P = .048, indicating that breast cancer is a risk factor for a frozen shoulder. And the test revealed no heterogeneity and pleiotropy, and the sensitivity analysis also showed robust results. In this study, genetic data were analyzed and explored using two-sample MR analysis, and the results showed that the incidence of frozen shoulder was higher in breast cancer patients, suggesting that screening for frozen shoulder in breast cancer patients should be increased.To investigate the causal relationship between breast cancer and frozen shoulder using a Mendelian randomization (MR) approach. Pooled data from a large-scale genome-wide association study were used. Genetic loci that were independent of each other and associated with breast cancer and frozen shoulder in populations of European ancestry were selected as instrumental variables. Inverse variance weighting was used as the primary analysis method. Weighted median (WME) and MR-Egger were used as complementary analysis methods to assess causal effects. To explore the causal relationship between breast cancer and frozen shoulder. Sensitivity test analysis was performed using heterogeneity test, multiple validity test, and leave-one-out analysis to explore the robustness of the results. Inverse variance weighting results showed an OR (95% CI) of 1.02 (1.00–1.04),  There are usually no significant findings in the patient’s history, clinical examination, or imaging evaluation to explain the loss of motion or pain.,4 Breast cancer is the most common cancer in the female population.,6 Breast cancer is most commonly treated surgically,,8 and mastectomy may negatively affect the size and movement of shoulder muscles, and patients treated with postoperative radiation therapy frequently develop arm and shoulder disorders. In recent years, several studies have investigated the relationship between breast cancer and adhesive capsulitis, but the findings have been mixed.,10Frozen shoulder, also known as adhesive capsulitis, In contrast, Mendelian randomization (MR), a genetic epidemiological method, is a useful tool to assess the causal role of breast cancer and frozen shoulder. By using genetic variants such as single nucleotide polymorphism (SNP) as instrumental variables that can modify disease risk factors or exposures, MR studies can strengthen causal inferences about exposure-outcome associations. According to Mendel law of inheritance, genetic variants are not susceptible to confounding factors because they are randomly assigned during gamete formation. In addition, confounding factors and reverse causality correlations can be minimized because genotypes cannot change with disease progression.In traditional epidemiological research methods, the causal inferences obtained are considered to be of limited value because of the influence of confounding factors and reverse causality.To this end, we conducted a two-sample MR study to examine the association of genetic susceptibility to breast cancer with frozen shoulder risk factors. We aimed to provide important evidence for the causal role of breast cancer in causing a frozen shoulder.The largest sample size of genome-wide association study (GWAS) data for breast cancer and frozen shoulder was obtained through the IEU OpenGWAS project (mr cieu. ac. UK). The website was accessed on 2023-06-06. The final population source for all data was Europe, of either sex. Including breast cancer (ieu-a-1162) containing 195,514 SNPs, 46,785 in the observation group and 42,892 in the control group; frozen shoulder (ebi-a-GCST90000512) containing 15,184,371 SNPs with a sample size of 451,099.This study was a reanalysis of previously collected and published data and therefore did not require additional ethical approval.F > 10 as a strong correlation criterion. Secondly, the instrumental variable was not directly correlated with the outcome, but only influenced the outcome through exposure, meaning that there was no genetic pleiotropy. In this study, the MR-Egger regression model with a nonzero intercept term (P < .05) indicated the absence of genetic pleiotropy. Third, instrumental variables were not related to unmeasured confounding. Finally, the human genotype–phenotype association database Phenoscanner V2 was searched for phenotypes associated with instrumental variables at genome-wide significance levels to determine whether these SNPs were associated with potential risk factors.First, the instrumental variables were highly correlated with exposure, with P < 5 × 10−8 was used as the screening condition); the linkage disequilibrium coefficient r2 was set to 0.001 and the width of the linkage disequilibrium region was 10,000 kb to ensure that each SNP was independent of each other. The above-screened breast cancer-related SNPs were extracted from the GWAS summary data of frozen shoulder, while SNPs directly related to the outcome index were excluded (P < .05). The F-value of each SNP was calculated, and SNPs with weak instrumental variables  were excluded. And the human genotype–phenotype association database was queried to screen for potentially associated risk factor SNPs and to exclude them.Significant SNPs were screened from the GWAS summary data of breast cancer  and outcome (frozen shoulder) was verified mainly using inverse variance weighting (IVW), supplemented by weighted median (WME) and MR-Egger MR analysis methods, using SNPs as instrumental variables.P < .05 suggests a potential causal relationship for MR analysis and is statistically significant. All statistical analyses were performed using the “TwoSampleMR” package in R software version 4.3.0.Various methods were used for sensitivity analysis. First, the Cochran Q test was used to assess the heterogeneity among the individual SNP estimates, and a statistically significant Cochran Q test proved that the analysis was significantly heterogeneous. Second, the MR pleiotropy residual sum and outlier (MRPRESSO) was used to validate the results in the IVW model, correct for the effects of outliers, and if outliers existed, they were excluded and the analysis was repeated. Third, the MR-Egger intercept test was used to test the horizontal multiplicity of SNPs. If the intercept term in the MR-Egger intercept test analysis was statistically significant, it indicated that the MR analysis had significant horizontal multiplicity. Fourth, leave-one-out analyses were performed by removing a single SNP at a time to assess whether the variation drove the association between the exposure and outcome variables. Fifth, funnel plots and forest plots were constructed to visualize the results of sensitivity analyses. P < 5 × 10−8) without chain imbalance . Fifty-three SNPs remained by taking intersection with SNPs in the GWAS pooled data from frozen shoulder and also excluding SNPs directly associated with outcome indicators. In our study, each SNP had an F value >10, indicating no weak instrumental variables  was performed using the IVW method and the results suggested that there was no heterogeneity. A funnel plot was drawn to show the heterogeneity results, as shown in Figure P = .066). The IVW method was used by default for the leave-one-out method, and as seen in Figure The heterogeneity test  of 1.02 (1.00–1.04), indicating that the risk of the frozen shoulder was 1.02 times higher in breast cancer patients compared to the general population. Ch et al retrospectively analyzed 785 patients and found that the incidence of frozen shoulder occurred in 3.8% of patients after breast cancer surgery, which is significantly higher than the general population. Another study followed up 217 female patients who underwent breast cancer surgery 13 to 18 months after surgery and found a cumulative incidence of the frozen shoulder of 10.3%, which was also significantly higher than the general population. A study by Pederse et al found that the risk of developing a frozen shoulder after breast cancer surgery was higher than in the population without breast cancer .In a cross-sectional study, found a 10-year incidence of the frozen shoulder of 3.6% (P = .317) in both the breast cancer and no breast cancer groups in a retrospective study of 52,524 women. cox regression analysis further showed no significant association between breast cancer and frozen shoulder .However, Louis et alDifferent conclusions emerged from previous studies, probably because retrospective studies are susceptible to confounding factors and reverse causality, and therefore the causal inferences obtained are considered to be of limited value. In contrast, MR analysis is a new epidemiological approach that uses genetic variation as an instrumental variable of exposure to enhance causal inferences. This approach reduces the effects caused by confounding factors.The present study confirms the risk factors for breast cancer and frozen shoulder from a genetic perspective. Although it is not clear how breast cancer plays this role, previous studies have suggested possible potential mechanisms. Since the majority of breast cancer patients are treated with aromatase inhibitors. Although aromatase inhibitor therapy may reduce the risk of disease recurrence, it may also increase the risk of a frozen shoulder.The results of the present study are consistent with the findings of most previous studies that breast cancer is a risk factor for the development of a frozen shoulder. People with breast cancer are more likely to develop frozen shoulders. Therefore, screening for frozen shoulder should be increased for the breast cancer population, early detection of patients with frozen shoulder and timely treatment will be beneficial to the prognosis of patients.At the same time, there are some limitations to this study. First, because all data were from a population of European ancestry, the results do not represent a truly randomized population sample and do not apply to other so races. Second, although various sensitivity analyses have been performed in this study to test the hypotheses of the MR study, it is also difficult to completely rule out horizontal pleiotropy of instrumental variables. Finally, the current sample size of GWAS data is still not large enough, and more in-depth studies using more GWAS data are needed in the future.In conclusion, this study used a two-sample MR analysis to analyze and explore the genetic data, and the results showed a higher incidence of frozen shoulder in breast cancer patients, suggesting that screening for frozen shoulder in breast cancer patients should be increased.Conceptualization: Yong-Kang Wei.Data curation: Guanghua Deng.Formal analysis: Guanghua Deng.Investigation: Guanghua Deng.Methodology: Guanghua Deng.Project administration: Guanghua Deng.Resources: Guanghua Deng.Software: Guanghua Deng.Supervision: Guanghua Deng.Validation: Guanghua Deng.Visualization: Guanghua Deng.Writing – original draft: Guanghua Deng.Writing – review & editing: Yong-Kang Wei.


