Improvements in early detection and treatment have resulted in improved long-term survival from breast cancer, which increases the likelihood of the occurrence of second primary cancers. We calculated the risk of second primary cancers among Israeli women receiving a first primary breast cancer diagnosis.By using data from the Israel National Cancer Registry, we identified 46,090 women with invasive breast cancer diagnosed between 1990 and 2006 and non–breast primary cancers diagnosed subsequent to breast cancer diagnosis. We used life table analysis to calculate the risk of a second primary cancer and calculated standardized incidence ratios (SIRs) by using age-specific cancer risk in the general population of Israeli women as the standard and stratifying by diagnosis period  and age at diagnosis (< 50 and ≥ 50 years).The probability of a second malignancy was 3.6% within 5 years, 8.2% within 10 years, and 13.9% within 15 years. The SIR for any second non–breast primary cancer was 1.26 . Significantly increased risks of colorectal, uterine, lung, ovarian, and thyroid cancer and leukemia were observed for the full follow-up period, which persisted after excluding the first 6 months after index diagnosis, although increased leukemia and colorectal cancer risks were no longer statistically significant. Women younger than age 50 years at initial diagnosis had a greater excess risk than women age 50 years and older .The findings likely reflect a combination of personal risk factors  as well as the effects of the initial cancer treatment and are unlikely to be explained by enhanced surveillance alone. The aim of the current study was to characterize the factors associated with subsequent diagnoses of any type of cancer in a cohort of Israeli women who received a diagnosis of breast cancer from 1992 to 2006.Breast cancer is the most frequently diagnosed cancer in Israeli women and constitutes approximately one third of all newly diagnosed tumors in both Jewish and Arab women every year. Improvements in early detection and treatment have resulted in increased long-term survival of breast cancer, which increases the likelihood of the occurrence of second primary cancers. Estimates from population-based studies of the increased risk of a second non–breast primary cancer after a breast cancer diagnosis range from 1% to 40%.The Israel National Cancer Registry (INCR) was founded in 1960. Cancer reporting by hospitals, pathology and cytology laboratories, and other health care providers has been mandatory since 1982. The INCR covers the entire Israeli population (approximately 8 million), of which the ethnic distribution is as follows: 75% Jewish, 20% Arab, and 5% other ethnic groups. The following groups of diagnoses are recorded in the registry: all malignant neoplasms, excluding basal cell and squamous cell carcinoma of the skin; carcinoma in situ/high-grade (grade 3) intraepithelial neoplasias; and benign neoplasms of the brain and nervous system15 Completeness of ascertainment has been estimated at 94% for solid tumors.16 Stage of disease at the time of diagnosis is determined on the basis of criteria established by the Middle East Cancer Consortium, of which INCR is a member.17 Middle East Cancer Consortium staging is primarily based on the criteria of the SEER Summary Staging Manual–2000.18 Demographic data and information on vital status are derived from the Central Population Registry of the Ministry of the Interior and updated at least annually. For purposes of disease surveillance, the Israeli population is divided, on the basis of data from the Ministry of Interior, into three ethnic subpopulations: Jewish, Arab, and other. Because previous work has shown that age-standardized cancer incidence in the Arab subpopulation is considerably lower than that in the Jewish or other subpopulations, we aggregated the Jewish and other subjects into a single group for the purpose of analysis.The registry currently includes information on approximately 800,000 people; 30,000 new cases are entered per year. Sources of information include pathology reports, hospital discharge summaries, death certificates, and patient listings from cancer centers. Registry staff review all documents submitted to the registry and assign site and morphology codes according to the International Classification of Diseases for Oncology, Third Edition.The study cohort consisted of women who met the following criteria: diagnosed with invasive cancer of the breast  between 1990 and 2006, excluding breast lymphomas; and no cancer diagnosis recorded before the date of breast cancer diagnosisFor all the women in the study cohort, we identified all cancers diagnosed at another site after the date of the first breast cancer diagnosis. We did not consider subsequent breast cancer diagnoses as second primary cancers for the purpose of this study. We considered two follow-up periods. The first period was calculated from the date of breast cancer diagnosis through the end of the observation period . The second follow-up time was calculated from 6 months after the initial diagnosis through the end of the observation period. Subjects with more than one cancer during the follow-up period were censored after the first subsequent cancer diagnosis. To allow for examination of the effects of changes in treatment strategies over time, we divided the cohort into three groups according to year of diagnosis: 1992 to 1996, 1997 to 2001, and 2002 to 2006.Crude