low 17 beta-estradiol levels, flax inhibited tumor size approximately 74%, while at high 17 beta-estradiol levels it inhibited approximately to 22%. Furthermore, the combination of flax and tamoxifen inhibited tumor size more than 53%, as compared with tamoxifen action alone .Other experimental studies conducted in mice injected with ER+ human breast tumor cells reveal that both at low- and high-estrogen levels , flaxseed either increased or kept tamoxifen’s effectiveness in decreasing tumor growth, cell proliferation, and increased apoptosis –42.There are currently no known results from clinical trials regarding flaxseed ingestion during tamoxifen therapy .In animal studies with mice injected with breast tumor cells, feeding them with flaxseed caused a decrease in tumor incidence, number, and size. These results were also revealed to be independent of the tumor’s stage .A research group from the University of Toronto has also demonstrated that ground flaxseed has an effective anticancer activity. Their experimental study was conducted in mice to which tumors were administered, along with the introduction in their diet of a mixture of lignan. The result was a decrease in the tumor load due to the presence of flaxseed and lignan SDG in the mice diet –45.Recently, the same research group injected another mice group with human breast tumor cells. While the cancer was progressing, the mice were on a regular diet for 8 weeks after cancer cells’ injection. One group was fed with 10% of flaxseed, while the other group kept the same kind of diet. The rate of the tumor growth was reduced by 45% due to flaxseeds –45.In several other experimental studies, diets including 5 or 10% of flaxseed  inhibited the growth of the ER+ in human breast cancer cells injected in mice , 46, 47.Observational studies indicate that flaxseed consumption (approximately 32 g/daily) can reduce breast cancer risk , 51, 52.A study revealed that 70% of newly diagnosed patients with breast cancer consume food rich in lignans, 52% consume flax bread, and 30% consume flaxseed at least once a week .A pilot study including 24 postmenopausal women with ER+ breast cancer was conducted to show the effects of flaxseed and the aromatase inhibitor, anastrozole (drug used in the treatment of breast cancer), and possible interactions between them in selected breast tumor characteristics and serum steroid hormone. These women were then divided randomly into four groups: Group 1 with 25 g/daily of ground flaxseed and 1 placebo pill daily; Group 2 with 1 mg/daily of anastrozole; Group 3 with 25 g/daily of ground flaxseed and 1 mg/daily of anastrozole; and Group 4 with 1 placebo pill daily. This study did not show any effects regarding flaxseed on the aromatase inhibitor activity in selected breast tumor characteristics and serum steroid hormone levels . FurtherIngestion of flaxseed or bread containing this ingredient is associated with a 20% reduction in the risk of breast cancer, in accordance with the protective effect observed in lignans from other vegetables. This risk decrease may be related to a reduction in inflammation, since the presence of large amounts of lignans can lead to a decrease in several inflammatory markers , 54.In two meta-analysis studies, it was found that a higher intake of lignans from dietary sources was associated with a significant reduction in postmenopausal breast cancer risk , 55. In A case-control study using the Ontario cancer registry database consisted of a random sample of women diagnosed with breast cancer, with the aim of analyzing the phytoestrogen intake (isoflavones and lignans) and their association with breast cancer risk. A food-frequency questionnaire was used, which also included foods rich in phytoestrogens. Lignan intake was associated with a reduction in the risk of breast cancer for all women, although this was only statistically significant in overweight women (BMI > 25). In premenopausal women, the total phytoestrogen intake was associated with a significant reduction in the risk of breast cancer, but only in overweight women. There was no association between breast cancer risk and the intake of phytoestrogen in postmenopausal women .Another case-control study also using the Ontario cancer registry database conducted a food-frequency questionnaire with the aim of establishing if phytoestrogen intake during adolescence could protect against breast cancer in adulthood. The results of this study revealed that a higher phytoestrogen intake (isoflavones and lignans) during adolescence can be associated with a reduced breast cancer risk .Ontario Women’s Diet and Health Study in Canada (2002–2003). Both the monthly and weekly/daily consumption of flaxseed (approximately 32.5 g) and flax bread  were associated with a significant reduction from 18 to 24% in the risk of breast cancer in all women. It was also showed that flaxseed only reduced breast cancer risk in postmenopausal women, while flax bread reduced breast cancer risk in both postmenopausal and premenopausal women  had a significantly decreased risk of breast cancer. The beneficial effects of lignans in this study were limited to ER+ breast cancer and progesterone receptor positive  and an increase in cell apoptosis. Researchers concluded that flaxseed has the potential of reducing tumor growth in patients with this type of cancer , 59.In another clinical trial, researchers selected about 45 premenopausal women with a high risk of developing breast cancer (either with suspicious breast biopsies or former breast cancer survivors) and they gave them 50 mg of SDG lignan daily, or the equivalent of two spoons of powdered flaxseed. The researchers conducted needle biopsies on the breast tissue, both before and after the study, which lasted a year. Results showed that, on average, women had less breast precancerous changes after a 1 year period of taking daily flaxseed lignans, than they had before they started being studied and also that 80% (36 out of 45) had a decrease in the Ki-67 levels––a biomarker that signals the increase of cell proliferation. According to this clinical trial, SDG lignan can reduce the risk of breast cancer .Some studies showed no association between risk of breast cancer and serum enterolactone levels , 61, 62.Five