Building health literacy about potentially modifiable risk factors for breast cancer may help to empower women to make more informed decisions about their breast health; however there has been limited qualitative research on this topic. This study aimed to explore current knowledge, understanding and experience of potentially modifiable risk factors for breast cancer, and views on current and future communication strategies for this information and related interventions.Qualitative study using online focus groups via Zoom in October-November 2022. A diverse sample of women from the Australian community aged 40–74 years were recruited.Fifty-one women from a range of socioeconomic backgrounds took part in nine focus groups. General knowledge of risk factors for breast cancer in the community is limited, particularly in relation to modifiable factors such as alcohol consumption and postmenopausal obesity, with many women describing feelings of ‘shock’ following this information. Women overwhelming believed that information on modifiable risk factors for breast cancer should be communicated more widely, however communication preferences for receiving this information varied. There was a strong preference amongst the women for a cascade of information which they believed may then help target greater number of women of all ages and backgrounds. Despite worry about long-term compliance, women also supported various lifestyle interventions which may help them and other women to reduce their overall risk.Findings from this study highlight the need for more widespread community communication and education about risk factors for breast, in particular potentially modifiable risk factors such as alcohol consumption and postmenopausal obesity. As breast screening programs in Australia and globally begin to evaluate the potential for risk-related screening this will provide an additional context for primary prevention, hence planning of messaging and piloting of lifestyle-related prevention strategies in breast cancer is needed now. Gaining an understanding of women’s preferences for communication and forms of interventions is vital to ensure their engagement. Breast cancer is the most commonly diagnosed cancer among women in Australia, and the second most commonly diagnosed cancer in Australia . AlthougBreast cancer risk factors vary over a woman’s lifespan. In women around the age of menopause and older, relatively modifiable risk factors for breast cancer  carry similar risks to non-modifiable more well-known risk factors such as family history . EpidemiWhile knowledge of risk factors does not guarantee actual lifestyle change – as demonstrated by evidence in the field of chronic disease research  – awarenBuilding health literacy about risk factors for breast cancer aligns with the proposed Cancer Plan for Australia . It may This study aimed to explore current knowledge, understanding and experience of potentially modifiable risk factors for breast cancer, and views on current and future communication strategies for this information and interventions among women living in the Australian community.A qualitative study using online focus groups was conducted which provided structured information about breast cancer risk factors via a presentation, interspersed with group discussions and opportunities for questions.The study was approved by the University of Sydney Human Research Ethics Committee (2022/282). Participants were sent an email containing the participant information sheet and the consent form, which was digitally signed prior to participating in the focus group.A community sample of women across Australia aged 40–74, who are approaching menopause or are post-menopausal were recruited. Women in this age group are either invited for biennial mammograms as part of the publicly funded screening program BreastScreen (aged 50–74), or are eligible to attend BreastScreen for a mammogram (aged 40–49). While it is recognised that there is no consensus on the balance of benefits and harms of screening women aged 40–49 and hence no recommendations in this age-range differs across countries, for the purpose of this study all women who are potentially screened through the BreastScreen Australia program were included. Recruitment was carried out through an independent research recruitment organisation (Taverner Research), who used random digit dialling and social media advertising to approach potential participants. Trained interviewers telephoned potential participants with a pre-recruitment eligibility check to ensure the participant fulfilled the recruitment criteria and that they had adequate equipment  to participate in the focus groups. Women were excluded if they had had a previous diagnosis of ductal carcinoma in-situ or breast cancer, did not speak adequate English, or did not have the capacity to consent.To gain a diversity in perspectives in the focus groups, quota sampling was used to ensure inclusion of participants with varying levels of education and health literacy backgrounds. The study aimed to recruit 25% of participants who came from culturally and linguistically diverse backgrounds (CALD) , which reflects the 22.8% of Australians who speak a language other than English at home .Focus groups were stratified across three age categories: 40–49; 50–59; 60–74. Three focus groups were run for each age group, totalling nine focus groups altogether, with the aim of recruiting six women for each focus group in order to optimise group dynamics – ensuring everyone was able to participate while having enough people to keep the conversation flowing. This number of participants also facilitated thematic saturation, as indicated by data redundancy . An additional pilot focus group was run with five women aged 40–74.Each participant was given a $100 gift voucher at the conclusion of the focus group as compensation for their time and any costs associated with attendance.Online focus groups were conducted via Zoom across October-November 2022. An additional pilot focus group was conducted in October 2022 to trial the presentation material with the study population. Minimal changes were made, namely to questions posed to participants to improve the flow of the presentation and focus discussions.Each focus group lasted approximately one and a half hours, and consisted of an introduction, a demographic questionnaire, a PowerPoint presentation interspersed with discussions and questions, and a final questionnaire regarding knowledge and attitudes towards breast cancer risk factors. Questionnaire links were sent in the Zoom chat during the focus group session, data was collected using Qualtrics.Each focus group was facilitated by one female moderator (BN) with a PhD in public health, alongside another female moderator (JA) with a Masters of Public Health who addressed participant technical queries and took notes. BN gave an audio-visual presentation at each focus group, which had been developed and reviewed by a multidisciplinary team of public health and medical researchers, breast clinicians, a health psychologist, BreastScreen staff, and a consumer representative. It was developed using high-quality and up-to-date research evidence interpreted for a lay audience –18. The At the beginning of each focus group, it was made clear that study researchers were not looking for a consensus in the discussions and that it was important to hear everyone’s honest thoughts and opinions. It was stated that disagreements were normal to have but asked that respect be maintained between all members of the group and moderators.Focus group discussions were audio recorded via a recording device external to Zoom, transcribed verbatim, and analysed thematically. The analysis initially took an inductive approach to ensure that the findings were grounded in participant responses and the data was analysed at semantic level. Notes were initially made during the focus group by one researcher. Alongside these, two researchers independently read the transcripts and developed an initial list of recurring themes. Using constant comparison, the two researchers looked for similarities and differences in the data and the initial coding framework was developed and discussed. Once the coding framework was finalised, coding was performed in NVivo 11 one researcher and checked by the second, with slight modifications made throughout and discussed. The final coding was then examined to identify overarching themes and concepts.Questionnaires were administered at the beginning and end of each focus group to capture participant characteristics and provide additional quantitative data to contextualise the qualitative data, using survey questions adapted from previous literature and purpose-designed questions. The initial questionnaire collected sociodemographic measures, along with self-rated health, family history of cancer, screening history, cancer history, breast cancer worry , and welTable The qualitative analysis identified four main themes. Participant quotes are presented throughout the results to illustrate common and diverse responses. There were no distinct differences observed between age groups, however outlined are a few points where age considerations were relevant.In general, there was poor knowledge about both non-modifiable and modifiable risk factors for breast cancer among women in the focus groups. Women discussed their knowledge about the importance of screening in relation to preventing breast cancer and that this was predominately the information they had seen or heard about prevention, but admitted they knew very little about risk factors in relation to primary prevention.Some women had heard of the link between family history and breast cancer, however women were unaware of specific information relating to this risk. This was also true for women who stated they had a known family history of breast cancer.Other non-modifiable risk factors including age and breast density were not well-known with only a few women having previous knowledge on these risk factors. There was an overall knowledge amongst the women that some risk factors tend to increase with age, yet women did not realise that there was a marked increase in risk of breast cancer related to increasing age. Breast density had only been heard about by a few women across the focus groups.“One thing that was new to me was the sharp incline in likelihood [of breast cancer] as women age. I didn’t realise that. And understanding that there’s a lot of the risks that you can’t control. You can’t control your age, you can’t control the breast density. Actually, I don’t think I knew about breast density.” .The majority of women in the focus groups also did not know that lifestyle (or modifiable) factors could increase one’s risk of breast cancer. While some women knew about certain risk factors such as smoking for lung cancer or sun exposure for melanoma, they were unaware about specific modifiable risk factors for breast cancer.“Some of the lifestyle factors in a way surprised me … of course we all think of smoking/lung cancer, things like that, but sometimes I don’t necessarily associate those lifestyle things with breast cancer or possible other cancers as well.” .The information presented to women on modifiable risk factors, specifically alcohol consumption and postmenopausal obesity, generated a lot of conversation amongst the women. This was mainly around the novelty of the information with most women never having heard that these factors were linked to risk of breast cancer.“I didn’t actually realise about the alcohol. I don’t think I’ve ever seen anything about risk factors and alcohol” .“I am quite shocked about the weight thing, and that I haven’t had that information, even though I think I’m really well-informed about most things.” .Women discussed that they had heard about risk factors such as alcohol and obesity in relation to other conditions, specifically heart disease, however not in relation to breast cancer.“I was personally unaware of the changes regarding the weight gain in relation to the hormone changes. I think that this is a piece of information that is underestimated. At least for me it was not known. I’ve never heard of the relation with how you put on weight and the stage of your life in relation to the chances of developing breast cancer. It was more just like a generic one in eight women will develop cancer in their lifetime, breast cancer. So, for the me the striking point was the weight gain and the BMI index.” .“I thought it was BMI and alcohol – well more waist circumference was more to do with heart disease, not breast, or the chance of getting breast cancer.” .Upon digesting the information, some women were left in what they described as being almost a state of shock about this new, and for some women, confronting information.“This has really shocked the life out of me. I don’t want to be at risk of getting breast cancer.” .“I’m just shocked about the alcohol. I’m shocked. I’m shocked.” .Women tended to be more vocal in their responses and the discussion that they felt was most relevant to their situation. If a woman felt she drank alcohol more often (e.g. one or two glasses with dinner every night) or had gained weight in recent years, the information felt more personal and she focused on those statistics more than others. These women also tended to have questions in relation to risk that were specific to their lifestyle e.g. risk of binge drinking compared to a glass or two per night.“I feel I’m somewhat overweight. I do drink quite a bit of wine and I’m over 50, so it’s quite depressing. Yeah, it’s hard content to hear.” .Some women expressed increased motivation to change their lifestyle behaviours after hearing about the risk factors.