incidence of subsequent cancers  was calculated as the number of cases per 1,000 person-years of follow-up from time 0 (diagnosis of first primary invasive breast cancer) and from 6 months after time 0. Cumulative rates of second primary cancers within 5 years of breast cancer diagnosis, by period of diagnosis and age at diagnosis, were calculated by life table analysis. Expected numbers of cancer cases  were calculated by using age-specific incidence data for Jewish Israeli women derived from the INCR database. Standardized incidence ratios (SIRs) were calculated as the ratio of observed to expected cases for several follow-up times . We based the expected number of cases on the rates in the Jewish population for two reasons: The majority of the women in the study population were Jewish, and the cancer rates are considerably higher in Jewish than in Arab women. Therefore, use of these rates resulted in a more-conservative estimate of the risk of second primary cancers in a population of women with breast cancer. Ninety-five percent CIs were calculated for SIRs that assumed a Poisson distribution. All data analyses were performed with SAS version 9.12 software .A total of 46,090 Israeli women with no previous cancer history were given a diagnosis of invasive breast cancer between 1990 and 2006 . Overall, 92% of cases were diagnosed in Jewish women, although the proportion of cases occurring in women in the Arab and other population groups increased with year of diagnosis .Of women with breast cancer between 1992 and 2006, 3,980 (8.6%) were given a diagnosis of a second non–breast primary cancer during the follow-up period. Ninety-five percent of these cases  were among Jewish women, 3% among Arab women, and 2% among women of other ethnic backgrounds . When thThe relatively small number of second primary cancers in the Arab population precluded stratification by age-group and cancer type. Therefore, all subsequent analyses, including calculation of SIR overall and for specific cancer types, focused on the Jewish and other subpopulations . This group contributed 363,333 person-years of follow-up beginning on the date of breast cancer diagnosis and 343,462 person-years when follow-up was assumed to begin 6 months after the breast cancer diagnosis. Mean available follow-up time per patient was 8.3 years .The most commonly diagnosed second primary cancers were colorectal, uterine, lung, ovarian, non-Hodgkin lymphoma, brain, malignant melanoma, thyroid, and leukemia . During The SIR for a second non–breast primary cancer in women with a previous breast cancer diagnosis was 1.26 . The corresponding SIR for follow-up that commenced at 6 months after breast cancer diagnosis was 1.21 . Significantly increased risks of colorectal, uterine, lung, ovarian, and thyroid cancer and leukemia were observed for the full follow-up period. When follow-up excluded the first 6 months after breast cancer diagnosis, the increased risk of these cancers persisted, although for colorectal cancer and leukemia, this finding was no longer statistically significant .Stratification by age at diagnosis demonstrated greater excess risk for a second cancer among women given a diagnosis of breast cancer before age 50 years than in those age 50 years and older. Both groups, however, had a risk that was significantly higher than that for the general population of women the same age .Life table analysis indicated a cumulative probability of a second malignancy of 4.4% within 5 years, 9.3% within 10 years, and 15.3% within 15 years of the first breast cancer diagnosis. Probability of a second malignancy within 5 years of initial diagnosis did not vary significantly with period of first breast cancer diagnosis ; the number of patients remaining for analysis at 10 years for the group diagnosed between 2002 and 2006 was insufficient to allow for a comparison among all periods . Women wIn a cohort of women with a first primary breast cancer diagnosed between 1992 and 2006, we observed a 25% increased risk of second non–breast cancers during follow-up compared with the risk in the general population, adjusted for age. Overall, the cumulative risk of a second non–breast primary cancer was 4.4% after 5 years of follow-up and 9.3% after 10 years.19 Our estimate of the overall risk of a second cancer among patients with breast cancer is consistent with that analysis. As in previous studies, we found that although all women with breast cancer experience an increased risk of second primary cancer, younger women have a greater excess risk for a second primary cancer than the general population of women of the same age. As has been reported in other studies,14 the most pronounced excess risks in the current study population were for cancers of the uterus, ovary, and thyroid.A recent meta-analysis of 15 population- and hospital-based studies from Europe, Asia, and North America resulted in a pooled estimate of the increased risk of second cancers among patients with breast cancer of 1.17  and found that the excess risk of a second primary cancer after breast cancer decreases with age at diagnosis of the index cancer .2 Hormonal and radiation treatment of cancer carry an increased risk for the development of cancer. Duration of use of tamoxifen (but not the daily dose) has been associated with an increased risk of uterine cancer.20 Cancers most likely to be related to radiotherapy for breast cancer include leukemia and cancers of organs close to the breast, such