Polygenic factors are estimated to account for an additional 18% of the familial relative risk of breast cancer, with those at the highest level of polygenic risk distribution having a least a twofold increased risk of the disease. Polygenic testing promises to revolutionize health services by providing personalized risk assessments to women at high-risk of breast cancer and within population breast screening programs. However, implementation of polygenic testing needs to be considered in light of its current limitations, such as limited risk prediction for women of non-European ancestry. This article aims to provide a comprehensive review of the evidence for polygenic breast cancer risk, including the discovery of variants associated with breast cancer at the genome-wide level of significance and the use of polygenic risk scores to estimate breast cancer risk. We also review the different applications of this technology including testing of women from high-risk breast cancer families with uninformative genetic testing results, as a moderator of monogenic risk, and for population screening programs. Finally, a potential framework for introducing testing for polygenic risk in familial cancer clinics and the potential challenges with implementing this technology in clinical practice are discussed. BRCA1 and BRCA2 (BRCA1/2), accounting for less than 25% of the familial risk for the disease [Breast cancer is a common disorder with a strong hereditary contribution. Women with a first-degree relative with breast cancer have a twofold increased risk of developing the disease , 2. Much disease . Recent  disease . Current disease . Additio disease , 9. Howe disease –12. Furt disease , 14.This article aims to review the evidence for testing for polygenic breast cancer risk and the different applications of the test, including for high-risk women with uninformative genetic testing results, as a modifier of monogenetic risk genes, and to guide population screening programs. This article also explores the potential benefits and limitations of this technology, as well as the challenges associated with implementing polygenic testing in clinical practice.There have been over 100 different breast cancer genome-wide association studies (GWAS), which have collectively led to the identification of over 182 variants associated with breast cancer risk at the genome-wide level of significance  . The firIn a follow-up study, a meta-analysis of 11 previous GWAS together with the data from the 41 studies genotyped in iCOGS was conducted. Data for 62,533 breast cancer cases and 60,976 controls of European ancestry was analyzed, leading to the identification of an additional 15 breast cancer associated variants along with replication of 71 of the 79 previously reported variants . ConsistIn the largest breast cancer GWAS to date, Michailidou et al.  genotypeThere have been increasing efforts to conduct GWAS in non-European populations, with most of the reported breast cancer variants discovered in European cohorts –25. MichBRCA1 mutation carriers was also reported [Most GWAS to date have been unselected for breast cancer subtype and as a result include a majority of the more common estrogen receptor (ER) positive subtypes. Consequently, most of the reported loci have been more strongly associated with ER-positive tumors. For example, out of the 61 new variants reported by Michailidou et al. , 19 showreported . SimilarIndividually, each breast cancer SNP has a minimal effect on breast cancer risk. However, their combined effect, in the form of polygenic risk scores (PRS), has been shown to provide a degree of risk discrimination that can be used to stratify individuals into different categories of disease risk. Studies examining the effect of PRS on breast cancer risk have consistently reported a higher PRS among women diagnosed with the disease when compared to population controls Table  7, 30–3, 39–42. Polygenic risk scores have been shown to differentiate risk for ER-positive and ER-negative disease. However, as noted, PRS is more effective at stratifying the risk of ER-positive disease , 45–52. The possibility that PRS may provide information on prognostic factors has also been examined. In one study, a high PRS was associated with an increased risk of being diagnosed with breast cancer during routine screening rather than between screening  . When coSeveral studies have assessed the discriminatory accuracy and calibration of breast cancer PRS. The discriminatory accuracy of PRS has been most commonly assessed by calculating the area under the receiver operating characteristic curve (AUC) Table . The AUCCalibration  was assessed in two studies, with both reporting excellent calibration for a PRS based on just 18 variants for a cohort of European ancestry , 41. In Determining the appropriate number of variants to include in the PRS calculation has remained a significant challenge. However, it is evident that increasing the number of variants has only had a minimal impact on the accuracy of PRS. For example, Mavaddat et al.  reportedSeveral studies have examined the effect of PRS on existing risk prediction models, including the Gail Model , 58–62, Currently, all studies of European populations have reported improved accuracy when PRS is added to the model Table . In a stA limitation of many of these studies is that they assume independence between the PRS and previously described risk factors. Ignoring the correlation between components in the model, most obviously between genetically determined risk and family history, is likely to result in an overestimation of risk among women with a family history of the disease. A recent study by Lee et al.  has addrDespite earlier concerns, the latest research has demonstrated that PRS is a strong predictor of breast cancer risk, with most studies of women from European ancestry suggesting a greater than twofold difference in risk between the lowest and highest PRS quartiles Table . ConsideBRCA1/2 result [Currently, most women at high-risk of breast cancer receive uninformative results from genetic testing of high- and moderate-risk genes. Uptake of breast cancer risk management strategies among this group of women is reported to be low , 68. Thu2 result , 56, 64.2 result , 31, 32,2 result . AdditioPolygenic testing is likely to be implemented in familial cancer clinics, alongside an assessment of family history, for women at increased risk of breast cancer with uninformative genetic testing results. Women with uninformative result and an increased PRS could be counseled about the higher risk of early-onset breast cancer, increased risk of contralateral breast cancer, no change in ovarian cancer risk, and reduced chance of a pathogenic variant in high-penetrance genes . This inBRCA1/2) and its familial implications. However, a shift towards a personalized model of care will be required as polygenic testing continues to be implemented into clinical practice. While genetic counseling for common complex disorders are available [Currently, there is no framework to support the implementation of breast cancer polygenic testing across clinical genetic services. Historically, genetic services have focused on testing of monogenic risk genes , Kuchenbaecker et al. [BRCA1 carries with a PRS in the 10th percentile of risk distribution had a 56% chance of developing breast cancer by age 80 years. In comparison, those with a PRS in the 90th percentile had a 75% breast cancer risk by age 80 years. Evidence of subtype-specific PRS was also reported, with a PRS weighted for ER-negative risk displaying the strongest association with breast cancer risk in BRCA1 carriers [BRCA1 carriers having the highest discrimination (AUC = 0.58). In another study, a PRS based on 77 variants was a significant risk factors for CHEK2*1100delC carriers [Polygenic risk scores have been shown to modify risk associated with high- and moderate-risk breast cancer risk genes , 74. Usir et al.  reportedCHEK2*1100delC carriers with increased risk PRS, while increased surveillance may be an appropriate strategy for those with the same pathogenic variant and reduced risk PRS. Nevertheless, if early data is replicated, incorporating PRS to high- and moderate-risk gene testing would allow for personalization of risk prediction and ultimately facilitate risk management decisions for women with pathogenic variants in these genes.Additional research is also needed to determine the clinical outcomes associated with implementing PRS in familial cancer clinics and guidelines for risk management strategies will need to be developed. For example, risk-reducing strategies may be recommended to Despite the strong evidence for the high variability of breast cancer risk within populations, most population screening programs only utilize age as a risk factor in determining recommendations for mammographic screening. However, there is growing evidence to support the inclusion of polygenic information to population screening programs, with studies reporting an age-specific effect for PRS , 52, 63.Implementation of PRS into population screening programs also requires consideration of the social, ethical, and psychological outcomes. For example, consideration needs to be given to the acceptability of risk-based surveillance (particularly for those with a reduced risk), training of non-genetics health professionals, how best to communicate this information, and cost-benefit analyses , 75, 76.Significant progress has been made in understating the genetic architecture of breast cancer and the role of polygenic information in familial breast cancer and for population screening programs. The studies presented in this review demonstrate that polygenic information has the power to effectively stratify breast cancer risk. These findings need to be considered in light of current limitations, including limited research on women from non-European ancestry and emphasis of ER-positive breast cancer. Equally, further research is needed to determine the best-performing PRS, with varying number of SNPs and statistical methods being currently used to calculate polygenic risk , 42. DesAdditional file 1.Breast Cancer GWAS catalog summary dated 20.10.19. This file contains a summary of all the breast cancer GWAS registered in the GWAS Catalog as of the 20th October 2019.


