Among Latinas and Hispanics (henceforth referred to as Latinas), breast cancer is the most commonly diagnosed cancer and the leading cause of cancer-related deaths. However, few interventions have been developed to meet the needs of Latina women undergoing active treatment for breast cancer.My Guide for Breast Cancer Treatment and the plans for conducting a multisite randomized controlled trial to investigate the feasibility and preliminary efficacy of this smartphone-based app for Latina women in active treatment for breast cancer.This paper aims to describe the procedures and methods of My Guide for Breast Cancer Treatment intervention or the enhanced usual care control condition for 12 weeks. Participants will have access to innovative features such as gamification via virtual awards to reinforce usage and an adaptive section that presents targeted material based on their self-reported concerns and needs. Using a stepped-care approach, intervention participants will also receive telecoaching to enhance their adherence to the app. Study outcomes and intervention targets will be measured at study enrollment (before randomization), 6 and 12 weeks after initial app use. General and disease-specific health-related quality of life (HRQoL) and symptom burden are the study’s primary outcomes, whereas anxiety, depression, fear of cancer recurrence, physical activity, and dietary intake are secondary outcomes.Study participants will be randomized to the Recruitment began in August 2019 and is expected to be completed by August 2020. We expect to submit study results for publication by fall 2020.My Guide for Breast Cancer Treatment has the potential to improve HRQoL and reduce symptom burden, and increase access to supportive care resources among Latina breast cancer patients.PRR1-10.2196/14339 Among Latinas/Hispanics (henceforth referred to as Latinas), breast cancer is the most commonly diagnosed cancer and the leading cause of cancer-related deaths . CompareMy Guide, a smartphone-based app designed specifically for Latina BCSs to improve HRQoL and reduce symptom burden after completing primary breast cancer treatment [My Guide app is available in both English and Spanish, expanding its reach to underserved Latina BCSs. Preliminary findings show that My Guide is feasible for Latina BCSs to use  [during treatment.To address poor HRQoL among Latina BCSs, our team previously developed and pilot tested reatment . The inifaction) . HoweverTo date, few interventions have been developed to meet the needs of Latina women undergoing active treatment for breast cancer . There iMy Guide pilot study and the dearth of literature regarding interventions for Latina breast cancer patients actively undergoing treatment, we have developed My Guide for Breast Cancer Treatment. The purpose of this paper is to describe the procedures and methods of this follow-up intervention. Guided by Bowen et al’s conceptual model of feasibility studies [My Guide for Breast Cancer Treatment for Latina women undergoing breast cancer treatment.In light of the limited technology-assisted interventions specifically designed for Latina women undergoing active treatment for breast cancer, more studies are needed to establish the feasibility of smartphone-based interventions for Latinas during active cancer treatment . In resp studies , we descMy Guide for Breast Cancer Treatment feasible for accessing information related to breast cancer and its treatment and for learning strategies to improve symptom management, self-efficacy, communication, and stress. We also hypothesize that women randomized to the My Guide for Breast Cancer Treatment app will have better primary outcomes  and secondary outcomes  than women randomized to an enhanced usual care control condition.We hypothesize that Latina women will find My Guide for Breast Cancer Treatment smartphone app for improving HRQoL and symptom burden in Latina women receiving treatment for primary breast cancer. After providing informed consent, participants will be randomized to the My Guide for Breast Cancer Treatment intervention condition or to the enhanced usual care control condition. Randomization will be stratified by recruitment site and language . Participants randomized to the My Guide for Breast Cancer Treatment intervention condition will have access to the smartphone app for 12 weeks and will be encouraged to use the app for 1.5 hours each week. The My Guide for Breast Cancer Treatment app is accessible on all smartphones  as well as tablets and computer websites. It is available in both English and Spanish, and participants will be provided the app in their preferred language. Participants randomized to the My Guide for Breast Cancer Treatment intervention condition will be oriented to the app and instructed to use it for 1.5 hours each week for a duration of 12 weeks. A 12-week intervention timeframe was selected based on previous studies indicating benefits in HRQoL and symptom burden outcomes after 10 weeks of behavioral interventions and the expected length of adjuvant treatments [My Guide for Breast Cancer Treatment app content. Intervention participants will also be assigned a bilingual telecoach for the duration of the study. Using a stepped-care approach [This RCT is designed to assess the preliminary feasibility and efficacy of the eatments -21. Thusapproach , interveData Collection and Outcomes for greater detail. Participants will be compensated US $100 for their participation in the study and receive partial reimbursement for telephone data usage plans. Participants without an internet-enabled device will be provided one for the duration of the study. All study procedures and assessments have been approved by the institutional review board (IRB) of record for this multisite study (Northwestern IRB).Study outcomes and intervention targets will be measured at study enrollment and before randomization (T1), 6 weeks postbaseline (T2), and 12 weeks postbaseline (T3). All assessment time points will consist of measures assessing our primary outcomes, intervention targets, and secondary outcomes. In addition, all participants will complete a sociodemographic questionnaire at T1, and participants randomized to the intervention condition will be asked to complete an exit survey at T3. Assessments are estimated to take approximately 35 min to complete. Participants randomized to the intervention condition will also be asked to complete brief, 3-min, weekly questionnaires throughout the course of the 12-week intervention. See section Participants will be 60 Latina women who have been diagnosed with stage I-IIIA breast cancer, have completed surgery , and are actively receiving adjuvant treatment for breast cancer . We will enroll participants from the Robert H. Lurie Comprehensive Cancer Center at Northwestern Memorial Hospital, the University of Illinois Health System, and various community-based support groups sponsored by ALAS-WINGS, a Chicago-based nonprofit organization for Latina breast cancer patients.We will identify participants through screening of the electronic medical record (EMR), and final determinations for study eligibility will be made based on a self-report questionnaire via telephone interview. To be included in the study, participants must (1) be female, because male breast cancer patients represent less than 1% of the breast cancer cases; (2) have a diagnosis of stage I-IIIA breast cancer; (3) have completed surgery for breast cancer; (4) be within any timepoint of the adjuvant treatment trajectory for breast cancer ; (5) be at least 18 years of age; (6) be able to speak and read English or Spanish; (7) be able to provide informed consent; and (8) self-identify as Hispanic/Latina ethnicity. Participants will be excluded from the study if they (1) have a hearing, motor, visual, or voice impairment that would preclude completion of study procedures; (2) have been diagnosed with a psychotic disorder, bipolar disorder, dissociative disorder, or any other diagnosis for which study participation would be inappropriate or dangerous; (3) endorse suicidal ideation, plan, or intent; (4) endorse illicit substance or alcohol dependence; or (5) have been diagnosed with dementia. Patients with metastatic disease will not be included in this study, as they have more extensive treatment regimens and substantially different needs relative to patients with earlier stages of breast cancer.My Guide for Breast Cancer Treatment) or the control condition  for a total of 3 months.Eligible participants who provide informed consent will be individually randomized using a 1:1 ratio to either the intervention condition  [My Guide for Breast Cancer Treatment has been adapted from My Guide to expand its reach to Latina women in active treatment for breast cancer. The My Guide app incorporates elements in the published literature on symptom management in breast cancer literature and investigators with ample clinical expertise and experience conducting behavioral and symptom management research with Hispanic BCSs. The content for both iterations of the intervention were informed by models of stress and coping, cognitive behavioral stress management [My Guide and My Guide for Breast Cancer Treatment are culturally informed by Latina values and beliefs including familism, fatalism, external locus of control, and culturally shaped gender roles  [eatment) . My Guidnagement -25, the nagement -28, and nagement ,27,29-31ianismo) ,32,33. IMy Guide for Breast Cancer Treatment expands the scope and focus of the intervention by including additional content specifically for women in active treatment. In addition, My Guide for Breast Cancer Treatment includes content related to diet, physical activity, and general health information for breast cancer patients. The My Guide for Breast Cancer Treatment intervention content is organized into 6 modules as described in Listen and Learn).My Guide for Breast Cancer Treatment app usage. In a given week, participants who use the app for less than 1 hour will be considered nonadherent to the recommended app usage and will receive a telecoaching call. Participants who use the app for 1 hour or more will be considered adherent to the recommended usage and will not receive a telecoaching call. Rather, adherent participants will receive a reinforcing SMS text message. The 1-hour cut-off was based on data from the previous My Guide trial for cancer survivors in which participants’ average use of the study app exceeded 1 hour per week [All intervention participants will be assigned a trained, bilingual telecoach who will provide telecoaching using a stepped-care approach  to enhanper week .My Guide for Breast Cancer Treatment using the principles of motivational interviewing [My Guide for Breast Cancer Treatment app.The telecoaching calls will be brief (15 min) and focus on encouraging adherence to rviewing . During All telecoaches will receive training in motivational interviewing and goal setting with a particular focus on sensitivity to issues relevant for Latina women . Telecoaches will have access to participants’ app usage through a study administrative site. All telecoaching calls will be audio-recorded, and approximately 20% of the telecoaching calls will be reviewed weekly in supervision with a licensed clinical psychologist to monitor intervention fidelity.My Guide for Breast Cancer Treatment will be individually tailored to each participant’s self-reported primary concerns/symptoms. Upon randomization, participants in the intervention condition will complete a questionnaire based on the MD Anderson Symptom Inventory [My Guide for Breast Cancer Treatment will then organize the app presentation such that content related to each participant’s 3 to 5 top-rated concerns/symptoms are most easily accessible in a separate tab titled “Just for Me.” Participants will complete this questionnaire every 2 weeks, with subsequent content-related changes made to their “Just for Me” tab. As tailored information is added to this tab, the most recent additions will appear at the top of this tab, and older content will move to the bottom. Notably, participants will still have access to all of the intervention content. However, this adaptive feature will help participants focus on and prioritize their primary concerns and needs.One of the most significant additions to the intervention app is that nventory  to assesMy Guide for Breast Cancer Treatment app. Gamification is