as esophagus, lung and pleura, thyroid gland, stomach, and soft tissue sarcomas of thorax and upper limb.3Several potential explanations exist for an increased risk of subsequent cancers in breast cancer survivors, including the effects of radiotherapy and hormone therapy, environmental factors, health behaviors, and genetics.21 Both radiation treatment and chemotherapy are associated with an increased risk of leukemia in patients with breast cancer22; the risk of leukemia in this population has been shown to increase with the intensity of treatment.23 SEER data indicate that the increased risk of a subsequent cancer associated with chemotherapy and radiation therapy is most pronounced in children and young adults and is not seen in older adults.6 This finding is consistent with the bulk of the literature that indicates that the excess risk of second primary cancers after breast cancer is most pronounced among younger women.Women treated with radiation after mastectomy have been shown to have an increased risk for lung cancer, although radiation after lumpectomy does not carry this risk.24 reported an increased risk of thyroid cancers in Israeli women previously treated for breast cancer and concluded that enhanced surveillance, common risk factors, and genetic predisposition were the likely causes for this finding. Mellemkjær et al3 reached a similar conclusion that although patients with breast cancer had an increased risk for subsequent thyroid cancer, this risk did not increase with latency and was accompanied by an increased risk of breast cancer occurring after thyroid cancer. Van Fossen et al25 noted a bidirectional association between breast and thyroid cancer, which suggests the existence of common risk factors for the two illnesses. We found that the exclusion of the first 6 months after breast cancer diagnosis from follow-up had little effect on the risk of subsequent thyroid cancer, which suggests that an increase in diagnoses of existing thyroid tumors at the time of breast cancer diagnosis is insufficient to explain the increased risk observed.Another possible explanation for the increase in diagnoses of subsequent cancers in women with a history of breast cancer is that these women are under more intensive surveillance after treatment and therefore have a higher likelihood of subclinical lesions being detected. Sadetzki et alWe used data from a large population-based national cancer registry to estimate the risk of second primary cancers a cohort of 46,090 Israeli women with a first diagnosis of breast cancer. The use of data from a well-established cancer registry for observational epidemiology research offers certain strengths. The INCR receives reports of cancer cases from all Israeli hospitals and pathology laboratories, thus the likelihood that cases of breast cancer and subsequent cancers diagnosed during the period of the study were excluded from the study cohort is minimal. All cases are reported by using a unique national identifier that allows for elimination of duplicate cases reported to the registry from different facilities. We focused on cases diagnosed between 1992 and 2006 to allow for an average follow-up time of 8.3 years. Population data available from the Israel Bureau of Statistics allowed us to calculated expected cancer rates in the general population for the purpose of calculating SIRs. Vital status information in the registry is supplemented with Israel Bureau of Statistics data to allow the censoring of patients who died during the follow-up period.BRCA1 and BRCA2 genes.26 The cumulative risk at age 70 years of breast cancer in Ashkenazi women who are carriers of the BRCA1 and BRCA2 mutations has been estimated at 46% and 26%, respectively.27 Because mutations of the BRCA1 or BRCA2 genes contribute to an increased risk for cancers in other sites, such as the ovaries, cervix, uterus, pancreas, and colon, their high prevalence in the Israeli female population may limit the generalizability of the current data to populations with a low prevalence of BRCA1/2 mutations.The INCR receives a limited amount of clinical data for patients with cancer. For this reason, we were unable to study the association of various types of breast cancer treatment on the occurrence of second cancers. No information on family history, personal risk factors , or genetic testing is available for the patients in the cancer registry; therefore, these factors could not be taken into consideration in estimating second cancer risk. Genetic predisposition to cancer is an important consideration in the Israeli population. Between 2.0% and 2.5% of Ashkenazi Jewish women carry one or more of the founding mutations in the 28 With prolonged survival, however, comes an increased likelihood that patients treated for breast cancer in the past will be receive a diagnosis of additional primary cancers as a result of underlying genetic and other risk factors related to the primary breast cancer and to treatment of the original illness. Breast cancer survivors tend to be more intensive users of medical services than other women their age.29 Specialist and primary care providers must take advantage of this continued contact to educate patients about their risk for second cancers and implement appropriate preventive and screening procedures tailored to their patients’ individual risks.Over the past 20 years, survival after breast cancer diagnosis has improved throughout the developed world, including Israel.