LncRNA MEG3 expressed abnormally in various cancers including breast cancer, but no studies reported the correlation between MEG3 SNPs and breast cancer susceptibility among Chinese women.This study is aimed to explore the association between three SNPs of MEG3  and breast cancer. The study is a population-based case-control study including 434 breast cancer patients and 700 healthy controls. Genotyping was performed using Sequenom MassArray technique. Function prediction of rs3087918 were based on RNAfold and lncRNASNP2 databases.P = 0.042; GG vs. TT + TG: OR (95%) = 0.69(0.48–0.99), P = 0.046], especially for women aged <=49 . Comparison between case groups showed genotype GG and TG/GG of rs3087918 were associated with her-2 receptor expression . We didn’t find statistical significance for rs11160608, rs7158663 and breast cancer. Structure prediction based on RNAfold found rs3087918 may influence the secondary structure of MEG3. The results based on lncRNASNP2 indicated that rs3087918 may gain the targets of hsa-miR-1203 to MEG3, while loss the target of hsa-miR-139-3p and hsa-miR-5091 to MEG3.Pooled analysis indicated that rs3087918 was related to a decreased risk of breast cancer [GG vs. TT: OR (95%) = 0.67(0.45–0.99), MEG3 rs3087918 was associated with a decreased risk of breast cancer. MEG3 haplotype TCG may increase the risk of breast cancer. The detail results were showed in Table Three SNP in MEG3 gene  were genotyped in all recruited subjects, and their detected rate were 99.1, 99.2 and 99.4%, respectively. The genotype distribution of the three polymorphisms in control groups accorded with HWE (rs11160608: 2 and BMI > = 24 kg/m2). No association was found between rs11160608, rs7158663 and breast cancer when stratified by age, BMI and menopausal status  = 2.37(1.24–4.63), P = 0.010; TG + GG vs. TT: OR (95%CI) = 1.50(1.01–2.24), P = 0.045]. We further divided the cases into luminal, Her-2 and triple negative breast cancer (TNBC) groups according to molecular classification. However, we found no association between three SNPs of MEG3 and the different molecular typing states of BC  = 2.97(1.66–5.31), %CI = 2.9http://rna.tbi.univie.ac.at//cgi-bin/RNAWebSuite/RNAfold.cgi) and LncRNASNP2 (http://bioinfo.life.hust.edu.cn/lncRNASNP/) database to predict the potential function of rs3078918. The centroid secondary structure of rs3087918 was shown in Fig. We used RNAfold  and breast cancer. Our study recruited 1134 subjects containing 434 breast cancer patients and 700 healthy controls. The results indicated that the mutant homozygous GG of rs3087918 may associated with a decreased risk of BC, especially in females age < = 49. Comparison between case groups showed genotype GG and TG/GG of rs3087918 were correlated with her-2 receptor expression. The results of haplotype analysis for MEG3 showed that compared with wild haploid TAG, TCG haplotype may increase the risk of breast cancer, while other haplotypes were not significantly correlated with breast cancer risk. Furthermore, we found rs3087918 may influence the secondary structure of MEG3 and affect the bind of MEG3 to some miRNAs.http://bioinfo.life.hust.edu.cn/lncRNASNP/) to predict the potential function of rs3087918 on MEG3 gene. The results indicated that rs3087918 may influence MEG3 binding to miRNAs. In detail, rs3087918 may gain the targets of hsa-miR-1203 to MEG3, while loss the target of hsa-miR-139-3p and hsa-miR-5091 to MEG3. A study performed by Tomoyuki Okumura et al. found has-miR-1203 significantly associated with tumor recurrence [Previous evidences showed that MEG3 was highly expressed in normal tissues such as brain, pituitary, placenta and adrenal gland, and its transcripts can be detected in several human organs including ovary, testes, spleen, pancreas, liver, and mammary gland . Howevercurrence . Downregcurrence –37, and currence . Thus, hcurrence . These wTo be best of our knowledge, this is the first study to explore the association between MEG3 SNPs  and breast cancer risk. However, there are some potential limitations need to be clarified. First, we failed to consider the potential influence of environmental, lifestyle and other unknow risk factors on our study. Secondly, this is a one center case-control study with a small sample scale, we should not ignore the selective bias. In the future, more complete and larger sample scale study need to accomplish.The wild-type homozygous GG of MEG3 rs3087918 was associated with a decreased risk of breast cancer. MEG3 haplotype TCG may increase the risk of breast cancer and it may owe to its effect on the structure and function of MEG3.Additional file 1: Figure S1. The prediction results of s3087918 affect the bind of MEG3 to miRNAs. (A) rs3087918 caused has-miR1203 target gain; (B) rs3087918 caused has-miR-139-3p target loss; (C) rs3087918 caused has-miR-5091 target loss. Table S1. Primers used for this study. Table S2. Stratified Analysis of rs11160608 and rs7158663 by age, BMI and menopausal status. Table S3. Association analysis between three SNPs inMEG3 and Molecular typing of breast cancer. Table S4. Rs3087918 influence MEG3 binding to miRNAs based on LncRNASNP2 database.


Cox proportional hazard regression analyses revealed that COP was associated with a hazard ratio of 0.67  for breast cancer after we adjusted for age, monthly income, geographic region, and comorbidities of hypertension, diabetes, and hyperlipidemia. Our result provides evidence for the potential protective effects of CO against breast cancer in humans. Further studies that directly evaluate the potential effects are warranted.Carbon monoxide (CO) is a toxic gas and an endogenous signaling molecule. Some studies involving cell lines have revealed the potential antibreast cancer effects of CO. Data on such effects in humans, however, are limited. Thus, we conducted a study on patients with CO poisoning (COP) to evaluate the effects of CO on the risk of breast cancer. We identified female patients who were diagnosed with COP over the period of 2002 and 2009 from the Nationwide Poisoning Database of Taiwan. For comparison, we selected females without COP from the National Health Insurance Research Database. Participants in the COP and comparison cohorts were matched on the index year, age, monthly income, and geographic region of residence at a 1:6 ratio. We followed up the two cohorts until the end of 2014 and compared their risks of developing breast cancer. We included 7053 participants with COP and 42,318 participants without COP. Participants with COP were at a lower risk of developing breast cancer than those without COP (0.7% vs. 1.0%,  Its toxic effects are generally exerted through hypoxia and inflammation2. CO poisoning (COP) may increase the risk of neurologic defects4, cardiac injury5, diabetes6, and death8.Carbon monoxide (CO) is an exogenous toxic gas and an endogenous signaling molecule9. The abnormal metabolism and functions of endogenous CO have been linked to numerous pathologies, such as neural and cardiovascular pathologies. Similar to exogenous CO, endogenous CO functions as a physiological signaling molecule in many systems, including the neural, cardiovascular, respiratory, gastrointestinal, immune, and reproductive systems10. CO has antiapoptotic, anti-inflammatory, and antioxidant activities in cell and tissue homeostasis, as well as vasodilative and antiproliferative effects in tissue regeneration10. A growing number of studies have shown that CO has potential applications in the treatment of cancer, cardiovascular diseases, sepsis, hematological diseases, hypertension, neurodegeneration, renal diseases, and liver diseases10.Endogenous CO can be produced through the action of heme oxygenases (HOs), which exist as three isoforms: HO-1, HO-2, and HO-31. CO might introduce protective effects against breast cancer through suppressing heat shock protein (HSP) 9011. Synthesized manganese carbonyl complex, a CO-releasing molecule (CORM), exerts toxic effects on breast cancer cells12. However, studies on the potential antibreast cancer effect of CO have been limited to cell and animal experiments. Therefore, we conducted an epidemiological study to investigate the potential effect of CO on the risk of breast cancer in human beings.Breast cancer is one of the most common cancers and is a potential target disease for the therapeutic effect of CO13.We conducted this nationwide population-based cohort study by using the Taiwan National Health Insurance Research Database (NHIRD). The NHIRD, which covers nearly 100% of the population in Taiwan, is maintained by the National Health Research Institute and is provided to scientists for research purposes14.We identified female patients who were diagnosed with COP over the period of 2002 and 2009 as the study cohort. We selected a comparison cohort of females without COP from the NHIRD. The two cohorts were matched at a 1:6 ratio by index year, age, monthly income, and geographic region. The index year was defined as the year of hospitalization or visit to the emergency department by the patient with COP  during hospitalization or a visit to the emergency department. A patient with breast cancer was defined as a participant who had been assigned ICD-9-CM diagnosis codes 174 or 175 during at least one hospitalization or at least three visits for ambulatory care. Those who were diagnosed with breast cancer before the index date were excluded from the study.3. Common underlying comorbidities, including hypertension (ICD-9-CM 401–405), diabetes (ICD-9-CM 250), and hyperlipidemia (ICD-9-CM 272), were included for analyses. A patient with these diseases was defined as a participant who had been assigned the relevant codes during at least one hospitalization or at least three visits for ambulatory care before the index date3. We categorized the participants into three groups in accordance with monthly income: < 20,000, 20,000–40,000, and > 40,000 New Taiwan Dollars (NTD)3.We categorized the participants into five groups on the basis of age: < 20, 20–34, 35–49, 50–64, and ≥ 65 yearst-tests to evaluate differences in continuous variables and χ2 tests to evaluate those in categorical variables. Cox proportional hazard regression with competing risk analysis was used to identify the independent predictors of breast cancer and evaluate their effects. We also performed multivariate regression to adjust for potential confounding effects. In addition, we applied the Kaplan–Meier method and the log-rank test to compare the breast cancer risks of the two cohorts during the follow-up period. Given that the risk of COP-associated breast cancer might change over time, we conducted further analyses by using a cutoff of 1 year for follow-up duration. All analyses were performed by using SAS 9.4 for Windows  at a two-tailed significance level of 0.05.We followed up the two cohorts until 2014 to compare their breast cancer risks. We applied independent The study protocol was reviewed and approved by the Institutional Review Board (IRB) at the Chi Mei Medical Center. Informed consent from the participants was waived by the IRB because the NHIRD contains anonymized information only. The waiver did not affect the rights and welfare of the participants.p < 0.001). The average age at diagnosis of breast cancer was similar between COP and comparison cohorts .We included 7053 female patients with COP and 42,318 females without COP in this study  (Table p = 0.009). The Kaplan–Meier’s method and log-rank test also showed that the COP cohort had a lower breast cancer risk than the comparison cohort  of 0.67  Table . The decort Fig. .Table 2Ip = 0.378) in the first year of follow-up (Table p = 0.377). The reduction in risk was larger than that observed over the whole follow-up period but did not reach statistical significance. COP was associated with a HR of 0.70  (Table p = 0.026). We divided COP cohort into those with one and multiple episodes COPs and compared them with the comparison cohort. The result showed that both those with one and multiple episodes of COP had a lower risk for breast cancer than the comparison cohort . However, the difference between those with one and multiple episodes of COP did not reach statistical