use of game-design elements to engage and motivate individuals to achieve a goal [My Guide for Breast Cancer Treatment contains 3 levels of virtual reinforcement in a given week. Participants may receive a virtual ribbon after completing 30 min of app use, a virtual medal after completing 45 min of app use, and a virtual trophy after completing 60 min of app use. Therefore, participants who use the app for a full hour each week for the length of the study can receive a total of 12 ribbons, 12 medals, and 12 trophies [Each week participants will be incrementally rewarded/reinforced for the time spent using the e a goal . Althouge a goal -38. My Gtrophies .My Guide for Breast Cancer Treatment intervention condition is currently in development with Bright Outcomes Company . Recruitment and retention rates of 70% or more will be considered acceptable based on our prior work and published studies [Consistent with past research, the feasibility of  the app . Accepta the app  that mea studies ,41,42.All measures will be administered in each participant’s preferred language. For assessments completed in Spanish, we will use measures that have either been previously translated to Spanish and validated or measures that were translated to Spanish for this study by IRB-approved translators.Participants will complete a self-report sociodemographic questionnaire at T1 including questions related to age, racial background, Latina ancestry, income, employment, relationship status, educational attainment, years living in the United States, and subjective social status using the MacArthur scale . ParticiMy Guide for Breast Cancer Treatment intervention condition will also complete the rapid version of the Functional Assessment of Cancer Therapy-General (FACT-G7) on their smartphones every week throughout the 12-week intervention. The FACT-G7 assesses the most prominent HRQoL concerns among cancer patients and is both valid and reliable [At T1 to T3, participants will complete the Functional Assessment of Cancer Therapy-Breast (FACT-B). The FACT-B has been extensively used among breast cancer patients ,47 and mreliable . The FACAt T1 to T3, participants will complete the Breast Cancer Prevention Trial (BCPT) symptom questionnaire. The BCPT is a 25-item questionnaire that asks participants to use a 5-point response scale to rate their level of discomfort with common breast cancer–related symptoms during the past 4 weeks .Anxiety and depressive symptoms will be measured at T1 to T3 using the Patient-Reported Outcomes Measurement Information System (PROMIS) ,51 via bAt T1 to T3, participants will complete the Concerns About Recurrence Scale to assess fears about breast cancer recurrence . Items aPhysical activity will be measured at T1 to T3 using the International Physical Activity Questionnaire (IPAQ)-short form ,54. ThisDietary intake will be measured at T1 to T3 using the Brief Dietary Assessment Tool for Latinas . This scA total of 3 self-report questionnaires will be used to measure cancer-relevant self-efficacy at T1 to T3. First, the Communication and Attitudinal Self-Efficacy scale for cancer (CASE-cancer) is a psychometrically valid 12-item measure. A total of 2 CASE-cancer subscales will be used to assess a person with cancer’s self-efficacy in communication and information seeking . ParticiMy Guide pilot study [The Knowledge about Breast Cancer questionnaire will be used to assess knowledge related to treatment at T1 to T3. This scale consists of 16 true or false statements regarding general breast cancer knowledge. The average number of correct responses will be calculated. This questionnaire was previously tested with a large sample of Spanish-speaking Latina BCSs  and usedot study .The Impact of Events Scale will be used to assess cancer-specific distress at T1 to T3. This measure comprises 2 subscales assessing the frequency of intrusive thoughts and avoidance following a stressful event ,64.U test for non-normal data, as appropriate. With 30 participants per study condition, there will be 80% power to detect approximately one-half SDs, assuming a 2-tailed test and a type I error rate of 5%. All power calculations were run using PROC POWER in SAS version 9.4.Descriptive statistics will be used to characterize the overall sample, each condition, and study acceptability and demand. To examine preliminary differences in feasibility between study conditions, we will use the chi-square test, Fisher exact test, and nonparametric Mann-Whitney For each study outcome, average changes from pre intervention to post intervention will be calculated via means (SD) and 95% CIs, and the mean changes within study condition will be converted to effect sizes. An analysis of covariance approach will be used to examine differences between the intervention and control conditions in follow-up scores, after adjusting for baseline score. Established cut-offs will also be referenced for clinically meaningful differences for the FACT-B and FACT-B subscales to identify ranges and patterns of changes in scores across conditions from baseline to follow-up.My Guide for Breast Cancer Treatment administrative interface will capture participants’ app usage and weekly questionnaire data, which will be uploaded to REDCap to centralize all research information. Once all data are collected, the data will be imported into SPSS for data cleaning and analysis.All study data will be managed and stored in Research Electronic Data Capture (REDCap), a secure Web-based research data management system hosted at Northwestern University. All IRB-approved research team members will have access to REDCap. REDCap will be used to organize EMR data and to administer all study questionnaires. The Recruitment began in July 2019 and is expected to be completed by August 2020. We expect to submit study results for publication by fall 2020.My Guide for Breast Cancer Treatment study is to improve HRQoL and reduce symptom burden among Latina women undergoing active treatment for breast cancer. To the best of our knowledge, this is the first bilingual, smartphone-based supportive care app for Latinas women with breast cancer in active treatment. Providing a supportive and behavioral intervention that focuses on cancer treatment education and self-management during active treatment has the potential to improve patient-reported outcomes and clinical outcomes during active treatment and into survivorship.The aim of the My Guide smartphone app, our team implemented substantial changes in this version of the My Guide for Breast Cancer Treatment app. Adding an adaptive functionality offers My Guide for Breast Cancer Treatment users a more personalized approach to delivering the intervention content, and the addition of a gamification via virtual ribbons, medals, and trophies provides users with encouragement to sustain use of the app across the length of the study. Unlike our first My Guide study [My Guide for Breast Cancer Treatment app and this study design better suited for women in active treatment.Compared with the first version of the de study  that incMy Guide for Breast Cancer Treatment does include a focus on the postsurgical recovery phase such as information related to postsurgical symptoms  and information related to reconstructive surgery.A few limitations of the study protocol warrant discussion. First, because the focus of this study is on breast cancer patients who are in active treatment, long-term cancer survivors will not be enrolled in this study, which limits study generalizability. In addition, women who are preparing for surgery will not be included in this study. However, My Guide for Breast Cancer Treatment across a nation-wide, heterogeneous sample of Latina women diagnosed with breast cancer. Currently, the My Guide for Breast Cancer Treatment app does not include any social media aspects; the potential benefit of adding a social media component to My Guide for Breast Cancer Treatment may be another important direction for future iterations of the app. In addition, given the multiple components of this feasibility trial , another important future direction will be to disentangle the effects of each component of the intervention on study outcomes.There are several areas for future directions. If found feasible, future studies should establish the efficacy of My Guide for Breast Cancer Treatment app are expected to contribute to the literature by establishing the efficacy of a smartphone-delivered intervention to enhance self-management during breast cancer treatment for improving HRQoL and symptom burden among Latina patients. Given the technology-based delivery of this app, the My Guide for Breast Cancer Treatment app has the potential for nation-wide scalability and therefore can increase access to supportive care resources among Latina breast cancer patients.Findings from this second study of the


Background: Breast Cancer susceptibility genes 1 and 2 are implicated in hereditary breast and ovarian cancer and women can test for the presence of these genes prior to developing cancer. The goal of this study is to examine psychological distress, quality of life, and active coping mechanisms in a sample of women during the pre-test stage of the genetic counseling process, considering that pre-test distress can be an indicator of post-test distress. We also wanted to identify if subgroups of women, defined based on their health status, were more vulnerable to developing distress during the genetic counseling process.Methods: This study included 181 female participants who accessed a Cancer Genetic Counseling Clinic. The participants were subdivided into three groups on the basis of the presence of a cancer diagnosis: Affected patients, Ex-patients, and Unaffected participants. Following a self-report questionnaire, a battery of tests was administered to examine psychological symptomatology, quality of life, and coping mechanisms.Results: The results confirm that the genetic counseling procedure is not a source of psychological distress. Certain participants were identified as being more vulnerable than others; in the pre-test phase, they reported on average higher levels of distress and lower quality of life. These participants were predominantly Ex-patients and Affected patients, who may be at risk of distress during the counseling process.Conclusions: These findings highlight that individuals who take part in the genetic counseling process are not all the same regarding pre-test psychological distress. Attention should be paid particularly to Ex-patients and Affected patients by the multidisciplinary treating team. According to the Italian Register of Cancer, in 2016 in Italy 50,000 and 5,200 women received a diagnosis of breast and ovarian cancer, respectively AIOM. In womeWomen who have been identified as genetically at risk for developing HBOC have the choice of several interventions: surveillance, prophylactic mastectomy, prophylactic salpingo-oophorectomy, and chemoprevention via, for instance, the use of tamoxifen  evaluate each individual case and decide whether a patient should be subjected to the genetic testing procedure. (B) Pre-testing stage: during this stage, the individual learns about all the familial, hereditary, and sporadic forms of cancer and the chances of developing these. Often a genetic counselor or geneticist conducts a full pedigree construction to estimate the risk. This pre-test interview is also conducted to discuss potential uncertainties, informed consent, and future preventative options. An inability to process information secondary to active psychiatric or cognitive impairment could interfere with informed consent and this should be taken into consideration by the multidisciplinary team  Post-test stage: the multidisciplinary team then communicates the test results to the individual and helps them understand what these results mean and their implications are discussed. The test results can either be: positive, negative, or inconclusive. A positive test result indicates that the individual has a mutation that increases their chances of developing cancer. A negative test result can reassure a woman that there is no BRCA1/2 mutation, but this does not rule out other mutations in less common genes. An inconclusive test result indicates that there are variants of unknown significance and the individual may be advised to undergo further testing.Genetic counseling is an intervention aimed at informing and