African American women in the state of Arkansas have high breast cancer mortality rates. Breast cancer risk assessment tools developed for African American underestimate breast cancer risk. Combining African American breast cancer associated single-nucleotide polymorphisms (SNPs) into breast cancer risk algorithms may improve individualized estimates of a woman’s risk of developing breast cancer and enable improved recommendation of screening and chemoprevention for women at high risk. The goal of this study was to confirm with an independent dataset consisting of Arkansas women of color, whether a genetic risk score derived from common breast cancer susceptibility SNPs can be combined with a clinical risk estimate provided by the Breast Cancer Risk Assessment Tool (BCRAT) to produce a more accurate individualized breast cancer risk estimate. A population-based cohort of African American women representative of Arkansas consisted of 319 cases and 559 controls for this study. Five-year and lifetime risks from the BCRAT were measured and combined with a risk score based on 75 independent susceptibility SNPs in African American women. We used the odds ratio (OR) per adjusted standard deviation to evaluate the improvement in risk estimates produced by combining the polygenic risk score (PRS) with 5-year and lifetime risk scores estimated using BCRAT. For 5-year risk OR per standard deviation increased from 1.84 to 2.08 with the addition of the polygenic risk score and from 1.79 to 2.07 for the lifetime risk score. Reclassification analysis indicated that 13% of cases had their 5-year risk increased above the 1.66% guideline threshold ) and 6.3% of cases had their lifetime risk increased above the 20% guideline threshold by the addition of the polygenic risk score ). Our data confirmed that discriminatory accuracy of BCRAT is improved for African American women in Arkansas with the inclusion of specific SNP breast cancer risk alleles. Racial disparities among women of color is evident. African American women have higher mortality rates, poorer breast cancer survival rates, and are more likely to develop early onset basal-like breast tumors that are non-responsive to hormone receptor therapy compared with European American women –3. In thBRCA1 and BRCA2 mutations. While the latter confer a large increase in individual risk, they are found in very low frequencies in the population. In contrast, SNPs confer only a small increase in risk but are found in much higher frequencies in the population. While no SNP is very informative on its own, a polygenic approach to genetic screening could improve estimates of individual risk and create the possibility of individualized screening strategies [A growing number of single-nucleotide polymorphisms (SNPs) that are associated with an increased risk of breast cancer have been identified through genome-wide association studies , 10. Mosrategies , 12. Sevrategies –16. Largrategies , 18. ThiThe present study was initiated to confirm whether a genetic risk score based on a panel of 75 SNPs that are associated with increased breast cancer risk in women of European and/or African ancestry –25, coulParticipants in this study were selected from a cohort of women recruited to study breast cancer in Arkansas . Accrualst degree or 2nd degree family relative  participated in any of the recruitment events. Participants under the age of 35 years were excluded since breast cancer risk assessment using the BCRAT algorithm is limited to women age 35 and older.Briefly, during recruitment to the cohort, baseline information on medical history, demographic factors, body weight, height, reproductive history, menstrual history, and family history of breast cancer, was obtained and a 2-mL saliva specimen from the participant was collected in an OrageneDNA Self Collection Kit. Self-reported race and ethnicity information was based on data obtained from questionnaires that were completed at recruitment. Participants also reported if a 1All participants in this study self-reported as African American ancestry and were selected using information in the cohort database. Study subjects included participants who had a previous diagnosis of breast cancer (n = 319), one age-matched unaffected control (n = 319) per breast cancer case, and the additional 240 unaffected controls recruited in Jackson, MS. This study and written informed consent procedure was approved by the University of Arkansas for Medical Sciences Institutional Review Board  and conducted in accordance with the Declaration of Helsinki.The SNP panel was based upon SNPs identified as being associated with breast cancer risk by large-scale genome-wide association studies and had previously been used to derive a validated polygenic risk score using a Caucasian data set . BecauseGenomic DNA was isolated from saliva specimens of the 319 cases and 559 controls using DNA Genotek’s prepIt·L2P DNA Extraction Kit  according to the manufacturer’s instructions. Genomic DNA was evaluated and quantified using a Nanodrop UV-spectrometer .Whole-genome amplification was conducted in the UAMS Genomics Core Facility using Qiagen RePLI-g Kits, which incorporates the method of multiple displacement amplification with input of 50 nanograms of genomic DNA per reaction. Amplified samples were purified and quantified on a Nanodrop 2000  before being plated for genotyping.Genotyping was performed using the Illumina GoldenGate Genotyping Assay at the Winthrop P. Rockefeller Cancer Institute’s Genomics Core Facility. The GoldenGate Genotyping Assay is a flexible pre-optimized assay that uses a discriminatory DNA polymerase and ligase to interrogate 96, or from 384 to 3,072, SNP loci simultaneously. Blinded duplicate samples (5–10%) were included to assess the reproducibility of the genotypes. An average reproducibility of 99% was obtained. Individual level genotypes are presented in The 5-year and lifetime absolute risk of invasive breast cancer at baseline was calculated using BCRAT , 28. We p) from a previously published study [p)2 + 2p (1 –p) OR + p2OR2 as previously described [We used the approach of Mealiffe et al.  to calcued study , assuminescribed . After tescribed , we calcescribed . Lastly,escribed .We log transformed the BCRAT risk score, SNP-based score, and combined risk score for all analyses. To test for associations between the BCRAT risk score, the SNP-based risk score, and the combined risk score, we used Pearson correlation.P(up|case)–P(down|case) + P(down|control)–P(up|control) as previously described [P value less than 0.05 was considered statistically significant.We used logistic regression to estimate risk associations for the BCRAT, SNP-based, and combined risk scores in terms of the OR per adjusted standard deviation (OPERA), where the log 5-year predicted risk was adjusted for age . We asseescribed . We usedescribed  for two The cases in the study population were oversampled for family history; in particular 49 (15.4%) of cases had 2 or more first-degree relatives, well in excess of that observed in population-based case samples , This reThe OPERA estimates of the OR, however, did confirm that the combined risk scores for 5-year and lifetime risk gave greater discrimination than the SNP-based risk score and the corresponding BCRAT 5-year and lifetime risk scores alone . FurtherReclassification tables were used to calculate the number of cases and controls whose risk classification changed with respect to the American Society of Clinical Oncology’s 5-year risk threshold of 1.66% for Tamoxifen chemoprevention and the American Cancer Society’s lifetime risk threshold of 20% for MRI screening is recommended Tables  and 5. RGenome-wide association studies conducted mainly in European or Asian populations have identified an increasing number of genetic susceptibility loci for breast cancer. In addition to the observation that SNPs are associated with increased risk of developing breast cancer, several studies have investigated the possibility of combining the SNP-based risk scores with conventional breast cancer risk prediction tools, particularly for women of European descent –16, 32 bWe have evaluated the effect of combining a polygenic risk score with the BCRAT risk score (incorporating the modified Women’s Contraceptive and Reproductive Experiences WeCARE model) for breast cancer risk estimation in African American women. SNP-based risk has been shown to be largely independent of family history with only a modest attenuation when adjusting for family history . In thiss, where s is the estimated SD of the risk factor in the population after adjusting for all other factors (and can be estimated using the controls). Under these terms of reference, the addition of the SNP-based risk score resulted in a 13% improvement in the OPERA for the BCRAT 5-year risk estimate and a 15% improvement for the BCRAT lifetime risk estimate. This improvement in risk assessment might help the medical community begin to tackle the differences in stage at diagnosis; significantly fewer Non-Hispanic blacks are diagnosed at a localized stage compared to non-Hispanic whites [We believe a better way to combine risk factors when they are measured using different scales is to utilize methodologies in which the standard deviation of the risk gradient is incorporated into the analysis. We have therefore, preferentially utilized the odds per adjusted standard deviation method (OPERA), as described by Hopper 2016 . The conc whites .We acknowledge that a limitation of the present study included small participant sample size and lack of data pathological subtypes of breast cancer among the participants. Within the cohort of women used for this study population, many were also unable to complete the BCRAT in its entirety . HoweverReclassification of individual risk is important if the reclassification results in an individual’s risk exceeding clinical guideline thresholds, such as those for chemoprevention or screening. Reclassification analysis showed that 22% of cases that were previously below the American Society of Clinical Oncology’s risk threshold of 1.66% for Tamoxifen chemoprevention would have their individual risk elevated above the threshold after incorporation of the SNP-based risk score. Similarly, 6.7% of cases who were previously below the 20% lifetime risk threshold for MRI screening would have their risk elevated above the threshold by the addition of the SNP-based risk score.The unique feature of our population-based cohort is that the women are representative of 75 counties, encompassing both rural and urban areas, within the state of Arkansas . ArkansaIn conclusion, our results indicate that discriminatory accuracy of BCRAT is improved for African American women in Arkansas with the inclusion of African American specific SNP breast cancer risk alleles. We anticipate that the SNP-based risk score will further improve when genome-wide association studies use Phase I data sets that are relevant to the African American population, and when fine mapping studies have been conducted within that population.S1 Table(DOCX)Click here for additional data file.S2 Table(CSV)Click here for additional data file.