“I’ve put on quite a lot of weight, but that’s due to inactivity … It’s kind of making me feel like I should do something about it. I have lost a bit of weight, but it seems like I should do some more.” .However, there were a few women also expressed reluctance to change their lifestyle behaviours after learning about this information, particularly in regard to alcohol consumption. These women acknowledged the lifestyle risk factors, but balanced the information with their personal preferences for quality of life and lifestyle.“There’s lots of things that you can’t change and you just have to – as I said, you’ve got to live a life and you can be aware of the things like smoking. I wouldn’t smoke. But I think by having – like certain amounts of risk that you’re willing to take to just have an enjoyable life.” .Overall, women discussed that this information would allow them to make better informed decisions about their health. Of the few women who had heard about various modifiable risk factors previously, they acknowledged that this information was not always in the public space e.g. in mammography screening settings and that you often had to actively look for it.“You’ve got to do a bit of digging around and reading yourself to access what you want to know. It’s not always out there in the public space.” .Women overwhelmingly felt that information about breast cancer risk factors, in particular potentially modifiable risk factors, should be communicated more broadly to women in the Australian community, particularly to women around the age of menopause. Although, it was also noted that this information should even be provided at an earlier age.“You can’t just wait until you’re 40, 50, even 30. It has to be something that us women, girls are aware since an earlier age. And just for the overall benefit of it, not just for the breast cancer, but the modifiable risk factors are going to have such an important chain effect onto a variety of other aspects of our lives … the earlier the better.” .Women had varying preferences for sources of communication about breast cancer risk information. Many women, particularly those in the 40–49 and 50–59 years focus groups, identified social media as a way of engaging in information about breast cancer risk factors, particularly those who felt that they would not seek this information out otherwise e.g., women who did not have a family history of breast cancer or any other known risk factors.“But I think that some sort of government sponsored information campaign on social media – maybe a campaign to target people who perhaps wouldn’t otherwise access that information.” .“Sometimes, I do click on some ads on Facebook, so that might be a way, if it was presented, if I was just scrolling anyway, I might stop and look at something if it was presented in quite an easy format.” .Women also identified GPs as a trusted source of information. However, women also expressed that they found GPs were often rushed and had limited appointment time or availability, and that they rarely saw GPs for prevention. Women’s health clinics were instead suggested as a place for discussion and to ask questions, if they were widely accessible.“GPs are always important because the credibility of the source of the information is probably important and GPs of course are trusted kind of person.” .“It’s hard to get in to see a GP these days. And they’re just, “What’s your issue, boom-boom-boom”, and you’re out.” .“So, if there was, like, a clinic or health women’s clinic where you could discuss anything, not just breast cancer, anything related to women” .Several women also preferred discussion-based methods .“I may stop and listen if it’s from a celebrity that I like and I know has been through breast cancer.” .“If you can relate to someone, or you see someone in advertising or someone telling their story and you can relate to them, like a mother with children and you’re a mother with children, you would be more likely to take notice because you can see yourself in their shoes.” .There were a number of women who also discussed BreastScreen Australia as being a potential source of information. Women identified that this information could be potentially provided in the screening invitation information, appointment reminders or results letter, or at the time of the appointment. They felt that this would be a point in time when the topic of breast cancer would be on their mind and that they would be more likely to engage in the information, rather than just thinking only about the importance of screening in relation to breast cancer prevention.“But perhaps with that message that you get as a reminder, or I don’t know if they email, a link to the causes and risks of breast cancer could be included, so that you’d become aware of the risks.” .“Or while you’re at the mammogram place, there could be information there. Because it’s sort of on your mind when your getting a mammogram, it’s a prime time to get the messages.” .A few women preferred interactive methods which they felt they would be more engaged in and would help make the information more personal.“I personally like some interactive, so you can put your own details or risk factors in and get some information about what your risk might be or – yeah, it makes it a bit more personalised, I guess.” .Other suggestions that were spontaneously mentioned included having brochures at GP offices and BreastScreen clinics or private screening clinics when receiving a mammogram; advertising in public domains ; and having warning labels on alcohol.There was a strong preference across the focus groups that women wanted the information presented as a ‘cascade of information’ where they would be presented with a bit of information with details, links or resources to further information which they could source if preferred. Women wanted the initial information to be eye-catching, engaging and relatable, where possible.“Pictures that usually grab my attention. If there’s something like a link to a website, then you can go there and look for further info. But yeah, it’s definitely pictures and graphs that grab my attention.” .Several women reported ‘information overload’ as a barrier to accessing and engaging with health information, particularly in the last few years with COVID-19 information.A few women also discussed that hearing too much information about health has led them to disregard the information and advice.“There’s just so much information about so many different types of cancer, I tend to just be like, yeah, okay, whatever.” .A few women also reported being confused by health messaging, due to the information changing over time, or the different information and advice from different health conditions.“And it’s confusing, because one health study will say “Yeah, red wine’s great for your heart, good for the brain” and now, yeah, you think, well, this one’s saying any alcohol is bad for the breast.” .Women identified needing a widespread approach in terms of the different methods and sources of information with a concern about culturally and linguistically diverse communities and women with lower health literacy.“I also want to say that there’s about a quarter of our population that may not be so fluent in English and the information needs to be in other languages and other formats, and we are all not all very literate in health literacy, health languages.” .There were several different interventions  that women showed interest in however, long-term compliance was discussed as a point of concern for women. They felt that often these types of interventions are not sustainable. Peer support was brought up by many women as a preferred lifestyle intervention that may be more sustainable. They felt that this would help hold them accountable. A few women in the older age groups wanted personalised coaching for the same reason.“We may as a generation tend to go towards that support group style and keeping each other accountable and motivating each other and supporting each other in triumphs and failures as well.” .“Someone [professional] to hold you accountable I guess.” .The suggestion of mobile applications (apps) received mixed opinions. Some women preferred apps as they felt this was an easy and convenient intervention, while others did not due to various reasons . For women who preferred apps, there was no clear pattern in age distribution.“I would say the apps, because I’m doing the health apps by phone, and I’m really sort of sticking to it and trying to lose weight and keep fit. And I think that for me personally is the way to go.” .“I have used apps before and they worked when you’re putting in the true information. You can choose not to put in things like that, if you know you’ve eaten too much or drank too much.” .Increased access to allied health services was mentioned by some women as a way of supporting health lifestyle changes, in particular in relation to exercise support.“I’d like to see more support through Medicare for allied health services.” .Table This qualitative focus group study of peri- or post menopausal women living in Australia found that general knowledge of risk factors for breast cancer is limited. Women highlighted the importance of breast cancer screening to prevent breast cancer, however had little to no knowledge about risk factors, particularly modifiable risk factors. Findings from this study are similar to those in previous Australian quantitative studies , 23 whicThe findings highlight the need to educate women in the Australian community about risk factors for breast cancer more broadly. While it is important to target women around the age of menopause, when risk factors for breast cancer change, education at an earlier age was mentioned in the focus groups and has been proposed by experts in the field of breast cancer prevention as an area in which prevention efforts could be expanded , 25. ForAnother specific time point worthy of attention for prevention efforts, which women in the focus groups raised, was during their breast screening process. Women discussed that information could be given alongside their screening invitation and information or results letter and/or at the time of their appointment. They believed that this was a time when breast cancer would be top of mind and that they would be more likely to engage in this information. Additionally, when directly asked about information preferences in the final questionnaire, a third of the women chose the BreastScreen Australia program, as their preferred way of receiving information about risk factors for breast cancer. If this was to be implemented by the BreastScreen program careful consideration about how and when to best to provide this information to women would be needed.Women in the focus groups overwhelmingly wanted to be told information on modifiable risk factors for breast cancer, however even within the age-range of women eligible for population-based screening, communication preferences varied widely. Findings, similar to previously mentioned work , highligTo the best of the researchers’ knowledge this is the first Australian qualitative study which explores current knowledge, understanding and experience of various potentially modifiable risk factors for breast cancer, and views on current and future communication strategies for this information and potential intervention preferences. The focus groups were made up of a diverse sample of women from across Australia varying in education and age pre/post-menopause. The information that was presented to women was based on the best and most up-to-date evidence, and the presentation was developed by a multidisciplinary team, a consumer representative and was rigorously piloted tested prior to commencing.The study may be limited by the complexity of some of the information presented to women. Participants’ understanding of the information was not testing although data indicated that most women engaged thoughtfully with the discussion. A formal assessment of women’s health literacy was also not collected and therefore, were not able to elaborate on how women’s health literacy might have impacted their overall responses. Conducting the focus groups with a small sample of women (4–6 in each group) face-to-face allowed for time to go through the information and to provide clarification where needed . FurtherIn conclusion, findings from this study highlight the limited awareness amongst women about lifestyle-related risk factors for breast cancer. It also highlights the need for more widespread community communication and education about these risk factors, in particular potentially modifiable risk factors such as alcohol consumption, postmenopausal obesity and physical activity. Building health literacy around these risk factors for breast cancer may support women to make informed decisions about their own breast health and potentially change behaviour or could motivate the uptake of effective prevention strategies. Furthermore, these findings are timely as breast screening programs in Australia and globally are beginning to evaluate the possibility of future risk-related screening for breast cancer which will provide an additional context for primary prevention. As planning of messaging and piloting of interventions regarding lifestyle prevention in breast cancer is needed now, gaining an understanding of women’s preferences for communication and forms of interventions is vital. Future studies can build on this work by further exploring some of the key issues identified, for example by tailoring communication about alcohol specifically in relation to breast cancer risk, or by canvassing knowledge, preferences and interest amongst younger age-groups and key stakeholders.