significance  to treat mice that had been xeno transplanted subcutaneously with pancreatic cancer cells1. The conversion of heme to biliverdin, ferrous iron, and CO is catalyzed by HO-1 and HO-21. Biliverdin is further reduced to bilirubin by biliverdin reductase1. The role of HO-3 is not fully understood. HO-3 is suspected to be a pseudogene that is derived from HO-2 transcripts19. HO-1 is found in the spleen, liver, vascular endothelial cells, and smooth muscle tissues1. It is the only inducible HO isoform, and its increase is stimulated by cellular stress1. HO-2 is responsible for neurotransmission and vascular tone regulation20. HO-2 and HO-3 are ubiquitously expressed in the brain, liver, and testes20. CO maintains cell and tissue homeostasis via its antiapoptotic, anti-inflammatory, and antioxidant effects1. CO also has antiproliferative and vasodilative effects and may participate in tissue regeneration and in strengthening the innate immune system10.Studies on endogenous CO may cast some light on the anticancer effect of CO. Endogenous CO is a byproduct of the oxidative conversion of heme1. COP may contribute to hypoxia and inflammation and subsequently to neurologic and cardiac dysfunction, injury to other organs, and even death8. In recent years, CORMs, a group of transition metal carbonyls or boranocarbonates that can release CO upon transformation, have provided another avenue for CO application20. High CO concentrations exert cytotoxic effects via the inhibition of the mitochondrial respiratory system, the induction of oxidative stress, and the production of reactive oxygen species21. CORMs may enable the localized release of high amounts of CO for specific cytotoxicity against targeted tumors1.Although CO may have therapeutic applications, its possible toxicity stemming from its effect on oxygen transport and toxic dose control from systemic CO gas administration are major concerns11. RuCO down-regulated the expression of growth-related proteins, including cyclinD1, CDK4, and hTERT11. Given that HSP90 stabilizes several proteins required for tumor growth, the feasibility of using HSP90 inhibitors as anticancer drugs has been investigated22. The contradictory effects of RuCO treatment on wild-type and mutant p53 proteins are similar to those of cells treated with geldanamycin, a HSP90 inhibitor; this similarity suggests that RuCO might affect HSP90 activity11. Fac-[MnBr(azpy)(CO)3], a manganese carbonyl complexes which is a photo-CORMs that release CO after irradiation with low-power visible light, was found to eradicate breast cancer cells in a dose-dependent manner and kill nearly 40% of breast cancer cells at the concentration of 75 μM12. In recent years, an increasing number of novel CORMs have shown potential as anticancer treatments. These CORMs include [FeII(CO)(N4Py)](ClO4)2 for prostate cancer23; [Mn(CO)3(tpm)]PF6 for colon cancer24; fac-[MnBr(azpy)(CO)3] for cervical cancer, in addition to breast cancer12; and CORM-2 for pancreatic cancer15, skin cancer25, lymphoma, and acute myeloid leukemia26. In addition to CDRMs, CO gas also showed anticancer potential against pancreatic cancer15 and lung adenocarcinoma27.A growing number of studies have revealed that CO administration is an emerging hope for cancer treatment. Lee et al. found that treatment with RuCO, a type of CORM, reduced the growth of human MCF7 and MDA-MB-231 breast cancer cells28. Therefore, we believe following up the participants for 12 years in the present study is sufficient to cover the age at the highest risk for a substantial portion of them. Fourth, we did not evaluate the survival advantage associated with COP or compare the distributions of breast cancer stage and ER/PR/HER2 status between patients with and without COP because they are out of the scope of the present study and the databases do not contain the some of the information. Separate studies are needed to clarify these issues. Fifth, the number of breast cancers was relatively small due to the relatively young age at the beginning of follow-up. Nonetheless, the size of patients was large enough to provide sufficient statistical power to detect the effect of COP on breast cancer. As to the potential antitumor effect, recruiting more patients and further animal and laboratory studies are needed to support its clinical application.The major strength of the present study is its nationwide population-based design with a large sample. While the novel finding of a decreased risk for breast cancer in COP patients has implicated the potential use of CO as a therapeutic agent, this study has several limitations. First, information on several risk factors, including family history, reproductive history, physical activity, and body mass index, is not available in the NHIRD. Consequently, we were unable to adjust for the effects of these potential confounders. Second, we did not recruit male participants given the rare incidence of breast cancer in the male population. Therefore, the results of this study might not be applied to the male population. Third, the participants were relatively young (about 34 years old on average at the beginning of follow-up). However, nearly half of patients (48.2%) were aged ≥ 35 years initially, and the peak age at the diagnosis of breast cancer in Taiwanese women was 45 to 50 yearsThis study demonstrated that female patients with COP had a lower risk of breast cancer than those without COP. This result may be attributed to the direct and indirect inhibitory effects of CO on tumor growth. Further studies involving collection of complete variables for possible confounders in the patients with breast cancer as well as animal and laboratory trial experiments on the mechanisms are warranted.Supplementary Legends.Supplementary Table S1.Supplementary Figure S1.Supplementary Figure S2.


Stress is a common belief among breast cancer patients and the public to explain variation in breast cancer incidence. Epidemiological studies interrogating the relationship between stress and cancer have reported mixed results. The impact of the topic and the lack of consensus has sparked this review of the literature to investigate gaps in knowledge and identify areas of research. We first present a brief summary of the biopsychosocial model generally used to conduct research on stress. We then divide the overview of the literature into areas of research focus. These include the role of distressing life events in breast cancer incidence, the role of adverse childhood events in later breast cancer incidence, the importance of race and socioeconomic status (SES) as social determinants of breast cancer incidence, and the specific role of chronic stress in relation to breast cancer. For each topic, we discuss the potential of stress as a risk factor and possible intervention strategies that could reduce the effects of stress. We then identify further research questions to be probed to fill the gaps in knowledge. We conclude with a discussion of future research directions for stress research as it relates to breast cancer incidence. Stress is a common idea in the general public to explain variation in breast cancer incidence. However, is stress related to breast cancer incidence, and, more importantly, can it be the target of an intervention to reduce breast cancer risk? This manuscript reviews evidence about the potential role of stress and identifies areas of future research activity to clarify and increase our understanding of stress in breast cancer.We first present a brief summary of the biopsychosocial model generally used to conduct research on stress. Next, we divided the overview of the literature into distinct areas, each a focus of research attention. These include the role of distressing life events in breast cancer incidence, the role of adverse childhood events in later breast cancer incidence, the importance of race and discrimination and socioeconomic status (SES) as a social determinant of breast cancer incidence, and the specific role of chronic stress in relation to breast cancer. For each topic, we discuss the potential of stress as a risk factor and possible intervention strategies that could potentially reduce the effects of stress. We conclude with a discussion of future research directions for stress research as it relates to breast cancer incidence.There is an emerging body of literature that puts forward the hypothesis that differential exposure to stressors and the co-occurrence of stressors may reflect part of the distinctive environmental contexts of demographic and exposure groups. As a result, these exposures contribute significantly to health disparities that have been observed in certain groups. We probe the existing literature on how to conceptualize and operationalize stress in order to examine how it affects health status. In turn, those exposures contribute in important ways to the observed patterns of disparities in health. The following text considers research on the conceptualization and operationalization of stress and how stressors can affect health status.Stress is a nebulous concept that is subject to various interpretations. Stress is not a discrete value but rather a continuous interplay between an individual and their environment. Wheaton and Montazer  distinguHowever, it is important to note that not every individual experience induces stress in the same way. The individual’s personal and social health stress , in addition to the severity of the stressor, affect the ability of the individual to cope with the resulting stress. Stress, described as “a biological state of the body—a generalized physiological alert—in response to threatening agents,”  is oftenThe ability to access resources that have the ability to meet the demands of the stressor greatly alters the response, both psychologically and physically, to the stressor(s). This governs whether a particular stressor will cause a state of distress, commonly characterized as “stress.” For some, an amplified physiological response has acute and long-term consequences . Portions of the brain that are central to emotional and stress-related processes, such as the amygdala, also contribute to the mediation of stress-induced reactions linked to physical health outcomes. Studies have shown that differences in amygdala reactivity are associated with stressor-induced changes in blood pressure and cardiovascular disease risk, and increased secretion of the stress hormone, cortisol . For othEarly stress research focused on the biological processes through which stress affects individuals. There was no particular focus on distinguishing between various types of stressors, although there were considerations of different, both internal and external, factors that may alleviate or amplify the impact of the stressors on an individual. An example used by Zinzi and Williams highlighted this concept by noting that “the average person would be alarmed by close proximity to a lion, activating stress hormones such as epinephrine. However, for a lion tamer, this would be part of a daily routine and he or she could have the psychological and physical resources to draw on that would minimize any potential negative effects” . While mThe exhaustion stage of Selye’s generalized adaptation syndrome describes what occurs when a chronically stressed individual is not given adequate time to “repair” or recover. In order to cope with the chronic exposure to the stressor in the absence of any respite, the body will raise its homeostatic set point for catecholamine  levels, and that of other hormones, so the body can continue to response without restocking its stores. This leads to unwanted consequences, such as the body being unable to repair and recover itself, or fight off external infection. The exhaustion of the body’s resources can cause long-term weakening of numerous physiological systems via hormone dysregulation and physical damage to the nervous system. Additionally, extended exposure to certain external stressors (such as extreme heat or cold) can be fatal.Disparate stressors trigger disparate patterns of response from the body’s systems. The sympathetic–adrenal–medullary (SAM) system and the hypothalamic–pituitary–adrenocortical (HPA) axis, for example, are highly active in response to psychosocial stress. However, their activity levels vary depending on the source and type of stressor that prompted the response . When thAs noted in review articles, the perception that women under stress are more prone to cancer is common and long-standing ,9. In 19Stressful life events trigger psychological processes that can affect health behaviors and neuroendocrine regulation through four main pathways—(1) stressors can lead to symptoms of distress and increase risk of mental disorders, adversely affecting psychological well-being due to the negative emotions associated with stress, (2) the negative emotional responses lead to biological dysregulation that can contribute to indicators of subclinical disease, (3) attempts to cope with negative emotional responses can lead to an increase in risky health behaviors , including (4) a reduction in healthcare-seeking behavior .Studies from molecular biology have revealed the physiologic effects of the stress hormone cortisol on mammary gland development, estrogen activity, and other intra-cellular pathways involved in breast cancer . Over tiStressful life events are discrete, psychosocial events that disrupt normal life. Stressful life events can be positive or negative, but most studies focus on negative or adverse life events. For example, stressful life events can include the death of a spouse, close relative or friend, end of a relationship , personal illness or injury, loss of a job or change , change in the health of a family member, and/or the gain of a family member . Differep = 0.003). The pooled odds ratio (OR) for severe striking life events and breast cancer was 2.07 (95% CI 1.06–4.03), suggesting that women that experienced severe striking life events were at two-fold greater risk of developing breast cancer. Other studies have found no link between stressful life events and breast cancer incidence [An extensive body of epidemiologic studies has interrogated the relationship between stressful life events and breast cancer incidence. This literature has been the subject of multiple systematic reviews and meta-analyses ,17,18,19ncidence ,28,29,30A critical issue relates to timing, both in terms of latency and windows of breast susceptibility over the lifespan . InvestiPetticrew et al.  performeBahri et al.  performeA recent study by Fischer et al. , not incGiven the complexity of breast cancer etiology, future studies on the significance of stressful life events would benefit from the combination of advances in molecular biology into study designs and the creation of transdisciplinary study teams. Investigators with the Nurse’s Health Study II began the Mind–Body Study (MBS), a nested study on 233 cohort participants, to understand the inter-relationships between various biologic measures and psychosocial factors previously identified as stress . The invInterventions—for women without breast cancer, several recent reviews have concluded that the evidence on mindfulness-based interventions (MBIs) is limited but suggestive of effects on biologic mechanisms thought to increase breast cancer risk ,36,37. IThere are a sizable number of studies on the association between adverse childhood events (ACEs) and the risk of breast cancer in adulthood ,40 ACEs From a biological perspective, an abstract  focused A challenge associated with the identification of ACEs is recall bias. The use of retrospective and prospective measures of adversity showed moderate agreement based on a comparative study conducted by Reuben et al. . One stuThe “Breakthrough Generations Study” was a prospective study of 106,612 women (median age = 46.6 years old) without a history of breast cancer in the United Kingdom, conducted between 2003 and 2012 . The assHowever, the authors of the study note “a lack of information on the intensity of stress, on stress in the workplace, and on the extent of social support or stress adaptive capacity” as a limitation in their study. A major finding in the stress literature is that failure to measure stress comprehensively markedly understates the role of stress. Hence, the key for future research is measures of cumulative stressors across multiple domains .Interventions—it seems that we are in the early stages of discovery related to this topic and it is ripe for further research analysis. There are no published studies of interventions that ameliorate or reduce the effects of ACEs on stress reactions.The American Psychological Association has conducted surveys of communities across the United States since 2007 to provide a yearly snapshot of the experience of stress and its impact. The experience and impact of stress related to the COVID-19 pandemic cannot be overstated. When compared to white people, Black, Indigenous, and People of Color (BIPOC) experience more stress around meeting their basic needs (61% versus 47%), being able to access health care if they are sick (59% versus 46%), and contracting COVID-19 (71% versus 59%) . While eIn introducing a framework for the study of racism and health, Williams  outlinesSeveral systematic reviews, systematic meta-analyses, and longitudinal studies have examined racism as a risk factor for negative health outcomes and specific immunological responses. They have also investigated the association between racism and breast cancer incidence, and the relationship between immunological response and breast cancer incidence. Briefly, studies have demonstrated the impact of racism—on known risk factors for breast cancer such as drinking alcohol, on markers of inflammation, on mental health outcomes such as depression, and on physical health. Furthermore, examinations of longitudinal data have demonstrated links between the experience of racism and breast cancer.p < 0.01) and racial identity  on cytokine levels. Furthermore, an interaction effect  was found, such that young people with negative racial identities who were exposed to high levels of racism at 17 had elevated cytokine levels three years later at 20 years old.While academia has yet to reach a consensus on the role of inflammation in breast cancer (BC), several compelling investigations must be noted. Brody et al.  examinedMoody et al.  examined2 = 51.0%) and a small number of breast cancer cases (n = 1024) suggest that the results should be interpreted with caution [2 = 45.9%), included 15 cohort and case-control studies representing international samples  and had 5286 cases of breast cancer. Change in C-reactive protein was related to breast cancer, with a combined OR of 1.16 (95% CI: 1.06–1.27) across the total sample. The association was stronger for Asian samples  than for European  and American  samples [While a 2009 meta-analysis concluded no significant association between C-reactive protein and breast cancer, Guo et al. noted high heterogeneity across studies  that prop up structural racism so that some of racism’s impacts on health are weakened. For example, high-quality interventions aimed at child development in children’s prenatal period and first five years of life have led to positive impacts throughout their lives. Notable outcomes include higher income for the intervention group compared to the control group, and more homeownership, lower rates of crime, fewer risky behaviors, higher education levels, lower Framingham risk score for coronary heart disease, less depression, and better blood pressure.The second strategy is to “build more health into the delivery of medical care.” A subset of interventions in this area includes addressing the social needs of patients at the same time as the delivery of healthcare and diversifying the healthcare workforce. A 2020 initiative from the Office of the California Surgeon General on ACEs, toxic stress, and health  exemplifThe third strategy is “raising awareness of inequities and building political will to address them,” which describes several interventions that aim to shift attitudes, build awareness of racial health disparities, enhance empathy, and dismantle racism.A key takeaway from their article is that there is a much larger body of evidence for effective interventions for racism than most scientists and lay audiences recognize.Many epidemiological and clinical studies have examined the interplay between stress, anxiety, depression, and breast cancer risk and progression ,60,61,62n = 6571) were followed from January 2000 to December 2013, or until cancer diagnosis, emigration, or death. The results from this study revealed no significant relationship between job strain and an elevated risk of any form of cancer. Results from a separate study—a meta-analysis of prospective individual participant data from 12 European cohort studies—suggested that job strain was not linked with an elevated risk of any form of cancer  [Studies focused on job-related stress indicate that there is no appreciable increase in risk for breast cancer associated with stress in the workplace ,56,58. F82–1.14) .n = 2739) responded to follow-up assessments in the following years. This study found no evidence that acute and chronic stressors played a role in increasing risk of breast cancer (acute stressors HR = 1.03 (0.99–1.08), p = 0.19; total chronic stressors HR = 1.0 (0.90–1.11), p = 0.98). The most recent systematic review on psychological stress and breast cancer incidence, which included 52 studies between 1966–2016, found that there is not enough evidence to state that chronic stress increases one’s risk of breast cancer [In a recent prospective study, researchers observed the association between social support, life event stressors, and the risk of breast cancer development among women that are genetically predisposed to cancer for 15 years . Previout cancer . Of the The research on the relationship between stress and breast cancer is mixed, with evidence suggesting no association between job-related stress and breast cancer, evidence on overall stress seeming equivocal, and suggestions of a positive association between stressful life events and breast cancer. Still, findings across studies remain in conflict. The contradictory findings can be attributed to significant diversity in methodological approaches, including inadequate power and control of potential confounders, measurement error, and failure to consider potential moderators of stressor impact, such as stressor severity and chronicity, social support, personality, and coping style . DetermiGiven what is known about the relationship between stress and breast cancer, interventions targeting stress reduction are not guaranteed to decrease the risk of developing cancer. It is established in the literature that excess stress can have negative effects on human health. There is literature regarding several stress-reducing interventions such as mindfulness-based interventions (stress reduction and cognitive therapy), exercise, and social support. Social support  has been highlighted as particularly important in terms of perceived stress or psychological strains with an inverse association between the two being highlighted in many studies. ,67,68,69We need to focus our research efforts on the places that will advance the field more rapidly and logically. For example, the best biologic and psychometric measures of psychosocial distress for community-based studies of stress and breast cancer risk, based on conceptual models of etiology and an assessment measure attribute, are not yet identified and used. This change could occur through the identification of the appropriate batteries of measures and models, and their use in large scale trials and observational studies of stress.The batteries of measures and models should be developed, normed, and tested with the inclusion of multiple groups that experience significant health disparities, such as immigrants, disabled people, Black, Indigenous and People of Color (BIPOC), older adults, LGBTQ populations, poor people, etc. This process will allow the measures to detect and measure specific stress construct consistently across groups. Accuracy is critical for effective testing of models and testing of moderating and/or mediating relationships.Together with this idea, we need to improve