Women at high risk of breast cancer face complex decisions about how to manage those risks. Substantial gaps in current knowledge include how women make these decisions and how decision making may differ across sub-populations. Among these critical gaps are the questions of (a) whether racial differences exist between the experiences of high-risk women navigating breast cancer risk, and (b) what consequences those racial differences might have on women’s ability to manage their cancer risks. The present study is designed to address these questions directly.Fifty semi-structured interviews were conducted with high-risk Black (n = 20) and white women (n = 30) between May 2015 and March 2016 in person in Ohio and by phone. Transcribed data were analyzed using grounded theory methods.Our analyses suggest that many of the core decision-making dynamics high-risk women navigate differ by race. The experiences of white and Black women in our study differ in terms of (a) contextualizing risk—how women make sense of their own breast cancer risk, the degree to which they worry about risk, and how they prioritize risk within the contexts of their broader lives; (b) conceptualizing risk management–how, how much, and from whom women learn about and conceptualize their options for preventing cancer and/or ensuring that cancer gets diagnosed early; and (c) constraints–the external barriers women face throughout their decision-making and risk-management processes. In sum, the Black women we interviewed reported feeling less well-situated to consider and cope actively with breast cancer risk, less well-informed about risk-management options, and more constrained in their use of these options.High-risk women’s accounts of the complex dynamics that shape breast cancer prevention decisions suggest that these dynamics vary substantially by race, such that Black women may experience disadvantages relative to whites. Women with strong family histories of breast cancer, genetic variants that predispose them to it, or substantial risk factors in their own medical histories can face between 20% and 80% lifetime risk of developing the disease . GeneticThere is much we do not know about prevention-related decision making among high-risk women. Increasing evidence shows that women’s choices and actions are shaped over time by a range of affective, emotional, cognitive, informational, interpersonal, and structural influences. These influences may include perceived risk of cancer and personal conceptualizations of what risk means for oneself and one’s family; family history of cancer and personal exposure to the cancers of others; general anxiety and specific cancer-related worries, medical and personal uncertainties, timing considerations, social networks and social support, and varied effects of socioeconomic status –6. In admore likely to have appropriately-timed mammograms he type of cancer I’m really not sure because everyone [in my family] died of so many different types of cancer.” Women with this “generalized” perception of cancer risk did not generally believe anything could be done to prevent cancer . As a rspecific risk for breast and/or ovarian cancer. Many white informants–and only a few Black informants–fit into this group. Molly’s  sense of risk, for instance, was strongly informed by the breast cancers in her own family:In contrast, informants inclined to pursue more aggressive risk-reduction options–such as chemoprevention or prophylactic surgery–perceived themselves to be at We were always aware of my grandmother[‘s breast cancer], and of course…the bold awareness was our mother[‘s breast cancer diagnosis]. I had gone away to school… we did not anticipate a radical mastectomy. So that was just total overwhelming shock, and unfortunately it was not a good prognosis.Decades later Molly could still relate painful details from the final difficult months of her mother’s life.Until she passed on December 15 of ’69, she, for a year and a half was paralyzed from basically the waist down…And I cared for her on a daily basis. Um, she succumbed at home. So all that became real…Both my sisters lived out of state. My brother was somewhat estranged from our family, so it kind of landed in my lap, and I dealt with it…Motivated by a desire to protect both herself and her daughter from pain and suffering she had witnessed, Molly became an early user of tamoxifen for breast cancer prevention by enrolling in the STAR chemoprevention clinical trial. Molly’s story illustrates a broader pattern revealed by our informants: that a specific and acute concept of breast cancer risk often corresponds with a strong motivation to take aggressive preventive action.if [I’ll] get breast cancer, I think about when [I’ll] get breast cancer.” Worried women frequently linked these feelings directly to their choices to pursue genetic testing or specific prevention options. We heard such stories about cancer worry motivating risk-reduction action much more frequently from white women. After living through multiple traumatic cancer cases and deaths among her close relatives, Kathryn  discovered her own BRCA mutation and became consumed by the need to do everything possible to prevent a cancer diagnosis of her own. She recalled the emotions both she and her husband experienced at that time:High-risk women experience varying degrees of worry about potential future cancers and cope with worry differently; Black women express less worry than white women, and more often connect worried feelings directly to their personal spirituality. For example, 75% of the Black women we interviewed exhibited low levels of worry about cancer, 20% exhibited moderate worry, and 5% expressed high worry. In contrast, only 37% of the White women we interviewed reported low levels of worry, 33% moderate worry, and 30% high worry. The content of women’s interviews paints a much more nuanced picture. Women who experienced moderate or high levels of cancer worry often expressed sentiments similar to those of Charlotte , who remarked: “I don’t think about It’s just what cancer does to people, as you know. It’s just unfathomable. And [my husband] said, "You need to get a mastectomy. We absolutely need you around for the kids." And so, yeah, I was in a bad place. I was constantly just, you know, trying to figure out what I could do…”In the end, Kathryn’s cancer worry led to a decision to have both her ovaries and breasts removed.Among Black informants more than white, discussions of cancer risk and worry included spontaneous comments about faith, spirituality, or religion. Genevieve , for instance, volunteered,We’re just a really spiritual family, we believe in God. And, when my sister… was diagnosed with breast cancer, we prayed even more… I might feel like I may have an increased risk, but I pray to God that it never happens… and that he watches over… my sister and makes sure that she doesn’t have any reoccurrences and things like that… I put my faith in God that everything will be alright.Our Black informants more often described relationships between faith and cancer risk , and expressed certain specific beliefs never articulated by our white informants . Lower levels of worry and a stronger sense of spiritual connection may offer mental health benefits to Black women, but these patterns also seem to be associated with less drive to use other methods of coping with breast cancer risk.future cancers because they were occupied coping with major current health issues. Other life priorities that competed with the risk-management activities of both white and Black informants included work and career considerations, child-rearing responsibilities, and other caregiving roles–all of which made it difficult to find the time or energy to manage frequent screening tests or consider preventive surgeries that would significantly disrupt daily life. Sharon  explained her decision to prioritize her children’s needs over paying for genetic testing,For many high-risk women, other life priorities compete with desire to manage breast cancer risk . This waI’m a stay-at-home mom. We get by. I worked from home until we had Harriet, and I was lucky enough that my husband had just gotten a promotion. So we’re still getting by. I think that if you were talking to me ten years from now, probably would have had the test because it’s going to be more affordable, or we’re going to have more money. And we have young children, so what resources we have go completely into them.major comorbidities: including having been diagnosed with chronic illnesses, struggling with multiple health issues at once, or being at risk for familial diseases other than cancer. In these cases, it may help for primary care providers and other specialist physicians to routinely help women keep cancer risk (and other risk-related conditions) on the radar even as they focus on proximal, highest-priority issues.The presence of personal health issues other than breast cancer risk stood out as a particularly common challenge for our Black informants. Only about 20% of White women had a major comorbidity, compared to about 40% of Black women. When other serious health problems were present, women focused less on managing breast cancer risk, as the physical demands of a current disease and the consequent devotion of resources often took precedence over preventing a potential future illness. Tiffany  had to focus on her HIV care, but found herself worrying more about her cancer risk as she got older, “My burden is the HIV…I try not to [think about getting cancer]. I go to a [HIV] support group and… It’s like, even this year, two of the people in the group… it’s not HIV that kills you, it’s cancer.” Although about half of informants in both Black and white groups reported comorbidities, Black women were twice as likely to report In order for high-risk women to have realistic opportunities to utilize the risk-management options that can reduce breast cancer illness and death, they must first obtain accurate and comprehensible information about those options. Our informants’ life stories reveal, however, that Black women have consistently less access to the specialists best equipped to provide risk-management information, are less aware of risk-management options appropriate for them, and less frequently use genetic testing to home in on their specific risk level and inform their choices.Access to knowledgeable specialists is a critical precursor to risk-management behavior, and one to which Black women often lack access. While all women in our study had contact with a primary care provider (PCP), white women were substantially more likely to have access to specialists than Black women (70% vs. 15%), and this difference had important implications for the kinds of information about cancer risk and prevention women received. Marsha’s  experience exemplified how specialists detailed and even encouraged risk-reduction behavior: her genetic counselor explained her individual risk, gave recommendations for prophylactic surgery, outlined an enhanced screening schedule, and provided information about chemoprevention. In contrast, many of our Black informants had only ever had conversations about their family history or cancer risk with their PCPs, and these conversations lacked both frequency and detail.Almost half of informants in each racial group described a healthcare provider as their main source of information about cancer risk or prevention. Among these women, however, more than three quarters of Black informants (but less than a third of whites) described a PCP as this information source. Jamila  talked about her breast cancer risk only with her long-time primary care doctor:Interviewer: What’s your perception of how high your risk actually is? What do you think your risk is, that you could get breast cancer at some point?Jamila: I would say, you know from 50 to 75% chances of me getting it.Interviewer: Okay. And where does your information about that sort of thing come from?