The study assessed the knowledge, attitudes and breast cancer screening practices amongst women aged 30–65 years residing in a rural South African community.A quantitative, descriptive cross-sectional design was used and a systematic sampling technique was employed to select 150 participants. The questionnaire was pretested for validity and consistency. Ethical considerations were adhered to in protecting the rights of participants. Thereafter, data were collected and analysed descriptively using the Predictive Analytics Software program.Findings revealed that the level of knowledge about breast cancer of women in Makwarani Community was relatively low. The attitude toward breast cancer was negative whereas the majority of women had never performed breast cancer diagnostic methods.Health education on breast cancer screening practices is lacking and the knowledge deficit can contribute negatively to early detection of breast cancer and compound late detection. Based on the findings, community-based intervention was recommended in order to bridge the knowledge gap. Breast cancer is a global health problem and the most common cancer amongst women, comprising 23% of the female cancers  show breast cancer as the leading cancer amongst women. South African women have a one in 29 lifetime risk of developing breast cancer, with an age-standardised incidence rate of 30.6 per 100 000 population  for easier comprehension by the participants. This was done by Venda educator in the Department of African Languages at the University. There was a back translation by another language educator in order to ensure English and Tshivenda equivalence. One hundred and fifty questionnaires were self-administered and were collected after three days from the respective households, with a response rate of 100%.® Excel was used to draw some charts. Descriptive statistics were used to describe the data and the Chi-square test was used to describe relationships amongst variables, with a significance level of p < 0.00.Statistical analysis was used to summarise the results of the study and to reduce, organise and give meaning to the data . Authorisation and approval for conducting the study were requested from Makwarani Royal Committee. The researchers ensured protection of the rights of the participants by informing the participants that their participation was voluntary, they would remain anonymous, they were free to withdraw from the study at any time without penalty and that all information would be kept confidential. Each participant signed a written consent; even those with no formal education were able to write down their names.Content validity concerns the degree to which the instrument has an appropriate sample of items for the construct being measured  of the participants had no formal education, whilst only 26 (17.3%) had a tertiary level of education, 47 (31.3%) had a secondary education and 37 (24.7%) had obtained a primary-level education. Twenty-six (17.3%) were professional workers whilst 50 (29.3%) were casual labourers and pensioners.n = 26; 56%) as opposed to coming from a health facility .One hundred and four (69%) of the women had never heard of breast cancer, whilst only 46 (31%) had heard of breast cancer, with their source of information being mainly from the media , followed by abscess  and accumulation of fluid in the breast . Nipple changes , skin changes  and swelling of the breast or armpit  were least known.Swelling of the breast or lump was cited by the majority of participants , lack of exercise  and overweight . Others, in order of percentage, were: hormonal changes , heredity and radiation , drinking alcohol  and smoking .The responses to the list of risk factors for breast cancer were as follows: high fat intake  of the participants never heard about breast diagnostic methods. Amongst the eight (5.3%) participants who said they had heard about breast cancer diagnostic methods, four (2.6%) knew of clinical breast examination, three (2%) knew of BSE and one (0.6%) mammography. Furthermore, 94 (62.5%) of the participants did not know the appropriate time to perform BSE, whereas 56 (37.5%) knew that BSE should be performed seven days after menstruation.Eight (5.3%) of the participants had heard about breast diagnostic methods, whereas the majority  disagreed and 35 (23.3%) strongly disagreed that breast cancer treatment worsens the condition, whereas 33 (22.0%) agreed and 7 (4.7%) strongly agreed that the treatment worsens the condition. Seventy (46.7%) of the women agreed that the possibility of a cure for breast cancer is determined by early detection and 38 (25.3%) strongly agreed with this statement, whereas 30 (20.0%) disagreed and 12 (8%) strongly disagreed that the possibility of a cure is not determined by early detection.Almost half of the women (One hundred and forty-two (94.7%) of the women said that they had never performed breast cancer diagnostic checks and only eight (6.3%) had practised one of the methods during their lifetime. Regarding health-seeking behaviour, 124 (82.7%) reported that if they noticed any change in their breast, they would consult the medical doctor, 21 (14.0%) said that they would consult the traditional doctor and only five (3.3%) would consult a prophet.N = 150) and describes the age distribution, level of education and occupational status. The items in this section attempted to obtain personal information about the participants in order to contextualise the responses concerning their knowledge, attitudes and practices regarding breast cancer.The strongest risk factor for breast cancer is age. A woman's risk of developing this disease increases as she gets older, however those who are at risk should be made aware of personal risk factors of developing breast cancer. Similarly, the participants in the older age group displayed low levels of knowledge regarding screening practices. Allam and Abd Elaziz :196 concet al. Employment status determines one's ability to access healthcare, as well as determining other factors in terms of cost, proximity and acceptance of medical services. Occupation and education show a positive association with breast cancer screening methods; women of intermediate and high occupational class are more likely to use screening methods as compared with those in the lowest class  of the participants had never heard about breast diagnostic methods. Knowledge about diagnostic methods is highly beneficial to the participants as it assists women regarding when and how to perform breast cancer screening for early detection in order to reduce late presentation of the disease that might complicate treatment of breast cancer. Furthermore, 62.5% of the participants did not know the appropriate time to perform BSE, whereas 37.5% knew that BSE should be performed seven days after menstruation. Kanaga et al. (Poor knowledge regarding breast cancer screening methods is responsible for late detection of the disease. Eight (5.3%) of the participants had heard about breast diagnostic methods, whereas the majority  of the participants in this study had never had a mammogram, whilst one (0.6%) had experienced a mammogram in the past and knew that it should be performed once every two years. This is attributable to the fact that mammography is not available in public hospitals in the region of Vhembe and there are no large-scale awareness campaigns regarding its existence as the majority cannot afford it. Khokhar :249 alsoet al.  reported that if they noticed any change in their breast, they would consult the medical doctor, whilst 14.0% said that they would consult the traditional doctor and 3.3% would consult the prophet. The issue of religious and cultural belief might play a significant role in the health-seeking behaviour of the participants in this study. McMullin et al. :35 reporOne hundred and forty-two (94.7%) of the women said that they had never performed breast cancer diagnostic checks before. The results showed no breast cancer screening programme campaigns had ever been conducted in Makwarani Community and participants did not even know how often screening be done. Similar findings were reported by Ojikutu and Adetifa :183, whoThe research was conducted in one municipality, so the results can therefore not be generalised to others. The results of this research may also not be generalised to larger groups, as they apply only to the rural women of Makwarani who participated in the study.There is a need for educational intervention to enhance knowledge about breast cancer, its risk factors and symptoms as well as breast diagnostic examination. The health awareness campaigns should be initiated at primary health level and community home-based carers within communities should be included in these campaigns so as to disseminate information.Breast cancer information should be accessible to everyone, particularly from the health information centres, through a visible display of posters, information leaflets and health education video clips or recorded health talks whilst clients are awaiting consultations in reception areas.Additional research is required to change the attitudes of women toward breast cancer and to investigate the various health belief models, as there are still women who believe in the traditional and spiritual dimensions of health and delay seeking help by going to a ‘special doctor’ as they do not understand the concept of speciality in the field of medicine.Women must be encouraged to practise breast cancer diagnostic examinations regularly. BSE is an economical, simple and basic procedure that can be integrated into all programmes of reproductive health such as adolescent health, pregnancy, post-partum and menopausal women.The participants’ level of knowledge about breast cancer was relatively low since the majority (69%) of the participants had never even heard of breast cancer before. This then would make them miss out on the practice of breast cancer screening methods and might also increase their chance of being diagnosed with breast cancer only at the later stages. A negative attitude was found amongst the participants as others still preferred going to traditional and spiritual healers for treatment and did not think that they have personal risk factors.Poor breast cancer screening was reported in the community since all the participants reported that no screening had ever been conducted in the community, which indicates that dissemination of health information is not working effectively since much information is acquired from the media rather than clinics and/or hospitals. The participants’ practices of breast cancer diagnostic methods were relatively low because only 5.3% had ever practised BSE or CBE or had a mammogram. Education about the importance of early detection in decreasing mortality rates might be of value in raising awareness about the various methods of early detection of breast cancer.