our research attention to the mechanisms of the development and maintenance of the stress response in multiple situations. This can only come about through the operationalization of conceptual models, the measurement of complete model variable sets, and the careful analyses of which variables are working in different situations. Some of the “outcomes” of stress reactions are ritually better conceptualized as possible mechanisms of stressful responding  and should be studied using mediational models to establish or refute their importance.Specific findings of the role of ACEs in the development and maintenance of stress responding. Many concrete examples exist of questions t that need to be asked about the role of ACEs in stress. For example, do women with ACEs have more aggressive  breast cancer? Do identification and interventions regarding ACEs affect the response to treatment of breast cancer? Can interventions for reducing or eliminating reactions to ACE change the course of stress response?The use of community-partnered participatory research methods is critical to building a nuanced picture of specific types of stress and their relationship with breast cancer. As noted earlier, there are disparate experiences of stress across ethnic groups, racism is a stressor that specifically impacts people of color groups, stress can act as a risk factor for behaviors that increase the likelihood of breast cancer incidence, and stress can produce changes in the body  that may be linked with breast cancer incidence. Participatory research involves the building of authentic partnerships between the community and academic institutions; the equitable sharing of power, budget, and agenda-setting; both community and academia participating equitably in all phases of a research project, including dissemination; and co-ownership of data from the project. Partnering with the community can create a path to effective cancer interventions by centering the topics that are of interest to the community and incorporating community knowledge . One exa


Pursuant to a Congressional act in 2008, the Department of Health and Human Services established the Interagency Breast Cancer and Environmental Research Coordinating Committee to address the burden of breast cancer in the United States. Subsequently, the Committee recommended researchers study the timing of exposure to breast cancer risk factors. Given the high breast cancer mortality rate on Staten Island, this paper presents a case-control study investigating breast cancer risk associated with puberty while living on Staten Island. The dataset combined New York City Department of Health and Mental Hygiene female death certificate information between 1985 and 2006, with life history information from newspaper obituaries. Data analyzed included: age, length of residence on Staten Island, birth on Staten Island, and residence on Staten Island during puberty. Cases were individuals who died of breast cancer and controls were individuals who died of non-malignant causes. Analysis included multivariate logistic regression on the full dataset and multiple replicates of randomized one case to two controls simulations. Results indicated that living on Staten Island during puberty (ages 9–19) was associated with an elevated risk of dying from breast cancer . This paper suggests the importance of studying puberty as a window of susceptibility for breast cancer risk. It is 153 square kilometers in area, located at the southern tip of New York State, approximately 8 kilometers from the borough of Manhattan Environmental exposures have been a topic of conversation on Staten Island since 1882 The New York City Department of Health and Mental Hygiene (DOHMH) has responded to the concerns of the SI community with three studies examining health consequences of environmental exposures While the risk for breast cancer increases with age and the majority are diagnosed after age 50 To address the “burden of breast cancer” in the United States, Congress passed Public Law Section 110–354  in 2008 The Center for Environmental Science at the College of Staten Island/CUNY, an outgrowth of the Master of Science in Environmental Science, has a mission to serve as a university and community focus for scientific, educational, and legal solutions to environmental problems. Inspired by the recommendations of the IBCERCC and responding to the concerns of the SI community and government about the high breast cancer rates on SI, the Center established the Staten Island Breast Cancer Research Initiative (SIBCRI).Puberty is a complex process with great variability in timing 2.Staten Island AdvanceA retrospective study investigating the risk of SI female breast cancer mortality during the years 1985–2006, using a case-control design, combined life history information from DOHMH death certificates with the Cases and controls were determined from death certificates by the NYC Department of Health and Mental Hygiene. Cases were identified as SI females with an International Classification of Disease (ICD) designation of malignant neoplasm of breast, either ICD 9 code 174 Staten Island Advance, a local newspaper providing information to the SI community since 1886 Additional life history information was obtained from obituaries in the database. Comparisons were made, and all discrepancies were corrected by referring to the source material. To ensure quality control, all data were double entered by independent staff in a relational.To examine “windows of susceptibility”, data were analyzed for risk using the following attributes: age, length of residence on SI (SI Years), born on SI (SI Birth = yes/no), and puberty on SI (SI Puberty = yes/no). The odds ratio (OR) for each attribute was defined as the ratio of cases to controls having that attribute divided by the ratio of cases to controls not having that attribute. SPSS  was used for calculating odds ratios from contingency tables. The dataset analyzed is available in In this study, age was an important confounding variable A second approach to include age as a variable was to use an age-matched case-control design . The large number of controls in the dataset allowed for a simulation of this technique with multiple random subsets of the entire dataset. A case was selected at random and then matched to two randomly picked age-matched controls. Logistic regression was performed on every random subset. The average of the odds ratios obtained as well as the standard deviation of these ratios was calculated. Details of this technique are available in The study received approval from the CUNY Institutional Review Board and underwent review through IRBnet.org.3.3.1.2X  = 40.2, p < 0.001. This analysis, however, does not include the important age differences between cases and controls.To analyze puberty risk, a 2 × 2 contingency table was formed . The odd3.2.Using multivariate logistic regression on the entire dataset (first approach) with age and SI Puberty as variables, an odds ratio of 1.35  was obtained.3.3.The dataset included SI Years and SI Birth as well as SI Puberty. Since there may have been correlations between these variables, multivariate logistic regression was done to investigate whether SI Puberty was the major risk.Using multivariate logistic analysis with age and SI Years, the odds ratio for length of residence on SI was 1.004 . When age, SI Years and SI Puberty were included, the odds ratio for SI Years dropped to 0.997  while the odds ratio for SI Puberty increased to 1.52 .Similarly, using multivariate analysis with age and SI Birth the odds ratio for SI Birth was 1.10 . However, when age, SI Puberty, and SI Birth were included the odds ratio for SI Puberty increased to 1.7  while the odds ratio for SI Birth decreased to 0.73 .4.This study has investigated the high rate of breast cancer mortality on SI using the variables age, length of residence on SI, born on SI, and residing on SI during puberty years. Since these attributes may not have been independent, the interactions between the variables had to be considered. The main result was that women who went through puberty on Staten Island are 35% more likely to die of breast cancer than women who went through puberty elsewhere.Because the average age of breast cancer cases were nine years younger than controls, it was apparent that age was needed as a variable in the investigation of risk factors. Since the percentages for cases compared to controls were higher for both SI Puberty and SI Birth an analysis was needed to separate these factors in determining risk. In contrast, since the average length of residence on SI of cases was less than controls, the number of years residing on SI was unlikely to be an important breast cancer mortality risk.Multivariate logistic regression (first approach), with age and SI Puberty as variables, determined an odds ratio for SI Puberty of 1.35. Adding either length of residence on Staten Island or birth on Staten Island did not improve the accuracy of this result. The analysis established that the 95% confidence interval for the odds ratio was 1.18 to 1.55.Using the alternate technique (second approach) of simulating random age-matched case-control studies yielded an average odds ratio of 1.43 with a 95% confidence interval of 1.35 to 1.51 . The oddIt is true that 70% of the cases that resided on SI during their puberty years were also born on SI. The multivariate analysis including age, SI Puberty, and SI Birth returned an odds ratio of less than one (negative risk) for SI Birth implying that the important risk was SI Puberty. Furthermore, the dataset included 65 women born on Staten Island who moved away before puberty and then returned to Staten Island. None of these women died of breast cancer. While additional study is needed, these two results suggest that the important exposure was during puberty and not in utero.Additionally, it is necessary to study Staten Island's unique environmental risks relating to breast cancer to identify possible exposures women had during the window of susceptibility. An unusual geological feature of SI are serpentine outcroppings. This ridge of serpentine makes up approximately one-quarter of the land area The Fresh Kills Landfill was established by the City of New York on SI SI Advance death notice was the family's desire for privacy or funeral arrangements off Staten Island. This was true for both cases and controls. The result in this paper should be corroborated by other studies where residence during puberty can be established by an alternate approach.The authors have concluded that there are several limitations to this study. Death certificate data was obtained from DOHMH in November 2008. Due to the complex nature of the dataset, merging various attributes required unanticipated extra resources and time. This study covered breast cancer mortality between the years 1985 and 2006. The results should be confirmed with studies on more recent time periods. Additionally, there are limitations associated with using obituary data. The two main reasons for a person who died on SI with a DOHMH death certificate but no 5.This paper examined breast cancer mortality risk associated with residing on Staten Island during puberty. Two independent statistical approaches obtained equivalent results suggesting that puberty was a significant window of susceptibility. This conclusion supports the recommendation of IBCERCC that researchers study the timing of exposure to breast cancer risk factors While this study has identified a window of susceptibility for breast cancer risk for Staten Island, it has not identified specific environmental exposures associated with that risk. It is possible that the improvements in environmental quality over time have reduced the breast cancer mortality risk faced by current Staten Island females during puberty. The next step in studying this question is to identify other geographic areas with similar environmental perturbations that have high breast cancer incidence and mortality rates to determine if there is a commonality with Staten Island.Click here for additional data file.Click here for additional data file.Click here for additional data file.