Inflammatory, insulin and oestrogenic pathways have been linked to breast cancer (BC). We aimed to examine the relationship between pre-diagnostic dietary patterns related to these mechanisms and BC survival.The diabetes risk reduction diet (DRRD), inflammatory score of diet (ISD) and oestrogen-related dietary pattern (ERDP) were calculated using dietary data from the European Prospective Investigation into Cancer and Nutrition (EPIC) study. Cox proportional hazards models were used to assess associations between dietary patterns and overall mortality and competing risk models for associations with BC-specific mortality.1–SD 0.92; 95%CI 0.87–0.96). Greater adherence to pro-inflammatory diets was borderline associated with 6% higher mortality HR1–SD 1.06; 95%CI 1.00–1.12. No significant association with the oestrogen-related dietary pattern was observed. None of the dietary patterns were associated with BC-specific mortality.We included 13,270 BC cases with a mean follow-up after diagnosis of 8.6 years, representing 2340 total deaths, including 1475 BC deaths. Higher adherence to the DRRD score was associated with lower overall mortality (HRGreater adherence to an anti-diabetic and anti-inflammatory diet prior to diagnosis is associated with lower overall mortality among BC survivors. Long-term adherence to these dietary patterns could be a means to improve the prognosis of BC survivors. Breast cancer (BC) accounts for one in four cancer cases and one in six cancer deaths among women worldwide . DeclineA comprehensive review of the literature concluded that the current evidence suggests that excess body fatness is a predictor of poor survival, while physical activity may be associated with better prognosis among BC survivors . The samProspective observational studies have found that dietary patterns defined as “healthy” or based on dietary guidelines  are associated with better survival among breast cancer survivors –8. AlthoBreast cancer is strongly influenced by hormones, especially oestrogens, which are involved in the aetiology of this disease . High leHerein, we examined the associations between adherence to three previously developed dietary patterns—the diabetes risk reduction diet (DRRD), the inflammatory score of diet (ISD), and the oestrogen-related dietary pattern (ERDP)—and breast cancer-specific and all-cause mortality among breast cancer survivors identified in the European Prospective Investigation into Cancer and Nutrition (EPIC) study. We hypothesised that greater adherence to a low-risk diet for T2D, an anti-inflammatory diet, and a more anti-oestrogenic diet, may be associated with better prognosis outcomes in breast cancer survivors.We used data from EPIC, a collaborative cohort study of more than half a million middle-aged adults recruited between 1992 and 2000. The methods have been previously described in further detail . BrieflyAfter excluding participants with prevalent tumours at recruitment, subjects without information on follow-up, lifestyle, and diet, as well those with implausible diet , a total of 318,686 women from nine countries participated in this study .Incident breast cancer cases and vital status were identified through population-based cancer registries in Denmark, Italy, the Netherlands, Spain, Sweden, and the United Kingdom. In France and Germany, a combination of follow-up methods was used including health insurance records, cancer pathology registries and active follow-up of study participants and their next of kin. Follow-up for cancer endpoints, vital status, and causes of death was available until 2015.We used the International Classification of Diseases for Oncology ICD-O-2) and breast cancer coded as C50-50.9 to define breast cancer cases. A total of 13,320 incident primary malignant breast cancer cases were identified; after excluding 7 cases with unknown vital status, 12 with inconsistent follow-up data, and 31 with non-epithelial morphology, a total of 13,270 breast cancer cases (of which 14 in situ) were included in the present analysis. During the follow-up 2,340 cases died, of which 1475 due to breast cancer. Specific causes of death of women included in this analysis are shown in Table S and breaLifestyle data collected at recruitment included questions on education, occupation, history of previous illness, lifetime history of smoking habit and alcohol consumption, and physical activity level. Usual diet during the previous 12 months was assessed at recruitment using validated country/centre-specific dietary questionnaires, mainly food frequency questionnaires and, to a lesser extent, diet history questionnaires , 22. TheThe three dietary patterns used have been previously described in detail , 24, 25.The DRRD, developed by Rhee et al.  and furtThe ISD was initially based on the Dietary Inflammatory Index (DII) . A modifSimilarly, the ERDP score is comprised of foods with assigned weights according to levels of unconjugated oestradiol and the ratio of 2- and 16-hydroxylated oestrogen metabolites . To calcWe used Cox proportional hazards models to prospectively analyse the association between the exposures (dietary patterns) and overall mortality. Fine-Grey competing risks models , consideAll survival models were stratified by country and menopausal status at diagnosis . Multivariable-adjustment for potential confounders included age at diagnosis (5-years categories), attained level of education , body mass index , physical activity , alcohol consumption reported at recruitment , smoking habits and intensity as cigarettes per day (cig/day) at recruitment , ever use of hormone replacement therapy for menopause at diagnosis , tumour stage , tumour grade , and tumour receptor status  for: oestrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2).The proportional hazards assumption was evaluated checking the graphs of the scaled Schoenfeld residuals. To further assess the association of mortality outcomes with dietary patterns on a continuous scale, restricted cubic spline models were used Fig. S, and nonWe fitted different models as follows: first, each dietary pattern was introduced independently as a categorical variable in quartiles, with the first quartile as the reference category. Tests for linear trend were performed using median value for each quartile of dietary patterns. Second, dietary patterns were used as continuous variables by 1–SD increase in the scores. On the other hand, mutually adjusted models were fitted by including the three dietary patterns as quartiles. The scores of the three dietary patterns were correlated; the Pearson correlation coefficients of DRRD with ISD and ERDP were –0.36 and –0.23, respectively, and the coefficient between ISD and ERDP was 0.12. Therefore, the residuals for each dietary pattern from a separate multiple regression model for each, including the other two patterns, were used as continuous variables to assess the association of mortality with a 1 SD increase in score.Furthermore, we also dichotomised DRRD and ISD  and assessed the cross-classification of these patterns according to low-low, high-high, high-low DRRD and ISD categories, respectively, compared to the reference category  in relation to overall mortality. We assumed that the mechanisms by which a low score of DRRD is associated with high risk of T2D is insulin resistance (IR). We used the label high-IR for women with DRRD below the median, and low-IR for those with DRRD score equal or above the median. Direct-adjusted survival curves by DRRD-ISD categories were derived from the multivariable Cox model with country and menopausal status as adjustment variables, followed by the rest of the covariates .Subgroup analyses by menopausal status, body mass index (BMI), physical activity, stage of tumour, and hormone receptor status, were performed for DRRD, ISD and ERDP scores . Heterogeneity across groups was determined using the LR test.Sensitivity analyses were performed by additionally adjusting the survival models for time from recruitment to diagnosis, to check the assumption of stability of dietary assessment, and for the period of diagnosis to check potential influence of improvements in treatment and diagnosis over time. Stratified analyses were explored by categories of these two variables: time from diet measurement to diagnosis ; period of diagnosis . The cut-off points for both variables were based on the distribution of quartiles 1, 2 and 3 of breast cancer cases. Additionally, multivariable models further adjusted by these two variables  were performed. An additional adjustment was made for the presence of co-morbidities (separate variables: reported cardiovascular (CVD) problem and diabetes) given the outcome is overall survival. Other models excluding diabetic BC survivors to assess the effect of the low-insulin diet in women without pre-existing influence on this pathway were performed. We finally excluded breast cancer survivors with unknown tumour stage and unknown status of HER2 receptor, in separate models, to test whether treatment differences associated with these characteristics might modify the magnitude of the associations.Our study included 13,270 incident breast cancer cases with a mean follow-up of 8.6 years from diagnosis (SD 4.9 years), of whom 2340 died and 1475 due to breast cancer. Breast cancer cases were predominantly 55–65 years old, non-smokers, moderate alcohol consumers, in the normal-weight range (mean BMI 24.9) and physically inactive. The majority were postmenopausal (77%) and had non-metastatic tumours (82%) , remaining the same for ISD. The ERDP score, however, was not associated with survival outcomes. The assessment of associations of dietary patterns and overall mortality by means of restricted cubic splines , presumably because it was not masked by obesity. However, none of the interaction terms were statistically significant, suggesting that there is no strong evidence for differential effects of these dietary patterns on mortality in subgroups of breast cancer survivors according to potential determinants of prognosis or features of the tumour.Associations between DRRD and ISD and overall mortality  were more apparent for postmenopausal, physically inactive women, with metastatic tumours, and in those with PR+, ER+ and HER2- (with DRRD), and ER- tumours (with ISD) Table . Women pSince DRRD and ISD appeared to show independent effects on overall mortality, a dichotomised version of each score (above and below median) was computed to assess their combined effect Fig. . CompareSensitivity analyses were performed to assess the potential influence of two aspects: a possible modification of diet between the time of recruitment and diagnosis, and the period time of diagnosis . Overall, the main results of DRRD and ISD scores, which were inversely and positively associated with all-cause mortality, respectively, remained stable Table . On the In this large, prospective cohort study of 13,270 breast cancer survivors followed for a mean of 8.6 years after diagnosis, we found that women with a higher adherence to a low-risk diet for T2D (higher DRRD score) before diagnosis had lower risk of all-cause mortality after BC diagnosis. In the opposite direction, a more pro-inflammatory diet (higher ISD) was positively associated, though borderline statistically significant, with risk of all-cause