Osteoporosis, an indicator of significant bone loss, has been consistently reported among older breast cancer survivors. Data are limited on the incidence of osteopenia, an earlier indicator of bone loss, and osteoporosis in younger breast cancer survivors compared with cancer-free women.We prospectively examined bone loss in 211 breast cancer survivors (mean age at breast cancer diagnosis = 47 years) compared with 567 cancer-free women in the same cohort with familial risk for breast cancer. Multivariable-adjusted Cox proportional hazards models were used to estimate HRs and 95% CIs of osteopenia and/or osteoporosis incidence based on physician diagnosis.During a mean follow-up of 5.8 years, 66% of breast cancer survivors and 53% of cancer-free women reported having a bone density examination, and 112 incident cases of osteopenia and/or osteoporosis were identified. Breast cancer survivors had a 68% higher risk of osteopenia and osteoporosis compared to cancer-free women . The association was stronger among recent survivors after only 2 years of follow-up . A higher risk of osteopenia and osteoporosis was also observed among survivors aged ≤ 50 years, estrogen receptor-positive tumors, and those treated with aromatase inhibitors alone or chemotherapy plus any hormone therapy relative to cancer-free women.Younger breast cancer survivors are at higher risk for osteopenia and osteoporosis compared to cancer-free women. Studies are needed to determine effective approaches to minimize bone loss in this population. Osteopenia and osteoporosis, both systemic skeletal conditions associated with varying degrees of bone loss, are prevalent among postmenopausal breast cancer survivors, with prior reports of up to 80% experiencing loss in bone density . UntreatOsteopenia and osteoporosis are also prevalent in the general population. Among women aged ≥ 50 years in the United States, approximately 15.4% have osteoporosis and 51.4% have low bone density , 6. AmonFew epidemiologic studies have examined osteopenia and osteoporosis in breast cancer survivors relative to cancer-free women within the same cohort –10. One BRCA1/2 mutation, (3) a diagnosis of breast cancer at ≤ 40 years of age without a family history of breast cancer, or (4) a diagnosis of ovarian cancer at any age without a family history of ovarian cancer. Participants completed a baseline questionnaire so that information could be collected on a variety of demographic, lifestyle, and health-related factors, including detailed information on medical history and breast cancer treatment. Subsequent follow-up questionnaires have been completed every 3–4 years thereafter (> 92% have completed at least one follow-up questionnaire). Completion of the second and third follow-up questionnaires is ongoing.The BOSS study is an ongoing prospective cohort study that includes women and men with familial risk for breast and/or ovarian cancer . Particin = 1173). Women with a physician diagnosis of osteopenia or osteoporosis at baseline  or bisphosphonate use at baseline (n = 5) were excluded. We further excluded women with missing responses for osteopenia or osteoporosis on baseline (n = 1) or follow-up (n = 5) questionnaires. For this analysis, breast cancer survivors were defined as women diagnosed with breast cancer  within 5 years prior to enrollment. The comparison group was restricted to women with no prior history of cancer at baseline except nonmelanoma skin cancer or cervical carcinoma in situ. After these exclusions, 778 women (211 breast cancer survivors and 567 cancer-free) became our analytic study population.For the present prospective analysis, women were included if they completed a baseline questionnaire and at least one follow-up questionnaire through September 30, 2017  as well as stage and hormone receptor status . Breast cancer treatment was reported in baseline questionnaires, and details were confirmed by medical record review (96% confirmed). Treatment information included surgery  and adjuvant therapy . Detailed information on type of chemotherapy and hormone therapy was also collected. We classified cancer treatment into mutually exclusive categories of surgery only, hormone therapy alone, chemotherapy alone, and chemotherapy plus hormone therapy. Hormone therapy was further classified as tamoxifen or aromatase inhibitor use.Osteopenia and osteoporosis diagnoses were ascertained in baseline and follow-up questionnaires. In each questionnaire, participants were asked to indicate whether they had received a physician's diagnosis of osteopenia or osteoporosis and the date of that diagnosis. Incident cases of osteopenia and osteoporosis were identified on follow-up questionnaires. Our outcome of interest was a composite outcome that included incident osteopenia  and/or osteoporosis. Participants also reported whether they had ever had a bone density examination and the year of examination on both baseline and follow-up questionnaires.Information on covariates  was available from the baseline questionnaire. Bilateral oophorectomy at a young age was defined as both ovaries removed prior to age 45 years and based on self-report. We calculated age at bilateral oophorectomy from the date that the second ovary was removed. Medical procedures and screening examinations, including mammograms, pap smears, sigmoidoscopy, and colonoscopy, were also reported on both baseline and follow-up questionnaires.2), bilateral oophorectomy at age < 45 years , physical activity (MET-h/wk), smoking status , and alcohol use (g/d). To account for a small percentage of missing data (< 1% missing) in covariates, we imputed missing data with the most common category for categorical covariates and the median value for continuous covariates among cancer-free women.Baseline characteristics of breast cancer survivors and cancer-free women were compared with frequency distributions for categorical variables and means (SDs) for continuous variables. We used Cox proportional hazards models with age as the time scale to calculate HRs and 95% CIs. Women contributed person-time from the completion date of the baseline questionnaire to the date of osteopenia or osteoporosis diagnosis or until the end of the last follow-up through September 30, 2017, whichever occurred first. The proportional hazards assumption was assessed with log-log survival plots and Schoenfeld residuals; neither method indicated that the assumption of proportional hazards was violated. Confounders were identified a priori as variables that may be associated with both breast cancer incidence and osteopenia/osteoporosis. Multivariable (MV) models were adjusted for menopausal status , HRT use , BMI  and an exploratory analysis by Finally, to examine whether risk of osteopenia and osteoporosis varied by time since diagnosis, we used time since enrollment as the time metric and restricted survivors to women diagnosed with breast cancer within 1 year prior to enrollment. Models were then stratified by follow-up time (≤ 2 years and > 2 years), and heterogeneity was tested using the likelihood ratio test.p values ≤ 0.05 were considered statistically significant.Analyses were conducted using SAS version 9.4  and Stata version 14.0  software. All statistical tests were two-sided, and Age and age-adjusted baseline characteristics were compared in breast cancer survivors and cancer-free women Table . CompareDuring an average of 5.8 years of follow-up, 66% of breast cancer survivors and 53% of cancer-free women reported having a bone density examination, and there were 112 incident cases of osteopenia and/or osteoporosis (75% osteopenia only). The incidence rates for osteopenia and osteoporosis were 44 cases/1000 person-years among breast cancer survivors and 19 cases/1000 person-years in their cancer-free peers. Overall, breast cancer survivors had a 68% higher risk of osteopenia and osteoporosis than cancer-free women  (Table BRCA1/2 carrier status (data not shown).The risk of osteopenia and osteoporosis in breast cancer survivors stratified by age at diagnosis, menopausal status at diagnosis, and ER status was compared with that of cancer-free women Table . Breast Next, the risk of osteopenia and osteoporosis in breast cancer survivors stratified by treatment compared with cancer-free women was examined Fig. . Breast p value for heterogeneity was not significant (p = 0.44)  and a nonsignificant 85% increased risk of osteopenia and osteoporosis after 2 years of follow-up , although the To our knowledge, this is the first study to prospectively assess risk of osteopenia and osteoporosis in young and recently diagnosed breast cancer survivors compared with their cancer-free peers in a familial high-risk cohort. In this prospective study, the incidence of osteopenia and osteoporosis was almost twofold higher in breast cancer survivors than in cancer-free women over an average of 5.8 years of follow-up. The results were also similar when we excluded women with premature menopause, suggesting an effect of cancer treatment on bone health that is independent of early menopause. Breast cancer survivors who were younger, had ER-positive tumors, received aromatase inhibitors alone, or received combined chemotherapy with aromatase inhibitors or tamoxifen had a higher risk of osteopenia and osteoporosis than cancer-free women. Importantly, this was after accounting for age, menopause, and other risk factors for bone loss.The majority of prior studies have examined bone health in breast cancer survivors without a cancer-free comparison group –20. SeveThe second study was a retrospective registry study in the Cancer Genetics Network conducted to assess early and late effects of cancer treatment . In thisThe third study was conducted among the U.K. General Practice Research Database to examine long-term health outcomes among older cancer survivors and cancer-free individuals  . The autThe most common cause of bone loss in women is menopause and aging. Aging is associated with greater bone resorption and less bone formation, whereas menopause induces accelerated bone loss due to lowering levels of endogenous estrogen . TherefoWe observed a greater than twofold increased risk of osteopenia and osteoporosis in women diagnosed with ER-positive tumors, which is likely due to hormone therapy rather than to differences in tumor biology. This is supported by the fact that the highest risk of osteopenia and osteoporosis was found among breast cancer survivors treated with aromatase inhibitors alone and chemotherapy plus aromatase inhibitors. These findings are in agreement with the underlying biology of aromatase inhibitors , as wellThe strengths of this study include the prospective study design, direct comparison with cancer-free women from the same cohort, and detailed information on cancer treatment. There are also several limitations to our analysis. First, our sample size may have limited our power to detect small to moderate associations. Second, osteopenia and osteoporosis incidence was ascertained on the basis of self-reported physician diagnosis and may be susceptible to misclassification. However, 96% of women who reported a diagnosis of osteopenia or osteoporosis also reported receiving a bone density examination. Third, breast cancer survivors may have increased surveillance for bone health and therefore may be more likely than cancer-free women to be diagnosed with osteopenia and osteoporosis. In our cohort, breast cancer survivors were slightly more likely than cancer-free women to have had a bone density examination at baseline  and in follow-up (66% vs. 53%). However, sensitivity analyses to further reduce the possibility of undetected prevalent or incident cases found that results were similar when restricted to women with bone density examinations prior to baseline  and during follow-up . Furthermore, both women with and without breast cancer in our cohort underwent close monitoring for their health. Specifically, overall health screening history at baseline was similar in breast cancer survivors compared with cancer-free women . Finally, our results may not be generalizable to other populations, because our study population was composed predominately of white and highly educated women at high risk for breast cancer. However, we believe that the underlying biology of cancer treatment and its effect on bone health are likely similar across ethnicities. The homogeneity of our study population also improves the internal validity of this study because it reduces the influence of potential unmeasured factors.In summary, our results demonstrate that incident osteopenia and osteoporosis are significantly higher in young breast cancer survivors within a few years of diagnosis than in cancer-free women and that risk varies by cancer treatment. These findings provide support for a baseline evaluation of bone density and fracture risk assessment close to breast cancer diagnosis, particularly among young survivors being treated with combined chemotherapy and hormone therapy, so that prevention strategies and appropriate monitoring can be implemented early. Future studies are needed to address the frequency of monitoring in breast cancer survivors by specific age and treatment groups.