Very limited data exist on the role of NLR and risk of BC. The BREOGAN study is a population-based case–control study conducted in Galicia, Spain. We examined the WBC- and NLR-BC relationships. The risk of BC increased with increasing levels of neutrophils percentage (NE%) (multivariable OR for the highest category (95% CI) = 2.14 (1.39–3.32), P-trend < 0.001) and of the NLR (multivariable OR for the highest category (95% CI) = 1.93 (1.26–2.97), P-trend < 0.001). Lymphocytes absolute (L#) and percentage (L%) were associated with a decreased risk of BC (multivariable OR for the highest category (95% CI) = 0.54 (0.35–0.83), and 0.51 (0.33–0.79), P-trend = 0.001 and < 0.001, respectively). The NLR-BC association was more pronounced among Luminal A BC (multivariable OR for the highest category (95% CI) = 2.00 (1.17–3.45), P-trend < 0.001), HER2-negative BC (multivariable OR for the highest category (95% CI) = 1.87 (1.16–3.02), P-trend < 0.001), and those with high total cholesterol and low H It was responsible for 6,421 deaths . Breast cancer is the most frequent cancer in Spain and ranks the fourth in cancer-related mortality. There has been a 30% increase in breast cancer incidence between 2012 and 20181.In 2018, 32,825 new breast cancer cases were diagnosed in Spain, representing 12% of all cancer cases, and 29% of all cancers in women3. Similarly, there is abundant evidence for an adverse prognostic value of neutrophil to lymphocyte ratio (NLR) on breast cancer. Multiple studies have shown that higher NLR was associated with poorer survival9, and a recent meta-analysis found that higher NLR was associated with both worse disease-free survival and overall survival6. Several previous studies have found that higher NLR was also associated with more advanced or aggressive breast cancer11.High concentration of blood neutrophils is seen in patients with advanced cancer and are associated with poor survival13. NLR is higher in patients with more advanced cancers10, and correlates with poor survival in many cancers15. Thus, NLR, a simple and inexpensive biomarker, has been introduced as a significant prognostic factor in many tumour types3. However, it has not been accepted in many clinical settings since neutrophilia can be also the result of elevated granulopoiesis and, therefore, may not be an adverse sign for cancer progression3. Another reason is that neutrophilia is associated with poor clinical outcome in all cancers except one, stomach cancer, in which a high NLR is a marker of good prognosis16. However, the evidence for a detrimental effect of circulating neutrophils and the NLR on cancer prognosis and survival altogether, with only the exception of gastric cancer, is very consistent.For this reason, the ratios between neutrophils in blood and other leukocytes, as the NLR, have been suggested as a prognostic value in cancer18. Two of the three studies compared breast cancer cases with benign breast disease (BBD) controls17, and the third one used healthy controls as reference group18. In one of the studies17, the NLR was significantly higher in breast cancer patients compared with the BBD group, and patients with NLR > 1.67 were related to an increased risk of breast cancer. This finding was consistent with the other two studies18, suggesting that NLR could be an independent risk factor for breast cancer.To our knowledge, only three small studies, conducted in Asian women, assessed the association between NLR and the risk of breast cancerIn the present study, we examined the association of WBC including neutrophils, lymphocytes and monocytes, and the NLR, on the risk of breast cancer overall, and by major subtypes, menopausal status, and grade and morphology, in Spanish women.21, obesity was associated with an increased risk of breast cancer (multivariable OR (95% CI) = 2.02 (1.30–3.17), P-trend = 0.003). Use of oral contraceptives was also associated with an increased risk of breast cancer (multivariable OR (95% CI) = 2.01 (1.22–3.30)). Similarly, ex-smokers and current smokers were associated with an increased risk of breast cancer (multivariable OR (95% CI) = 2.18 (1.14 – 4.14), and 1.86 (0.87–3.93), for ex-smokers and current smokers, respectively). A history of first- and/or second- degree relatives with breast and/or ovarian cancer was associated with an increased risk of breast cancer (multivariable OR (95% CI) = 2.46 (1.49–4.06)). Consistent with previous studies, invasive ductal carcinoma was the most frequent histological type (80%), and the distribution of the Luminal A, Luminal B, HER2 overexpressed, and TNBC subtypes were 63%, 13%, 8% and 15%, respectively. Mean tumor size in cm was 2.1.Table 2O2) (multivariable OR for the highest versus the lowest category (95% CI) = 0.26 (0.13–0.51), P-trend < 0.001).Table Table 2O2 levels. The NLR-breast cancer association was more pronounced for women with high total cholesterol levels (multivariable ORs (95% CI) = 2.79 (1.60–4.91), and 1.41 (0.66–3.04), P-trend < 0.001 and 0.09), for high and low total cholesterol levels, respectively), and low urinary H2O2 levels (multivariable ORs (95% CI) = 1.74 (0.59–5.43), and 3.30 (1.12–10.40), P-trend = 0.31 and 0.056, respectively), for high and low urinary H2O2 levels, respectively).Table We also examined the NLR-breast cancer association by tumour grade, stage, and histology  = 1.68 (1.12–2.58), P-trend = 0.01). We also examined PLR by tumor grade, stage, and histology 17, and only one used healthy controls as comparison group18, as in our study. In one of the studies17, NLR was significantly higher in the breast cancer group compared with the BBD group, and patients with NLR > 1.67 were associated with an increased risk of breast cancer. This finding was consistent with those of the other two studies18, suggesting that NLR could be an independent risk factor for breast cancer. In one study, the best cut-point value for NLR was 2.96 and it was replicated, giving a sensitivity and a specificity of about 80% and 76%, respectively, in patients with breast cancer. In another study, the cut-point value for the NLR was 2.56.There is abundant evidence for the adverse prognostic value of NLR on breast cancer. Multiple studies have shown that higher NLR was associated with adverse survival24. There is evidence for a detrimental role of neutrophils during tumour progression, but there is also solid evidence of an anticancer effect. Activated neutrophils can kill tumour cells in vitro25 and in vivo 26. Neutrophils only possess this antitumor effect after they have been activated. It was shown that a colon adenocarcinoma cell line transfected to express G-CSF (Granulocytic Colony Stimulating Factor) lost tumour activity after massive concentration of neutrophils at the tumour site27. In that study, purified neutrophils from SR/CR mice directly killed cancer cells in vitro and entirely conveyed resistance to recipient wild-type mice27. In addition, the cancer progressively disappeared after penetration of a big amount of neutrophils and a lesser amount of lymphocytes into the rest of the tumour tissues28. Neutrophils from tumour-bearing animals displayed enhanced reactive oxygen species (ROS) such as superoxide anion generation and phagocytosis, which led to reduced tumours and less metastatic foci in lungs30.Neutrophils are the most frequent (40% to 75%) type of white blood cells in mammals, and a crucial part of the innate immune system32. In resting neutrophils cells, NADPH oxidase is inactive. Neutrophils migrate from blood to tissue and it is at the tissue level where they become activated through release of ROS such as H2O2, and then subsequently kill cancer cells. As neutrophils-induced ROS have not just been found extracellularly but also intracellularly33, accumulating that they participate as signalling molecules in cellular pathways such as apoptosis of tumour cells34.To do their anti-cancer effect, neutrophils have a remarkable ability to produce a high amount of ROS which is the phagocyte nicotinamide adenine dinucleotide phosphate (NADPH) oxidaseThis anticancer, pro-apoptotic, effect of activated neutrophils in tissue underlies our finding of an elevated risk of breast cancer with increasing levels of blood NE% and NLR. Higher neutrophil levels in blood, where they are inactive, may indicate a low corresponding concentration in tissues, where they are active. Inactive neutrophils are unable to release ROS or cause ROS-induced apoptosis of tumour cells. Neutrophils leave their patrol zone in the blood and go to the tissue where they commit suicide after becoming activated by releasing ROS and inducing apoptosis.17. In another study of ovarian cancer cases, total neutrophil counts and WBC were significantly increased in premenopausal women who were Jewish35, and premenopausal women who had a family history of breast or ovarian cancer also had higher NLR and lower lymphocyte counts35.In the present study, we found NE%- and NLR-breast cancer associations to be more apparent when restricted to postmenopausal women. The mechanism underlying this finding is unknown. One possibility is reduced statistical power in premenopausal women, since, although we did find an increased risk in both, postmenopausal and premenopausal women, our study had smaller sample size and therefore limited precision for the latter . Another possibility is that a different mechanistic pathway may exist between breast cancer patients and healthy controls by menopausal status, however, we found no evidence in the literature in support of this. A previous study conducted in Chinese women using BBD as controls examined the NLR-BC association by menopausal status and found that intermediate and high NLR levels significantly increased breast cancer risk compared to very low NLR levels in both, pre- and postmenopausal women2O2, by neutrophils is called oxidative burst and it may be responsible for their anticancer effect. We measured urinary hydrogen peroxide H2O2 in these patients and found that the detrimental effect of NLR on breast cancer was more pronounced among women with low levels of H2O2 in urine, as expected (multivariable ORs (95% CI) = 3.30 (1.12–10.40), P-trend = 0.056, and 1.74 (0.59–5.43), P-trend = 0.31 for low and high levels of H2O2, respectively).The rapid release of ROS such as superoxide radical and hydrogen peroxide, H2• − , which are transformed into another ROS such as H2O2. It has been found that one of the consequences of an increase of total cholesterol amount is an inhibition of the activity of NADPH oxidase in the presence of proinflammatory signals. This would imply a modification of the response to the signalling regulation36.We also found that total cholesterol may modify the NLR-breast cancer relationships. Specifically, we found that the NLR effects on breast cancer risk were more pronounced in women with high levels of total cholesterol. One possible reason is that cholesterol inhibits NADPH oxidase, the crucial enzyme for ROS production and ROS-induced apoptosis of the cancer cell. NADPH oxidase catalyses a very intense production of superoxide ions O38. In another study including young European women and men (median ages 25 years), neutrophil counts were observed to be higher in women39. Higher neutrophil counts in women were found in a study of Africans of 18–55 years of age40. In another study of healthy adults of several races, females had higher granulocyte counts but lower monocyte counts41.Breast cancer is much higher in women than men. Several prior studies have reported higher blood neutrophils rates in females than males37. In a prior study, it has been shown that in healthy women aged around 50 years of age, there is an important drop of NE% and a significant rise of LY%, with a subsequent substantial fall in the NLR; however, in women older than 70 the NLR increased again37.Early age at menopause is an established protective factor for breast cancer, and, in healthy women, menopause decreases the NLR43. Estradiol has been shown to inhibit neutrophil apoptosis44, and decrease lymphocyte production in the bone marrow46. Therefore, in healthy women after menopause, the significant reduction of estradiol levels will likely result in higher neutrophil apoptotic rates and increased lymphocyte production, leading to reduced NE% and risen LY%, and reduced NLR compared to healthy premenopausal women. The neutrophil-apoptotic