mortality. The ERDP, a dietary pattern capturing the oestrogenic potential of diet, showed no association with mortality among breast cancer survivors. None of the three dietary patterns were associated with breast cancer-specific mortality. To our knowledge, this is the first time that insulinemic, inflammatory and oestrogenic potential has been assessed through dietary patterns in relation to breast cancer survival.In line with previous excellent research on the subject, the role of diet as a protective factor in cancer survival appears to be still limited. Obesity is a strong predictor of prognosis; in fact, in our study, the HR (95%) of mortality for obesity was 1.29 (1.14–1.47). One may think that part of the relationship between diet and mortality could be mediated by BMI. However, we have accounted for the effect of obesity by including BMI in all models. Furthermore, the potential confounding effect of BMI on the associations between the anti-diabetic and anti-inflammatory patterns and mortality seem to be small: when BMI is taken out from the model the HRs (95% CI for 1–SD) increase from 0.92 (0.87–0.96) to 0.91 (0.87–0.95) for the DRRD, and from 1.06 (1.00–1.12) to 1.07 (1.01–1.14) for the ISD.These scores were chosen because they are related to underlying biological processes or mechanisms that have been found to be associated with breast cancer risk or progression. T2D is linked to insulin resistance, which has been shown to have a negative impact on breast cancer prognosis , 29. InsAnother mechanism that is believed to contribute to BC progression is chronic low-grade inflammation . The posAccording to our results, it appears that dietary patterns related to mechanisms of insulin resistance and inflammation may have a more evident effect in postmenopausal, normal-weight, physically inactive women. This could be partially explained by the potential effects of a low-insulin resistance diet and an anti-inflammatory diet becoming evident only among women for whom hormonal pathways are less relevant and without other strong determinants of these mechanisms such as obesity and physical activity. In addition, previous studies have consistently reported that inflammatory cytokines and higher insulin levels increased oestrogen synthesis by aromatase activation , 38, 39.On the other hand, breast cancer hormone receptor status is considered a predictor of prognosis, and diet might have differential effects on overall survival depending on this. In stratified analysis by hormone receptor status, associations between DRRD and ISD with overall mortality were observed among PR+ subtype tumours, although interactions were not statistically significant. Owing to the high proportion of missing data on hormone receptor status we had limited power to detect differences in overall mortality between these subtypes. Indeed, we found no association with the oestrogenic dietary pattern, which is an unexpected result; we have no explanation for it.Given the potential inter-relationship between the pathways represented by the DRRD and ISD scores, it was worth exploring the combination of DRRD and ISD on mortality among breast cancer survivors. Survivors following a low-IR and anti-inflammatory diet had a 17% lower risk of all-cause mortality compared to those following a high-IR and pro-inflammatory diet. The combination of these two dietary patterns that previously showed an individual effect on mortality is of interest to explore new dietary strategies to improve survival after breast cancer. The adjusted mean intakes , the long follow-up from the date of diagnosis, and detailed information on potential confounders. Furthermore, the availability of dietary components from which dietary patterns are derived from standardised dietary intake using means and standard deviations derived from EPIC captures the main food groups consumed by the European population.One important limitation of our study is the lack of information on treatment, which is a strong determinant of prognosis and survival. To mitigate this issue, at least partially, we used the available information on tumour stage at diagnosis, grade of tumour differentiation and receptor status as a potential surrogate for treatment, since these characteristics often determine the therapeutic approach in these patients. In addition, we also considered the hypothesis that patients with an older diagnosis would have a worse prognosis than newly diagnosed patients due to advances in treatment. However, the effect estimates remained similar in sensitivity analyses for different time periods. Secondly, dietary intakes were measured only once at baseline, which may not be sufficient in determining the patient’s usual intake over the years and after diagnosis. Despite this, sensitivity analyses concluded that the association for high adherence to DRRD and to a lesser extent to ISD was maintained across the different time periods from diet measurement to diagnosis. Finally, as in every observational study, residual confounding is possible, although we controlled for a wide range of predictors of diet and breast cancer mortality.In conclusion, our findings from a large prospective cohort study suggest that anti-diabetic (or low insulin resistance) and anti-inflammatory diets prior to breast cancer diagnosis are associated with mortality among breast cancer survivors. This may be tempered by the fact that we did not see a clear association with improved breast cancer outcomes; moreover chronic inflammation and hyperinsulinemia maybe be related to a variety of causes of death. Nevertheless, although we do not fully understand the pathways and mechanisms, the long-term adherence to anti-diabetic and anti-inflammatory dietary patterns could be a means to improve the prognosis of breast cancer survivors, and hence could help provide dietary recommendations. Further studies using dietary patterns related to biological mechanisms, especially nutritional intervention studies, are warranted.Where authors are identified as personnel of the International Agency for Research on Cancer/World Health Organisation, the authors alone are responsible for the views expressed in this article and they do not necessarily represent the decisions, policy, or views of the International Agency for Research on Cancer/World Health Organisation.Restricted cubic splines models of the scores and overall mortalitySpecific causes of deathDescriptive of breast cancer survivors across EPIC countriesFood items included in the DRRDFood items included in the ISDFood items included in the ERDPModels for different versions of DRRD scoreAdjusted mean intakes of food groups for ISD and DRRD scores


Current or recent use of combined oral contraceptives (containing oestrogen+progestagen) has been associated with a small increase in breast cancer risk. Progestagen-only contraceptive use is increasing, but information on associated risks is limited. We aimed to assess breast cancer risk associated with current or recent use of different types of hormonal contraceptives in premenopausal women, with particular emphasis on progestagen-only preparations.Hormonal contraceptive prescriptions recorded prospectively in a UK primary care database  were compared in a nested case–control study for 9,498 women aged <50 years with incident invasive breast cancer diagnosed in 1996 to 2017, and for 18,171 closely matched controls. On average, 7.3 (standard deviation [SD] 4.6) years of clinical records were available for each case and their matched controls prior to the date of diagnosis. Conditional logistic regression yielded odds ratios (ORs) and 95% confidence intervals (CIs) of breast cancer by the hormonal contraceptive type last prescribed, controlled for age, GP practice, body mass index, number of recorded births, time since last birth, and alcohol intake. MEDLINE and Embase were searched for observational studies published between 01 January 1995 and 01 November 2022 that reported on the association between current or recent progestagen-only contraceptive use and breast cancer risk in premenopausal women. Fixed effects meta-analyses combined the CPRD results with previously published results from 12 observational studies for progestagen-only preparations.p < 0.001), 1.26 , 1.25 , and 1.32 , respectively. Our meta-analyses yielded significantly raised relative risks (RRs) for current or recent use of progestagen-only contraceptives: oral = 1.29 , injected = 1.18 , implanted = 1.28 , and IUDs = 1.21 . When the CPRD results were combined with those from previous published findings (which included women from a wider age range), the resulting 15-year absolute excess risk associated with 5 years use of oral combined or progestagen-only contraceptives in high-income countries was estimated at: 8 per 100,000 users from age 16 to 20 years and 265 per 100,000 users from age 35 to 39 years. The main limitation of the study design was that, due to the nature of the CPRD data and most other prescription databases, information on contraceptive use was recorded during a defined period only, with information before entry into the database generally being unavailable. This means that although our findings provide evidence about the short-term associations between hormonal contraceptives and breast cancer risk, they do not provide information regarding longer-term associations, or the impact of total duration of contraceptive use on breast cancer risk.Overall, 44%  of women with breast cancer and 39%  of matched controls had a hormonal contraceptive prescription an average of 3.1 (SD 3.7) years before breast cancer diagnosis . About half the prescriptions were for progestagen-only preparations. Breast cancer ORs were similarly and significantly raised if the last hormonal contraceptive prescription was for oral combined, oral progestagen-only, injected progestagen, or progestagen-releasing intrauterine devices (IUDs): ORs = 1.23 , including almost 10,000 women aged <50 years with breast cancer, to assess the relationship between a woman’s recent use of hormonal contraceptives and her subsequent risk of breast cancer.In our study, current or recent use of hormonal contraceptives was associated with a similarly increased risk of breast cancer regardless of whether the preparation last used was oral combined, oral progestagen-only, injectable progestagen, progestagen implant, or progestagen intrauterine device.When our findings for progestagen-only contraceptives were combined with those of previous studies, there was evidence of a broadly similar increased risk of breast cancer in current and recent users of all four types of progestagen-only preparations.Our findings suggest that there is a relative increase of around 20% to 30% in breast cancer risk associated with current or recent use of either combined oral or progestagen-only contraceptives.When our findings for oral contraceptives are combined with results from previous studies (which included women in a wider age range), they suggest that the 15-year absolute excess risk of breast cancer associated with use of oral contraceptives ranges from 8 per 100,000 users (an increase in incidence from 0.084% to 0.093%) for use from age 16 to 20 to about 265 per 100,000 users (from 2.0% to 2.2%) for use from age 35 to 39.These excess risks must be viewed in the context of the well-established