PALB2 gene are associated with an increase of breast cancer risk. The purpose of this study was to characterise the spectrum of PALB2 mutations in women affected with breast or ovarian cancer from South-West Poland and West Ukraine. We applied Hi-Plex, an amplicon-based enrichment method for targeted massively parallel sequencing, to screen the coding exons and proximal intron–exon junctions of PALB2 in germline DNA from unrelated women affected with breast cancer (n = 338) and ovarian cancer (n = 89) from Poland (n = 304) and Ukraine (n = 123). These women were at high-risk of carrying a genetic predisposition to breast and/or ovarian cancer due to a family history and/or early-onset disease. Targeted-sequencing identified two frameshift deletions: PALB2:c.509_510del; p.R170Ifs in three women affected with breast cancer and PALB2:c.172_175del;p.Q60Rfs in one woman affected with ovarian cancer. A number of other previously described missense (some predicted to be damaging by PolyPhen-2 and CADD) and synonymous mutations were also identified in this population. This study is consistent with previous reports that PALB2:c.509_510del and PALB2:c.172_175del are recurrent mutations associated with breast cancer predisposition in Polish women with a family history of the disease. Our study contributes to the accumulating evidence indicating that PALB2 should be included in genetic testing for breast cancer susceptibility in these populations to enhance risk assessment and management of women at high-risk of developing breast cancer. This data could also contribute to ongoing work that is assessing the possible association between ovarian cancer risk and PALB2 mutations for which there is currently no evidence.Loss-of-function germline mutations in the  PALB2 loss-of-function mutations is now well established. All published estimates of penetrance of PALB2 mutations  [PALB2 Interest Group estimated that the average cumulative risk of breast cancer risk ranged from 33%  for a female carrier without affected relatives to 58%  for a female carrier with two first-degree relatives who had breast cancer diagnosed by 50 years of age [Breast cancer risk associated with carrying ed by us ) are com 95% CI, 1–56% [PAPALB2 loss-of-function mutations. Recent consolidated efforts including (i) those of the PALB2 Interest Group that estimated the relative risk for ovarian cancer to be 2.31 , (ii) the assessment of two protein truncating mutations PALB2:c.1592delT; p.L531Cfs and PALB2:c.3113G > A;p.W1038* on iCOGS  and (iii) a study of PALB2:c.509_510delGA and PALB2:c.172_175delTTGT in 344 Polish families with breast and ovarian cancer  all failed to reach statistical significance [There is currently no evidence for ovarian cancer risk to be associated with PALB2 in women from South-West Poland and West Ukraine affected with breast or ovarian cancer.This study aimed to apply massively parallel sequencing to characterise the mutation spectrum of Participants in this study were unrelated women diagnosed with breast or ovarian cancer recruited after or during the oncological treatment from Wroclaw Medical University, Lower Silesia, Poland, between 2004 and 2008, or Lviv State Oncology Regional Treatment and Diagnostic Center, Lviv, Ukraine between 2004 and 2010. Genetic testing was requested when hereditary cancer was suspected . The time from cancer diagnosis to blood draw ranged from 1 to 12 months.BRCA1  and in BRCA2 (c.5946delT) were excluded from this study.The Polish cohort consisted of 226 women affected with breast cancer and 78 women affected with ovarian cancer. Of the 226 women with breast cancer, 85 had hereditary breast cancer, 17 had familial breast cancer and 124 were sporadic cases, according to the criteria described by Berliner et al. [The Ukrainian cohort consisted of 112 women with breast cancer and 11 women with ovarian cancer. Seventy-four women affected with breast cancer were diagnosed with hereditary cancer and 38 with familial