Hormone replacement therapy (HRT) remains the most effective treatment for menopausal symptoms and has been shown to prevent bone loss and fracture. The progestogen is added to provide endometrial protection in women with an intact uterus. After the publication of the initial WHI  results in 2002 reporting an overall increased risk of breast cancer, many women discontinued HRT. Despite the re-analysis of the results by subgroups of patients and updates with extended follow-up, much controversy remains, which we will analyze later in the text. Different types of estrogen or progestogen, as well as different formulations, doses, and durations, may play a role in HRT’s effects on breast tissue. Evidence states that conjugated equine estrogen (CEE), compared to estro-progestin therapy, shows a better profile risk  and that, among different type of progestins, those structurally related to testosterone show a higher risk . Chronic unopposed endometrial exposure to estrogen increases the risk of endometrial hyperplasia and cancer, whereas the association with progestins, especially in continuous combined regimen, seems to reduce the risk . HRT was also associated with a protective effect on colon cancer risk . Data about ovarian and cervical cancer are still controversial. The estrogen deprivation following the menopause status may impact on several aspects of health and quality of life determining vasomotor symptoms (VMS), genitourinary syndrome of menopause (GSM), cognitive dysfunction, sleep disturbance, and changes in bone metabolism. Hormone replacement therapy (HRT) remains the most effective treatment for VMS and GSM and has been shown to prevent bone loss and fracture. A progestogen is added to provide endometrial protection in women with an intact uterus.Despite this high prevalence of symptoms, it has been claimed that only 10–15% of women seeking medical help because of fear of the treatment and diffidence of clinicians in prescribing therapy [After the publication of the initial WHI  results in 2002 reporting an overall increased risk of breast cancer, heart disease, stroke, and venous thromboembolism, many women discontinued HRT. HRT prescriptions in the United States rapidly decreased over one year by approximately 40% down to 20% . In a EuThe WHI remains the largest randomized controlled trial of HRT, but it only compared conjugated equine estrogens (CEEs) and medroxyprogesterone acetate (MPA) versus placebo in patients with an elevated average age (44% between 60 and 69 years old). The North American Menopause Society, on the contrary, suggests starting HRT before than 60 years or within 10 years of menopause onset because the benefit-risk ratio is most favorable. The design of the WHI led to an overestimation of the risks for women aged less than 60 years and at low risk of cardiovascular disease and breast cancer. Despite the reanalysis of the results by age and years since menopause and the updates with extended follow up, much controversy remains, which we will analyze later in the text. The cancer risk of HRT differs depending on many factors, so treatment should be individualized to identify the most appropriate dose, regimen, duration, and route of administration, using the best available evidence, with periodic reevaluation of the woman’s benefit-risk profile [In a study published in 2017 by Simin et al., an increased risk of any cancer of 9% appears among hormone replacement therapy ever-users . The risk results lower among estrogen-only use, and the risk increases with age, reaching a peak in women ≥70 years old. Stratifying by tumor type, the risk varies among female reproductive organ cancers ; on the contrary, the risk of all gastrointestinal tract cancer is decreased by 10% in HRT users . In the analysis by subgroups study, evidence shows that the risk changes depending on the type of formulation and regimen of therapy [Breast cancer is the most frequently diagnosed cancer and is the leading cause of cancer-related death in women. It affects up to one of eight women who survive up to the age of 85 years in Western countries. The disease reaches a peak of incidence in the 50–59 years age range . The WHI study results suggested a breast cancer increase in HRT users , but no data about mortality were reported because of a short follow-up period (mean of 7.9 years). This risk, in absolute terms, corresponds to 9 additional breast cancers per 10,000 women using estrogen-progestin therapy for five or more years . Breast The North American Menopause Society (NAMS) position statement of 2017 asserts that different types of estrogen or progestogen, as well as different formulations, doses, durations, times of initiation, and patient characteristics, may play a role in HRT’s effects on breast tissue. Other risk factors need to be also considered in prescribing HRT, such as BMI, cardiovascular diseases, and lifestyle factors including smoke, physical activity, and alcohol intake.p = 0.02), especially in infiltrating ductal carcinoma . No differences emerged for receptor-positive and -negative tumors. Results also showed a reduction in deaths for breast cancer in the CEE group . However, the risk reduction was restricted to patients without benign breast disease (p = 0.01) and a family history of breast cancer (p = 0.02) [Anderson et al. randomized women aged between 50 and 79 years with prior hysterectomy to conjugated equine estrogen (CEE) therapy versus placebo. Patients receiving estrogen alone had a significant reduction in overall breast cancer incidence after an extended follow up of 11.8 years  .The update of WHI trial outcomes published in 2013 with extended post-intervention follow-up of 13 years analyzed 27,347 patients treated with conjugated equine estrogen  with medroxyprogesterone acetate  or CEE alone. During the intervention phase, HR for breast cancer was 1.24 (CI 1.01–1.53) with CEE-MPA use and 0.79 (CI 0.62–1.02) with CEE use. Estrogen-progestin use significantly increased the risk of breast cancer during cumulative follow-up , even if a year-to-year reduction after stopping was observed. By contrast, the use of unopposed estrogen seemed to significantly reduce risk during cumulative follow-up time  in patients with an intact uterus ,13,14.Not all treatments are equal, and in the literature, some authors suggest a lower impact of transdermal estrogens rather than oral ones because of a difference in levels of estrone in breast tissue and serum. However, prospective randomized trials comparing the effects of oral and transdermal estrogens on breast cancer risk are lacking. In a sub-analysis of the Million Women Study, no statistically significant differences were found in relation to the route of administration  . In combined estro-progestin therapies, the estrogen component is usually estradiol, but preparations may contain a large variety of progestins that may impact on breast cancer risk. Large epidemiological studies, such as the French E3N Study  and CeciTo avoid the proliferative effect of estrogen on breast tissue and the endometrium, a new class of molecules has been developed. TSECs (tissue-selective estrogen complexes) are a combination of estrogens and SERMs (selective estrogen receptor modulators): CE 0.45 mg plus Bazedoxifene 20 mg has been available in Italy since 2015. Bazedoxifene guarantees a safety profile on endometrium and operates as an ER antagonist and, in the breast, antagonizes estrogen-stimulated cell proliferation. This combination demonstrated effects on bone mineral density and VMS with a significant improvement in vaginal dryness, dyspareunia, and sexual function compared to placebo. In addition, Bazedoxifene does not affect age-related changes in breast density, suggesting a possible better profile on breast cancer risk compared to estro-progestin therapy, even if data from large randomized trials are lacking ,17.Breast cancer risk is also influenced by the duration of treatment and by the interval between menopause and the beginning of HRT. The increased risk is generally observed for five years use or longer and significantly decreases five or more years after cessation of HRT use . Beral ep < 0.001). Estrogens alone have a lower impact on mammography density. Mammography density changes with age and in response to exposure to hormones. Increased breast density may influence mammographic interpretation and is more strongly associated with the risk of aggressive breast tumor subtypes, especially among postmenopausal women using combined estrogen plus progesterone therapy. The mechanism for the association between breast cancer risk and breast density is unknown, but recently, it was postulated to result from an increase in tissue synthesis of estrogen from aromatase in dense tissue ,20. In tIn support of the association between HRT and breast cancer risk, in a first analysis, the decline in breast cancer incidence starting in 2003 was attributed to HRT prescription reduction . WachtelChronic unopposed endometrial exposure to estrogen increases the risk of endometrial hyperplasia and cancer. Progestin association is important in ensuring endometrial protection in women with an intact uterus. The previously cited study of Watchel et al. that analyzed the relationship between the HRT prescription and cancer incidence, highlights an increase in the incidence rate of endometrial carcinoma after the dramatic drop in HRT prescription consequent to WHI result publication: the 2012 rates were 1.46 times higher than those in 2001, whereas other study found only a change in trend for mortality but not in the incidence .In the WHI trial, a small non-significant reduction in endometrial cancer risk was observed with estrogen plus progestin use in a continuous combined regimen  compared to a cyclic regimen. The reduction became significant in the post-intervention phase lasting up to 2010  and after cumulative follow-up of 13 years  . The MilThe influence of estrogen in promoting the development of epithelial ovarian cancer is still controversial. The WHI study did not find an association of CEE+MPA use with an increased risk of ovarian cancer after a mean of 5.6 years  and neither after a 13 years cumulative follow-up  . The stuA study published in 2017 evaluated the association between HRT and serous borderline tumors: Compared with non-users, women using HRT had a statistically significant 32% increased risk of developing serous borderline tumors without a correlation with the duration of use .In literature, very few studies evaluate HRT and cervical cancer risk. In a large study on 308,036 women recruited in the EPIC (European Prospective Investigation into Cancer and Nutrition) cohort, a reduction in cervical cancer risk among peri- and post-menopausal women using HRT was found , and the effect became stronger with longer duration of use . The risk reduction of cervical cancer could be overestimated: One possible bias is that women taking HRT are more frequently screened than non-users, and they are being diagnosed and treated earlier. The intrinsic mechanisms that might explain the biology of these potential associations are currently unknown. Data from HPV transgenic mouse models suggest that estrogens promote cervical carcinogenesis and progesterone inhibits cervical cancer [Although the WHI trial identified greater health risks than benefits among women in the HRT-users group, the use of estrogen plus progestin was associated with a significant decrease in the incidence of colorectal cancer. Women in the hormone group had fewer cases of cancer of all histologic types . In comparison between women taking CEE alone and placebo, no difference was found in the incidence of colorectal invasive cancer, thus the protective effect may be attributed to progestins. In the decade following the publication of the WHI trial, other studies confirmed these data. Predominantly, increasing benefits for CRC risk reduction was seen in current and recent HRT users. Questions remain as to how long the CRC prevention benefits of HRT persist after discontinuation of these therapies. In post-intervention and 13 years cumulative follow up of WHI study, the HRs were neutral [p = 0.005) and also a reduction in death from colorectal cancer  and all-cause mortality  in HRT users [A study by Simin et al. published in 2017 assessed that HRT ever-use is associated with a 10% decreased risk of all gastrointestinal cancers; in particular in liver and colon cancers, the reduction of risk is statistically significant  [RT users . A possiRT users .Although there are protective effects, the balance of risks and benefits does not make HRT suitable for primary prevention in the general population.