supporting individuals who must undertake a medical path that searches for and manages genetic defects or pathologies , patients with a history of cancer, hereinafter called Ex-patients (n = 69) and patients with no cancer diagnosis, Unaffected participants (n = 38). Eligibility criteria included: (1) being at least 18 years old; (2) being able to read and understand Italian; and (3) agreed to voluntarily participate in the research. No women with severe psychiatric or neurological disorders were excluded from the study as there were none that presented these symptoms. Furthermore, no participants refused to take part in the study and all women satisfied our inclusion criteria. Informed consent was obtained from all individual participants included in the study. The study was reviewed and approved by the Medical Ethical Committee of the IRCCS San Raffaele Hospital.This study included 181 female participants who accessed the Cancer Genetic Testing Service by the Medical Oncology, Breast Surgery, and Gynecology Units in a Hospital in the North of Italy between January 2012 and December 2016. The participants were subdivided into three groups on the basis of their health status: patients currently being treated for cancer, or Affected patients , the Coping Orientation to Problems Experienced questionnaire (COPE), and the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30).socio-demographic data collected included questions regarding age, marital status, and presence of children. Regarding the medical information, the following were investigated: presence of a cancer diagnosis , treatments that were carried out, and the pedigree relationship to any relatives that may have been diagnosed with cancer. Lastly, we also asked patients if they had ever undergone any previous psychological or psychiatric treatments, or taken any psychopharmacological drugs.The Subsequently, patients completed the following standardized questionnaires:SCL-90-R , have been applied.To identify differences among Unaffected patients, Affected patients, and Ex-patients on the psychological constructs of interest and due to the non-normality of the examined psychometric scales, a Kruskal–Wallis test, the nonparametric counterpart to standard ANOVA, followed by PMCMR package, developed in R, was used to implement the Kruskal–Wallis test and post-hoc analysis for pairwise multiple comparisons , ranging from 21 to 80 years. As mentioned previously, the participants were divided into 3 groups on the basis of their health status: Affected patients , “Ex-patients” (38.12% n = 69), and Unaffected participants . In Table The mean age of the study participants was 48.54 years SD = 1.54, ranDescriptive statistics of variables of interest, along with group comparisons, are presented in Tables p < 0.0001), Anxiety (p = 0.0221), Somatization (p < 0.0001), and Depression (p = 0.0028).Focusing on the SCL-90-R, no group reported any scores of clinical relevance. Based on the Kruskal–Wallis test, groups of participants were significantly different in terms of GSI (p = 0.0012), Anxiety (p = 0.023), Somatization (p = 0.0023), and Depression (p = 0.0146). For both GSI and Somatization, the group of Affected patients significantly differed from those with no cancer diagnosis (p < 0.0001). Moreover, their scores significantly differed on the Depression scale (p = 0.0027).In particular, a significant difference emerged between Ex-patients and Unaffected participants in the mean scores of the GSI (p = 0.0045), Physical (p < 0.0001), Cognitive (p = 0.0156), Social (p = 0.0012), and Role Functioning (p = 0.0001). The scores of the Global health scale, Physical, Cognitive, Social, and Role Functioning are significantly different between the Affected patients and the Unaffected participants . The healthy group also differed from the group of Ex-patients regarding Physical, Cognitive, Social, and Role Functioning .Relatively good levels of health-related quality of life were reported by all groups in all functional domains. Overall, groups were significantly different in terms of their Global health (p = 0.0171). In detail, there was a significant difference between patients without cancer and those with cancer, both in the present or in the past . We did not find any significant differences between the Affected patients and Ex-patients on the considered constructs.The only coping strategy that revealed statistically significant differences among the subgroups was the social support coping mechanism  and live with a history of illness.The literature concerning coping mechanisms shows that people favor either a problem-focused approach or an emotional-focused one  and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. All subjects gave written informed consent in accordance with the Declaration of Helsinki.VD was responsible for the conception, interpretation and design of the research project and approving the final copy. LC was responsible for drafting the work, revising it critically, drafting the study design and data acquisition. MB and RB were responsible for drafting the work, data collection, revising the manuscript and conducting research of the intellectual content. CB and FC were responsible for statistical analyses and data interpretation. ER and MZ were the oncologists responsible with organizing the project and helping with data collection and proof checking of the manuscript. MC, LS, and OG were responsible for the conception and design of the research project, critical analysis and approving the final copy. All authors are thus accountable for all aspects of the work, also with respect to the integrity and accuracy of it.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


The mitochondrial genome encodes for thirty-seven proteins, among them thirteen are essential for the oxidative phosphorylation (OXPHOS) system. Inherited variation in mitochondrial genes may influence cancer development through changes in mitochondrial proteins, altering the OXPHOS process and promoting the production of reactive oxidative species.To investigate the association between mitochondrial genetic variation and breast cancer risk, we tested 314 mitochondrial SNPs (mtSNPs), capturing four complexes of the mitochondrial OXPHOS pathway and mtSNP groupings for rRNA and tRNA, in 2,723 breast cancer cases and 3,260 controls from the Multiethnic Cohort Study.MT-CO2  in Complex IV (cytochrome c oxidase) and MT-ND2  in Complex I (NADH dehydrogenase (ubiquinone)) were significantly associated with breast cancer risk.We examined the collective set of 314 mtSNPs as well as subsets of mtSNPs grouped by mitochondrial OXPHOS pathway, complexes, and genes, using the sequence kernel association test and adjusting for age, sex, and principal components of global ancestry. We also tested haplogroup associations using unconditional logistic regression and adjusting for the same covariates. Stratified analyses were conducted by self-reported maternal race/ethnicity. No significant mitochondrial OXPHOS pathway, gene, and haplogroup associations were observed in African Americans, Asian Americans, Latinos, and Native Hawaiians. In European Americans, a global test of all genetic variants of the mitochondrial genome identified an association with breast cancer risk . In mtSNP-subset analysis, the gene MT-CO2 and MT-ND2 may play a role in breast cancer risk among European Americans. Further replication is warranted in larger populations and future studies should evaluate the contribution of mitochondrial proteins encoded by both the nuclear and mitochondrial genomes to breast cancer risk.In summary, our findings suggest that collective mitochondrial genetic variation and particularly in the  Breast cancer is the most common cancer in women in the United States. In 2019, it has been estimated there will be 271,270 new cases of breast cancer in the United States . To dateThe mitochondrial genome is a small circular DNA molecule that spans 16.6 kb and has no intronic sequences . This geThe primary function of the mitochondrion is the production of the energy molecule, adenosine triphosphate (ATP), through the metabolic pathway of OXPHOS. In addition, the mitochondrion also serves as the major source of reactive oxygen species (ROS). ROS are involved in many cellular processes such as apoptosis, inflammation and oxidative stress. They are generally considered as toxic agents that contribute to aging, a wide variety of degenerative diseases, and cancer , 26. MorVariations in mtDNA have the potential to alter mitochondrial function and lead to increased oxidative stress and breast cancer risk –39. CantTo investigate the association between mitochondrial genetic variation and breast cancer risk across multiple racial/ethnic groups, we tested 314 mtSNPs among 5,983 subjects  in the Multiethnic Cohort Study (MEC).Our study included 2,723 incident breast cancer cases and 3,260 controls nested within the MEC, a large population-based cohort of more than 215,000 subjects comprised of African Americans, European Americans, Japanese Americans, Latinos, and Native Hawaiians, who were recruited from 1993 through 1996 at the ages of 45 and 75 years . Blood sMitochondrial SNPs were genotyped using the Sequenom platform (n = 186 mtSNPs)  and the http://www.haplogrep.uibk.ac.at) and based on Phylotree build 16 [-4 (0.2/300) for ~300 mtSNPs tested and p-value = 0.01 (0.2/20) for the ~20 mitochondrial gene-based tests.For the mitochondrial genome, pathway, complex, gene-based analysis, we used the sequence kernel association test (SKAT) , 47. TheT=12n) , 49. Forbuild 16 , 51. Addbuild 16  of 0.20 Study characteristics of the 5,983 study subjects  are presented in MT-ND2; P = 0.004, q = 0.19) and cytochrome c oxidase II  were associated with breast cancer risk in European Americans . In vitro studies have reported over expression of MT-CO2 in human breast cancer epithelial cells and reduced breast tumor growth with treatment of a MT-CO2 inhibitor [MT-ND2 gene, a member of the OXPHOS pathway that encodes for the subunit of NADH. It is reasonable to hypothesize that mtDNA coding variants in MT-CO2 and MT-ND2 genes may have cis-acting effects on the expression of these genes that may be distinct to European ancestry populations as a recent study reported specific SNP-gene expression patterns between African and Caucasian populations [In European Americans, the most significant association was seen with the nhibitor , 54. Theulations . In addiulations –58.BRCA1/2 mutation carriers in the CIMBA consortium , haplogroup T1a1 was inversely associated with breast cancer risk  among BRCA1 carriers of European ancestry [BRCA1/2 carriers and differences in study power. A small study of European women (164 breast cancer cases/ 164 controls) reported haplogroup H to be associated with breast cancer risk  [In a large study of ancestry . Our stu1.1–3.5) . In our MT-ND5 gene.Two small case-control studies reported mtDNA G13708A to be associated with breast cancer risk in African American and South Indian women, but three other studies , 35, 40 Our study has several strengths. Given the wide spectrum of rare, low-frequency, and common genetic variants in the mitochondrial genome, the use of the SKAT common/rare approach to collectively test multiple risk alleles has improved statistical power to detect modest effects than single SNP tests and overcomes the limitation of previous methods that upweight rare variants , 59. UsiIn summary, our findings suggest that collectively multiple mtDNA variants may play a role in breast cancer risk in European Americans. The findings of association between the mitochondrial OXPHOS pathway and multiple mitochondrial complexes and genes warrant replication in other European population. Further studies in larger populations should evaluate both the mitochondrial genome and nuclear encoded mitochondrial genomes to fully examine their contribution to breast cancer risk. A recent study examined the association between nuclear genetic variation and mitochondrial transcript abundance based on genotyping data and RNA sequencing data for 36 tissues/cell types, and found 64 nuclear loci associated with expression level of 14 genes encoded by the mitochondrial genome that included missense variants of genes involved in mitochondrial function .S1 Table(XLSX)Click here for additional data file.S2 Table(XLSX)Click here for additional data file.S3 Table(XLSX)Click here for additional data file.