…Jamila: My doctor, mostly. My primary care doctor, I’ve had her since I was 8. I ask her about that and now she told me that it’s pretty high chance, especially cause my aunt, was in her mid 40s and my grandmother, she was, you know, she was in her 50s, right, so my chances were higher. She, every time I see her she tells me, you know, when I should get a mammogram and all the other stuff.We heard many stories that illustrated the difficulty posed by Black women’s’ reliance on PCPs instead of specialists: PCPs rarely initiated conversations about cancer risk, offered fewer details when asked about cancer risk, and rarely discussed risk-reduction options beyond screening with their patients.In keeping with less frequent access to the specialists that tend to provide specific information about risk-reduction options, the Black women we interviewed were less frequently aware of potential methods for reducing breast cancer risk. The vast majority of our white informants  had heard of prophylactic mastectomy, prophylactic oophorectomy, or both; in contrast, only 75% (15/20) of Black informants had heard of at least one surgical risk-reduction option. Chemoprevention was less well-known than prophylactic surgeries within both racial groups, but more than half of whites (vs. only a fifth of Black informants) had heard of risk reduction with anti-estrogen medications. Jamila for instance (quoted above), had been told that she should do breast self-exams and start mammograms early, but was told nothing about any of the potential preventive interventions that would be considered clinically appropriate to her high risk. Dorothy  was highly proactive about taking care of her health and took pains to reduce her risk of breast cancer, but had never heard of the most effective methods for women at her risk level to do so:Interviewer: Has anybody ever recommended to you anything else that you should do or could do to prevent cancer…?Dorothy: I take vitamins… I just try to eat fish and chicken… I don’t smoke, and I don’t use illegal drugs. So… I would like to think that I’m doing most of the right things to reduce the risk.Interviewer: Yeah. Have you ever heard about this genetic test that they have for breast cancer-related gene [mutations]?Dorothy: It sounds familiar. It sounds familiar to me, but um…that’s about it.White women more often possessed detailed knowledge about the prevention-related options suggested to them. For example, when asked whether her doctor recommended anything other than mammograms and ultrasounds, Diana  responded, “Just you know, regular breast exams… [and] she told me about going to get genetic testing.” In contrast, Kaitlyn’s  meeting with a breast surgeon was more informative: “He said, ‘here are your options’… He said I can continue on with surveillance… a once-a-year MRI [magnetic resonance imaging], a once-a-year mammogram, and seeing my doctor every six months. Second option is to get a prophylactic bilateral mastectomy, and a salpingo-oophorectomy.”Although genetic testing is generally appropriate for all individuals at high risk, Black women are tested much more rarely than white women. Almost all white and Black women in this study were candidates to be tested for BRCA and other predisposing genes based on their high or severe risk status. Most had heard of genetic testing, but testing itself was substantially less frequent among Black women despite similar risk levels . ConversInterviewer: Have you ever talked to a genetic counselor or had genetic testing? Do you know what that is?”Naida: Yes I do [know what it is]. No I haven’t [done it].Interviewer: And that’s never been suggested?Naida: No. Probably because of insurance issues and stuff like that.Among expressed reasons for delaying or avoiding genetic testing, financial barriers were the most common. Tamara  related the impact of this barrier:I was talking to my then gynecologist who I’m still seeing to this day. And she said, ‘I know you need this more than anybody Tamara, but you know… your insurance will not pay for it.’ And I said, ‘Well, how much is it?’ And when she told me, I was in shock. It was expensive and …because of that, I couldn’t have it.Sarah’s  genetic counselor said that the appropriate family member to be tested for BRCA mutations was her cancer-affected mother. Her mother said, “I’ll do it if the insurance covers all of it,” and then refused to have the test once they found out that the out-of-pocket payment would be $500. Understanding that getting tested herself could be uninformative without her mother’s result, Sarah decided not to “waste the money” on her own genetic test either. Like lack of specialist access and lack of specific information about risk-reduction methods, lack of consistent access to genetic testing is another example of the ways Black high-risk women miss out on information that could inform proactive risk-management decision making.Our informants’ narratives also demonstrate that neither making risk-management decisions nor implementing these decisions is driven entirely by a woman’s own preferences and values. Of the many types of constraints women experienced, financial constraints were particularly common and disproportionately affected the ability and willingness of Black informants to engage in preventive care. In this sample (as in the U.S. more broadly) white women were more often in the highest socioeconomic status (SES) group, while Black women were more often in the lowest. Many more Black women experienced periods of time when they did not have insurance (40% vs. 3% of whites) and suffered significant financial difficulties in coping with health issues (40% vs. 13%). Keri’s  experiences were similar to those of several others:have [an illness] and you can’t do anything.I did have a period of time where I didn’t have health insurance… When I was going through my divorce, and that was difficult. I had to go a free clinic, and then… through my church… I would get my mammograms done there, you know, in the mobile home thing versus at a doctor’s office. It really let me know that insurance is very important… because if you can’t afford to even prevent things, imagine how it is to High insurance co-pays also caused notable stress for Charity , who described taking pains to combine and streamline her medical questions so as to minimize the number of costly specialist visits she would need. Black women were also less likely (30% vs. 50%) to describe their insurance as excellent or very good, and some described how this influenced their willingness to investigate or consider medical procedures. Teresa  reflected on the prophylactic mastectomy option: “I’ve thought about it, but I mean, financially, I’ve often felt like that’s not something that I’d be able to do.” . Other The contexts within which white and Black women make prevention decisions differ in important ways. These contexts are complex, involving past experiences, current health challenges, emotional states, access to and interactions with healthcare providers, and resource availability and constraints. But the broad patterns revealed by this study suggest that Black women may be less equipped to focus on breast cancer risk as an issue to be addressed proactively, may less frequently possess the information that would facilitate risk-management decision making, and may be more constrained in their ability to make and carry out those health-protective decisions. These patterns likely originate from a range of causes, which may include differential access to financial and other resources , cultural differences in orientation toward healthcare providers and options, differences in personal exposure to cancer and cancer treatment in loved ones, differential access to specialists or risk-informed PCPs, and distinct experiences of respect or discrimination in healthcare settings.Women’s exposure to the cancers of loved ones forms the backdrop that shapes their own thinking about breast cancer risk and prevention. Due to their life experiences with many different types of cancer, the Black women we interviewed were less likely than the white women to think of themselves as at high risk specifically for breast and ovarian cancer. Although Black women may indeed be at higher-than-average risk for other cancers as well, underestimating specific biological risks for breast and ovarian cancers that run in their families may substantially affect how women cope with those risks . Women wAnalysis of the interview data in this study also suggest that Black women at elevated risk may generally be less worried about cancer than their white counterparts. Several other dynamics observed in the interviews may account for this apparent difference: (1) Black informants more commonly have a generalized perception of cancer risk that may be too diffuse to focus a specific sense of worry; (2) they are more often worried about serious current health or economic concerns that likely take precedence over worry about possible future cancers; and (3) they have less specific information than white women about breast cancer risk and prevention options. Given that cancer worry usually motivates information-seeking, screening, and prevention-oriented behaviors, it is possible that low levels of worry among Black women may undermine their engagement with risk-management activities –28. HoweOur finding that the Black women in our study more often connect their faith to thoughts and worries about cancer suggests a possible foundation for helping some women cope proactively with cancer risk. Across research on cancer survivorship and other health issues, spirituality is usually found to be an effective coping mechanism, and to provide helpful avenues for social and emotional support. In rarer situations, reliance on spirituality has also been shown to undermine positive health behaviors , 19. ProThe existence of non-cancer-related health problems or risks in a woman’s life may reduce her investment in understanding or addressing breast cancer risk. This situation was more common among the Black women in our sample, likely reflecting population-based racial disparities in rates of chronic and acute disease , 30. A sOther important patterns in our data were the relatively low rates of cancer, breast, and genetics specialist use among Black women  and the correspondingly greater reliance of Black women on PCPs for information regarding breast cancer risk and prevention. Prior research has documented that management of high-risk women by PCPs is generally poor, as these providers have rarely received specific training about familial predisposition for cancer, and therefore lack sufficient knowledge about genetic screening, counseling, and risk-management methods recommended