There are known short-term benefits in breastfed infants versus bottle-fed infants in terms of lower risks of infection and obesity in infancy and childhood, but the long-term effect on the risk of adult cancers is unclear. In a cohort of 1 in 4 UK women born in 1935–1950 we report the incidence of adult cancers in relation to having been breastfed in infancy. In median year 2001 (interquartile range 2000–2003) 548,741 women without prior cancer reported whether they had been breastfed. There was 81% agreement between women’s report of having been breastfed and information on breastfeeding recorded when they were 2 years old. Participants were followed by record-linkage to national cancer registration, hospital admission and death databases. Cox regression yielded adjusted relative risks (RRs) and 95% confidence intervals (CI) by having been breastfed or not for eight cancer sites with > 2000 incident cases and for related conditions, where appropriate. Of the eight cancers examined here one association was highly statistically significant: an increase in colorectal cancer incidence among women who had been breastfed versus not . To investigate further the findings for colorectal cancer, we studied eight other gastro-intestinal conditions, and found increased risks in women who had been breastfed versus not for benign colorectal polyps  and for appendicitis . The greater risks of adult colorectal cancer, colorectal polyps and appendicitis associated with having been breastfed in infancy suggest possible long-term effects of infant feeding practices on the gastrointestinal tract. Further studies are required to clarify this novel association. There are known short-term benefits in breastfed infants versus bottle-fed infants in terms of lower risks of infection and obesity in infancy and childhood , and somhttp://www.millionwomenstudy.org).In 1996–2001 about 1 in 4 UK women born in 1935–1950 was recruited into the prospective Million Women Study . At recrA sample of Million Women Study participants had, at the time of their birth in March 1946, been included in a UK-representative birth cohort study  . When th2), smoking , strenuous exercise , and alcohol consumption   and confidence intervals (CIs) for cancer and for selected other conditions in women who reported having been breastfed versus not. All analyses were stratified by single year of birth and single year at baseline, and using time since baseline as the underlying time variable. Unless otherwise specified, RRs were also adjusted for area deprivation   using information obtained through linkage to the National Health Service Bowel Cancer Screening Programme in England (NHSBCSP) [The Million Women Study is funded by Medical Research Council UK and Cancer Research UK. The funders played no role in the collection, analysis, and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication.Overall 72%  of eligible women without prior cancer reported that they had been breastfed as babies. Table p < 0.0000001; Fig. p > 0.05). For breast cancer there was no association overall  or when analyses were restricted to women whose mother had had breast cancer .During 9.8 million person-years (12.7 years per woman) of follow-up, 57,998 incident cancers were registered across the eight most common cancer sites. After stratification by single year of birth and single year at baseline and adjustment for 14 additional factors, women who had been breastfed had a significantly higher risk of colorectal cancer , nor when women who had been invited for bowel cancer screening were excluded from the analysis . The risk was significantly elevated separately both for colon cancer and for rectal cancer  and appendicitis  but less likely to have had inflammatory bowel disease . These associations with risk of benign colorectal polyps, appendicitis, and inflammatory bowel disease were not sensitive to adjustment by potential confounding factors   and the Strengths of this study include its large size, virtually complete follow-up through routinely collected NHS databases, and ability to adjust for many potential confounding factors, including smoking, body mass index, and diet. The prospective design minimises possible recall bias between those with and without incident cancer, but as in other observational studies the possibility of confounding by unmeasured or unknown factors, for example childhood diet characteristics, cannot be excluded. Due to the age restrictions in recruitment and the exclusion of individuals who had incident cancer or died prior to study baseline, as required by the prospective design, these findings cannot be generalised to younger ages or extrapolated to lifetime cancer risks. Selection bias may arise if we have not controlled for other determinants of selection into the study that are also determinants of colorectal cancer risk. To explain our findings, any such bias would have to be due to the equivalent of an unknown factor that is an important, independent cause of colorectal cancer, but not of other cancers, which is also a cause of selection into the study but is essentially uncorrelated with the other factors for which we have controlled. This seems unlikely but again cannot be categorically ruled out. We were unable to investigate associations with the length of breastfeeding or with other infant feeding practices (such as exclusive breastfeeding) in this cohort. It is also unclear if these findings could be generalised to other populations where infant feeding practices differ.There are definite and important benefits of being breast-fed, which would far outweigh any increased risk of colorectal cancer and colorectal polyps in adulthood. Nevertheless the evidence presented here suggests possible long-term effects of infant feeding practices on the risk both of colorectal cancer and of colorectal polyps. This could imply novel mechanisms of colorectal carcinogenesis, but further studies are required to reproduce and to clarify this novel association.