cancer. There were 78, 18 and 2 cases of invasive ductal, lobular and medullary breast cancers, respectively. Of the 11 Ukrainian women with ovarian cancer, two had moderately differentiated carcinoma, one had endometroid adenocarcinoma, one had serous papillary adenocarcinoma, one had low-grade differentiated adenocarcinoma and six had adenocarcinoma not otherwise specified. Additional information on the participants is presented in Table All participants provided informed consent for participation in this research program, which was approved by the Commission of Bioethics of the Institute of Hereditary Pathology of the National Academy of Medical Sciences of Ukraine, the Ethics Committee of Wroclaw Medical University (Poland), the Ethics Committee of University of Rzeszow (Poland) and the University of Melbourne Human Research Ethics Committee .PALB2 (NM_024675.3) was performed on lymphocytes-derived genomic DNA using the Hi-Plex protocol [Amplicon-based massively parallel sequencing of the coding regions and proximal intron–exon junctions of 2 NM_02465.3 was p2 NM_02465.3 was pprotocol .PALB2 were damaging to protein function was assessed with PolyPhen-2 [DNA sequence variant annotation  was performed using CAVA . The prolyPhen-2  and CADDlyPhen-2 . The thrlyPhen-2 .PALB2 genetic variants were observed in the DNA from 427 women  and cancer of the larynx in her father. The third carrier of PALB2:c.509_510del was diagnosed at 53 years with infiltrating ductal carcinoma. This woman’s mother had also been diagnosed with breast cancer at an unknown age.Two Polish women were identified as carriers of PALB2:c.172_175del was a Polish woman diagnosed with papillary serous ovarian cancer at the age of 57 years. She had a family history of cancer that included lung cancer (brother diagnosed at 36 years), liver cancer (sister diagnosed at 60 years), mouth cancer (mother diagnosed at 69 years) and gastric cancer .The carrier of PALB2:c.509_510del was first identified by Dansonka-Mieszkowska et al. in a study of women with breast or ovarian cancer from South Poland [PALB2:c.172_175del was initially reported as a Czech Republic founder mutation (4/409 high-risk breast cancer cases) [PALB2:c.509_510del and PALB2:c.172_175del are recurrent in the Polish population [PALB2:c.509_510del carriers and PALB2:c.172_175del carriers to be 4.09  and 5.02 , respectively, consistent with breast cancer risk estimates obtained for PALB2:c.1592del;p.L531Cfs and PALB2:c.3113G > A;p.W1038* [PALB2 mutation was 48.0% , compared with 74.7%  for non-carriers  [Both frameshift deletions observed in this study have been reported previously to be recurrent in the Polish population. h Poland . They obr cases) . Furtherpulation –17. CybuPALB2 in the population of South-West Poland and West Ukraine.Most of the previous studies have applied genotyping to detect these deletions, except for , where wPALB2 should be included in genetic testing for breast cancer susceptibility in these populations. For women who meet criteria for genetic testing in Poland, testing for the known Polish founder mutations in PALB2, together with Polish founder BRCA1 mutations could be recommended. For those found negative, gene-panel testing by massively parallel sequencing (next-generation sequencing) could be applied to facilitate risk assessment and management for these women at high-risk of developing breast cancer.Our findings further support that PALB2, especially the rare missense variants, is challenging. As discussed by us and others, there has been no evidence so far that rare missense variants in PALB2 are associated with increased risk of breast cancer [PALB2 on gene-panel tests for breast cancer susceptibility will contribute to the accumulation of data that could be used to estimate cancer risks associated with missense variants in PALB2 (and other genes included on these panels), on a variant-by-variant basis.Interpretation of the rare genetic variation observed in t cancer , 18, 19.