for high-risk women. It has also been found that PCPs rarely refer patients to relevant specialists unless the patient initiates the conversation , 32. SpeBRCA testing among Black women with breast cancer [Financial constraints also affected Black women in our study more profoundly than white women. This is consistent with the positive association between income and t cancer . The U.St cancer . In thist cancer , 41. Onet cancer , 43.Limitations of this exploratory study include the small sample. However, the study design maximizes in-depth data that accurately reflects the phenomenological experience of women at elevated breast cancer risk, whose own stories and realities have often been omitted from research on risk management and cancer prevention. Our sample size was sufficiently large to achieve theoretical saturation with respect to all the emergent themes of the study, to capture previously unstudied dynamics of prevention decision making, and to enable important comparisons that can inform the design of future research and tailoring of clinical care to meet the needs of diverse women. The observational nature of the study and the convenience sample of women mainly from Ohio does not enable definitive claims about broader racial patterns or cause-and-effect relationships. These findings should be confirmed with larger and more representative samples; methods to quantify objective severity of risk should be used; and the experiences of other racial and ethnic groups should be explored. Larger samples would also enable further analysis of the heterogeneity of experience within groups of women who identify as Black.The study results offer an important roadmap of future research questions. Issues particularly deserving of attention include: (1) the ramifications of breast/ovarian cancer specific risk perception vs. general cancer risk perception on prevention behavior; (2) whether and how provision of risk and prevention information might motivate risk-reducing behavior without inducing avoidance behaviors and/or excess worry that might cause negative mental health; (3) methods for increasing the competence and confidence of PCPs both in providing specific information and/or resources about cancer risk and risk-management, and in referring appropriate patients to specialists; and (4) the impacts of financial constraints on women’s coping with breast cancer risk, and racial variations in the prevalence of such constraints.This study also has important implications for the future of healthcare, suggesting clinical care and health system changes that could improve women’s ability to understand and cope with elevated breast cancer risk, and simultaneously ameliorate health disparities that render the management of elevated breast cancer risk particularly challenging for Black women. Methods should be developed to aid healthcare providers in exploring the psychosocial characteristics that shape their patients’ approaches to risk management: their prior experiences with cancer among loved ones, the degree to which they worry about cancer, and the role of faith and other social supports in how they cope with health issues. If confirmed through future research, these findings also point toward the need to make clinicians aware that many Black women have been exposed to less information and support related to breast cancer risk reduction options; such clinician education could facilitate specific efforts to reverse these trends. Conversations about cancer risk should acknowledge that this may be only one of several health challenges women are facing, and that plans for preventive action must take the demands of multiple comorbidities into account. The resulting insights may help clinicians understand how women perceive risk and respond to prevention options, leading to17 new routes for empowering preventive behavior among patients. As part of these conversations, decision aids may be used to help improve women’s understanding of their options and their ability to make choices consistent with their personal values and priorities .At the level of the healthcare system, a variety of changes could be made to improve the access of Black women to risk-reduction information, options, and behavior. First, new continuing education programs and revisions to clinical guidelines could improve the ability and consistency of PCPs in collecting family history information, educating patients about cancer risk, and making appropriate specialist referrals. Both patients and clinicians should be made aware that health insurance generally covers genetic counseling and testing for women with sufficient family history. Changes in health insurance regulations to improve access to specialists could have significant impact on women’s understanding of their risk and empower them to take health-protective actions. The prevention of future cancers could render these changes cost-effective at the long-term system level. If future research confirms racial disparities in specialist access, genetic testing, and prevention information, particular effort should be made to rectify these disparities by bringing these innovations to clinicians and healthcare organizations that serve Black women.To address important gaps in our knowledge of how women at high risk of breast cancer make difficult decisions about complex risk-management options, this study directly addressed the questions of racial difference in women’s decision-making dynamics, and the consequences of these differences. While both white and Black women contend with complicated personal, interpersonal, and structural landscapes as they navigate risk management, Black women seem to face some additional systematic disadvantages. Understanding that one is specifically at risk for breast cancer and being able to invest resources  in coping with that risk are critical contexts for successful risk-management, and Black women often face barriers to both. Understanding the medical interventions that can prevent cancer or diagnose it earlier is a necessary precursor to using those options successfully; our data suggest that Black women may have less personalized information about their own genetic risk, less knowledge of about risk-management options, and less access to the specialists who usually explain them. In addition, our data suggest that Black women’s decisions may more often be constrained by financial and other limitations–which prevent risk-management behavior from aligning with women’s preferences and choices. These racial disparities will need to be studied further and addressed directly, if ongoing attempts to improve access to enhanced screening, preventive surgeries, and preventive medication are to be equally effective for all high-risk women.S1 Checklist(PDF)Click here for additional data file.S1 Appendix(DOCX)Click here for additional data file.S1 Table(DOCX)Click here for additional data file.


Polygenic Risk Scores (PRS) are a major component of accurate breast cancer risk prediction and have the potential to improve screening and prevention strategies. PRS combine the risk from Single nucleotide polymorphisms (SNPs) associated with breast cancer in Genome Wide Association Studies (GWAS) and explain over 30% of breast cancer heritability. When incorporated into risk models, the more personalised risk assessment derived from PRS, help identify women at higher risk of breast cancer development and enables the implementation of stratified screening and prevention approaches. This review describes the role of PRS in breast cancer risk prediction including the development of PRS and their clinical application. We have also examined the role of PRS within more well-established risk prediction models which incorporate known classic risk factors and discuss the interaction of PRS with these factors and their capacity to predict breast cancer subtypes. Before PRS can be implemented on a population-wide scale, there are several challenges that must be addressed. Perhaps the most pressing of these is the use of PRS in women of non-White European origin, where PRS have been shown to have attenuated risk prediction both in discrimination and calibration. We discuss progress in developing and applying PRS in non-white European populations. PRS represent a significant advance in breast cancer risk prediction and their further development will undoubtedly enhance personalisation. In 2020, there were 2.3 million women diagnosed globally with 685,000 of these women dying from the disease [BRCA1, BRCA2 and TP53, who benefit from high-risk screening , most of the population receives screening based upon age alone. The use of risk models including standard risk factors, such as family history and hormonal/reproductive factors, integrated with mammographic density and DNA testing now offers the opportunity to more accurately discriminate risk to introduce true population-based risk stratification [Women with breast cancer have much higher chances of survival the earlier the cancer is diagnosed  and earl1.1Breast cancer is a heritable disease with epidemiological studies indicating around 4–5% is due to highly penetrant autosomal dominant predisposition [Since the discovery of well-validated high and moderate risk genes, recent research has focused on more common, lower penetrance gene variants that, in combination, increase breast cancer risk significantly. Single Nucleotide Polymorphisms (SNPs) are the most common type of variant within a DNA sequence, with over 10 million SNPs estimated to occur within the human genome . SNPs of1.2P-value of <5 × 10−7) in disease-affected vs unaffected (control) individuals [Genome Wide Association Studies (GWAS) have genotyped between hundreds of thousands to millions of SNPs with the purpose of discovering variants that occur at a significantly higher frequency  tumours which cannot be prevented by endocrine therapies) as well as including individuals of diverse ethnicities beyond those of white European origin.1.3Polygenic Risk Scores (PRS) describe the combined result of numerous risk-inducing susceptibility variants, identified in GWAS . PRS conp2 + 2pq + q2 = 1 where p is the risk allele and q is the non-risk allele.The expected allele frequency (EAF) and OR for each SNP is used to calculate the risk score for each genotype using: P2 is the homozygous risk allele frequency, 2pq is the heterozygous risk allele frequency q2 is the homozygous non-risk allele frequency.p2* published OR2) + (pq*published OR) + (q2*1)The average population risk for the non-risk allele genotype is then calculated using the equation:  for two risk alleles (published OR/average population risk) for one risk allele (1/average population risk) for no risk alleles.,35.1.4For a PRS to have clinical utility it is vital to have accurate discrimination and calibration. Discrimination is defined by correctly classifying whether an individual is either a case (BC affected) or control (BC non-affected). Calibration describes the agreement between observed and estimated incidences in the population ,37.Traditionally, many studies have used the discriminatory ability to assess the validity of a PRS. The area under the curve (AUC), defined as the probability that a randomly selected individual with a disease will be assigned a higher risk than a randomly selected individual without the disease, is the most