Clinical Treatment Score post-5 years (CTS5) is a promising prognostic tool to evaluate late distant recurrence (DR) risk for breast cancer after 5-year adjuvant endocrine therapy.Among 560 postmenopausal women with pathological stage I–III estrogen receptor-positive (ER+) primary breast cancer, 383 women who had received 5-year adjuvant endocrine therapy without any recurrence at 5 years after surgery were included in this study. The CTS5 was calculated for each patient using a previously published formula, and the patients were stratified by their CTS5 values into the low-, intermediate- and high-CTS5 risk groups.According to the CTS5, 205 (53.5%), 106 (27.7%) and 72 (18.8%) patients were classified into the low-, intermediate-, and high-CTS5 risk groups, respectively. A higher ER expression level was significantly associated with the low CTS5. The increased administration of adjuvant chemotherapy was significantly associated with a high CTS5. The occurrence of DR was higher in the intermediate and high CTS5 groups than in the low CTS5 group. The DRFS in the low CTS5 risk group was significantly better than that in the intermediate- or high-risk groups. In the ER-high or HER2-negative (HER2−) group, the DRFS in the low-risk group was significantly better than that of the intermediate- or high-risk groups. However, in the low-ER or HER2-positive group, there was no significant difference in DRFS among the three risk groups.In postmenopausal women with ER+ breast cancer, low CTS5 was considered to be associated with a very low risk of late DR. Thus, extended endocrine therapy may be unnecessary for patients with low CTS5 scores. Extended endocrine therapy should be offered for patients with intermediate or high CTS5 scores, especially those with high-ER and HER2− breast cancer. Breast cancer is one of the most common cancers worldwide . The incN = 4735) and BIG 1-98 (N = 6711) trials, was used. The CTS5 is expected to be used to predict the risk of late DR and to select the patients for extended therapy.The Clinical Treatment Score post-5 years (CTS5) was developed to estimate residual risk of late distant recurrence (DR) after 5 years of endocrine treatment . To creaIn the present study, we retrospectively evaluated the clinical significance of the CTS5 score in predicting the risk of late DR, after 5-year adjuvant endocrine therapy without any recurrences, in postmenopausal women with ER+ early breast cancer who were treated in our own department.A total of 1253 patients with pathological Stage I–III primary breast cancer, who underwent surgery without neoadjuvant systemic therapy in the Department of Breast Oncology, National Hospital Organization Kyushu Cancer Center between 2003 and 2009, were screened for the present study. Among them, 825 were postmenopausal women, and 560 had ER+ breast cancer. Finally, 383 postmenopausal women with ER+ breast cancer who had received 5-year (> 4.5 years) adjuvant endocrine therapy without any recurrence at 5 years after surgery were included in this study ], which is the final model induced by the combined ATAC and BIG 1-98 set [The CTS5 was calculated using the previously published formula . This CT1-98 set . The patχ2 tests. Distant recurrence-free survival (DRFS) was defined as the time from the date of curative surgery to the detection of DR. We used the Kaplan–Meier method and Cox proportional hazards regression was used to perform the survival analysis. P values of < 0.05 were considered to indicate statistical significance.All statistical analyses were performed using the JMP software package . The associations between the clinicopathological characteristics were assessed using The characteristics of the patients included in this study are shown in Table p = 0.0113) and adjuvant endocrine therapy with selective estrogen receptor modulator (SERM) alone (p = 0.0387) were significantly associated with a low CTS5. An increased administration of adjuvant chemotherapy (p < 0.0001) was significantly associated with a high CTS5. On the other hand, there were no significant associations between the CTS5 risk groups and age, the expression of PgR or the HER2 status.The relationships between the CTS5 and the clinicopathological characteristics are shown in Table p = 0.0353). The incidence rates of DR at 5–10 years and later than 10 years after surgery in the low, intermediate and high CTS5 risk groups was 1.5% (n = 3) and 0.5% (n = 1), 3.8% (n = 4) and 2.8% (n = 3), 7.0% (n = 5) and 4.2% (n = 3), respectively  CTS5 groups were significantly poorer in comparison to the low CTS5 group  years. The occurrence of DR in the intermediate and high CTS5 groups was higher in comparison to the low CTS5 group p = 0.053. The i years. Tp = 0.0019)- and high -CTS5 groups were significantly poorer in comparison to the low-CTS5 group - and high -CTS5 groups were significantly poorer in comparison to the low-CTS5 group  . ProsignThe strength of this study is that these data are from a single institution and that the follow-up time was significantly long, with high-quality follow-up and updated clinical data. However, the present study is also associated with several limitations. All data are retrospective, the sample size was relatively small, and the number of events for DR was also relatively small, which made it difficult to draw a distinctive conclusion.In conclusion, based on the results obtained from our analysis in postmenopausal women with ER+ breast cancer, tumors with a low CTS5 risk score have a very low risk of late DR; while, intermediate- and high CTS5 risk scores were associated with late DR after 5-year adjuvant endocrine therapy. The extension of endocrine therapy is considered to be unnecessary for patients with low CTS5 scores. For patients with intermediate or high CTS5 scores, extended endocrine therapy should be offered, especially in the patients with high-ER and HER2− breast cancer.


Is ductal carcinoma in situ (DCIS) associated with lifetime risk of dying of breast cancer?In this cohort study of 144 524 women treated for DCIS, 1540 women died of breast cancer, while based on national incidence and case-fatality rates, the expected number of deaths from breast cancer was 458. Women with DCIS had a 3-fold increased risk of dying of breast cancer compared with women without DCIS.These findings suggest that the current treatment of DCIS does not eliminate the risk of breast cancer mortality. This cohort study examines risk of dying of breast cancer among women with ductal carcinoma in situ compared with women in the general population. It is not clear to what extent a diagnosis of ductal carcinoma in situ (DCIS) impacts a woman’s lifetime risk of dying of breast cancer. Under ideal circumstances, treatment will eliminate the risk of invasive ipsilateral recurrence and prevent subsequent mortality from breast cancer. The risk of dying of breast cancer after a diagnosis of DCIS had not been compared with that of women without cancer in the general population.To determine the risk of death from breast cancer in a large cohort of patients treated for DCIS and to compare the risk with that of women in the general population.This cohort study included data for women who had first primary DCIS diagnosed between 1995 and 2014 from the Surveillance, Epidemiology and End Results (SEER) registries database. Women with DCIS underwent surgical treatment, and approximately half also received radiotherapy. These women were followed from the date of DCIS diagnosis until death from breast cancer or date of last follow-up. Women in the general population without breast cancer were analyzed as controls. Follow-up information was available up to December 2016. The data were analyzed in March 2020.Patients with DCIS who underwent surgical treatment.Breast cancer death was the main outcome. Standardized mortality ratios were estimated by comparing deaths from breast cancer among women diagnosed with DCIS with expected deaths from breast cancer among women in the general population who did not have cancer. Expected probability of death from breast cancer in the general population was calculated by an incidence-based mortality approach using standardized SEER-based incidence and case-fatality rates. Probability of breast cancer death was estimated based on the assumption that a cancer-free control was cancer free on the date the woman with DCIS was diagnosed and was studied until the end of follow-up.A total of 144 524 women diagnosed with first primary DCIS were included . There were 1540 deaths from breast cancer in the cohort. Based on SEER-based incidence and case-fatality rates, 458 breast cancer deaths were expected in an equivalent number of cancer-free women from the general population with equal follow-up. The standardized mortality ratio for death from breast cancer among women with DCIS was 3.36 . The elevated risk of death persisted more than 15 years after diagnosis.In the population studied, the risk of dying of breast cancer was increased 3-fold after a diagnosis of DCIS. This suggests that our current treatment focus on preventing invasive recurrence is insufficient to eliminate all deaths from breast cancer after DCIS. The 2 goals of treatment are to prevent invasive ipsilateral recurrence and to prevent death from breast cancer. It is proposed that death from breast cancer following a diagnosis of DCIS is a consequence of the intervening invasive breast cancer and that control of invasive ipsilateral recurrence is a critical step in preventing death from breast cancer. Treatment options include surgical procedures , radiation, and hormonal therapy.Under ideal circumstances, all local invasive recurrences would be prevented, as would all deaths from breast cancer following DCIS. If the absolute risk of dying of breast cancer for women with DCIS fell below that of the general population, this would be a strong argument in favor of current treatment protocols for DCIS and an endorsement of screening in general. On the other hand, if the mortality rate from breast cancer among women with DCIS was found to be much higher than that of the general population, this would require reevaluation of the underlying 2-step model as well as reconsideration of the current treatment paradigm. In this study using Surveillance, Epidemiology and End Results (SEER) registry data, we estimated the risk of dying of breast cancer after a diagnosis of DCIS and compared this with the risk of a woman in the general population who is breast cancer–free at the time of follow-up.STROBE) reporting guideline.This cohort study was deemed exempt from research ethics board approval and informed consent by Women’s College Hospital because study participants were ascertained through a deidentified and publicly available database. Our study adheres to the Strengthening the Reporting of Observational Studies in Epidemiology . We excluded cases with microinvasion (7.7% of DCIS cases). Among the cases classified as Tis, we excluded those associated with lobular carcinoma in situ, nonepithelial histological presentations, Paget disease of the nipple, or diffuse DCIS. We also excluded cases with unknown laterality or no surgical intervention on the primary tumor. We excluded cases diagnosed in women younger than 25 years or aged 80 years or older.We used the SEER*Stat version 8.3.6 to conduct a case-listing session and retrieved all cases of first primary DCIS (stage 0) diagnosed between 1995 and 2014 in the SEER18 registries research database (November 2018 submission). We selected all cases with the American Joint Committee on Cancer primary tumor classification survival time months. The SEER*Stat program estimates survival time by subtracting the date of diagnosis from the date of last contact (the study cutoff). The study cut-off date was December 31, 2016. The data were analyzed in March 2020.For each case, we retrieved information on the year of breast cancer diagnosis, age at diagnosis, median annual household income, race/ethnicity, tumor laterality, tumor