benefits of contraceptive use in women’s reproductive years.The lack of complete information on a woman’s prescription history means that this study was unable to assess the long-term associations of contraceptive use on breast cancer risk, but this should not have unduly affected the findings regarding their short-term associations. A meta-analysis of the worldwide evidence on breast cancer risk associated with use of combined (containing oestrogens plus progestagens) oral contraceptives in 1996 found a slightly increased risk in current or recent users that declined after use ceased, with no apparent excess risk 10 or more years after cessation –12.Use of the different types of hormonal contraceptives has changed over time, with recent increases in use of progestagen-only preparations, both as oral and as long-acting parenteral formulations such as injectables, implants, and progestagen-releasing intrauterine devices (IUDs). In England, for example, prescriptions for oral progestagen-only contraceptives almost doubled in the last decade (from 1.9 to 3.3 million from 2010 to 2020); and in 2020, there were almost as many prescriptions for oral progestagen-only contraceptives as for oral combined contraceptives (3.3 million of each) . Given tWe aimed to assess breast cancer risk associated with current or recent use of different types of hormonal contraceptives in premenopausal women, with particular emphasis on progestagen-only preparations. We present new data on breast cancer risk associated with prospectively recorded prescriptions for hormonal contraceptives in women aged <50 years in the United Kingdom (UK) primary care Clinical Practice Research Datalink (CPRD) and conduct meta-analyses of breast cancer risk associated with current or recent progestagen-only hormonal contraceptives, combining the new and previously published findings.This study is reported as per the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guideline  and the The CPRD is a computerised UK primary care database containing anonymised, linked, and prospective medical records for approximately 11 million individuals registered with a National Health Service (NHS) general practitioner (GP) . As of 2The association between use of hormonal contraceptives and invasive breast cancer risk in CPRD was studied using a nested case–control design. Although the original protocol allowed for the assessment of hormonal contraceptive use in relation to both in situ and invasive breast cancer, we present findings here for invasive breast cancer only since this was the primary outcome of interest. Cases are all women aged 20 to 49 years with incident invasive breast cancer recorded between 1 January 1996 and 20 September 2017, with no prior record of incident in situ breast cancer. Invasive breast cancer was defined using CPRD Read codes for the disease  16]. Oe. Oe16]. For each case, the “observation period” (the period during which reliable prescription data were available before diagnosis) was defined as starting either from 1 January 1995 or from the date of entry into an up-to-standard CPRD practice (whichever was later) and ending at the date of diagnosis. Two controls were selected for each case, matched on index date (date of diagnosis of the case), year of birth (+/−2 years), general practice, and observation period (the duration of observation prior to the index date for the control had to be at least as long as that of the case). Controls were selected from women with no record of invasive or in situ breast cancer before 20 September 2017. The resulting sample size was deemed sufficient to detect relevant effect sizes . To ensuWomen were defined as having a prescription for hormonal contraceptives if they had one or more prescriptions for any hormonal contraceptive during the observation period. Nonusers were defined as women having no such prescription. We used the British National Formulary system (BNF sections 7.3.1 and 7.3.2 ) to clas2), and alcohol intake . For alcohol intake and BMI, we used the most recent record in the 10 years prior to 6 months before the index date. All of these adjustment variables had been specified in the original study protocol except for time since last birth, which was additionally adjusted for due to its observed association with case control status in these data, and its likely relationship with recent use of hormonal contraceptives. In a slight deviation from the original protocol, no adjustment was made for smoking status as it was not considered to be a substantial risk factor for breast cancer in premenopausal women. Women with missing values were assigned to a separate category, and sensitivity analyses were done restricting analyses to women with known values for these variables. Likelihood ratio tests were used to assess evidence of heterogeneity in risks across subgroups of women.A matched analysis was done using conditional logistic regression to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for incident invasive breast cancer in women with one or more hormonal contraceptive prescriptions compared to women with no such prescription during the observation period. We also examined ORs separately in women with one or more hormonal contraceptive prescriptions by type of preparation last prescribed. Previous evidence suggests that the effect of hormonal contraceptive use on breast cancer risk lasts for up to 10 years after use ceases  OR "contraceptive devices"[MeSH Terms] OR "contracept*"[Title/Abstract] OR "intrauterine device*"[Title/Abstract] OR "IUD"[Title/Abstract]) AND )) AND 1995/01/01:2022/11/01[Date—Publication]) NOT Embase:intrauterine contraceptive device/contraception/ or contraceptive agent/ or contracept*.mp.IUD.mp.1 or 2 or 3breast cancer/4 and 5limit 6 to humanlimit 7 to yr = "1995 -Current"limit 8 to adult <18 to 64 years>Eligible studies are those that reported RRs and CIs for breast cancer associated with current or recent use of progestagen-only contraceptives in premenopausal women. Studies that lacked information on recency of use, were restricted to specific patient populations, or included postmenopausal women only were excluded. Information was extracted from each of the included study reports by one reviewer (DF) and checked by another (KP). Information was sought on study characteristics , study participants , analysis characteristics , and study results . This information was tabulated in order to confirm that each study met the eligibility criteria, and to enable assessment of each study in terms of factors that may lead to biased estimates, such as study design and adjustment for confounding. Sensitivity analyses explored the likely impact of potential sources of bias by restricting analyses to studies with particular characteristics. Funnel plots were produced to assess small study effects. This literature review was not registered, and a protocol was not prepared. Where necessary, results reported by fine categories of time since last use were combined in order to produce categories that were more comparable with other studies . SummaryThe main analyses of CPRD data included 9,498 breast cancer cases and 18,171 closely matched controls . By desiDuring the observation period, 4,195 cases (44%) and 7,092 controls (39%) had one or more prescriptions for a hormonal contraceptive, and around two-thirds of these women  had been prescribed only one type of hormonal contraceptive during their observation window. Prescriptions varied considerably by age: for example, among 20- to 29-year-olds, 67% had received a prescription for any hormonal contraceptive in the previous 5 years ; among 30- to 39-year-olds, 48% had received a prescription ; and among 40- to 49-year-olds, 25% had received a prescription .p < 0.001). The mean time between the last hormonal contraceptive prescription and diagnosis of breast cancer  was 3.1 (SD 3.7) years. p = 0.9). For the oral combined, oral progestagen-only, injectable progestagen, progestagen implant, and progestagen IUD, the ORs were, respectively, 1.23 , 1.26 , 1.25 , 1.22 , and 1.32 ; every OR was significantly elevated, except for implanted progestagens, where the numbers were small and the CI correspondingly wide. To examine the extent to which these associations may have been affected by confounding with prior use of other types of hormonal contraceptives, we repeated this analysis among the 7,473 women with an observation period of at least 10 years, and restricting to women with no recorded use of any other hormonal contraceptive type within their observation period. The results were broadly similar for each type of hormonal contraceptive, respectively, with estimated ORs of 1.32 , 1.35 , 1.17 , 1.39 , and 1.40 . All of these ORs were significantly elevated with the exception of those for injected progestagens and implanted progestagens, for which the numbers of exposed cases were extremely small , but there was no evidence that these ORs were materially different from the corresponding estimates from the main analysis.Compared to women with no hormonal contraceptive prescriptions during the observation period, women with at least 1 prescription had significantly increased odds of incident breast cancer . The ORs declined by time since last use (test for heterogeneity p = 0.01), although only around a quarter of all cases had their last prescription more than 5 years previously. In every category of time since last use, ORs did not differ between users of oral combined and of oral progestagen-only contraceptives: for example, among the current users, the ORs were 1.38  and 1.28 , respectively.Oral contraceptives (either combined or progestagen-only) are effective only while they are being used, whereas injected, implanted, and intrauterine hormone-releasing contraceptives can be effective for months or even years . To examp = 0.02 for 1 year versus longer durations) but no significant variation in the ORs between phasic and nonphasic formulations, by the progestagenic component of the preparations, by whether or not other hormonal contraceptive types had been used beforehand, by estimated ER status of the breast tumours, or across categories of women defined by their age or BMI.p = 0.8). We also examined whether use of nonhormonal  IUDs was associated with breast cancer risk; the reference group for these analyses was women with no prescription for either a hormonal contraceptive or a nonhormonal IUD during the observation period. For women last prescribed nonhormonal IUDs, the OR for breast cancer was not significantly elevated , although this OR was not significantly different from that associated with progestagen-releasing IUDs  (ORs for breast cancer were increased in women last prescribed a progestagen-releasing IUD . To inve< 0.001) .p = 0.7), antibacterial eye preparations , or corticosteroids for asthma and other respiratory diseases   .p < 0.001) for all 4 preparation types , injected progestagens , implanted progestagens , and progestagen-releasing IUDs . There was no heterogeneity between the RRs for the 4 types of progestagen-only contraceptives (test for heterogeneity p = 0.3). Results were similar when restricted to studies that only included premenopausal women, to studies with prospectively recorded information, and to studies where women in the reference group had used neither progestagen-only