studies published between 2010 and 2011, which included patients diagnosed with breast cancer who were observed for a period of 6–10 years, with the aim of finding out if lignans could prolong the survival of patients with breast cancer. Through the measurement of food records or of serum lignan levels, researchers concluded that there was an increased exposure to lignans, which led to a significant reduction of approximately 40–53% in mortality and a 33–70% reduction in mortality by breast cancer. This increased exposure to lignans was mostly observed in postmenopausal women. There is a possibility that lignans could prolong the lifespan of patients with breast cancer, but further studies are needed to confirm this , 56.Breast cancer survivors who have higher levels of lignans in their bloodstream and on their diet seem to survive for a significantly longer period of time , 65.Since breast cancer has been considered one of the most common cancers with the highest mortality rate worldwide, it is important to include nutrition as part of this disease treatment. With the improvement in eating habits and the practice of physical activity, more than 30% of the cancers diagnosed could be avoided. It has been shown that an individualized nutritional intervention can reduce treatment complications and can improve the patients’ life quality. Flaxseed has been a vastly studied food due to the relation that it may have with breast cancer. Some experimental studies have been conducted in animals, but only a few clinical trials have been done in humans with the aim of discovering the effects of flaxseed on tumors and on the risk of this type of cancer.Some studies revealed that the ingestion of omega-3 fatty acids is associated with the reduction of breast cancer. Animal studies showed that ALA can decrease the growth, size, and cell proliferation and can increase the death of breast tumor cells.The majority of experimental studies conducted showed that flaxseed increases or maintains tamoxifen’s efficacy on the decrease of tumor growth on cell proliferation and on the increase of apoptosis. It is however necessary to conduct more clinical trials to confirm the association and respective efficacy of flaxseed with tamoxifen.In several experimental studies, diets including 5 or 10% of flaxseed  inhibited the growth of the ER+ in human breast cancer cells injected in mice. The same happened with the growth of the ER−. Flaxseed also reduced the metastasis of ER− breast tumor.During clinical trials, researchers have concluded that flaxseed has the potential to reduce the growth of tumors in patients with breast cancer, mainly postmenopausal women, and decrease the risk of this type of cancer.Although many of the studies reported in this paper concluded that flaxseed intake may be related to the decreased risk of breast cancer and also to the reduction of the tumor’s growth and size, some studies including premenopausal and postmenopausal women did not show the same results.However, more studies are still necessary, especially clinical trials, to verify the benefits of flaxseed on the treatment of breast cancer.None sought.AC conceived the study, participated in its design and coordination, and drafted and authored the manuscript. PR participated in the study design, interpretation of the data, and helped to draft manuscript revisions. TS and PN were responsible for scientific writing and manuscript editing. All authors have read and approved the final manuscript.None of the authors reported any financial interests or potential conflicts of interest.


I2 test was used to assess heterogeneity. In the AMORIS study, 10,863 women were diagnosed with breast cancer (mean follow-up: 19 years). We found an inverse association between total serum calcium and breast cancer when comparing the fourth quartile to the first quartile  and similar results using albumin-corrected calcium. In the systematic review, we identified another two prospective cohorts evaluating pre-diagnostic serum total calcium and breast cancer. Combining these studies and our findings in AMORIS in a meta-analysis showed a protective effect of serum calcium against breast cancer, with a summary RR of 0.80 (95% CI: 0.66–0.97). No substantial heterogeneity was observed. Our findings in AMORIS and the meta-analysis support an inverse association between serum calcium and breast cancer risk, which warrants mechanistic investigations.To investigate the association between serum calcium and risk of breast cancer using a large cohort and a systematic review with meta-analysis. From the Swedish Apolipoprotein Mortality Risk (AMORIS) Study we included 229,674 women who had baseline measurements of serum total calcium and albumin. Multivariable Cox regression was used to assess the association between total and albumin-corrected calcium and breast cancer risk. For the systematic review, an electronic search of MEDLINE and EMBASE databases was performed to identify other prospective cohorts assessing the relationship between serum calcium and breast cancer risk. We pooled the results of our AMORIS cohort with other eligible studies in a meta-analysis using a random effects model.  There is ongoing debate surrounding the role of calcium in cancer prevention. In the context of breast cancer, current findings are mostly focused on dietary calcium with limited evidence on biomarker levels, denoting an unclear role of the calcium metabolism. For instance, an inverse association with dietary calcium intake was shown in a meta-analysis including fifteen observational studies , with anIn addition to 1,25(OH)2D, calcium metabolism is also regulated by other hormonal factors, such as parathyroid hormone (PTH), which altogether maintain serum ionized calcium, the active form, within a tight physiological range of approximately 10% . NeverthCharacteristics of study participants are displayed in p-value for trend 0.04). Similarly, an inverse association was observed when albumin-corrected calcium was assessed (HR: 0.93 (95% CI: 0.88–0.99) for the fourth compared to the first quartile, p-value for trend 0.05). When serum albumin was assessed, no association with breast cancer risk was found . On the other hand, evaluation of age- and sex-specific categories of