pathway could be one underlying mechanism behind the significant drop of NE% and substantial rise of LY% in women of around 50 years of age and that women of < 50 years of age have significantly higher NE% and lower LY% than women of 51–70 years of age from that study37. These findings, shown by this37 and other studies47, are also consistent with our own study results, as our mean neutrophil and NLR values in healthy women (controls) are higher in premenopausal than postmenopausal women .In healthy women, estradiol levels dramatically fall (by ~ 70%) during menopause, which commonly occurs around 50 years of age48. HER2 over-expression occurs in approximately 15–30% of breast cancers49, and it is strongly associated with poor prognosis50. However, we found a more pronounced risk from NLR among HER2-negative breast cancer.We also found an increased risk among both HER2-negative breast cancer, and, less pronounced, HER2-positive breast cancer. In a study, HER2 expression, among other factors (increased tumour size and PLR), was significantly associated with an elevated NLRWe will next describe the relationships between NLR, ROS and stem cell divisions. Peripheral blood neutrophils could be a marker of baseline apoptosis levels in tissues. Decreased peripheral blood neutrophils may indicate increased baseline apoptosis level in tissues, as a marker of the innate levels of ROS-induced apoptosis.Among the mechanisms of tumour cell killing, activated neutrophils clearly have the potential of directly killing tumour cells, through ROS that can directly kill tumour cells. In addition to this direct anti-cancer effect, another cell killing mechanism relates to the immune system, also through the rapid release of ROS or the stimulation of T-cell response.51. Mesenchymal stem cells (MSCs) have been shown to suppress neutrophil activation through the inhibition of ROS release and subsequent apoptosis. Therefore, NE% and/or NLR could be a marker of the number of stem cell divisions. An increased number of stem cells divisions would imply a decreased activation of neutrophils and elevated numbers in blood52.It has been shown that the number of endogenous mutations resulting from stem cell divisions correlates with cancer incidence53. PD-L1 functions as an immunomodulatory molecule, and it is broadly expressed in a variety of immune cells including neutrophils, T cells, B cells, dendritic cells, and monocytes. Increased NLR has been reported to be an independent poor prognostic indicator and its normalization following treatment has been found to predict progression-free survival in cancer patients undergoing treatment with PD-1/PD-L1 inhibitors54.Human tumour macrophages express PD-L1Results of this study must be interpreted in light of its limitations. First, measurement of WBC can be difficult, and misclassification can occur. Our WBC levels were measured in standard clinical hospital laboratories, so measurement error is expected to be reduced. Also, any misreporting of blood WBC is unlikely to be influenced by tumour subtype. Residual confounding from alcohol intake, mammographic density, and female steroid hormones such as HRT can also influence the WBC-BC association. Also, for some breast cancer subtypes, such as HER2 overexpressing tumours, we lacked precision. Another limitation of our study was the lack of pre-diagnostic data from the cases to be able to conclude that NLR is positively related to breast cancer. Another limitation is lack of data on TILs in the tumors of our patients, which would strengthen the mechanistic pathway of apoptosis being one mechanism responsible for neutrophils anti-cancer effect. Another limitation is that we did not have enough follow-up on breast cancer survival or recurrence and thus could not explore the NLR-breast cancer effect on survival and/or recurrence, although this association has been confirmed by multiple studies. Conversely, strengths of our study are the direct measurements of WBC in our study population, and the available information on HER2, in addition to hormonal receptor status.2O2, and among grades II and III than among grade I breast cancer. Neutrophils, which are inactive in blood, must migrate to tissue to become activated and liberate ROS to kill tumour cells, after which, they commit suicide and die. If there are increased neutrophils in blood it may indicate that they are not being sufficiently activated and therefore not releasing ROS, implying low ROS levels in tissues. Our finding that increased NE% and NLR in blood is associated with increased risk of breast cancer may indicate that neutrophils are not being sufficiently activated in breast tissue to induce neutrophil-induced apoptosis. Increased peripheral blood neutrophils could be a marker of decreased baseline or innate apoptosis levels in tissues.We found elevated NLR to be associated with increased risk of breast cancer, principally Luminal A and HER2-negative breast cancer. To our knowledge, this is the first study examining the association between NLR and risk of breast cancer in non-Asian women, overall and by major breast cancer subtypes. The NLR-breast cancer associations appeared to be more pronounced among women with high levels of total cholesterol and low levels of H57. Cases comprised 1,766 women with invasive breast cancer diagnosed and treated between 1997 and 2014 at the Clinical University Hospitals of Vigo (CHUVI) and Santiago (CHUS), as described in previous studies. Controls were 1,205 women free of cancer, except non-melanoma skin cancer, living in the same population health area as cases. Response rates were 98% and 99% for cases and controls, respectively. Ethics approval for this study was obtained from the CEIC, Comité Ético de Investigación Clínica de Galicia , responsible for the oversight of both university hospitals, CHUVI and CHUS, and family, primary clinics from where all participants were recruited. All participants provided written informed consent. The study was conducted in accordance to the Helsinki Principles of 1975, as revised in 1983.The Breast Oncology Galician Network (BREOGAN) includes a population-based case–control study conducted in the cities of Santiago de Compostela and Vigo, Spain, within a geographically defined health region that covers approximately one million inhabitants. Data collection methods have been previously described56, risk factor information was collected through a risk factor questionnaire adapted from the Ella Binational Breast Cancer Study59 to meet the needs of the population in Spain. Clinical and histopathological information was abstracted from computerized medical records by trained physicians. The following variables were recorded: level of education , lifetime breastfeeding , age at menarche, age at first full-term pregnancy, parous (categorized as never vs. ever pregnant), number of pregnancies , age at menopause , menopausal status at diagnosis , oral contraceptive use , hormone replacement therapy , smoking status , family history (categorized as none vs. one or more first and/or second degree relatives with breast and/or ovarian cancer). Alcohol consumption was evaluated by the number of alcoholic drinks consumed regularly per week in last year before reference date. The alcohol categories correspond to the CDC definition  of light/moderate and heavy drinking among women.Similar to previous studiesData on circulating WBC including neutrophils, monocytes, and lymphocytes before date of diagnosis for cases and date of interview for controls were abstracted from Ianus, the Galician universal computerized medical history. WBC count was done through automated machine counting of cells. Briefly, withdrawal of peripheral blood by venipuncture was performed during fasting. Total WBC and differential counts were performed on the peripheral blood samples by using the ADVIA 2120 Hematology analyzer . We calculated neutrophil to lymphocyte ratio (NLR) by dividing the number of neutrophils by number of lymphocytes from peripheral blood sample.56, histopathological information was abstracted from computerized medical records by trained physicians. Immunohistochemistry (IHC) analyses on paraffin-embedded material have been previously performed following standard procedures in Galician hospitals to determine the status of ER and PR. In every tumour, 4-μm histological sections were cut and stained with haematoxylin and eosin for histopathological examination according to the criteria of the World Health Organization60. Histological grading was evaluated using the Nottingham modification of the Bloom-Richardson system61. Similar to previous studies56, immunohistochemistry (IHC) analysis on paraffin-embedded material was performed using a universal second antibody kit that used a peroxidase-conjugated labelled dextran polymer , with antibodies for ER , PR . Negative and positive controls were concurrently run for all antibodies with satisfactory results. Cells were considered immunopositive when diffuse or dot-like nuclear staining was observed regardless of the intensity of the staining,only nuclear immunoreactivity was considered specific. The number of positive cells was counted by two different observers independently. Whenever necessary, a consensus was reached using a double-headed microscope. ER and PR were considered positive when the percent of immunostained nuclei was ≥ 10%.Similar to our previous studies56, IHC analyses were performed to determine HER2 status (Dako). No immunostaining (0) or weak membrane immunostaining (1 +) was considered low HER2 expression (HER2). Strong membrane immunostaining (3 +) was considered HER2 overexpression (HER2 +). Moderate membrane staining , grade , histology type , and tumour size (cm). As previously described in previous studies21, of the 1766 women who participated in the study, 100 had unknown ER status, 114 had unknown PR status, and 340 had unknown HER2 status. In the same manner, one hundred and eighty-four women had unknown grade, 14 had unknown histological type and 144 had unknown tumour size21. Sixty-two women had unknown age at menarche, and 48, out of 1,443 parous women, had unknown lifetime breastfeeding21. Urinary H2O2 was measured by ELISA test using K034-F1 Hydrogen Peroxide Fluorescent Detection Kit, de Arbor, 339,00 Arbor Assays DetectX® Hydrogen Peroxide Fluorescent Detection Assay, with all 4 °C stable reagents.Similar to previous studies2O2, were calculated based on distribution among controls. Briefly, cut points for NLR, based on tertile distribution among control group, were comparable to cut points based on previous studies on the effect of the NLR on breast cancer survival and/or prognosis13. Similarly, cut points for PLR were based on tertile distribution among control group, which were comparable to cut points based on previous studies on the effect of the PLR on breast cancer62. Cut points for serum total cholesterol levels were based on tertile distribution among the control group , which are equivalent to standard levels of normal and borderline/high total cholesterol levels . Cut points for urinary H2O2 levels were also based on tertile distribution among the control group . All statistical analyses were performed using the R statistical software version 3.3.3. All reported test significance levels  were two-sided.The association of breast cancer with circulating WBC and NLR was measured by odds ratios (ORs) and corresponding 95% confidence intervals (CIs) using unconditional polytomous logistic regression. Analyses were initially adjusted for the following established risk or protective factors for breast cancer: reference age (age at diagnosis for cases and age at interview for controls), age at menarche, parity, breastfeeding, menopausal status, weight, height, oral contraceptive use, hormone replacement therapy and family history of first-degree relatives with breast and/or ovarian cancer. Results were virtually unchanged after adjustment for all these variables or only age, age at menarche, parity, menopausal status, and BMI, therefore we present results adjusted for the latter. Outcome (dependent) variables were breast cancer subtypes defined by ER, PR, and HER2 status ), compared to controls (comparison group), and explanatory variables were circulating WBC . Cutoff points for subgroup analysis, i.e., NLR, PLR, total cholesterol and urinary HSupplementary information.