The purpose of this research was to examine the relationships of self-reported physical activity to involvement with messages that discuss the prevention of heart disease and breast cancer through physical activity, the explicit believability of the messages, and agreement (or disagreement) with specific statements about the messages or disease beliefs in general.N = 96) read either a breast cancer or heart disease message first, then completed a corresponding task that measured agreement or disagreement and confidence in the agreement or disagreement that 1) physical activity ‘reduces risk/does not reduce risk’ of breast cancer or heart disease, 2) that breast cancer or heart disease is a ‘real/not real risk for me’, 3) that women who get breast cancer or heart disease are ‘like/not like me’, and 4) that women who get breast cancer or heart disease are ‘to blame/not to blame’. This task was followed by a questionnaire measuring message involvement and explicit believability. They then read the other disease messages and completed the corresponding agreement and confidence task and questionnaire measures. Lastly, participants completed a questionnaire measuring physical activity related attitudes and intentions, and demographics.A within subjects’ design was used. Participants (There was no difference in message involvement or explicit believability of breast cancer compared to heart disease messages. Active participants had a higher confidence in their agreement that physical activity is preventive of heart disease compared to breast cancer. Multinomial regression models showed that, in addition to physical activity related attitudes and intentions, agreement that physical activity was preventive of heart disease and that women with heart disease are ‘like me’ were predictors of being more active compared to inactive. In the breast cancer model only attitudes and intentions predicted physical activity group.Active women likely internalized messages about heart disease prevention through physical activity, making the prevention messages more readily available within memory, and active women may therefore process such information differently. The study of how health-related beliefs are created and are related to perceptions of prevention messages is a rich area of study that may contribute to more effective health promotion. Physical activity is preventive of both breast cancer  and hearBelievability can also be related to specific aspects of a message, and may be automatically activated. In such cases, the ‘belief’ is not easily controlled and the measurement of the construct is considered implicit . Huang aIt has been shown that women feel heart disease is more preventable and controllable than breast cancer and that breast cancer poses a greater risk than heart disease . Thus, hO’Cass and Griffin  reportedThe purpose of this research was to examine the relationships of message involvement, the general believability of messages that discuss physical activity as preventive of heart disease and breast cancer, automatically activated agreement (or disagreement) with specific statements related to the messages or diseases , and physical activity-related attitudes and intentions to self-reported physical activity. The specific statements represented the message read during this research , reflected more general perceptions of risk for breast cancer and heart disease , reflectOne hundred women aged 18 to 80 years  were recruited using posters and e-mail list-serves from a university campus community, a senior’s club, and a religious institution. Given that participants contacted the researchers if they wanted to participate after seeing recruitment information, it is not possible to determine response rate.Modifiable risk factors for heart disease are factors that can be changed. These are factors that we have more influence over and can affect us throughout our lives. Modifiable risk factors include behaviors such as physical activity, drinking alcohol, and smoking. We are able to influence our level of exposure to many of these factors. By learning about them, you can take steps to reduce your heart disease risk.” This definition was followed by information about how and why physical activity and a healthy body weight are related to heart disease or breast cancer, and some risk statistics. For example, the physical activity and breast cancer message included: “Regular physical activity helps improve your overall physical, emotional and social health and well-being. Another important reason to get more active is that this can lower your risk of breast cancer by as much as 25–30 per cent.” The messages were shown on a computer and participants read them at their own pace.The breast cancer and heart disease messages were created based on content from the Canadian Breast Cancer Foundation and the Heart and Stroke Foundation of Canada. The messages were as similar as possible across the diseases and behaviors and were 155–165 words each. Each message started with the same definition of modifiable risk factors: “As outlined by Huang and