used statistic for assessing discrimination. AUCs of 50% and 100% indicate that a model has no or perfect discrimination, respectively. Typically, PRS alone have modest discrimination at ∼0.60 however when considering PRS use in breast cancer, modest discrimination still has the potential to identify a large portion of the population at higher risk of disease development .Calibration is typically assessed by calculating an observed and estimated odds ratio so that an O/E ratio of 1.0 demonstrates perfect calibration . It is w1.5Discovery of novel SNPs associated with breast cancer development in the larger GWAS, have resulted in expansion of the number of these SNPs incorporated in PRS to improve risk stratification. The history of the development of breast cancer PRS has been summarised in BRCA1/2 genes [Evans et al. conducted a case-control study where SNP18 was used to discover the role of this PRS in predicting risk of women who have no pathogenic variant in either of the /2 genes . SNP18 w/2 genes .Beyond SNP18, SNP77 was one of the next well-validated breast cancer PRS’. In a study of ∼33,000 breast cancer cases and ∼33,000 controls of European origin, SNP77 was shown to stratify breast cancer risk in women with family history as well as those without . Lifetim−66 and P < 10−325 in the two validation cohorts used. Odds ratios per SD were also highly consistent between validation sets .As more BC associated SNPs were identified a panel of 94 SNPs were examined with the best discriminatory accuracy coming from 86 of these 94 SNPs. These 86 SNPs thus made the SNP86 PRS . This PRSNP143 is the next largest well-validated PRS for breast cancer risk and was described by Brentnall et al. when they developed this PRS from a panel of 172 SNPs linked to breast cancer by GWAS . This stSNP313, developed from studies conducted by the Breast Cancer Association Consortium, is predictive of breast cancer risk with an OR of 1.61 (95% CI 1.57–1.65) and an AUC of 0.630 (95% CI 0.628–0.651), demonstrating a good discriminatory ability in white European populations .1.6In breast cancer risk prediction models, the use of other known risk factors in combination with PRS has been shown to enhance prediction . Well-vaIt has been shown that total risk stratification is improved for mammographic density when a SNP77 PRS is also taken into consideration, as shown by Vachon et al.  This stuBrentnall et al. showed that SNP143 used in combination with mammographic density and classic risk factors improved risk stratification . Adding A comprehensive study by Evans et al., in 2022 showed the incremental effects of adding mammographic density and different PRS’ comprising increasing number of SNPs on risk stratification in a cohort of ∼500 cases and ∼1500 controls . This st1.7BRCA1 cases; 4330 BRCA2 cases) from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) with the use of a PRS [CHEK2 pathogenic variant , SNP86 was still able to modify risk prediction in carriers of ATM, PALB2, BRCA1 and BRCA2 with odds ratios ranging from 1.20 for BRCA1 to 1.37 in ATM [PRS have been shown to stratify risk beyond the ability of single high-risk gene pathogenic variants. Kuchenbacker et al. demonstrated large changes in the absolute risk of breast cancer development in a cohort of women . On a clinical level, this may provide significant reassurance and help to plan the most appropriate screening and preventive measures.Another study examining 26,798 cases and 26,127 controls from the Cancer Risk Estimates Related to Susceptibility consortium evaluated each participant for pathogenic variants in various high and moderate risk genes including and NF2.  In this 1.8Most genetic studies linking risk prediction to breast cancer focus on generalised breast cancer risk with no specified age group. A large portion of breast cancer occurs in women aged >50 years, however, women affected by breast cancer at younger ages stand to have a greater number of life-years saved with successful early detection and treatment than their older counterparts. One study estimated that there is a 77% 10-year survival if diagnosed aged <40 years vs an 87% 10-year survival if diagnosed >50 years) . Young-oThere is a need to expand GWAS to include more young women and potentially identify SNPs that are linked to an early-onset diagnosis of breast cancer. There is also the need to enrich for ER-negative SNPs in a PRS used in a young population due to the higher proportion of triple negative cancers seen in this cohort.1.9BRCA1 pathogenic variant carriers (BRCA1 predisposes predominantly to ER-negative tumours in younger women) within databases such as CIMBA, as well as BCAC ER-negative association results could be combined to perform a meta-analysis which enriches the ability for GWAS to discover ER-negative SNPs. Until then, research has shown some evidence of breast cancer PRS having some subtype specific predictive ability.To improve the ability to construct a subtype-specific PRS, there is a need to carry out GWAS in populations of patients that develop ER-negative and TN tumours. Alternatively, to increase the power for identification of ER-negative variants, association results for BRCA1 carriers  with reduced but still significant associations with ER-positive and overall breast cancers in both BRCA1 and BRCA2 carriers [The SNP143 PRS has been shown to be a risk factor for both ER+ and ER-negative breast cancers . Using pcarriers .The most comprehensive study investigating the use of PRS for prediction of specific breast cancer subtypes was carried out by Mavaddat et al., in 2019 and used both the SNP77 and SNP313 PRS . In a saER-negative risk prediction was still attenuated when compared to ER-positive breast cancer risk, most likely reflecting the fact that ER-negative disease is less common than ER-positive disease with correspondingly fewer cases in GWAS. However, a study by Michailidou et al. estimated the heritability of ER-negative disease is like that of overall breast cancer, indicating that increasing sample sizes should improve the power of ER-negative PRS ,62.Mavaddat et al. further assessed the associations between SNP313 PRS and breast cancer risk by first-degree family history of breast cancer. They found a smaller ER-positive PRS OR  for women with a family history, indicating that PRS ORs for this subtype are higher in women without a family history (OR = 1.71 (95% CI 1.65–1.78)) than with a family history (OR = 1.55 (95% CI 1.48–1.65)). When they compared ER-negative breast cancers, there was also a higher OR for women without a family history (OR = 1.45 (95% CI 1.36–1.57)) than with a family history (OR = 1.40 (95% CI 1.27–1.55)) however the disparity was not as large as in ER-positive breast cancers .1.10A major challenge within the formulation and use of PRS is ensuring that they are equally suitable across patients of all ethnicities. Should PRS not be appropriately recalculated, their use in these populations is limited, further exacerbating existing ethnic disparities within healthcare systems . This isTo date most BC variants have been discovered in GWAS’ of white European populations. However, many of these genetic risks are not transferrable to other populations, with some variants causing risk in one population and being protective in another. One study found that out of approximately 100 variants identified to increase risk in European and Asian individuals, 30–40% were protective in a population of African heritage . These sEvans et al. carried out a retrospective case-control study where they evaluated the role of the SNP18 and SNP143 PRS’ in populations of ethnic minorities having been historically well-validated in white European populations . They foSome commercially available PRS include women of Ashkenazi Jewish ancestry in an ethnic group with white European women, although we have shown that risk is overpredicted in this group. In a study examining an Ashkenazi group from Manchester with a larger validation cohort from Israel, the Ashkenazi population from Manchester showed ∼20% overprediction for breast cancer risk when using SNP142. When the per-allele odds ratios were adjusted using published Ashkenazi Jewish effect allele frequencies and published odds ratios, risk prediction was successfully recalibrated with controls’ mean PRS correcting back to unity (unpublished data).GWAS research in non-white Europeans needs to be improved with one 2019 study demonstrating that >78% of participants in published GWAS are of white European descent with 71.8% of this population being from only three countries, namely the United States, the United Kingdom and Iceland ,66. WhilNature Genetics in 2020, with the purpose to track GWAS participants in real time, by August 2022 over 95% of participants in all known GWAS were white European, demonstrating the continuing lack of diversity and unmet clinical need to perform GWAS in non-white European populations. Of the remaining ∼4%, only 0.30% are of African descent, 0.25% Hispanic/Latin American, 0.65% mixed with the extra ∼3% constituting Asian participants [When checking the GWAS diversity monitor, launched in icipants .It is vital that an individual's PRS is compared to population specific distribution, often done using Principal Component Analysis, to ensure that the right adjustments can be made depending on which ethnicity the individual has , as in m1.11Research studies continue to demonstrate the capabilities of PRS for breast cancer risk prediction, but PRS have not yet been implemented fully in any clinical setting ,70. WhilHowever, to implement PRS at a clinical setting, there must be an understanding as to how a PRS would affect a patient on an individual level. Should a breast cancer PRS stratify a woman at higher risk of breast cancer development, this could lead them to make informed decisions regarding preventative measures such as taking medication, undergoing bilateral mastectomies and/or lifestyle modifications . NeverthAs PRS are relatively novel in breast cancer risk prediction, it is yet to be determined about the best approach to communicate a personalised risk score to a patient and if patients want to know this information compared with standard screening. PROCAS (Predicting the Risk of Cancer at Screening), WISDOM (Women Informed to Screen Depending on Measures of Risk) and MyPeBS  are all large-scale studies that investigate the viability of breast cancer PRS’ and how their clinical implementation could be facilitated .2Breast cancer PRS’ remain a keystone in personalised risk prediction medicine and have been shown to refine a patient's risk beyond classic risk factors. PRS have the potential to prevent many cancer deaths via early detection and risk-reducing measures. However, further work needs to be done to improve the use of PRS in women of non-white European ancestry as currently these groups are having their risk significantly overpredicted. To implement PRS on a clinical scale, research must devise how to effectively communicate this risk on an individual scale.Ethical approval not required.Manchester National Institute for Health Research (NIHR) Biomedical Research Centre (IS-BRC-1215-20007). ER is funded by Cancer Research UK ACED International Alliance for Cancer Early Detection C19941/A27859.DGE and SJH are supported by the No authors have conflicts of interest to disclose.