nor combined oral contraceptives , oral progestagen-only contraceptives, injectable progestagens, and progestagen-releasing IUD contraceptives were found to be at increased risk of breast cancer. The ORs for each of these hormonal contraceptives were statistically significant but comparatively small, at around 1.2 to 1.3, with no material difference between the different hormonal contraceptive types. The average time between the last prescription and breast cancer diagnosis was about 3 years, so these results generally apply to current or recent use of these hormonal preparations.p < 0.005), although with substantial heterogeneity in risks for injected progestagens.The ORs for breast cancer among current or recent users of each of these hormonal contraceptives were of similar magnitude to previously reported risks associated with use of oral combined oestrogen-progestagen contraceptives . Fewer sDoses of oestrogen and progestagen constituents in combined oral contraceptives are generally lower than they were in previous decades . AlthougWe considered the possibility that breast cancers might be selectively diagnosed among women who regularly seek prescriptions from their GPs. Any such selective detection might be expected to be greater for oral preparations that require more frequent prescriptions than for long-acting preparations (such as IUDs), but no such differences were found. Further evidence against possible detection bias is that no excess breast cancer risk was associated with other common prescriptions that are often repeated .A major strength of the CPRD analysis presented here is that information on hormonal contraceptive prescribing was recorded prospectively, with reliable information on specific preparations, thus avoiding bias associated with selective recall of contraceptive use after breast cancer has been diagnosed, and misclassification of exposures due to reporting errors. The analyses of CPRD data presented here were matched on GP practice, providing some degree of adjustment for socioeconomic status, and were also adjusted for established risk factors for breast cancer, which might be expected to confound the association between contraceptive use and breast cancer risk. The only exception to this was family history of breast cancer, as information on this factor was relatively incomplete, particularly for controls, as this information was often only recorded around the time of breast cancer diagnosis. While it is unclear what effect, if any, adjustment for family history of breast cancer would have made to our findings, previously published findings for combined oral contraceptives  were unaA limitation of the CPRD data, shared with some other prescription databases, is that the prescriptions are recorded during a defined period only, with information before entry into such databases generally being unavailable. While a lack of complete prescription data makes it difficult to assess the long-term effects of contraceptive use, it does not unduly affect estimates of the short-term effects of such use, which is the main focus of these investigations. The lack of information on hormonal contraceptive use prior to the start of the observation period also means we were unable to allow for the effect of possible differences in duration of use of the different types of hormonal contraceptives on their relative associations with breast cancer risk. Since our analyses of risks associated with specific types of contraceptives categorised women according to the preparation last prescribed, it is possible that prior patterns of contraceptive use could have confounded associations of breast cancer risk with type of preparation last prescribed. However, when we examined risks in women with an observation period of at least 10 years and no prior use of other types of hormonal contraceptives, the results were similar, suggesting that any such confounding had little effect on our results. It is possible that some hormonal contraceptives were prescribed outside UK general practices, but this is uncommon and would, if anything, attenuate any estimated ORs. Furthermore, although some women may not fill the prescriptions they received, those with repeated prescriptions would be more likely to have done so, and their ORs were similar to those in the main findings. While use of primary care data, as opposed to cancer registration data, for ascertainment of breast cancer cases may have led to a small degree of misclassification with respect to breast cancer status, a recent validation study found that the vast majority of breast cancers identified through primary care data (approximately 96%) can be verified through cancer registry data .Perhaps the greatest potential source of bias in the findings from studies included in our meta-analysis is that due to recall bias in studies where information on hormonal contraceptives was recorded after a diagnosis of breast cancer. However, restriction of the meta-analysis to studies with prospectively collected information on contraceptive use yielded similar results, and so recall bias is unlikely to have had a major impact on our findings. Inadequate adjustment for important confounders could also have biased the results of certain studies, but in those studies that assessed the impact of adjustment for other factors in addition to age, ethnicity, and sociodemographic status , it appeThe excess RRs for breast cancer appear to be of similar magnitude in current or recent users of combined oestrogen-progestagen and of progestagen-only contraceptives, be they orally or parenterally administered. In nonusers of hormonal contraceptives, breast cancer incidence is extremely rare before age 30 but increases sharply with age. The estimated absolute excess incidence of breast cancer in current or recent users of oral contraceptives is, therefore, much smaller for use at younger than at older ages . Given that the RRs are similar for oral preparations, injected progestagens, implanted progestagens and progestagen-releasing IUDs, these estimated absolute excess risks would be broadly similar for all types of hormonal contraceptives. These results, which are based on the combination of data from a large number of worldwide studies, are expected to be generalisable to other populations; however, breast cancer incidence is lower in middle-income and low-income than in high-income countries, and, thus, the absolute excess risks would also be expected to be lower. These risks need, of course, to be considered in the context of the benefits of contraceptive use in the childbearing years.The mechanisms underlying the effects of progestagens on the development of breast cancer are poorly understood. It is clear that among postmenopausal women, breast cancer RRs are considerably greater with use of hormonal therapies containing both progestagens and oestrogens than oestrogens alone . HoweverS1 STROBE Checklist(DOCX)Click here for additional data file.S1 PRISMA Checklist(DOCX)Click here for additional data file.S1 Protocol(DOCX)Click here for additional data file.S1 File(DOCX)Click here for additional data file.S2 File(DOCX)Click here for additional data file.S1 Table(DOCX)Click here for additional data file.S2 Table(DOCX)Click here for additional data file.S3 Table(DOCX)Click here for additional data file.S4 Table(DOCX)Click here for additional data file.S1 Fig(DOCX)Click here for additional data file.S2 Fig(DOCX)Click here for additional data file.S3 Fig(DOCX)Click here for additional data file.


This study assessed the effects of 12-week supervised resistance training combined with home-based physical activity on physical fitness, cancer-related fatigue, depressive symptoms, health-related quality of life (HRQoL), and life satisfaction in female breast cancer survivors.A parallel-group, outcome assessor-blinded, randomized controlled trial included 60 female breast cancer survivors who had completed their core treatments within the previous 10 years. Through computer-generated simple randomization, participants were assigned to resistance training  or control . Outcomes were evaluated at baseline and week 12. Muscular strength was assessed with electromechanical dynamometry. A standardized full-body muscular strength score was the primary outcome. Secondary outcomes included cardiorespiratory fitness, shoulder mobility, cancer-related fatigue, depressive symptoms, HRQoL, and life satisfaction.P < 0.001, Cohen's d = 1.04). This increase was consistent for the standardized scores of upper-body  and lower-body  strength. There was no effect on cardiorespiratory fitness, shoulder flexion, cancer-related fatigue, depressive symptoms, HRQoL, or life satisfaction. The sensitivity analyses confirmed these results.Thirty-two participants were assigned to RTG (29 achieved ≥ 75% attendance) and 28 to CG . Intention-to-treat analyses revealed that the standardized full-body muscular strength score increased significantly in the RTG compared to the CG (0.718; 95% CI 0.361–1.074, and implication for cancer survivors.In female breast cancer survivors who had completed their core treatments within the past 10 years, adding two weekly sessions of supervised resistance training to a prescription of home-based physical activity for 12 weeks produced a large increase in upper-, lower-, and full-body muscular strength, while other fitness components and patient-reported outcomes did not improve.Trial registration number.ISRCTN14601208.The online version contains supplementary material available at 10.1007/s11764-022-01192-1. Breast cancer is the most commonly diagnosed cancer type (~ 2.1 million new cases every year) and the leading cause of death in women worldwide . CurrentThe abovementioned reduction in breast cancer mortality over time denotes that an increasing number of women are living long after their initial cancer diagnosis and treatment, which implies facing many short-, mid-, and long-term treatment side effects. Consequently, addressing the management of the breast cancer-related side effects is of major clinical and public health interest. Common side effects following breast cancer includes lymphedema , cardiacCurrent guidelines for the management of breast cancer survivors include counselling regarding physical activity . ConsequHowever, the exercise interventions in oncological exercise-based clinical trials, including breast cancer trials , are pooThe aim of this clinical trial was to evaluate the effects of a 12-week supervised resistance training program combined with a prescription of home-based physical activity, compared with home-based physical activity alone, on muscular strength, physical fitness, cancer-related fatigue, depressive symptoms, health-related quality of life, and life satisfaction in female breast cancer survivors.physical exercise for breast cancer survivors) randomized controlled trial is a parallel-group, randomized controlled trial prospectively registered (ISRCTN14601208) on August 1, 2019, before the enrolment of participants begun . A comprehensive description of the rationale and methodology has been published ) on 31/07/2019.Interested women filled out an online form with basic sociodemographic and disease-related information, and potentially eligible participants were invited for an in-person screening, where medical doctors (MD) assessed