size, tumor grade, estrogen receptor (ER) status, progesterone receptor (PR) status, use of radiotherapy, and type of surgical treatment. Measures in the follow-up period included ipsilateral invasive recurrence, contralateral invasive breast cancer, a new non-breast primary cancer, death, and cause of death. We assessed the vital status at the time of last follow-up. We extracted the information on survival time from the variable Women with DCIS were followed from DCIS diagnosis until death from breast cancer, death from another cause, loss to follow-up, 20 years after DCIS diagnosis, or December 31, 2016, whichever occurred first. We counted the observed number of deaths from breast cancer for the cohort.To estimate the expected number of deaths from breast cancer in the cohort we calculated the expected probability of death from breast cancer for each of the women with DCIS under the assumption that she was cancer-free at the time of DCIS. That is, if a woman received a diagnosis of DCIS at age 50 years and was followed until age 60 years, we asked: what is the probability that a women without cancer at age 50 years would develop and die of breast cancer by age 60 years? We calculated the expected probability of death from breast cancer using an incidence-based mortality approach. We acquired age- and calendar year–specific breast cancer incidence rates from the SEER incidence registry between 1995 and 2014. We derived age- and calendar year–specific breast cancer mortality rates by year of follow-up among women diagnosed with a first primary invasive breast cancer (stage I to IV) between 1995 and 2014. Calendar year–specific values were defined based on 4 equally sized calendar year intervals: 1995 to 1999, 2000 to 2004, 2005 to 2009, and 2010 to 2014.For each woman in the DCIS cohort, we calculated an expected probability of death from breast cancer for a woman in the general population who was cancer-free and with an equal follow-up time. To calculate the expected probability of death within a given interval we multiplied the age- and year-specific incidence rates of breast cancer by the breast cancer mortality rates, which are conditional on age at diagnosis, year of diagnosis, and time since diagnosis. To estimate the total expected number of breast cancer deaths in the cohort we summed the individual probabilities of death from breast cancer for each of the women in the cohort.We compared the observed number of deaths to the expected number of deaths as a standardized mortality ratio (SMR) for the entire cohort and for subgroups defined by age, race/ethnicity, and surgical treatment. We performed bootstrap sampling (1000 sampling iterations) to obtain 95% CIs for the SMR values.P values were 2-sided, and statistical significance was set at P < .05.Data were analyzed using SAS statistical software version 9.4 (SAS Institute). Among the cohort of 144 524 women with DCIS , 1540 women died of breast cancer . The earBased on national incidence and case-fatality rates, the expected number of deaths from breast cancer in the cancer-free cohort was 458 deaths. This comparison assumes that each woman was cancer-free at the time of DCIS diagnosis in the cohort of women with DCIS. The SMR for death from breast cancer given a diagnosis of DCIS was 3.36  .The SMR for women younger than 40 years was 11.95 , for women aged 40 to 49 years was 4.15 , for women aged 50 to 59 years was 2.82 , for women aged 60 to 69 years was 2.65 , and for women aged 70 to 79 years was 3.72  . The SMRAll women with DCIS underwent surgical treatment, and 68 118 women (47.1%) also received radiotherapy. Among women not treated with radiotherapy, the SMR was 4.12  for those treated with unilateral mastectomy and 4.14  for those treated with bilateral mastectomy . Among wThere were 1540 women who died of breast cancer in the cohort. Of these, 703 (45.7%) experienced an ipsilateral invasive recurrence or contralateral invasive breast cancer in the interval between DCIS and death from breast cancer. Among women who died, 428 (27.8%) were known to have undergone a mastectomy.The annual mortality rate from breast cancer over the entire follow-up period was 0.12% per year. The mortality rate increased for the first 10 years of the follow-up period and was sustained through years 15 through 20 . The cumIn this cohort study, we found that the risk of dying of breast cancer in the 20-year period following a diagnosis of DCIS was approximately 3-fold greater than that of a woman of the same age who did not have breast cancer. Our SMR reflects the relative risk of dying of breast cancer in the 20-year period following the diagnosis of DCIS and may not be an accurate reflection of the lifetime increase in the risk of dying of breast cancer after DCIS. Ideally, we would follow all the patients in the cohort until age 80 years to get the most accurate SMR, but we had limited follow-up, and most of the patients were younger than age 80 years in 2016. The mean age at diagnosis in the cohort was 57.4 years, and the mean follow-up time was 9.2 years. It may be that the risk of death from breast cancer tapers off with time from diagnosis. If so, the SMR reported here should not be extrapolated beyond the actual period of follow-up. However, as is seen in 3 While this number is accurate in the appropriate context, in the earlier study, we underestimated the SMR because women in the comparison group may have had breast cancer diagnosed prior to the age at which DCIS was diagnosed in the exposed women. In this study, we restricted our comparison group to women who were cancer-free at the age of diagnosis for women in the DCIS group; consequently, there should be fewer deaths from breast cancer in the controls in this study than in our previous study. This study design allows for a better representation of the impact of a new diagnosis of DCIS on subsequent death from breast cancer. A third approach would be to compare the risk of death from breast cancer in women with DCIS with the risk in women of the same age after a screening mammogram with negative results. In this study, the control arm was derived from observed breast cancer incidence and case-fatality rates, and we do not have screening histories. In this sense, the SMR for death from breast cancer in a woman with screening-detected DCIS is an underestimate of the impact of having screening-detected DCIS, compared with having a mammogram with negative results. Several other studies have also reported an increased risk of breast cancer death following a diagnosis of DCIS compared with the risk in the general population.6 In 2000, Ernster et al4 reported a 2-fold increased risk of dying of breast cancer for patients with DCIS diagnosed from 1984 to 1989 in the SEER registry, compared with the general population . In the Swedish Cancer Registry,5 patients with DCIS diagnosed from 2000 to 2011 were 3-fold as likely to die of breast cancer as women in the general population . In the Netherlands Cancer Registry,6 patients with DCIS diagnosed from 1989 to 2004 (followed for median of 9.8 years) were 3-fold as likely to die of breast cancer than women in the general population . In a subgroup analysis of patients who did not develop a subsequent invasive breast cancer in the follow-up period , the risk of dying from breast cancer after DCIS was still 2-fold that of the general population . The SMRs reported in these studies are comparable to those reported in this study; however, they are also likely to be underestimates of the mortality ratios because the comparison group were all women  rather than women who were initially cancer-free.Using an earlier version of the SEER DCIS cohort, we previously reported a relative risk of dying of breast cancer of 1.8 for DCIS patients , compared with the general population.7 focus on patients with low-risk DCIS and have too few patients to evaluate mortality differences between those who undergo surgical treatment and those who do not. Given the similar SMRs for women with mastectomy and those with lumpectomy, it is possible that the mortality for women who had neither form of surgical treatment would be similar to these.To our knowledge, to date there is no empirical evidence that surgical treatment of DCIS reduces the subsequent mortality from breast cancer. Studies that offer a watch and wait approach, such as the Comparison of Operative versus Monitoring and Endocrine Therapy trial,In this cohort study, breast cancer death was the principal end point. We did not include invasive recurrence as a primary end point because this information is not necessary to estimate the SMRs. Moreover, we are more confident about the diagnosis of DCIS and the date and cause of death in the SEER database than we are about local recurrences and distant recurrences that were not recorded. Furthermore, some of the deaths might have been from contralateral breast cancer, but the SMR associated with unilateral and bilateral mastectomy were similar.This study is not designed to generate information on clinical managements of DCIS. The lifetime risk of death following DCIS is approximately 3%, and this level of risk is too low to recommend chemotherapy. There were some women  for whom the mortality rate approached 10%, and at this level, chemotherapy might be considered. Ideally, we would be able to identify the few women with DCIS with metastatic potential from the outset and offer them systemic therapy. The current approach is to identify women with a high risk of local recurrence and treat them with radiotherapy initially and with chemotherapy at time of invasive cancer according to the clinical profile. Given that not all women who die of cancer following DCIS experience a local recurrence, the impact of this approach is necessarily limited. It is challenging to identify patients with DCIS who are at high risk of dying; it might be possible to address this question using a case-control approach and compare pathological specimens and molecular expression and other demographic criteria for those who died and those who survived.8 The difference in the SMR between mastectomy and lumpectomy should not be interpreted in favor for lumpectomy. In general, mastectomy patients are younger and have more extensive disease.8 Among those with mastectomy, the risk of death was similar for women with bilateral mastectomy and unilateral mastectomy. From this, we interpret that incident contralateral cancers were unlikely to contribute in large part to the overall number of deaths from breast cancer.This study has some limitations. Treatment was not assigned at random, and we report associations but cannot make causal inferences based on observational data. All patients in this study underwent surgical treatment. We did not attempt to compare the relative benefits of various forms of surgical treatment in this cohort—to do so would have required fine matching, and we have done this previously.It may be that treatments have improved in the past decade and that in the future, mortality rates will be lower than the rates observed in this study. Unfortunately, the use of tamoxifen and other antihormonal therapies is not recorded in SEER. Also, we did not include an untreated group of patients with DCIS for comparison.9 There may be some residual misclassification, such that patients who died of breast cancer may have had an overrepresentation of microinvasion, but we have used the standard definitions and reporting practices available through SEER.We excluded women with microinvasion from the study cohort .This cohort study found that women with DCIS had a 3-fold increased risk of death from breast cancer after surgical treatment. The SMR was lower among women who received lumpectomy plus radiation compared with women who received lumpectomy alone. The rate of breast cancer death was nearly 12-fold higher among women diagnosed with DCIS before age 40 years and 7-fold higher in Black women diagnosed with DCIS compared with the general population.