Evidence of cardiotoxicity risk related to anthracycline or trastuzumab exposure is largely derived from breast cancer cohorts that under-represent socioeconomically marginalized women, who may be at increased risk of cardiotoxicity because of high prevalence of cardiovascular disease risk factors. Therefore, we aimed to estimate cardiotoxicity risk among socioeconomically marginalized breast cancer patients treated with anthracyclines or trastuzumab and describe clinical consequences of cardiotoxicity.We linked electronic health records with institutional registry data from a Comprehensive Community Cancer Program within a safety-net health system. Eligible patients were adult females, diagnosed with first primary invasive breast cancer between 2013 and 2017, and initiated anthracyclines or trastuzumab as part of first-line therapy. We estimated cumulative incidence (risk) of cardiotoxicity with corresponding 95% confidence limits (CL) using the Aalen-Johansen estimator with death as competing risk.Our study population comprised 169 women with breast cancer (103 initiated anthracyclines and 66 initiated trastuzumab). Cumulative incidence of cardiotoxicity was 21%  at one year and 25%  at three years among women who initiated trastuzumab, whereas cumulative incidence was 3.9%  at one year and 5.9%  at three years among women who initiated anthracyclines. More than half of patients with cardiotoxicity experienced interruption of cancer treatment.Our findings suggest high risk of cardiotoxicity among socioeconomically marginalized breast cancer patients after initiation of anthracyclines or trastuzumab. Strategies are needed for optimizing cancer treatment effectiveness while minimizing cardiotoxicity in this population.The online version contains supplementary material available at 10.1007/s10549-022-06695-0. Anthracyclines and trastuzumab contribute to improved survival among women with breast cancer, but these drugs have well-documented adverse effects such as cardiotoxicity –6. CardiThe estimated risks of cardiotoxicity related to anthracyclines and trastuzumab reported in prior studies may not apply to socioeconomically marginalized breast cancer patients . SocOur study population was derived from the JPS Health Network Oncology and Infusion Center, which is a Comprehensive Community Cancer Program in an urban safety-net health system . The JPSSupplementary Materials, Appendix A, Supplementary Table S1) that were confirmed by supporting documentation in EHR, or cardiac dysfunction indicated by drop of LVEF ≥ 10% from baseline to < 55%[Our outcome of interest was cardiotoxicity, defined as heart failure or cardiomyopathy using the International Classification of Diseases 9th (ICD-9) or 10th Edition (ICD-10) diagnosis codes  cumulative incidence  of cardiotoxicity with corresponding 95% confidence limits (CL) using the Aalen-Johansen estimator–22 to acFor clinical consequences of cardiotoxicity, we described impact on trastuzumab or anthracycline therapy completion, cardiotoxicity management, and cardiotoxicity outcome. Impact on treatment completion were categorized as cardiotoxicity occurred after treatment completed, completed treatment without interruption, treatment interrupted but resumed and completed, or treatment interrupted and did not complete. Cardiotoxicity management was categorized as treated with new medication or new doses of existing medication, continued with medications for existing cardiovascular disease, or observed/not treated with medications. Cardiotoxicity outcome was categorized as reversed or partially reversed  resulted in lower estimates for cumulative incidence among women who initiated trastuzumab , but cumulative incidence estimates did not change for women who initiated anthracyclines .Our sensitivity analysis using a stricter definition of cardiac dysfunction . This assumption may be violated  in studies of clinical cohorts based on routinely collected data , 29, sucOur socioeconomically marginalized population has barriers to care, which raises questions about potential selection bias because of challenges distinguishing between prevalent and incident heart failure or cardiomyopathy. For example, 57% of cancer patients (51% of women with breast cancer) in our health system did not have a documented primary care visit within 2 years prior to cancer diagnosis . If heart failure or cardiomyopathy were prevalent but undiagnosed, then these cases would have been ineligible for our study. The potential consequence of this selection bias is overestimated cardiotoxicity risk, but the effect of this bias may be inconsequential considering that prevalent cases would have been detected for the 90% of patients who had LVEF measurements prior to trastuzumab or anthracycline initiation. Therefore, the net effect of these misclassification and selection biases may be underestimated cardiotoxicity risk in our study.Several meta-analyses reported cardiotoxicity risk following trastuzumab or anthracycline exposure , 30–35, To facilitate comparability with our study, we identified prior studies included in meta-analyses, 30–35 tOur study population had a higher proportion of racial/ethnic minorities than prior studies  , 41, 45.Our findings address a gap in the evidence about cardiotoxicity among socioeconomically marginalized breast cancer patients. The high risk of cardiotoxicity following trastuzumab observed in our study raises questions about whether shorter duration  may be a reasonable option to reduce potential cardiotoxicity for socioeconomically marginalized breast cancer patients. Evidence regarding the effectiveness of shorter duration trastuzumab therapy is inconsistent but generally indicates reduced effectiveness and may not justify reduced harms –59. NeveSupplementary file1 (PDF 294 KB)Below is the link to the electronic supplementary material.