Breast cancer is a major life-threatening global public health problem. It is the most common form of cancer in females in many developing countries including Ethiopia. Social networks could change the course of cancer and can influence the quality of life among breast cancer patients. Therefore, the purpose of this study was to assess social networks and quality of life among female breast cancer patients attending in Tikur Anbassa Specialized Hospital, Addis Ababa, Ethiopia 2019.An institutional-based cross-sectional study was conducted in Tikur Anbessa Specialized Hospital Addis Ababa, Ethiopia from March 1 to April 30/2019. A total of 214 female breast cancer patients were included Binary and multiple logistic regression was used to show the association of social networks and quality of life.A total of 214 females with breast cancer were recruited with a mean age of 41.85. Participants who had children , and other relatives , were more likely to have good social networks. Participants who were not married , had no parents living , no close friends , and no neighbors  had poor social networks.The quality of life was relatively low and social support were found to be poor in women with breast cancer. Health-care providers in oncology departments need to focus on addressing the side effects of therapy and social networks which may help to improve the quality of life of females with breast cancer. Breast cancer refers to cancer originating from breast tissue, most commonly from the inner lining of milk ducts or the lobules that supply the ducts with milk. It is the most common cancer and the principal cause of cancer-related deaths in females worldwide . A breasAnnually in Ethiopia, around 60,000 new cases of breast cancer are diagnosed . The AddSocial networks defined the network of social relationships that surround an individual and the characteristics of those bonds . The mosIn a meta-analysis of 87 papers, larger social networks were found to be meaningfully connected with lower cancer mortality . In otheBreast cancer is a worldwide problem, with 1.7 million new cases being diagnosed per year . In a stA meta-analysis of 87 studies summarizing the literature on the association between social networks and cancer survival stated that having larger social networks and being married were connected with declines in risk ratios for mortality of 20, and 12%, respectively  and otheSocially-isolated individuals are less able to buffer the impact of health stressors than others and consequently are at greater risk of adverse health effects such as poor quality of life (QOL), illness or death . The impThe study was conducted at the Oncology center, TASH, located in Addis Ababa. Addis Ababa is the capital and the largest in Ethiopia. Tikur Anbassa Specialized Hospital (TASH) is a large government-owned referral teaching hospital, located in Kirkos sub-city under the administration of Addis Ababa University, College of Health Sciences. The oncology center at the Hospital is the only referral center in the country.An institutional-based cross-sectional study was conducted from March 1 to April 30/ 2019.All breast cancer patients being evaluated and treated in oncology units were considered as a source population.Those breast cancer patients visiting the hospital and being evaluated or treated at the oncology unit during data collection time and who met the eligibility criteria were invited.All-female breast cancer patients who visited the hospital during the data collection were eligible for participation in the study.Patients who are unable to respond and those who didn’t take chemotherapy treatment were excluded from the study.To describe the distribution of quality of life scores, social networks, and associated factors, the sample was calculated by using the prevalence of breast cancer patients of 14.8% , by addiAccording to the one-year record of female breast cancer, 8000 cases were seen in the oncology unit at TASH. Since the duration of the study was 4 weeks, the calculated flow within the 4 weeks was 667 and the required sample size was 214, “K” was 3, so every 3 eligible women were enrolled in the study during the data collection period. This included women who came to the hospital for initiation of treatment or follow-up during the data collection period.Social networks among female breast cancer patients and Quality of life among female breast cancer patients.Socio-demographic , Socioeconomic (occupation and monthly income), Clinical factors: Body mass index (BMI), stage of the diseases, time since diagnosis and type of treatment, Lifestyle .Social networks of the respondents were assessed using Cohen’s Social Network Index (SNI) which contains 12 items (at Cronbach’s Alpha coefficient of 0.72 was obtained) . This inQuality of life was assessed by using functional scales  for the total score was high  symptom scales, and global health status scales . The funData was collected by face to face interview using structured questionnaires that were adapted from SNI and Quality of life and global health status scales  for the total score was high  , 21, 22.Thus, the 53 questions from EORTC (30 questions QLQ-C30 and 23 questions QLQ-BR23) were used to assess QOL. From the EORTC-C30 questions 1–15 were used to assess functional scale, from question 16–28 were used to assess symptom scale and the last 2 questions (29–30) were used to assess global health status scale. And from the EORTC-BR23 questions 1–8 were used to assess functional scales and 9–23 were used to assess symptom scales. The participants of the study were requested to select only one answer from  for the first 28 questions and they were asked to select one between the range from 1 (which means Very poor) to 7 (Excellent) in the EORTC QLQC30 items for global health status questions. When it comes to EORTC QLQ-BR23 questions, the participants were requested to select only one answer  for each question.Six BSc nurses and two MSc supervisors were used for data collection. One day training was given for clarification of some terms and assessment tools. Ethical clearance was obtained from the institutional review board of Addis Ababa University, College of Health Sciences, School of Nursing and Midwifery. Informed written consent was gained from all study participants and for those under age 16, consent was obtained from their parents/guardians. After information was provided about the purpose of the study, non- invasiveness of the data collection procedure, confidentiality of the information and respondents were reassured that they would be anonymous (unnamed). Then respondents were given a chance to ask anything about the study and were free to refuse or stop at any moment during the study.P-value< 0.2 in the binary logistic regression were entered into multivariate analysis and strength of association was declared at P value< 0.05.Descriptive statistics were used to analyze demographic characteristics. Logistic regression models were used to evaluate associations between social networks, and quality of life. Bivariate and multivariate analysis with 95% CI was employed. Variables found to have a A total of 214 participants were included in this study. The mean age was 41.85 and the range of age was from 20 to 80 years. Most of the participants were Christian 142 (66.4%) followed by Muslim 41 (19.2%). Sixty-six (30.8%) of the participants were illiterate. From the total respondents, 104 (48.6%) were not employed outside the home. Ninety (42.1%) of the respondents had a monthly income greater than or equal to 2000 ETB (Ethiopian Birr). Regarding to time since diagnosis, more than two-third of participants, 155(72.5%) were diagnosed before 12 months. Among the total participants, 129 (60.3%) of them had received surgery with chemotherapy treatment  of them were married and 28 (13.1%) were divorced. Half of the respondents, 109 (50.9%) had one to three children whereas 45 (21%) had no children. Most of them, 196 (91.6%) had other relatives  and 136 (63.6%) of them had close friends. The majority of the respondents, 199 (93%) participated in religious activity. Participants who were involved in regular volunteer work were 203 (94.9%) . Whereas, in the QLQ-BR23 functioning scales, the best score was observed for future perspective mean = 78 and SD = 33.6). Participants also had a low mean score  for sexuTo assess the quality of life of the participants, there are three subscales:- functional scale, symptom scales and global health status scale. Based on this, participants who scored 75 and above for functional and global health status scale and 25 and below for symptom scale classified as not affected the quality of life whereas, participants who scored below 75 for functional and global health status scale and above 25 for symptom scales classified as the affected quality of life. Among the total participants, 48(22.4%), 150(70.1%) and 192(89.7%) of them had affected QoL, in global health status scale, functional scales and symptom scales respectively. Participants who had not affected QoL were 16 (7.48%)  had children. It was found that participants who had children were 5 times more likely to have good social networks than participants who had no children . From the total study participants, 189 (88.3%) of them had other relatives. It was found that participants who had other relatives were 6 times more likely to have good social networks than those who had no other relatives . However, participants who were not married , had no parents living , no close friends , no job , did not belong to a church  and had no relationship with neighbors  had poor social networks Table .p-value = 0.008). Among the total study participants, 45(21%) reported systematic therapy side effects. It was found that participants who had systematic therapy side effects were 3.8 times more likely to have affected QoL than who had no systemic therapy side effect . Among the total participants, 45(21%) reported a loss of appetite. It was found that participants who had appetite loss were 3.5 times more likely to have affected QoL than those who did not report appetite loss . In addition, those participants who had good social networks were 4.5 times ) more likely to have good quality of life when compared with women with poor social networks.  were illiterate. It was found that participants who were illiterate were 3 times more likely to have affected QoL than educated  . The simIn the EORTC functional scales scores, the role functioning was the lowest (23.8 ± 32.80) and the highest observed in social functioning (75.5 ± 26). The finding is comparable to the study conducted in Ethiopia with a mean score of 74.1 ± 28.5 . The simIn QLQ-BR23 functioning scales, the highest mean score (78 ± 33.6) was observed in a future perspective scale. The finding is comparable in the study done in Addis Ababa Ethiopia’s mean score (82.1 ± 30.3) . WhereasIn the QLQ-C30 symptom scales, a higher mean score (67.8 ± 22.8) was observed on pain scale. The finding was greater than the study conducted in South India with the mean score of (19.6 ± 26.64) , EthiopiThe study participants who were married, had children, and participated in religious activities in this study had good social networks compared with those who were unmarried, had no children and did not participate in religious activities. This finding is supported by the studies from the US , in CaliStudy participants who were illiterate were nearly 3 times more likely to have affected QoL than those who were educated. This finding is supported with a study conducted in Shanghai, China  more eduHigh monthly income in the current study was more likely to be associated with a good quality of life. This finding is in agreement with the study done in Shanghai, China  in whichParticipants who reported fatigue, nausea and vomiting, appetite loss and financial difficulty in this study were more likely to have affected QoL. Whereas, in a study conducted in Ethiopia  those whThis study revealed that those study participants who had poor social networks were 6.4 times more likely to have an affected/lower quality of life. This is in line with two studies done in the US , 27, 28,The nature of this study was a cross-sectional one; it hinders the possibilities of assessing cause and effect associations. Furthermore, the design limits the progressive investigation of social networks and quality of life improvements following a series of intervention strategies. Results are also possibly subject to social desirability bias as the study outcome is self-reported.Based on the finding of this study above half of the total respondents having a diverse social network are a positive factor in determining a woman’s quality of life following a breast cancer diagnosis. Being married, having children, living parents, other relatives, close friends and belonging to a church were significantly associated with social networks. Whereas, education, monthly income, emotional functioning, role functioning, pain, fatigue, financial difficulty, systemic therapy side effect, and social networks were significantly associated with quality of life (QOL).Healthcare providers in specially working in oncology departments should teach community, attendants as well other stakeholders to address diverse social networks based on female needs and desires and the side effects of treatment, Strengthen awareness in collaboration with public medias about social networks, QoL and their association with breast cancer to improve social networks and the quality of life of females with breast cancer.Additional file 1: Table S1. Quality of life of participants among female breast cancer patients at TASH, Addis Ababa, Ethiopia 2019. Table S2. Bivariate and multivariate logistic regression analysis of social networks and its explanatory variables among female breast cancer patients at TASH, Addis Ababa, Ethiopia 2019. Table S3. Bivariate and multivariate logistic regression analysis of Quality of life and its explanatory variables among female breast cancer patients at TASH, Addis Ababa, Ethiopia 2019.