calcium did not show any clear association  for breast cancer of 0.78% and 95% confidence intervals (CI) of 0.63 to 0.97. This inverse trend was also seen when analyzing total calcium using its quartiles (HR: 0.94 (95% CI: 0.88–0.99) for the fourth compared to the first quartile, ociation , which mociation . NeverthDescription of eligible studies identified from literature search is displayed in Quality assessment of the selected studies did not identify possible biases that could compromise the internal validity of the study leading to misinterpretation of the results. The longest follow-up duration was a mean of 19.40 years from the AMORIS cohort. Serum calcium was measured with standard laboratory procedures in all included studies. Each of studies included in our qualitative and quantitative analysis have described the adjustments made for potential confounding factors. Adjustments for age at baseline, educational level, and parity were performed in all included studies. Additionally, the studies identified in the systematic review aside from the AMORIS cohort also adjusted for additional breast cancer risk factors such as age at menarche and body mass index.I2 = 0%). A funnel plot assessing the risk of publication bias showed symmetric distribution, indicating a lack of publication bias  Study has previously been described . The cohDetails of breast cancer diagnosis were acquired from the Swedish National Cancer Register and the Stockholm Clinical Quality Register of Breast Cancer, which has 97% coverage and is validated in terms of the records of the National Cancer Register. The International Classification of Diseases version 7 (ICD-7) was used to identify breast cancer cases (ICD-7: 170). Follow-up time was defined as the period between baseline measurement and diagnosis of breast cancer, death, emigration, or end of study (31 December 2011), whichever occurred first.Total serum calcium was measured using colorimetry (coefficient of variation <2.5%), and albumin was measured using a bromcresolgreen (BCG) method (coefficient of variation <1.8%) . Levels We also collected information on baseline age (years), parity  to account for reproductive risk factors, and categorized the level of education into low (primary school or less), moderate (high school) and high (higher education). There was a lack of information on potential lifestyle-related determinants of serum calcium including body mass index (BMI), smoking, and alcohol consumption  for all n = 3427) and only including those with calcium levels within normal range, i.e., 2.2–2.6 mmol/L . Findings were stratified by age of 50 years as a proxy of menopause. Statistical significance was defined at two-sided p-value <0.05. All analyses were conducted with Statistical Analysis Systems (SAS) release 9.4 .Multivariable Cox regression was used to assess the association between continuous levels and quartiles of total and albumin-corrected calcium in addition to age- and sex-specific categories of calcium. A test for trend was conducted by using assignment to categories as an ordinal scale. Adjustments were made across all models for age, education, parity, history of fractures, CCI, and season at index examination. The Cox proportional hazards models were also adjusted for albumin levels as a continuous variable when testing the association between uncorrected total calcium and breast cancer risk. Sensitivity analyses was conducted by excluding those with follow-up time less than two years  with 95% confidence intervals (CI), or provide sufficient data to estimate these. We excluded publications when results from the same study had been published previously. The eligibility of each study was assessed by two independent investigators.dosresmeta package in R version 3.1.2  to obtain linear dose-response estimates. The assignment of interval scores of serum calcium categories from the original studies were based on medians or means when available. Category midranges were applied for the remaining closed-ended categories. For upper open-ended categories with ib as the lower bound of the ith interval and the intervals indexed by i = 1, …, n, interval scores were assigned as nb + 0.5(nb − n-b1) [b2 − 0.5(b2 − b1).The following information was obtained from eligible studies: study design, population, risk estimates, and their 95% CIs. We extracted the relative risk for serum calcium as a continuous variable when available, and contacted study authors to request this data if not already described. All measurements were transformed into a common measurement unit (mmol/L) to allow comparability. For studies which only reported relative risk in categories e.g., quartiles, the covariance-corrected method of Greenland and Longnecker  was empl − bn-1) . CorrespWe assessed the methodological quality of included studies using three components which may influence the strength of association between serum calcium and breast cancer risk: duration of follow-up, validity of serum calcium measurement, and extent of adjustments made for potential confounders.2I statistic as a measure of the proportion of total variation in estimates attributable to random error, where any values >50% indicated substantial heterogeneity. Publication bias was examined with a funnel plot. Sensitivity analysis was performed for prospective cohort studies. All quantitative data synthesis was performed in RevMan version 5.3 .Qualitatively, we summarized and tabulated information about study participant characteristics, serum calcium measurements, length of follow-up, and definition of breast cancer diagnosis as the outcome. A random effects model using an inverse-variance method was used to obtain the average effect estimates of breast cancer risk by each unit increment in calcium levels. We evaluated heterogeneity with the In the AMORIS study, higher baseline serum calcium was associated with a lower risk of a breast cancer diagnosis. The meta-analysis confirmed this inverse association between calcium and subsequent breast cancer risk in prospective cohort studies. To elucidate pathways linking calcium and breast carcinogenesis the findings need to be confirmed in mechanistic studies and observational studies integrating information from dietary supplementation of calcium.