Two complementary studies in separate components of the Women’s Health Initiative (WHI) examined relationships among weight loss, diet composition and breast cancer incidence and outcome in postmenopausal women. In the WHI Observational Study, 61,335 postmenopaus al women had their weight change determined over a 3-year period with subsequent follow-up. Women with weight loss greater than or equal to 5% had significantly lower breast cancer incidence compared to women with stable weight. In the WHI Dietary Modification randomized clinical trial involving 48,835 postmenopausal women, implementation of a low-fat eating pattern significantly reduced deaths after breast cancer. Thus, moderation regarding dietary composition and body weight maintenance can reduce a postmenopausal woman’s risk of being diagnosed with breast cancer and of dying after breast cancer. Obesity has become a major health problem for the 40% of postmenopausal women in the US who are currently obese (body mass index [BMI] ≥ 30 kg/m2) . The IntThe study population included 61,335 postmenopausal women, entered between 1993 and 1998 at 40 US clinical centers, who were aged 50–79 years and had no prior breast cancer with a normal baseline mammogram. Anthropometrics were measured and BMI calculated at baseline and year 3. Weight change at year 3 was categorized as stable (<5% change), loss (≥5% decrease) or gain (≥5% increase). Participants were followed annually for clinical outcomes. Breast cancer incidence was determined through 11.4 years (mean) follow-up after the year 3 weight status assessment and all breast cancers were verified by central medical record review. Survival findings were augmented by serial National Death Index (NDI) queries, which capture 98% of all deaths  7.5%)  and was The important question of whether dietary change or weight loss will alter outcome for women following a diagnosis of early-stage breast cancer  was not The association between implementation of a low-fat eating pattern and reduction in deaths after breast cancer was unchanged by the addition of baseline weight and weight change to the analysis , 14. As In summary, complementary findings from the WHI OS and the WHI DM full-scale randomized cancer prevention clinical trials indicate two distinct routes to improve breast cancer outcomes. A low-fat diet rich in vegetables and fruits can improve breast cancer outcome. In addition, for overweight or obese postmenopausal women, modest weight loss can improve breast cancer outcomes, and may enhance the benefits of a healthy low-fat diet. The current message should be encouraging for postmenopausal women, namely, moderation regarding dietary composition and weight can significantly reduce a woman’s chance of being diagnosed with breast cancer and of dying after a breast cancer diagnosis.Jacques Roscoe, Shari Ludlum, Dale Burden, Joan McGowan, Leslie Ford, and Nancy Geller - National Heart, Lung, and Blood Institute, Bethesda, MD, USA.Garnet Anderson, Ross Prentice, Andrea LaCroix, and Charles Kooperberg - Fred Hutchinson Cancer Research Center, Seattle, WA, USA.JoAnn E. Manson - Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA; Barbara V. Howard - MedStar Health Research Institute/Howard University, Washington, DC, USA; Marcia L. Stefanick - Stanford Prevention Research Center, Stanford, CA, USA; Rebecca Jackson - The Ohio State University, Columbus, OH, USA; Cynthia A. Thompson - University of Arizona, Tucson/Phoenix, AZ, USA; Jean Wactawski-Wende - University at Buffalo, Buffalo, NY, USA; Marian Limacher - University of Florida, Gainesville/Jacksonville, FL, USA; Robert Wallace - University of Iowa, Iowa City/Davenport, IA, USA; Lewis Kuller - University of Pittsburgh, Pittsburgh, PA, USA; Rowan T. Chlebowski - Los Angeles Biomedical Research Institute, Torrance, CA, USA; Sally Shumaker - Wake Forest University School of Medicine, Winston-Salem, NC, USA.


Published findings on breast cancer risk associated with different types of menopausal hormone therapy (MHT) are inconsistent, with limited information on long-term effects. We bring together the epidemiological evidence, published and unpublished, on these associations, and review the relevant randomised evidence.Principal analyses used individual participant data from all eligible prospective studies that had sought information on the type and timing of MHT use; the main analyses are of individuals with complete information on this. Studies were identified by searching many formal and informal sources regularly from Jan 1, 1992, to Jan 1, 2018. Current users were included up to 5 years (mean 1·4 years) after last-reported MHT use. Logistic regression yielded adjusted risk ratios (RRs) comparing particular groups of MHT users versus never users.vs 1·93, 1·84–2·01; heterogeneity p<0·0001). For a given preparation, the RRs during years 5–14 of current use were much greater for oestrogen-receptor-positive tumours than for oestrogen-receptor-negative tumours, were similar for women starting MHT at ages 40–44, 45–49, 50–54, and 55–59 years, and were attenuated by starting after age 60 years or by adiposity (with little risk from oestrogen-only MHT in women who were obese). After ceasing MHT, some excess risk persisted for more than 10 years; its magnitude depended on the duration of previous use, with little excess following less than 1 year of MHT use.During prospective follow-up, 108 647 postmenopausal women developed breast cancer at mean age 65 years (SD 7); 55 575 (51%) had used MHT. Among women with complete information, mean MHT duration was 10 years (SD 6) in current users and 7 years (SD 6) in past users, and mean age was 50 years (SD 5) at menopause and 50 years (SD 6) at starting MHT. Every MHT type, except vaginal oestrogens, was associated with excess breast cancer risks, which increased steadily with duration of use and were greater for oestrogen-progestagen than oestrogen-only preparations. Among current users, these excess risks were definite even during years 1–4 , and were twice as great during years 5–14 . The oestrogen-progestagen risks during years 5–14 were greater with daily than with less frequent progestagen use (RR 2·30, 2·21–2·40 If these associations are largely causal, then for women of average weight in developed countries, 5 years of MHT, starting at age 50 years, would increase breast cancer incidence at ages 50–69 years by about one in every 50 users of oestrogen plus daily progestagen preparations; one in every 70 users of oestrogen plus intermittent progestagen preparations; and one in every 200 users of oestrogen-only preparations. The corresponding excesses from 10 years of MHT would be about twice as great.Cancer Research UK and the Medical Research Council. A previous meta-analysis of the worldwide evidence found that current and recent users of menopausal hormone therapy (MHT) were at an increased risk of breast cancer, but little information was available about the effects of different types of MHT, or about long-term risks after MHT use had ceased.MHT has been used mostly in western countries, with about 600 million woman-years of use since 1970 .2 Use inEvidence before this studyReliable assessment of the association between menopausal hormone therapy (MHT) use and breast cancer requires avoidance of appreciable confounding or bias, with important features of MHT use  classified similarly. Review of published data cannot provide this. We reported in 1997 that current and recent users of MHT were at increased risk of breast cancer, but little information was then available about different types of MHT or about their long-term effects. Systematic searches for published and unpublished studies have been done regularly since 1992 from collaborators and from review articles and reference lists, augmented by periodic searches of MEDLINE and PubMed; search terms included combinations of “breast cancer risk”, “cohort”, “prospective”, “case-control”, “HT”, “hormonal contra*”, “hormone replacement”, “menopaus*”, “reproduc*”, “hormon*”, and “HRT”. The cutoff date for searches was Jan 1, 2018. The randomised evidence, also reviewed here, is largely for hormone use starting after age 60 years.Added value of this studyIn an individual participant meta-analysis of all eligible prospective studies, conclusions can now be based on over 100 000 postmenopausal women who developed breast cancer. Half of these women had used MHT, most starting around the time of the menopause at ages 40–59 years. Prospective studies avoid the potential biases in retrospective studies, and the large number of cases limits the play of chance. All types of MHT, except vaginal oestrogens, were associated with increased risks of developing breast cancer. The risks were greater for oestrogen-progestagen than for oestrogen-only preparations, particularly if the progestagen was given daily rather than intermittently. The associations with MHT were much stronger for oestrogen-receptor-positive tumours than for oestrogen-receptor-negative tumours. Among current users, there were definite excess risks even during 1–4 years (mean: 3 years) of MHT use, and progressively greater risks with longer use. During 5–14 years of MHT use, the relative risks (RRs) were similarly increased if MHT use had started at ages 40–44, 45–49, 50–54, and 55–59 years; RRs appeared to be attenuated if MHT use had started after age 60 years. They were also attenuated by adiposity, particularly for oestrogen-only MHT (which had little effect in obese women). After MHT use ceased, some excess risk of breast cancer persisted for more than a decade, which was greater with longer durations of prior MHT use. There was little risk following less than 1 year of use.Implications of all the available evidenceIf the associations are largely causal, MHT use in western countries has already caused about 1 million breast cancers, out of a total of about 20 million since 1990. For women of average weight in western countries, 5 years use of oestrogen plus daily progestagen MHT, starting at age 50 years, would increase 20-year breast cancer risks at ages 50–69 years from 6·3% to 8·3%, an absolute increase of 2·0 per 100 women (one in every 50 users). Similarly, 5 years use of oestrogen plus intermittent progestagen MHT would increase the 20-year risk from 6·3% to 7·7%, an absolute increase of 1·4 per 100 women (one in 70 users). Finally, 5 years use of oestrogen-only MHT would increase the 20-year risk from 6·3% to 6·8%, an absolute increase of 0·5 per 100 women (one in 200 users); this excess would be greater in lean women, but in obese women oestrogen-only MHT is associated with little excess risk. For 10 years of use, the 20-year increases in incidence would be about twice as great as for 5 years of use.Most individual studies were too small to assess reliably the long-term breast cancer risk associated with just a few years of MHT use. Furthermore, some epidemiological evidence remains unpublished, and studies completed before the 2000s