Rationale: Epidemiological studies that focus on the relationship between dietary isoflavone intake and the risk of breast cancer still lead to inconsistent conclusions. Herein, we conducted a meta-analysis of the latest studies to explore this issue. Method: We performed a systematic search using Web of Science, PubMed, and Embase from inception to August 2021. The robust error meta-regression (REMR) model and generalized least squares trend (GLST) model were used to establish dose–response relationships between isoflavones and breast cancer risk. Results: Seven cohort studies and 17 case-control studies were included in the meta-analysis, and the summary OR for breast cancer was 0.71 (95% CI 0.72–0.81) when comparing the highest to the lowest isoflavone intake. A subgroup analysis further showed that neither menopausal status nor ER status has a significant influence on the association between isoflavone intake and breast cancer risk, while the isoflavone intake doses and study design does. When the isoflavones exposure was less than 10 mg/day, no effects on breast cancer risk were detected. The inverse association was significant in the case-control studies but not in the cohort studies. In the dose–response meta-analysis of the cohort studies, we observed an inverse association between isoflavone intake and breast cancer: a 10 mg/day increase in isoflavone intake was related to reductions of 6.8%  and 3.2%  in breast cancer risk when using REMR and GLST, respectively. In the dose–response meta-analysis of the case-control studies, the inverse association for every 10 mg/day isoflavone intake was associated with breast cancer risk reductions by 11.7%. Conclusion: present evidence demonstrated that taking in dietary isoflavone is helpful in reducing the breast cancer risk. Breast cancer is the most commonly diagnosed cancer among women worldwide, with an estimated 2.3 million new cases in 2020, and the leading cause of cancer death, with 685,000 deaths in 2020 . The numSeveral meta-analyses have been performed in the past trying to draw a conclusion on the relationship between isoflavone intake and breast cancer risk ,10,11. HIn this systematic review, a comprehensive meta-analysis was performed to evaluate the probability association between dietary intake levels of isoflavones and breast cancer risk. Subgroup analyses were also carried out to assess the varieties of breast cancer risk among baseline characteristics such as menopausal status and ethnic groups. In addition, to provide a more clarified picture of the relationship between isoflavone intake levels and breast cancer, we conducted a dose–response meta-analysis to interpret our results.This study is a systematic review and meta-analysis of isoflavone consumption and the risk of breast cancer in female humans. The recommendations of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) were followed. The protocol of this study was registered in the International Prospective Registry for Systematic Reviews (PROSPERO) in advance (CRD42021289115).This review included observational studies (cohort or case control) undertaken in the adult female population that reported on the association between isoflavone consumption and the risk of breast cancer from January 2000 to August 2021, with a detailed description of the isoflavone intake dose, as well as the estimated effects in the form of a hazard ratio (HR) or odds ratio (OR) with a 95% confidence interval (95% CI). If data from the same cohort were used for different publications, we only included the latest published study to avoid replicated data. Due to the low absolute risk of breast cancer, all measures of relationships, including RR, IRR, and HR, are more likely equal to the estimates of the OR , which wStudies conducted in vitro or with animals, reviews, notes, reports, short surveys, conference letters, and case reports were excluded. Studies that used urine or serum markers instead of pathological methods for the diagnosis of breast cancer were excluded. Studies without normalization or without analysis of 95% CIs were excluded as well.The PICO strategy  was used to determine an article’s eligibility . A systeAfter automatically removing the duplicates using Endnote X9, all titles and abstracts considered for potential inclusion were screened by two independent authors (J. N. Y. and H. S). Multiple publications by the same author, cohort, or institution were rigorously reviewed, and the studies with the most cases were included to avoid incorporating duplicates.Two authors (J. N. Y. and H. S.) applied a standardized method to extract data independently. The following parameters were extracted: authors’ information, publication year, study design, country, study period, number of cases and subjects, age, diagnosis of breast cancer, isoflavone exposure range, exposure assessment, risk estimates with corresponding 95% CIs, and adjustment for potentially confounding factors.Any disagreements during the study selection or data collection were resolved by discussion until a consensus was reached or by consulting another author (Y. Q.).Using the Newcastle–Ottawa Scale (NOS), two authors (J. N. Y. and H. S.) independently assessed the quality of each study . Any disp-Values were considered significant at the level of p < 0.05.The statistical analyses were conducted using STATA version 16 (Stata Corp). 2 statistics [p < 0.1 was considered significant. For the I2 statistic, a low level of heterogeneity was considered when I2 was less than 40%, a medium level for 40% < I2 < 60%, and a high level for I2 > 60%. A multivariate meta-regression analysis was conducted to identify the source of the heterogeneity.The ORs and their 95% CIs were used to report the results. We performed a random-effects meta-analysis to estimate the pooled effect size for the highest in comparison with the lowest intakes of isoflavones. To assess the heterogeneity among studies, we calculated the Cochran Q and the Iatistics . For theFor additional insight, subgroup analyses were conducted based on the study design (cohort study or case-control study), population (Asian or non-Asian), publication year (2001–2010 or 2010–2021), study quality (NOS score ≥ 7 or NOS score < 7), menopausal status , isoflavone intake doses (≥10 mg or <10 mg), and estrogen receptor (ER) status (positive or negative).We selected the mean values of the isoflavone intake doses in each category to represent the average intake level. For studies that reported a range of isoflavone intakes, the midpoint of the upper and lower boundaries was regarded as the intake dose of each category. When the highest categories were open-ended, the dose was considered 1.2-fold that of the highest boundary .p-Values were considered significant at the level of p < 0.05.The dose–response meta-analysis was performed in the cohort studies and case-control studies. In this analysis, we utilized a one-stage, robust error meta-regression (REMR) model  and a twSensitivity analyses were performed to identify whether the overall estimates were dependent on the effect size from a single study by excluding each study in turn . PublicaAs shown in The overall quality of the included studies was relatively high. The average NOS score of the 24 included studies was 7.6, ranging from 6 to 9. Among these studies, eight achieved a score of 7, nine achieved a score of 8, and four achieved a score of 9. Detailed outcomes of the quality assessment for each study are presented in A summary of the characteristics of the included studies is provided in p < 0.001 for heterogeneity, I2 = 82.6%).From each study and all studies combined, the estimated ORs for the highest versus lowest levels of isoflavone dietary intake are shown in p = 0.017), population (p = 0.009), and isoflavone intake dose (p = 0.038) were identified as potential sources of heterogeneity.Therefore, a meta-regression was conducted to determine the possible sources of heterogeneity. In the meta-regression analysis, we explored the study design (cohort vs. case-control study), population (Asian vs. non-Asian), publication year, study quality, menopausal status , and isoflavone intake dose and case number. As a result of the meta-regression, study design (p for interaction <0.001), population (p for interaction <0.001), and study design (p for interaction <0.001) could explain the between-study heterogeneity.We performed a subgroup analysis according to the study design (cohort vs. case-control study), population (Asian vs. non-Asian), publication year (2001–2010 vs. 2010–2021), study quality (NOS score ≤ 7 vs. NOS score > 7), menopausal status , isoflavone intake doses ≥ 10 mg vs. <10 mg), and ERs status (positive vs. negative). The pooled ORs are presented in A statistically significant protective effect of isoflavone intake on breast cancer was observed in the case-control studies , while no such effect was observed in the cohort studies . In addition, the pooled OR showed an inverse relationship between isoflavone intake and breast cancer in Asian women , while the relationship did not exist in n7uon-Asian women . When the highest isoflavone intake was lower than 10 mg/d, the negative relationship between isoflavone intake and breast cancer disappeared , whereas OR = 0.63, 95% CI 0.53–0.75, when the highest isoflavone intake was above 10 mg/d. However, a statistically significant difference in the protective effect of isoflavone intake on breast cancer was observed regardless of whether the women were pre- or postmenopausal and regardless of whether they were ER positive or negative.Next, we assessed the dose–response relationship between isoflavone intake and breast cancer risk using both REMR and GLST methods for the case-control studies and cohort studies, respectively.p-value for the nonlinear association was 0.0081. Therefore, the curvilinear dose–response REMR was used. We found that a 10 mg/day increase in isoflavone intake was associated with a 6.8% lower risk of breast cancer  , which means there was a 3.2% decrease in the risk of breast cancer for an increase of 10 mg isoflavone intake per day  A. When u per day B. It canp nonlinearity = 0.0129). With each 10 mg/day increment in isoflavone intake, the pooled risk of breast cancer was reduced by 11.7% . When using the GLST method, we found a curvilinear association between isoflavone intake and breast cancer (p nonlinearity = 0.0002), an increase of 10 mg/day isoflavones intake was associated with a 19.3% lower risk of breast cancer   D. The dep = 0.001), and the Egger’s test found virtual publication bias (p < 0.001). However, the trim-and-fill method failed to identify any potentially missing studies  and estrogen receptor , suggesting that menopause status and estrogen receptor had little effect on the correlation between isoflavone and breast cancer risk. Previous laboratory studies show that the sexual hormone was an important risk factor for breast cancer, and estrogen therapy is effective and validated . MechaniThe subgroup analysis of the publication year and NOS score showed that the negative correlation was stronger in studies with an NOS score above seven than below seven, and it was stronger in studies published before 2010 than after 2010. The results suggest that some characteristics of the study may influence the risk estimate, although the combined ORs were still significant. One explanation could be the uncertainties in the isoflavone intake assessment. Soy, an isoflavone-rich food, is more often used as an ingredient in transformed food nowadays than in earlier times ,48. ThisThe subgroup analysis of the study design showed that the negative correlation between dietary isoflavone intake and breast cancer risk was only significant in case-control studies but not in cohort studies. Zhao et al.  also dreConsidering the vital role of the isoflavone intake dose in breast cancer risk, we further performed a dose–response