the inclusion and exclusion criteria and obtained participants’ informed consent. The enrolled participants attended the exercise laboratory at the University of Almería to complete the baseline assessments. This study adheres to the CONSORT guidelines . The funThe sample size was calculated for muscular strength. A between-group difference in the change from baseline in upper-limb muscular strength of at least 6.9 kg would be considered clinically relevant . AssuminEach participant was randomized (1:1 ratio) either to a resistance training group (RTG) or a waiting list control group (CG). Before the participant’s recruitment, a blinded investigator (AS-M) created a computer-generated simple randomization sequence. Individual allocations were held in sealed, opaque, and consecutively numbered envelopes. After baseline assessments, a blinded member of the staff opened the envelopes in front of each participant and assigned them to the intervention groups. The data analyst and the primary outcome assessors were blinded to the participant allocation.All the participants were requested to continue their habitual lifestyle and their eventual medications during the trial. All the study participants were requested to perform home-based physical activity defined as undertaking ≥ 10,000 steps per day , 43. ComTo maximize transparency and replicability, this exercise protocol follows the Consensus on Exercise Reporting Template (CERT) , and the2).The supervised training sessions were led by exercise professionals with a degree in Physical Activity and Sport Sciences and with specific training in exercise for breast cancer and < 1 year of experience. The exercise program was carried out in a fitness room at the Almería town hall . The baseline assessments were carried out during 14 days prior to the beginning of the intervention, and the follow-up assessments were conducted within 10 days following the intervention period. The principal investigators (AS-M and AJC-A) were responsible for the dataset.r = 1.00; systematic bias < 13.9 N; random error < 52.1 N) for assessing peak force during the isometric mid-thigh pull (IMTP) test  / standard deviation) of the changes from baseline to week 12 in the two upper-body tests depicted in Fig. The primary outcome measure was a standardized full-body muscular strength index, defined as the average of the normalized scores  of the change from baseline to week 12 in 2 different tests, including (i) the sum of the right and left unilateral isometric seated bench press  of the change from baseline to week 12 in 2 different tests, including (i) the sum of the right and left unilateral isometric knee extension in closed kinetic chain at 90°  was estimated through the Siconolfi step test as described elsewhere [Cardiorespiratory fitness  through digital goniometry  following the protocol described elsewhere . Each paCancer-related fatigue was assessed with the patient-reported Functional Assessment of Cancer Therapy-Fatigue (FACT-F) . The scoDepressive symptoms were assessed with the patient-reported Center for Epidemiologic Studies-Depression Scale (CES-D) . The finHealth-related quality of life was assessed with the patient-reported Functional Assessment of Cancer Therapy-Breast (FACT-B) . The gloLife satisfaction was assessed with the Spanish version  of the pBoth the baseline and the follow-up assessments were conducted at the Exercise Laboratory of the University of Almería. Each participant begun filling out a general sociodemographic questionnaire and all the patient-reported outcomes. Thereafter, anthropometric measures were taken in a private room, followed by the shoulder joint mobility, upper- and lower-body muscular strength, and cardiorespiratory fitness. This sequence was performed to minimize fatigue for the primary outcome assessment.Due to recruitment difficulties, the eligibility criterion regarding time from completion of cancer treatments was changed from 5 to 10 years. In the protocol, several muscle strength variables were listed as primary outcomes. To avoid problems with interpretation of results from many primary outcomes, the primary outcome has been set as the standardized full-body muscular strength index alone; the muscular strength of the upper and lower body have been moved to secondary outcomes. The main analyses, initially set as per protocol, have been changed to intention to treat (ITT) to reduce the risk of bias.d [d equal to 0.2, 0.5, and 0.8 were considered small, medium, and large effects, respectively. We checked the homoscedasticity and linearity assumptions of the linear regression models, as well as the normality, non-multicollinearity, and non-autocorrelation of the residuals. The primary analyses were performed under the intention-to-treat principle using baseline observation carried forward (BOCF), and sensitivity analyses were conducted using per-protocol analyses (defined as ≥ 75% adherence to the intervention). A blinded investigator (AS-M) handled all hypothesis testing under the supervision of professional statisticians (EA-R and MAC-A). The main analyses were conducted with Stata v.16.1 . Statistical significance was set at P < 0.05.The distribution of the study variables was assessed through histogram and Q-Q plots. Descriptive characteristics are presented using the mean and standard deviation for quantitative variables and the number and frequency for categorical variables. The comparability of the groups at baseline was checked. The between-group differences in the primary and secondary outcomes were assessed through linear regression, including the baseline outcome value as a covariate. The effect sizes were assessed with Cohen’s d , and valn = 32) and the CG (n = 28). Two participants in the RTG and none in the CG discontinued the intervention. The two participants in the RTG who discontinued the intervention were also lost to follow-up, whereas all the participants in the CG completed the trial. There were two adverse events in the RTG; one participant had a muscular overload in session 15 and one participant presented shoulder discomfort during session 17; both events persisted until the end of the intervention, although they did not impede the participants completion of the majority of the exercises (except those directly involving the affected muscle groups). The median attendance to the resistance training sessions was 23 out of 24 sessions. Of the 32 participants allocated to RTG, 29  attended ≥ 75% of the exercise sessions. Of them, one reported general discomfort and did not perform the muscular strength assessment at week 12. The adherence to the intensity, repetitions, and volume was exactly as prescribed, except for the above-referenced adverse events. The subjective level of effort for each of the four main resistance training exercises throughout the intervention  is presented in Supplementary Figure The CONSORT flowchart of the study participants throughout the study is presented in Fig. The between-group difference in the change from baseline to week 12 in physical fitness and patient-reported outcomes is presented in Tables P < 0.001, d = 1.04, Table P > 0.05).The mean changes (SE) in the standardized full-body muscular strength index from baseline to week 12 were 0.335 (0.122) in the RTG and -0.383 (0.130) in the CG  corroborated the results although with relatively larger effect sizes for muscular strength (Table S3).The main findings of this study indicate that, in female breast cancer survivors who had completed their core treatments within the past 10 years, adding two weekly sessions of supervised resistance training to a prescription of home-based physical activity based on step count for 12 weeks, produced a large increase in upper-, lower-, and full-body muscular strength, although other relevant outcomes such as cancer-related fatigue, depressive symptoms, HRQoL, or life satisfaction did not improve.d > 1), as well as in the muscular strength of the upper and lower body. This increase in muscular strength was not influenced by the time since the core treatments ended. The muscular strength in the bilateral seated bench press and bilateral seated row increased by 35 and 41 N, respectively, which represents a slightly lower increase in the upper limb compared with the meta-analysis by Strasser et al. [We observed that the 12-week supervised resistance training program produced a large increase in the standardized scores for full-body muscular strength . Some or et al. . For insr et al.  and implr et al. , these rThe training intervention failed to improve cardiorespiratory fitness and shoulder mobility. Cardiorespiratory fitness has shown to improve following aerobic or combined training interventions in breast cancer survivors. However, in this trial, both groups were recommended to maintain high levels of physical activity to ensure that the international guidelines were met by all. Interestingly, both groups surpassed the average 10,000 steps/day, indicating that both were physically active. However, step count does not relate to exercise intensity and this might explain the lack of improvements in either group regarding cardiorespiratory fitness, where a combined intervention with aerobic training, perhaps of high intensity , could hThe intervention did not produce a significant improvement in patient-reported outcomes. Regarding cancer-related fatigue, the effects of resistance training in breast cancer survivors are not currently clear. While exercise is globally understood as an efficient therapy against cancer-related fatigue following cancer treatments , some reThis study has limitations that must be underlined. First, this is a relatively small study. The participants were compliant, not only with the face-to-face intervention but also with the home-based part. Although this is the strength of the study, the external validity of our results could be threatened by the possibility that the most motivated individuals tended to volunteer participation, which would limit generalizability. Also, we included women who had undergone breast cancer surgery and finished the core treatments up to 10 years before enrolment, which might result in a rather heterogeneous and relatively physically active sample of breast cancer survivors. In addition, we did not collect pre- and postintervention physical activity levels, which might have influenced the results. We cannot ascertain that the precise relative loads (%1RM) the participants trained with throughout the intervention were exactly as they were prescribed, because we used the CE for prescribing the training intensity. Nevertheless, the participants reported an increasing perceived effort as can be observed in Figure S1, suggesting an increasing intensity progression. Further research is needed to determine the equivalence between the perceived effort using the OMNI-RES and the %1RM in breast cancer survivors. However, the intervention was clearly effective as it produced large increases in muscular strength. The major strength of this study is that it accounted for the deficiencies of previous exercise-based clinical trials identified by Neil-Sztramko et al. . We accoIn Supplementary file1 (PDF 348 KB)ESM 1(PNG 137 kb)High resolution (TIFF 10084 kb)Supplementary file2(ZIP 381 MB)Below is the link to the electronic supplementary material.