necessarily had limited information about long-term effects of past use.The Collaborative Group on Hormonal Factors in Breast Cancer has therefore sought to bring together for central analysis published and unpublished individual participant data from eligible epidemiological studies with information on the type and timing of MHT use. Bringing these studies together has yielded extremely large numbers of cases of breast cancer among women who started MHT in their 40s or 50s.Although relatively few women in the prospective studies had started MHT in their 60s, most women in the randomised trials of these same preparations were older than 60 years when recruited, as these trials were designed primarily to evaluate possible protective effects against vascular disease (which is less common at younger ages). These and other relevant randomised trials are reviewed separately here.This collaboration began in 1992.Prospective studies were included using a nested case-control design, with up to four randomly selected controls per case of invasive breast cancer matched on age, year of birth, and region . All anaIndividual information was sought on sociodemographic, reproductive, and anthropometric factors, and on last reported MHT use prior to the date of cancer diagnosis for cases and the equivalent date for matched controls . Women were classified, using as similar definitions as possible across studies, by age at first MHT use, duration of use, time since last use, and preparation last used. Results for the two common MHT categories, oestrogen-only and oestrogen-progestagen preparations, are examined separately; few women switched between them .In prospective studies, information on whether women had been using MHT was necessarily recorded some time before the index date. Some never users or past users might have started after information was last recorded, but this would be uncommon, as the average age at last reported non-use was 63 years, and few women start MHT after age 60 years . AnalyseConversely, women who last (before the index date) reported that they were using MHT might have stopped before the index date. They were included as current users only if the index date was less than 5 years after the last report. Breast cancers that arose within this period did so after mean 1·4 years (SD 1·4). Based on typical annual continuation rates, an estimated 1·1 years of additional use would have accrued among them, far less than the average of 8·9 years (SD 6·5) up to the last reported use. In current users, duration of use was the last-reported duration plus the estimated small additional duration up to the index date . About 9Breast cancers were classified, where possible, as oestrogen-receptor-positive or oestrogen-receptor-negative (ER+ or ER–); as ductal or lobular; and as localised to the breast or not .A draft protocol was circulated to collaborators and preliminary results were discussed at a meeting of investigators in 2011 and, after additional data collection and analyses, by correspondence with them in 2017 and 2018. During this collaborative process, the analysis plans evolved.Conditional logistic regression models comparing particular groups of MHT users with never users yielded odds ratios , which are described as relative risks (RRs). To ensure that women in one study were compared directly only with similar women in the same study, all analyses were routinely stratified by study, centre within study, BMI, and fine divisions of age at index date, and adjusted for alcohol consumption, family history of breast cancer, parity, and age at first birth . To presAge at menopause, an important determinant of breast cancer riskTo help assess the clinical relevance of the RRs, they were combined with the 2015 age-specific breast cancer rates in England, which are typical of many western countries,The funders of the study had no role in study design, data analysis, data collection, data interpretation, manuscript preparation, or decision to publish. The writing committee had full access to all the data in the study and had final responsibility for the decision to submit for publication.Anonymised information on individual participants was obtained from 58 studies , includiOverall, breast cancer risk was greater in MHT ever users than never users . Since tAmong women who developed breast cancer in the prospective studies, mean age at menopause was 50 years (SD 5), mean age at first MHT use was 50 years (SD 6), and mean duration of MHT use was 10 years (SD 6) in current users and 7 years (SD 6) in past users. Hysterectomy largely determined MHT type; the proportions of women reported to have had the procedure were 2710 (7%) of 37 951 for oestrogen-progestagen users, but 31 187 (84%) of 37 213 for oestrogen-only users.RRs were consistently greater for oestrogen-progestagen than oestrogen-only preparations, were greater in current than in past users, and (in both current and past users) increased steadily with duration of use . For eacFew women had started MHT at ages 30–39 years, but among those who were still current users 15 years later, there were significant risks with oestrogen-progestagen and oestrogen-only preparations . SubstanSensitivity analyses left the main findings largely unchanged . The RRsDuring years 5–14 of use of an oestrogen-progestagen combination, the RR was greater for oestrogen plus daily progestagen than for oestrogen plus intermittent progestagen ; RR 2·30 (2·21–2·40) and RR 1·93 (1·84–2·01), respectively, heterogeneity p<0·0001. In general, the RR did not differ substantially by the progestagenic constituent of the combinations, including rarely used hormones, such as micronised [natural] progesterone , although the RR appeared to be somewhat lower for oestrogen plus dydrogesterone . The RR Most studies provided data on tumour characteristics. RRs in current users during years 5–14 were substantially greater for ER+ than ER– tumours and for lobular than ductal tumours, but were similar for localised tumours and tumours that had spread beyond the breast . The appThe RRs during years 5–14 of MHT use varied little with any personal characteristics except BMI . Figure To estimate the absolute risks of breast cancer by age 70 years that would be associated with starting various types of MHT at age 50 years and continuing for 5 years or for 10 years, we combined prospective study RRs for women who began any oestrogen-progestagen MHT at ages 45–54 years  with estThese absolute risks of developing breast cancer during the 20-year age range 50–69 inclusive are shown in Users of systemic hormone therapy who started around the time of menopause were at greater risk of invasive breast cancer than apparently similar never users. Excess risks were greater among current than past users, but some risk persisted for more than a decade after MHT use ceased. There was little excess risk after use of MHT for less than 1 year, but there were definite excess risks associated with just 1–4 years of use, and progressively greater risks with longer use. For a given duration of use, the excess risk among current users of MHT was greater for ER+ than for ER– disease. The risk was greater for oestrogen-progestagen than for oestrogen-only preparations, particularly if progestagen use was daily rather than intermittent. Risks did not differ substantially between the main oestrogenic constituents, or by whether oestrogens were administered orally or transdermally. There appeared to be little risk, however, from topical vaginal oestrogen preparations, which limit systemic exposure.Ovarian function ceases with menopause; thereafter, oestrogen levels fall substantially and progesterone levels fall to near zero. Endogenous oestrogen synthesis in post-menopausal women occurs mainly in adipose tissue, catalysed by the enzyme aromatase. Postmenopausal oestrogen levels therefore correlate strongly with the amount of adipose tissue, and hence with BMI,−10). Hence, among postmenopausal women oestrogen-only MHT might be expected to increase ER+ breast cancer incidence rates, as is indicated by the prospective studies.Among postmenopausal women in western countries, ER+ breast cancer accounts for about three-quarters of all breast cancer cases and deaths, and postmenopausal oestrogenic activity is a strong determinant of the incidence of ER+ breast cancer. Among postmenopausal women, the incidence of ER+ breast cancer correlates with age at menopauseAs postmenopausal adiposity increases endogenous oestrogenic activity and increases ER+ breast cancer incidence, the magnitude of any effect of MHT on breast cancer incidence might be expected to differ by adiposity, and it does. BMI is associated with increased incidence of ER+ disease in postmenopausal never users of MHT (an association that does not weaken with age), but not in women who have been using MHT for some years . ObesityMHT use is associated with much greater proportional increases in ER+ than ER– disease. Moreover, the excess breast cancer risks in MHT users are strongly duration dependent. Although MHT users differ in various ways from non-users, these biologically plausible findings suggest that the excess of ER+ breast cancer associated with MHT use, which accounts for most of the overall excess of breast cancer associated with MHT use, is largely causal . Although it is unclear why oestrogen-progestagen preparations would have a greater effect than oestrogen-only MHT, there is no good reason to distrust this statistically reliable finding.There was extensive information in the prospective studies on the effects of starting MHT use at various ages throughout the range 40–59 years. For women who had started anywhere in this age range the RRs among current users were similar, and were all highly significant. Comparatively few women, however, had started such treatment well after the menopause, for example at ages 60–69 years. Among them, the excess risk was statistically definite for oestrogen-progestagen but not for oestrogen-only preparations, although this non-significant result should not be considered in isolation from the highly significant excess risks in the younger age groups.Further evidence about the effects of starting the use of such treatments well after the menopause is provided by the randomised trials , in whicIn the oestrogen-only trials the average age at randomisation was 64 years and the mean between-group difference in the duration of hormone treatment during the scheduled intervention phase but before breast cancer onset was about 3·9 years, after allowing for non-compliance . During Z=3·4; p=0·0007).In the oestrogen-progestagen trials  a total One limitation of all the available epidemiological evidence is that there is still not long enough follow-up after cessation of prolonged MHT use by women who had started some years of hormonal treatment at around the time of menopause. If excess risks in past users are real and persist much longer than 15 years, there will be some additional