meta-analysis of isoflavone consumption and the risk of breast cancer. As the study design is another important factor that contributes to the heterogeneity, we performed a dose–response meta-analysis within the case-control studies and cohort studies, respectively. The GLST approach used in this article is a commonly used two-stage dose–response meta-analyses method. Using this method, we found a 3.2% decrease in the risk of breast cancer for an increase of 10 mg isoflavone intake per day in the cohort studies, which is consistent with Wei et al.’s results using the GLST method  , the dosAlthough the association between isoflavone and breast cancer is dose-dependently inverse, the potentially detrimental effects of isoflavone at very high doses cannot be neglected. The leading concern is the potential detrimental effects on postmenopausal women, since high concentrations of estrogen could lead to endometrial carcinoma in aged women . One RCTThere are several limitations in this study that should be noticed. First, in order to have a full view of the correlation between dietary isoflavone consumption and breast cancer risk, we included as much clinical evidence as possible according to our criteria, leading to the inevitable heterogeneity among study designs. In addition, quite a few of the studies included were case-control studies (17 of 24 studies). Therefore, recall and selection biases should be noticed. However, we tried to limit these biases by only keeping the cohort study data when a parallel case-control study was taken using the same cohort of this cohort study. Second, the isoflavone intake might be underestimated in Western countries, since soy is used as an ingredient in many transformed dishes, which might lead to a bias in the subgroup analysis stratified by intake dose. Third, in each study included in the present meta-analysis, different methods of assessing the intake dose of isoflavone were employed. For example, self-administered questionnaires, mail survey questionnaires, and multitype food-frequency questionnaires were used in these studies, which could potentially lead to bias. Fourth, the adjusted factors were different in each included study and, thus, might bias the association between dietary isoflavone intake and breast cancer risk. Fifth, genistein, daidzein, and glycitein are the major food-derived isoflavones, with different distributions in different food legumes and soy products . In addiIn conclusion, evidence from observational studies suggest a dose–response inverse association between dietary isoflavone intake and breast cancer risk. However, heterogeneity and biases in the present studies require further well-designed prospective cohort and RCT studies to confirm our findings.This updated meta-analysis showed that dietary isoflavone intake has a protective effect on breast cancer risk, with a significant dose–response correlation, regardless of premenopausal or postmenopausal conditions. Future prospective cohort studies or RCTs are also needed to determine the causality of this relationship.


Night work has been classified as probably carcinogenic to humans by the International Agency for Research on Cancer, but epidemiological evidence was considered limited due to variability in findings and potential bias. This study aimed to investigate the risk of breast cancer in a cohort with detailed and registry-based data on night work.The cohort comprised 25 585 women (nurses and nursing assistants) employed 1 year or more between 2008 and 2016 in the healthcare sector in Stockholm. Information on work schedules was obtained from employment records. Breast cancer cases were identified from the national cancer register. HRs were estimated by a discrete time proportional hazards model, adjusting for age, country of birth, profession and childbirth.There were 299 cases of breast cancer, 147 in premenopausal and 152 in postmenopausal women. The adjusted HR of postmenopausal breast cancer in association with ever versus never working nights was 1.31 (95% CI 0.91 to 1.85). Eight or more years of night work was associated with an increased risk of postmenopausal breast cancer, HR=4.33 (95% CI 1.45 to 10.57), based on five cases only, though.This study is limited by a short period of follow-up and a lack of information on night work before 2008. Most exposure metrics showed no association with breast cancer risk, but there was an elevated risk of postmenopausal breast cancer in women after 8 or more years of night work. Night shift work has been classified as probably carcinogenic to humans by the International Agency for Research on Cancer. The epidemiological evidence was considered limited due to variability in findings, potential bias and the quality of the exposure assessment in some of the studies.This study was based on detailed data on work schedules obtained from employment records and showed an elevated risk of breast cancer in postmenopausal women having worked at night for 8 years or more. However, the conclusions are limited due to a short period of follow-up and lack of information of night work before 2008.This study gives some support to the evidence for an association between night work and breast cancer. A prolonged follow-up will give a more precise conclusion from this study.Breast cancer is the most common cancer among women, causing over 2 million deaths worldwide in 2019.Studies on breast cancer aetiology and occupational exposure have during the last two decades been focused on the role of night and shift work. Work at night is hypothesised to be associated with an increased risk of breast cancer due to disruption of the circadian rhythm.The International Agency for Research on Cancer (IARC) has evaluated the evidence for a cancer hazard from exposure to shift or night work at two occasions, most recently in 2019.This study aimed to investigate the risk of breast cancer in association with night work in a cohort with individual and very detailed registry-based data on work schedules.The cohort comprised healthcare workers employed by Region Stockholm (formerly Stockholm County Council) for at least 1 year from 1 January 2008 to 31 December, 2016. Details on the formation of the cohort have been published earlier.Working hours in healthcare in Sweden is typically organised in the following way: Day-time workers start at 7:00 or 8:00 and work 8 hours. Afternoon shifts start at 14:00 and end at 21:00 hours. Night shifts start at 21:00 and end at 7:00 hours.Information on working schedules hour by hour from 1 January, 2008 up to 31 December, 2016 was obtained from the HEROMA system. These data were used to define start and end of work shifts, which in turn were classified as (A) a night shift (≥3 hours of work between 22:00 and 06:00 hours or (B) a non-night shift, which could be either a daytime shift (starts after 06:00 and ends no later than 18:00 hours), or an afternoon shift (starts after 12:00 and ends later than 18:00 hours but not a night shift). The definition of night work and shift types follows closely to the definition suggested by IARC Monograph Volume 124: Night Shift Work (at least 3 hours between 23:00 and 06:00 hours),First time diagnoses of breast cancer  were obtained from the Swedish National Cancer Registry. Information on vital status, country of birth and emigration were obtained from Statistics Sweden, and information on childbirths (back to 1973) was obtained from the National Medical Birth Registry. Data were linked by the civil registration number, unique to every Swedish resident.The risk of breast cancer in association with night work was investigated by a discrete time proportional hazards model, stratifying the follow-up period in calendar years.We used SAS software V.9.4 for Windows (SAS Institute) for all statistical analyses.The cohort comprised 25 585 women, 58% were registered nurses, including midwives, and 42% were nursing assistants or had corresponding occupations , . At the The cohort comprised 160 200 person-years of observation during the period 2009–2016 . The maxThe risk of breast cancer was subdivided according to menopausal state . In postThe conclusions from this study are limited by a short period of follow-up and lack of information on night work before 2008. There was an increased risk of postmenopausal breast cancer in healthcare workers in Stockholm after 8 or more years of work that included nights shifts. The risk estimate was statistically significantly elevated but based on five cases only and must be interpreted with caution. There was no evidence of increased risk after shorter periods of work, and analyses of dose response in terms of number of years of night work or total number of nights worked showed no statistically significant trends. No elevated risks were found among premenopausal women, but there were no women with breast cancer who had worked at night for at least 8 years in this group. In the entire cohort, the adjusted risk estimate in association with 8 years of night work or more was non-significantly elevated, HR 2.80 (95% CI 0.96 to 6.52).The current finding gives some weak support to previous studies indicating an association between night work and risk of breast cancer.This study indicated an increased risk after 8 years of night work or more. However, the number of years of night work may have been underestimated in this study, since information on night work before 2008 was not available. Some of the earlier studies of nurses have shown an increased risk first after about 20 years of exposure or more, for example, the large Nurses’ Health Study from the USAThis study has a strength in the detailed and record-based data on night work. Several previous findings, especially from case–control studies, have been criticised for potential problems in the exposure assessment, and the findings have not been replicated in cohort studies.The study also has limitations. First, we had no information on employment and night work before 2008, even if some of the cohort members may have worked at nights during that period. This means that the number of night years may have been underestimated for some of the cohort members. The category of 8 or more years of night work, in which we found an excess of breast cancer is an open class, and some of the women may have worked at night for longer times. This does not affect the magnitude of the HR for this group, though. The second limitation is the relatively short period of follow-up.We have very detailed data on how many nights each subject had worked for the period 2008–2016, but a subdivision with regard to number of nights per time unit was not possible in view of the small number of cases in the 8+ years group. The fact that we found an excess risk in postmenopausal women after 8 years involving nights, but no significant trend in terms of number of night years may seem contradictory. However, the five cases in the highest category have a small influence in the trend test in view of the much larger groups with shorter durations of night work.The conclusions from this study are limited due to a short follow-up period, a low number of cases with long-term night work, and lack of work histories before 2008. However, an excess risk of breast cancer was found in the longest available category of duration (8+ years), but this observation was based on five cases only and must be interpreted with caution. The study gives some weak support to earlier observations of an elevated risk of breast cancer in women in association with night work. The concentration of risk to postmenopausal breast cancer is in opposition to some but not all earlier findings. Further analysis of risk in relation to the quantities of night work per time unit was not possible due to low numbers. A prolonged follow-up is necessary for more precise conclusions from this cohort regarding the risk of breast cancer in association with night work.