The World Cancer Research Fund/American Institute for Cancer Research (WCRF/AICR) introduced in 2007, and updated in 2018, nutrition-related recommendations for cancer prevention. Previous studies generally reported inverse associations of breast cancer with the 2007 recommendations, while no study has yet evaluated the association with the 2018 guidelines. We investigated the association between adherence to the 2018 WCRF/AICR recommendations and breast cancer risk in a case–control study from Italy and Switzerland (1991–2008) including 3034 incident histologically-confirmed breast cancer cases and 3392 hospital controls. Adherence to the 2018 guidelines was summarized through a score incorporating eight recommendations , with higher scores indicating higher adherence. Odds ratios (OR) were estimated using multiple logistic regression models. We also conducted a meta-analysis including 15 additional studies using random-effects models. In our case–control study, adherence to the 2018 WCRF/AICR guidelines was inversely associated with breast cancer, with ORs of 0.60 , 0.51–0.70) for a score ≥5.5 vs. ≤4.25, and of 0.83  for a 1-point increment. In our study, 25% of breast cancers were attributable to low-to-moderate guideline adherence. In the meta-analysis, the pooled relative risks (RRs) were 0.73  for the highest vs. the lowest WCRF/AICR score category, and 0.91  for a 1-point increment. This work provides quantitative evidence that higher adherence to the WCRF/AICR recommendations reduces the risk of breast cancer, thus opening perspectives for prevention. After lung, breast cancer is the second most common neoplasm worldwide. In women, it accounts for almost 1 in 4 cancer cases and is the first cause of cancer death in most countries . PrimaryThus far, only very few modifiable risk factors for breast cancer have been recognized, including overweight/obesity, menopausal hormone replacement therapy (HRT), low physical activity and sedentary behavior, with possible differential associations in the life course of women ,5. DespiIn 2007, the World Cancer Research Fund/American Institute for Cancer Research (WCRF/AICR) published the Second Expert Report, in which defined a set of evidence-based public health recommendations on body fatness, physical activity and diet with the aim of reducing the burden of cancer . In the Previous studies showed that higher adherence to the 2007 WCRF/AICR nutrition-related recommendations reduced the risk of total cancer and of specific cancers . An inveIn the current report, we assessed the relation between adherence to the WCRF/AICR nutrition-related recommendations for cancer prevention and breast cancer risk in a large Mediterranean population, and conducted a meta-analysis of available studies on the topic.Data came from a multicentric case–control study carried out between 1991 and 1994 in 6 Italian areas  and between 1992 and 2008 in the Canton of Vaud, Switzerland ,26. Over2). The interviewers measured the waist circumference (2 cm above the umbilicus). We collected information on occupational/household and leisure time physical activity at different ages . Cases and controls defined their level of occupational/household physical activity as very heavy, heavy, intermediate, standing or sedentary, depending on their occupation/household activity. Leisure time physical activity was based on the total number of hours of physical activity  per week . Women were asked for menopausal status at the time of cancer diagnosis. Information on dietary habits during the two years before diagnosis (for cases) or hospital admission (for controls) was assessed through a food frequency questionnaire (FFQ), which included 78 foods and recipes. The FFQ was tested for its validity and reproducibility with satisfactory results [In each centre, a structured questionnaire was administered to both cases and controls by trained interviewers. The questionnaire included questions about sociodemographic factors, dietary and lifestyle habits , anthropometric measurements, menstrual and reproductive factors, a personal medical history, and a family history of cancer. As for anthropometric measures, the questionnaire collected information on body shape at 12 years , and self-reported height and average weight at age 30 and 50, as well as before diagnosis (cases) or interview (controls). Body mass index (BMI) was calculated as weight (kg) divided by squared height  of breast cancer and the corresponding 95% confidence intervals (CI) for each individual recommendation, for the overall WCRF/AICR score, and for the diet WCRF/AICR score were estimated using unconditional multiple logistic regression models. We fitted a first model with terms for age, study centre, and education, and a second one with further terms for parity, menopausal status and age at menopause, use of oral contraceptive and HRT, tobacco smoking, non-alcoholic energy intake (according to quintiles among controls), family history of breast cancer, and diabetes. When evaluating the association with individual recommendations, analyses were also adjusted for BMI, physical activity, and alcohol intake . We performed tests for trend including the variable in its ordinal form. In addition, we carried out a sensitivity analysis by excluding alternately each component in turn from the original 2018 WCRF/AICR score to evaluate the relative importance of each recommendation. The potential effect modification of menopausal status was tested using a likelihood ratio test comparing the likelihoods of models with and without terms for interactions between menopausal status and the WCRF/AICR score variable. We also estimated the population attributable fraction, representing the proportion of breast cancers that would be avoided if the whole population were highly adherent to the WCRF/AICR recommendations .The aforementioned analyses were conducted using the SAS software, version 9.4 .Using PubMed with terms breast, cancer/neoplasm/carcinoma and World Cancer Research Fund/WCRF in October 2019, we identified observational studies on the association between adherence to the WCRF/AICR guidelines (measured by means of an a priori score) and the risk of or mortality from breast cancer. Fifteen publications were identified and considered in the meta-analysis ,39,40,41p < 0.1) [2 statistics [2 > 50% representing substantial heterogeneity). We conducted both an extreme quantile meta-analysis  and a linear dose-response meta-analysis . Studies were included in the extreme quantile and/or dose-response meta-analyses based on data availability. One study providing only the RR for 1-SD increase in the score was also considered in the dose-response meta-analysis [We calculated the pooled RR and the corresponding 95% CI by means of fixed or random effects models, based on the results of the Cochrane Q test (heterogeneity was defined as p < 0.1) . Inconsiatistics  that meaanalysis . For theanalysis ,21,37 oranalysis . In the analysis . From thanalysis . A sensiThe statistical analyses for meta-analysis were conducted using the STATA software .The distribution of selected characteristics in breast cancer cases and controls is shown in Adherence to the recommendations on physical activity, wholegrains, vegetables, fruit and beans, fast foods and other processed food high in fat starches or sugar, sugar sweetened drinks, and alcohol was associated with a significant lower risk of breast cancer, with significant decreasing trends for increasing adherence . AdherenSimilar results (but apparently less strong) were observed when analyzing the 2007 version of the score . The ORsIn a sensitivity analysis, consistent results were found when omitting each recommendation one by one from the score: the ORs comparing extreme categories varied between 0.54 and 0.69. In particular, the OR was 0.56  when removing from the score the recommendation on breastfeeding.2 = 73.5%)  and cohort studies , and for pre-  and post-menopausal women . When we included for the study by Nomura et al. [The description of the studies included in the meta-analysis is provided in = 73.5%)  panel A.a et al.  the resu2 = 70.2%) RR reduction, based on 16 studies (15 publications) including the present one (2 = 49.4%) for cohort and 0.83  for case–control studies. The exclusion of each study in turn did not appreciably influence the summary result, and the estimated RRs were always significant. In particular, the pooled RR was still 0.91  when omitting the pooled analysis by Jancovic et al. [In the linear dose-response meta-analysis, each 1-point increase in the score was associated to a 9% .p = 0.143).No significant publication bias was detected (In the present large case–control study, higher adherence to the diet, adiposity, and physical activity recommendations provided by the WCRF/AICR Third Expert Report was associated with reduced breast cancer risk, independently of menopausal status. The results from the sensitivity analysis suggest that the association was not driven by adherence to one specific recommendation, but rather by the combined and synergic effects of the various score components. The meta-analysis indicates that women who highly adhere to the recommendations had an approximately 30% lower risk of breast cancer compared to those with low adherence and that each 1-point increment in the WCRF/AIRC score is associated with a significant 9% reduced risk. Published studies vary in design, baseline population characteristics, data collection, number and definition of recommendations operationalized in the score, and adjustment factors; the observed heterogeneity is therefore not surprising. In any case, they are largely supportive of the preventing role of following the WCRF/AICR guidelines on breast cancer. Indeed, estimates of the RR of breast cancer comparing extreme score categories were below unity in all but one studies , and werOnly a few reports investigated the association between the 2018 release of the WCRF/AICR recommendations and cancer risk ,46,47,48Our findings are in agreement with the conclusions of a systematic review  and withIn our case–control study, we observed a significant inverse association between a score reflecting adherence to the WCRF/AIRC dietary recommendations and breast cancer, in agreement with the study by Lavalette et al. , which rTo improve the comparability of our results with those from future studies relying on the 2018 WCRF/AICR guidelines, in the construction of the score, whenever possible, we followed the standard scoring approach recently proposed by a NCI-led collaborative group, which included, among the others, researchers from AICR and WCRF International . HoweverThe current analysis is based on data collected between 1991 and 2008 while looking at associations with more recent recommendations. Thus, the observation that the protection associated to the adherence to the WCRF/AICR recommendations was found in a population unaware of those guidelines supports the absence of major information bias and hence the validity of the association. The data were collected at multiple centres across two countries. However, similar structured questionnaires and coding manuals were used in all study centres, and interviewers were centrally trained, thus improving the reliability of data collection across study centers. In addition, a comparison across countries indicated a similar distribution of age, menopausal status, and family history of breast cancer, while Swiss women were more educated and more often nulliparae than Italian ones [Hospital controls may have different dietary habits from those of the general population, but we minimized bias by excluding from the control series patients admitted to hospital for conditions which may have led to long-term diet modifications. The strengths of the present case–control study lie in the satisfactory reproducibility and validity of the FFQ ,28,57, tIn conclusion, the present work provides quantitative evidence that greater adherence to the nutrition-related WCRF/AICR recommendations is favorably related to breast cancer risk, and thus suggests that encouraging adherence to the guidelines is a valuable public health strategy for breast cancer prevention.