hazard after age 70 years. Another limitation is that the collaboration sought information only on breast cancer incidence, not mortality, and incidence can depend on the sensitivity and frequency of mammographic screening. Breast cancer detection rates could have been reduced somewhat by the increase in breast density that is caused by hormonal treatment,Cases continue to accrue in the prospective studies, but there is no good reason to expect further follow-up would materially alter the main findings for current users. To limit biases, the main analyses were restricted to prospective studies, allowed for early menopause decreasing breast cancer risk and bringing forward the age when MHT is started, and adjusted for various other potential confounding factors . Current users were included up to no more than 5 years after their last reported MHT use; among them there were, on average, only 1·4 years between the last report about their MHT use and their index date. Some additional use must have occurred during that period, as must some discontinuation, but both have been allowed for . With all these safeguards, the findings are trustworthy for the main patterns of use in the prospective studies.The clinical relevance of the main findings lies in the magnitude of the absolute risks during and after MHT use for women who start MHT at ages 40–59 years , but theThe corresponding risks with 10 years of use starting at age 50 years would be about twice as great. In western countries there have been about 20 million breast cancers diagnosed since 1990, of which about 1 million would have been caused by MHT use.ceu.collaborations@ndph.ox.ac.ukCorrespondence to: Secretariat, Cancer Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, Oxford OX37LF, UK The principal investigators of each contributing study are responsible for access to the data.


Mammography relies on a visual interpretation of imaging results that is often confounded by dense breast tissue. Dense tissue affects the ability and accuracy with which the radiologist is able to detect cancer. Dense tissue may mask the presence of a breast cancer, and breast density is well recognised as an independent risk factor for the development of breast cancer. In the dense breast, detected cancers tend to be larger, more often lymph node positive and of a higher stage than those diagnosed in fatty tissue. The incidence of tumour multifocality and multicentricity is higher, decreasing the chances for breast conserving treatment. The literature convincingly supports the use of supplemental imaging modalities in women who present with increased breast density. There are clear advantages and disadvantages to each set of diagnostic imaging tests. However, there is no simple, cost-effective solution for women with dense breasts to obtain a definitive detection status through imaging. Suggestions are put forward as to what supplemental imaging choices should be included for the imaging of the dense breast with reference to the current South African setting. Use of supplemental screening modalities should be tailored to individual risk assessment. In a resource-constrained environment, international recommendations may need to be adjusted. Dense breast tissue reduces the effectiveness of mammography and increases the risk for developing breast cancer.The density of breast tissue is that portion of the breast that is composed of glandular and connective tissue. A dense breast is one in which there is more tissue than fat and this type of tissue is more common in younger women. About 40% of women over the age of 40 years have dense breasts.8:The Breast Imaging Reporting and Data System (BI-RADS) breast density categories are used in mammographic reports to indicate the degree of mammographic breast density 8:The breasts are almost entirely fatty.There are scattered areas of fibroglandular density.The breasts are heterogeneously dense.The breasts are extremely dense.7 The fifth edition of BI-RADS, when compared to the fourth edition, places more emphasis on the masking effects of breast density. This edition specifies that when there are regions of sufficient density to obscure small masses, the mammogram should be categorised as heterogeneously dense rather than with scattered fibroglandular tissue, even if the overall volume of density would not typically place that study in the heterogeneous category.9The last two categories are considered ‘dense’. When considering women aged in their early 40s, about 13% have extremely dense breasts and 44% have heterogeneously dense breasts. By the early 70s of age, 2% have extremely dense breasts and 24% have heterogeneously dense breasts.10 and correlation with volumetric density as measured by magnetic resonance imaging (MRI).11Because of inherent inter- and intra-reader variability of BI-RADS density classification, computer-based methods have been developed to improve consistency. Several automated density programmes have demonstrated high reproducibility12 Extremely dense tissue poses a four to six times increased likelihood of developing breast cancer when compared to the risk with fatty involuted tissue and twice the likelihood when compared to scattered fibroglandular density type.12Many studies have concluded that there is at least a moderate association of mammographic breast density and the risk of breast cancer.13 reported that women with extremely dense tissue were 17 times more likely to have an interval cancer than women with fatty involuted tissue. Interval cancers represented 15.7% of cancers in extremely dense breasts compared with 4.5% of cancers in fatty tissue.14 It has been reported that cancers detected in dense tissue are larger, more likely to be lymph node positive and of a higher stage than in women without dense tissue, more often multifocal or multicentric, and mastectomy is more often performed.17 Dense breast tissue increases the risk of breast cancer and impairs detection of non-calcified cancers on mammography, which can result in a more advanced stage at diagnosis.Women with dense breast tissue on mammogram are at increased risk for interval cancer (cancer that presents because of symptoms during the time between regular screening) because of the mammographic challenges and limitations of cancer detection for women with dense tissue. Boyd et al.18; however, supplemental screening in addition to mammography may be indicated for women with dense tissue allowing for earlier detection of cancers in the dense breast.Digital mammography improves cancer detection in dense tissue compared with film-screen mammographySupplemental screening can include the following:Digital breast tomosynthesis (DBT): Many studies have shown that there is an improvement in invasive cancer detection with DBT, but fewer studies have addressed its performance in differing density categories. Ciatto et al.19 showed an incremental cancer detection rate because of DBT of 2.8 per 1000 mammograms with fatty or scattered fibroglandular tissue and 2.5 per 1000 in dense tissue. Digital breast tomosynthesis improves cancer detection compared to standard digital mammography in women with heterogeneously dense breasts but may be less effective in women with extremely dense breasts. A single centre study found that DBT reduced the interval cancer rate across all densities but most studies lack sufficient follow-up to substantiate this.20Ultrasound: Ultrasound improves detection of early stage invasive breast cancer and is the most frequently used supplemental screening modality. Data from many studies have revealed an increase in the rate of cancer detection each year when supplemental ultrasonography was utilised.26 The adjunct screening with tomosynthesis or ultrasound in mammography-negative dense breasts (ASTOUND) trial is the first published prospective trial directly comparing sonar and 3D mammography after negative 2D mammography in dense tissue.24 Hesitation still exists in implementing routine, supplemental ultrasonography screening despite the data from the aforementioned studies. Using handheld 2D ultrasonography to detect small masses is labour intensive. Operator variability, shortages of trained personnel and reductions in radiologist efficiency for image acquisition all contribute to the widespread discouragement for whole-breast surveys.26 In order to combat some of these challenges, 3D automated whole-breast ultrasonography has been introduced as an alternative modality. Multiple studies substantiate that supplemental breast ultrasonography – whether 2D handheld or 3D automated whole-breast ultrasonography – can improve rates of cancer detection.26 Ultrasonography is in common use for diagnostic breast imaging, but its role in screening remains unclear. Studies utilising screening ultrasonography demonstrate its capability for detecting invasive malignancies in dense breasts at small sizes and localised stages that could potentiate an increase in breast cancer survival rate; however, more studies are needed to determine the impact on mortality.26 The best indications for screening ultrasonography in dense breasts may be for women with intermediate risk or in those women at high risk but with a contraindication to MRI.22MRI: The evidence supporting MRI screening of the breast continues to evolve. A multicentre trial by Sardanelli et al.27 determined MRI to be more sensitive (91%) than clinical breast examination (18%), mammography (50%), ultrasonography (52%) or mammography plus ultrasonography (63%). In addition, 31% of cancers were detected by MRI alone. Many other studies have shown similar results.26 MRI is recommended for supplemental screening in women at high risk of breast cancer regardless of breast density, but cost and availability limit its use for general screening. Although cost, patient tolerance and accessibility are major detriments to using breast MRI to screen women with the sole indication of dense breast tissue, some investigators are developing abbreviated examinations that show promising results.28Contrast enhanced digital mammography (CEDM): This technology is being explored for screening. Based on diagnostic work in women with known cancer,30 sensitivity is likely comparable to MRI and specificity may be higher. In the diagnostic setting, CEDM has been demonstrated to be superior to standard mammography in women with dense breasts.32Molecular breast imaging (MBI): Studies using 99mTc-sestamibi have been performed for supplemental screening of women with dense breasts.33 Studies are typically time consuming and the typical dose of about 740 MBq (20 mCi) has been considered excessive for use as a screening test.34 The radiation exposure to the whole body, and not just the breast, is five times that of digital mammography, and twice that of combination digital mammography and DBT. These facts, taken in conjunction with the knowledge that there is no data on interval cancer rates, make it unlikely that MBI will be implemented in common