To investigate the relation between a diabetes risk reduction diet (DRRD) and ovarian cancer.We used data from a multicentric case-control study conducted in Italy, including 1031 incident ovarian cancer cases and 2411 controls admitted to hospital centres for acute non-malignant disease. Subjects’ diet prior to hospital admission was collected using a validated food frequency questionnaire. Adherence to the DRRD was measured using a score based on 8 dietary components, giving higher scores for greater intakes of cereal fiber, coffee, fruit, nuts, higher polyunsaturated to saturated fatty acids ratio, lower glycemic index of diet, and lower intakes of red/processed meat, and sweetened beverages/and fruit juices. Higher scores indicated greater adherence to the DRRD. Multiple logistic regression models were fitted to calculate the odds ratios (OR) of ovarian cancer and the corresponding 95% confidence intervals (CI) for approximate quartiles of the DRRD score.The DRRD score was inversely related to ovarian cancer, with an OR of 0.76 (95%CI: 0.60–0.95) for the highest versus the lowest quartile of the score (p for trend = 0.022). The exclusion of women with diabetes did not change the results . Inverse associations were observed in strata of age, education, parity, menopausal status, and family history of ovarian/breast cancer.Higher adherence to a diet aimed at reducing the risk of diabetes was inversely associated with ovarian cancer. Further evidence from prospective investigations will be useful to support our findings.The online version contains supplementary material available at 10.1007/s10552-023-01722-x. Women with diabetes mellitus are at increased risk of ovarian cancer , but theDiets high in glycemic index (GI) and glycemic load (GL) have been associated to type 2 diabetes risk , 6 and ttrans fatty acids. In 2020, fruit was added among the protective components and fruit juices were added among the unfavorable components of the sugar-sweetened beverages [Rhee et al.  proposedeverages . In a laeverages . The DRReverages , 15, 16,everages , pancreaeverages , 19, andIn the present study, we investigated the relation between adherence to the DRRD and ovarian cancer using data from a multicentric Italian study.Data were derived from a multicentric case-control study of ovarian cancer conducted between January 1992 and September 1999 in four Italian areas: the greater Milan area and the provinces of Pordenone, Padua, and Gorizia in northern Italy; the province of Latina in central Italy; and the urban area of Naples in southern Italy . The stuCases were women with a histologically confirmed incident invasive epithelial ovarian cancer admitted to the major university and general hospitals of the study areas. Controls were women admitted to the same network of hospitals as cases for a wide spectrum of acute non-malignant illnesses: traumas (26%); non-traumatic orthopedic disorders (28%); acute surgical conditions (15%); and miscellaneous other illnesses including eye, nose, ear, throat, or dental disorders (31%). Controls were excluded if they had undergone bilateral ovariectomy or if hospitalized for hormone-related, gynecological conditions, digestive tract diseases, or any clinical condition leading to long-term dietary modifications. Less than 4% of women approached refused to take part in the study and the participation rate did not vary across catchment areas or hospitals. The Ethics Committees of the Hospital “Niguarda Ca’ Granda”, Milan, and of the National Cancer Institute “Centro di Riferimento Oncologico, IRCCS”, Aviano, provided the study approval .Centrally trained personnel interviewed cases and controls during their hospital stay, using the same structured questionnaire and coding manual. Interviewers could not be blinded to case/control status. The questionnaire included information on sociodemographic and anthropometric features, lifestyle behaviors, personal clinical information, family (first-degree relatives) history of cancer, menstrual and reproductive factors, and use of oral contraceptives (OC) and hormone replacement therapy (HRT).The dietary habits during the 2 years preceding cancer diagnosis (for cases) or hospitalization admission (for controls) were investigated through a valid  and reprA DRRD score was computed according to the last approach proposed in the literature , withoutWe categorized the DRRD score into approximate quartiles with cutoffs derived from controls . Logistic regression models were fitted to calculate the odds ratios (OR) of ovarian cancer and the corresponding 95% confidence intervals (CI) for approximate quartiles of the DRRD score, using the lowest quartile as the reference category. The OR for a one-point increment in the score was also estimated. Models included terms of age , center, year of interview, years of education , total energy intake (in quintiles), history of diabetes, menopausal status, parity , use of OC, and family history of ovarian or breast cancer. The 7 women with missing menopausal status were all aged less than 49 years. Thus, they were considered as pre-menopausal.In sensitivity analyses we repeated the main analysis excluding women with diabetes, excluding one component at a time from the overall DRRD score, and adding further adjustment for alcohol intake. We carried out stratified analyses by age, education, parity, menopausal status, and family history of ovarian/breast cancer. We tested for heterogeneity across strata using the likelihood ratio test comparing models including and not including interaction terms between the DRRD score and the stratification variable.All statistical analyses were conducted with SAS statistical software version 9.4 .Table Table When we excluded from the calculation each component of the score at a time, we found similar results in terms of direction and magnitude of the association; however, some of the confidence intervals became larger (Supplementary Table S3).In subgroups analyses, no heterogeneity was found in strata of age, education, parity, menopausal status, and family history of ovarian/breast cancer Table .In this multicentric Italian study, high adherence to the DRRD was inversely associated with ovarian cancer. After allowance for several potential confounders, including measures of endogenous estrogen exposure, use of OC, family history of ovarian/breast cancer, and total energy intake, women with the highest DRRD adherence scores had a 24% reduced risk of ovarian cancer, as compared to those with the lowest scores.No conclusive evidence on the role of diet in ovarian cancer risk is available , with seAs concerns the components of the DRRD with a protective role on diabetes, a meta-analysis including only cohort studies found no significant association between the intake of caffeine or different types of coffee and the risk of ovarian cancer . Anotherversus low GL [Diets high in GI and GL could lead to chronic hyperinsulinemia and insulin suppresses IGFBP concentrations , 42; in s low GL . In a prs low GL . Likewiss low GL . In anots low GL . Howevers low GL . Anothers low GL . The rems low GL –50.A meta-analysis of 8 prospective studies published up to 2011 found no appreciable association with red and processed meat . AnotherA pro-inflammatory diet was associated to ovarian cancer risk in studies conducted in African American , AustralPotential study limitations include the inability to account for trans fatty acids in the DRRD score since the they are not available in the Italian food composition tables. In addition, despite the window of dietary recall up to two years prior to cancer diagnosis, we could not exclude the pre-clinical symptoms modified the diet. Among the strengths, the catchment areas and the interview setting were similar for cases and controls and the participation rate was almost complete. In addition, the exclusion of women admitted for hormone-related or gynecological conditions, or any clinical condition leading to long-term modifications of diet reduced selection bias. Other strengths are the large sample size, the use of a valid  and reprIn conclusion, this study suggests that high adherence to a diet able to reduce the risk of diabetes may also be inversely associated with ovarian cancer. Further evidence from prospective investigations is needed to support our findings.Below is the link to the electronic supplementary material.Supplementary Material 1