practice.35The use of supplemental imaging modalities has been shown to be advantageous in the assessment accuracy for dense breast tissue, and there are clear advantages and disadvantages to each type of diagnostic imaging test.36 particularly in countries with national screening protocols and programmes.Awareness is increasing amongst the public and medical professionals regarding breast density as a risk factor for breast cancer, as well as the limitations of mammography in women with dense breasts. With this awareness comes legislation and notification laws in relation to breast density,1 Although neither clinical breast examination (CBE) nor breast self-examination (BSE) has yet to be established as screening tools, the utility of these interventions in limited resource areas is advocated by this policy document, as they promote breast health awareness. Breast self-examination as part of breast health awareness has been advocated for early detection in low-resource settings.1 Unfortunately, breast density cannot be determined by touch, by feel or by the appearance of a breast during the physical examination. It can only be determined by evaluating a mammogram.South Africa does not have a national screening programme for breast cancer, nor notification laws in connection to breast density. Across South Africa, in both the public and the private sectors of health care, there is a large discrepancy in breast imaging availability and quality. According to the South African National Health Policy document of 2017, screening mammography should not be introduced unless resources are available to ensure effective and reliable screening of at least 70% of the target group. Lack of resources and infrastructure in the South African public health care system renders a national screening programme untenable.37 with the addition of one or more of the supplemental imaging modalities according to the patient’s individual breast cancer risk profile.36Understanding breast cancer risk conferred by density in the setting of a patient’s history, as well as an appreciation of the imaging tools available, will help aid clinicians in developing the most appropriate screening plan for each of their patients. Mammography remains the most appropriate modality for population-based screening


We investigated the relationship between perceived cognitive function and emotional vulnerability of breast cancer survivors while examining the moderating effect of various risk factors. Results confirmed that perceived cognitive function predicted emotional vulnerability with grade of breast cancer moderating this relationship. Age at diagnosis exhibited a trend towards significance for emotional vulnerability, and time since diagnosis as well as grade significantly predicted quality of life. Our findings imply that (younger) women with a higher breast cancer grade are at a greater risk for emotional and cognitive vulnerability and can benefit from interventions designed to reduce emotional vulnerability through training cognitive efficiency. Breast cancer is the most prevalently diagnosed malignancy among women , with a Interestingly, strong evidence has linked systemic chemotherapy treatment to cognitive dysfunction in around 16–75 per cent of breast cancer survivors, a phenomenon commonly known as the ‘chemo-brain’ . In partA majority of women following the diagnosis of breast cancer are at greater risk of developing depression, anxiety and post-traumatic stress disorder (PTSD) , which aA considerable body of research has explored the effects of key breast cancer demographic factors (risk factors) in relation to women’s emotional health. For example, The grade of breast cancer diagnosed has only recently been investigated as a possible factor influencing quality of life of survivors. Despite long-standing evidence that a higher grade is associated with a greater chance of premature death  and moreFurthermore, it has been reported that women diagnosed at a younger age exhibit a greater level of emotional distress  during tIt is clear from recent evidence that women experience the most severe levels of emotional vulnerability straight after the diagnosis and immediately after the completion of active anti-cancer treatment . AlthougWhile a substantial proportion of evidence has alluded to the existence of a noteworthy bidirectional relationship between the cognitive function and emotional well-being of breast cancer survivors , only a The concept that cognitive flexibility plays a determining role in maintaining a healthy emotional well-being has received increasing support from recent research that has successfully targeted cognitive dysfunction(s) using cognitive control training (CCT) to boost emotional well-being in depression , as wellA recent training study conducted by The current study investigated the relationship between breast cancer survivor’s perceived cognitive function and their perceived emotional vulnerability and examined the predictive power and moderating role of four key demographic factors including (1) age at diagnosis, (2) time since diagnosis, (3) endocrine therapy status and (4) grade of breast cancer in this relationship, as well as in relation to the survivor’s quality of life. We elected to analyse these four particular demographic factors, as research has consistently pinpointed them to be highly salient influencers on breast cancer survivor’s emotional health and/or quality of life. Based on current research, we predicted that perceived cognitive function would significantly relate to perceived emotional vulnerability and quality of life. We also predicted that the four demographic (risk) factors would be associated with the severity of emotional vulnerability reported and moderate the relationship between survivor’s perceived cognitive function and their perceived emotional vulnerability.The design was cross-sectional. Participants were instructed to complete a battery of six online questionnaires on cognitive and emotional health. The first variable we measured was the participant’s perceived cognitive function; this was measured at two levels through the execution of the FACT-Cog and Perception of Cognition Questionnaire (PCQ). The second variable measured was the participant’s perceived emotional well-being; we measured this on four levels through the implementation of one mainstream questionnaire ) and three cancer-specific questionnaires , Quality of Life Questionnaire (QoL) and Cancer Worry Scale (CWS)).N = 132, mean age = 48.86, SD = 8.84; mean age at diagnosis = 45.58, SD = 8.41; mean number of months since diagnosis = 39.95, SD = 34.80) (one participant failed to specify their diagnosis as primary or secondary) who had previously received a clinical diagnosis of either primary  or secondary  breast cancer.The participants recruited to partake in the present research were women (Participants had to be in a post-active treatment phase not receiving anti-cancer treatment(s) including chemotherapy and/or radiotherapy. The participant could, however, be administering a regular hormone blocker therapy medication (i.e. Tamoxifen) or receiving target treatments (i.e. Herceptin injection). Participants with a current or former diagnosis of either a neurological or psychiatric condition (i.e. anxiety or depression) were eligible to take part.http://briccentre.bbk.ac.uk/). This research received ethical approval from the Research Ethics Committee of the Department of Psychological Sciences at Birkbeck College, University of London, and in accordance with the guidelines, all of our participants provided informed consent before completion of the study.Participants were recruited using voluntary sampling through online advertisements placed on social media platforms including the ‘Building Resilience in Breast Cancer Centre’ , clinical characteristics of their tumour , and the programme of active anti-cancer treatment they received . In addition, the GDQ also collects information relating to the general health habits , neurological and psychiatric medical history.The FACT-Cog, Version 3  consistsThe PCQ  is a 7-iDiagnostic and Statistical Manual of Mental Disorders  criteria for PTSD and assesses three key symptoms including avoidance, hyperarousal and intrusion. Individual’s responses are based on their own personal experience(s) with the symptoms over the last 7 days, with a higher combined score reflecting a greater PTSD symptom severity.The IES-R is a standardised questionnaire by The HADS  is a broThe shortened QoL questionnaire  includesThe CWS  that re-directed them to the battery of self-report questionnaires. Before the study could commence, participants were presented with an online consent form. After the completion of this form, eligible participants were directed to fill in the 29-item GDQ regarding their personal breast cancer history followed by the two cognitive and four emotional well-being questionnaires.A series of statistical analyses were performed using Statistical Package for the Social Sciences . Pearson’s correlation analyses were conducted between the two cognitive and four emotional well-being questionnaires to examine whether perceived cognitive function related to the emotional symptoms (vulnerability)  and quality of life encountered by breast cancer survivors.1 and the second to investigate the influential factors on survivors’ perceived quality of life. In step 1 of our regression analyses, we included only the four selected demographic factors: (1) age at diagnosis, (2) time since diagnosis, (3) endocrine therapy status and (4) grade of breast cancer diagnosed. Measures of perceived cognitive function were then added in step 2.Two hierarchical regression analyses were performed: the first to examine the relationship between the breast cancer–specific demographic factors (i.e. grade of breast cancer), perceived cognitive function and perceived emotional vulnerability (IES-R + HADS + CWS),Supplementary Material 1). In addition, post hoc analyses for achieved statistical power were conducted.Using analysis of standardised residual, we found no outliers in the data . Checks for violations of the assumptions of collinearity, independent error, normality, homoscedasticity and linearity were also conducted for each of the regression models using residuals  in predicting perceived emotional vulnerability (IES-R + HADS +CWS), as well as quality of life. Mean-centred values for perceived cognitive function and quality of life were used. Checks for violations of the assumption of heteroscedasticity were also carried out, and all standard errors in the model were based on the Heteroscedasticity-Consistent Standard Error (HC3) estimator.We decided to use the FACT-Cog total score in place of the four subscales for perceived cognitive function to increase power in our analyses.Of the 147 breast cancer survivors who originally volunteered to participate in our study, only two participants failed to meet the initial inclusion criteria (both were receiving active anti-cancer treatment). A further nine eligible participants, however, failed to complete the seven questionnaires during a single session, and four participants withdrew from the study without providing a reason see . Three aPerceived cognitive functioning as measured by the FACT-Cog correlated negatively with the three emotional symptomology questionnaires . These results indicate that higher levels of impaired cognitive functioning were associated with higher levels of emotional vulnerability inclusive of experiencing worse cancer recurrence worries, anxiety, depression, and PTSD symptoms see . SimilarPredictably, our analyses also showed strong positive correlations between the QoL questionnaire and both perceived cognitive function questionnaires (FACT-Cog and PCQ) suggesting that a higher perceived cognitive function is associated with a better overall quality of life see .F = 8.77, p < .001. Of the four demographic factors included, only age at diagnosis exhibited a trend towards statistical significance (p = .12) in our final model, and FACT-Cog remained a significant predictor (p < .001). These results indicate that cognitive function predicts emotional vulnerability above and beyond the four demographic factors, with lower levels of perceived cognitive function meeting higher levels of perceived emotional vulnerability.Our first regression analysis see  showed tSupplementary Material 1). Moreover, post hoc analysis showed that this regression had a medium effect size (Cohen’s ƒ2 = 0.29) and an achieved statistical power of (1 – ß error probability) = 1.00.Checks for violation of assumptions using residuals revealed that assumptions of collinearity  < 10), independent errors , normality and homogeneity of variance and linearity were all met for this regression model  = 16.08, p < .001. Importantly, both the grade of breast cancer diagnosed (p = .02) and the time since diagnosis (p = .02) as well as FACT-Cog (p < .001) functioned as significant predictors in the final model. These results show that perceived cognitive function predicts overall quality of life above and beyond that of the four demographic factors included. Specifically, lower perceived function meets a poorer quality of life.FACT-Cog explained an extra 31 per cent of the variance at a significant level, Supplementary Material 1). Post hoc analysis revealed that this regression analysis had a large effect size (Cohen’s ƒ2 = 0.52) and an achieved statistical power of (1 – ß error probability) = 1.00.Checks for violation of assumptions using residuals showed that assumptions of collinearity , independent errors , normality and homogeneity of variance and linearity were met in this regression model  = 10.14, p < .001). The R2 change due to the interaction was significant, p = .01. In addition, the analyses also revealed that none of the four demographic factors functioned as significant moderators in the relationship between perceived cognitive function and the quality of life of breast cancer survivors. All of the corresponding standard errors in the models were heteroscedasticity consistent, and thus, the assumption of heteroscedasticity was met.Our moderation analyses revealed that of the four moderators assessed, grade of breast cancer diagnosed significantly moderated the relationship between breast cancer survivor’s perceived cognitive function (as measured by the FACT-Cog) and their perceived emotional vulnerability. The result indicated that approximately 32 per cent of the variation in the severity of emotional vulnerability reported could be explained by the main effects (grade of breast cancer and cognitive vulnerability) and the interaction effects (grade of breast cancer × cognitive vulnerability) (p = .04) and 3 (p < .001) (see The line chart of the simple slopes equations in 001) see  suggestiThis study investigated the relationship between perceived cognitive function and perceived emotional vulnerability and quality of life in breast cancer with a specific focus on demographic risk factors such as age at diagnosis, time since diagnosis, endocrine therapy status and grade of breast cancer.As predicted, our results established a link between perceived cognitive functioning and emotional vulnerability as well as quality of life. We found that age at diagnosis showed a trend towards being a significant predictor of emotional vulnerability, while both the grade of breast cancer and the time since diagnosis significantly predicted women’s perceived quality of life. Moreover, our moderation analyses unveiled that women’s grade of breast cancer also significantly moderated the effects of cognitive function in predicting perceived emotional vulnerability.Our findings on the link between cognitive function and emotional vulnerability extend on Imperatively, the results from the regression analysis further revealed that breast cancer survivors’ perceived cognitive function was the strongest predictor of their perceived level of emotional vulnerability, with grade of breast cancer significantly moderating this relationship. We found that a higher (more severe) grade resulted in a stronger relationship in which lower perceived cognitive function was coupled with a higher level of emotional vulnerability see . The preIn line with previous research, age at the time of breast cancer diagnosis was found to show a strong trend for predicting emotional vulnerability in women, with a younger age inferring higher levels of emotional vulnerability. Notably, our results appear to largely support recent evidence that women diagnosed at a younger age experience more intense emotional distresses  such as, as younContradictory to past research, which has reported that the demographic factors such as endocrine therapy  and timeCorresponding with previous research , we founMoreover, we identified time since diagnosis to be a predictive factor of survivor’s overall quality of life, with a longer period of time since diagnosis corresponding to a lower perceived quality of life. Conceivably, our study found this novel result as women with a longer time since their diagnosis are more likely to experience more intense ruminative thinking regarding the possibility of cancer recurrence. Women with a longer time since diagnosis are also more likely to have come to terms with the long-term detrimental effects that receiving a breast cancer diagnosis and undergoing anti-cancer treatment have on their life . These findings are highly substantial, not only as they demonstrate predictive links but also as they reiterate the importance of acknowledging time since diagnosis, grade and their effects on breast cancer survivor’s overall well-being in future research.As a collective, our findings have vital implications for researchers and health care services; in particular, they indicate that further research should be carried out to explore the effects of CCT on the perceived cognitive function, emotional well-being and quality of life of younger breast cancer survivors. As it stands currently, women with a breast cancer diagnosis are not routinely offered any form of CCT, despite strong evidence showing that it profoundly improves emotional well-being .The present study displayed some methodological limitations that need to be taken into consideration when interpreting our results. A particular limitation within our study was that the questionnaires were only implemented at the one-time point, meaning that answers could have been influenced by mood or unusual events (i.e. cancer recurrence scare) that may have changed the participants’ current psychological state. Assessing trends of cognition and emotions throughout the diagnosis, treatment trajectory and a few years post-treatment would provide us with valuable data on patterns of perceived cognitive function and emotional vulnerability in breast cancer survivors. A second limitation is that we assumed that all of the women recruited had a sound understanding of the clinical characteristics of their breast cancer diagnosis (i.e. type and grade of tumour) and the treatment received. Although clinical characteristics like grade are very well documented in patient’s official diagnostic  letters and are focal during discussions with breast cancer clinicians, future research should conduct more individual checks (i.e. via interviews with clinicians or pathologist reports) to ensure that all the demographic information reported is correct. A final limitation of our study is that all of the participants were recruited using advertisements placed on social media platforms including Facebook and Twitter. As a consequence, our sample of women might not be representative of the much broader breast cancer population. In the future, researchers should, therefore, recruit survivors through a broader range of sources including patient oncology clinics.Considering the current findings of our study, recommendations for future research can be made. We suggest that this study is replicated on a much larger scale to provide a more in-depth account of younger breast cancer survivors’ cognitive and emotional health concerning specific demographic factors and moderator variables. In addition, future studies may wish to adopt a mixed methods approach incorporating qualitative, quantitative, and objective measures, as well as implementing longitudinal studies. This would provide a more thorough personal portrayal of breast cancer survivor’s experience and would also permit for assessing the long-term impact a breast cancer diagnosis and its treatment may have on survivor’s cognitive and emotional health. Finally, given the high association between cognition and emotional vulnerability in this sample, we advocate that future research and clinicians should further explore CCT in the breast cancer population to evaluate its effectiveness as this would aid the development of new interventions that primarily aim to improve emotional resilience in breast cancer survivors.This study bestows crucial and novel findings that highlight the detrimental effects that perceived cognitive function, as well as various demographic (risk) factors, can have on breast cancer survivor’s emotional vulnerability and quality of life. Vitally, we established that perceived cognitive function significantly relates to the severity of emotional vulnerability endured by breast cancer survivors with grade of breast cancer moderating this relationship. Considering the shortfall of obtainable psychological interventions at an individual level, our findings are highly pertinent for clinicians and health care settings treating individuals with psychological concerns as a repercussion of a breast cancer diagnosis and its treatment.Click here for additional data file.Supplemental material, Supplement_Table for Perceived cognitive functioning and its influence on emotional vulnerability in breast cancer by Bethany Chapman, Stefanie Helmrath and Nazanin Derakshan in Health Psychology Open