Hutchinson , four stThe statement “The messages related to breast cancer/heart disease are…” was rated on a 1–7 point scale with 8 adjective pairs such as believable/unbelievable, convincing/unconvincing, conclusive/inconclusive, and trustworthy/untrustworthy , 4. The The statement “The messages related to breast cancer/heart disease are…” was rated on a 1–7 point scale with 8 adjective pairs such as unimportant/important and irrelevant/relevant . The intr = .80, and a mean of reverse scored items was calculated such that a higher score represents higher affective attitude.Affective attitude toward physical activity was assessed with two items on a 1–7 scale with the pairs: pleasant – unpleasant, and enjoyable- unenjoyable. These items were highly correlated, Intention to engage in physical activity was assessed with one question: “I intend to be physically active for at least 150 minutes a week” on a 1 (extremely unlikely) to 7 (extremely likely) scale.Self-reported LTPA was assessed with an item validated by Johansson and Westerterp  using doParticipants reported their age (in years), height and weight , smoking status, highest level of education, marital status, household income (in increments), and ethnicity (open-ended). Participants also reported if they had ever been diagnosed by a doctor or nurse with high blood pressure, high cholesterol, heart disease, stroke, angina, diabetes, or cancer .All procedures were approved by a university health research ethics review panel and written informed consent was obtained. A within subjects’ design was used. Each participant read either the breast cancer or heart disease message first, then completed the corresponding implicit believability task and questionnaires. They then read the other disease messages and completed the corresponding measures. Order of message was randomly assigned to participants such that half read the breast cancer message first and half read the heart disease messages first.A belief confidence index (BCI) was calculated for each of the statement pairs in the implicit believability measure using response (agree/disagree) and confidence, as advocated by Huang and Hutchinson n = 23), the moderately active group remained at n = 27, and the active and very active groups were combined to create an active LTPA group (n = 46). There were no differences between order of reading and measures  in any demographic variable, nor in involvement with the heart disease or breast cancer messages, heart disease or breast explicit believability or physical activity belief confidence index, affective attitudes, intentions, or LTPA group . There was also no difference in age, p = .35, BMI, p = .55, nor smoking status, p = 49, by LTPA group. Three smokers were inactive, one was moderately active, and four reported being active.Incomplete data from three participants were not used, and one participant diagnosed with heart disease and breast cancer was also omitted from the analysis, leaving a final sample of 96 who ranged in age from 18 to 80 years. Demographic data are reported in Table p = .18, nor was there a difference in message involvement by LTPA group, F  = .71, p = .50. There was also no difference in explicit believability of the messages, F  = 1.83, p = .18, nor was there a difference by LTPA group, F  = .18, p = .83. There was no overall difference in breast cancer compared to heart disease physical activity BCIs, F  = 1.07, p = .30, but there was a difference by LTPA group, F  = 3.90, p = .02. Post hoc tests showed no differences in the inactive or moderately active groups but the active group had a higher heart disease physical activity BCI than breast cancer physical activity BCI, p = .01, Cohen’s d = 0.54. There was a significant difference in risk BCIs, F  = 9.54, p = .003, Cohen’s d = 0.27, but no difference by LTPA group, F  = 1.12, p = .33. There was no difference in BCIs that women with breast cancer are ‘like me’ compared to women with heart disease are ‘like me’, F  = 2.10, p = .15, and no difference by LTPA group, F  = 0.99, p = .38. There was a significant difference in blame BCIs, F  = 32.52, p < .001, Cohen’s d = 0.67, but no difference by LTPA group, F  = 1.21, p = .30.Table The multinomial regression model predicting physical activity group after reading the breast cancer messages is summarized in Table The model predicting physical activity group after reading the heart disease messages is summarized in Table This research examined message involvement, and the automatically activated and explicit believability of messages about breast cancer and heart disease prevention, and the relationships of these variables, in conjunction with physical activity related attitudes and intentions, to self-reported physical activity behavior. The correlations showed that, in partial support of the first hypothesis, involvement with both the breast cancer and heart disease messages was related to explicit believability of the respective messages. However, contrary to the hypothesis, message involvement was not related to any BCI score. O’Cass and Griffin  also repIntention to be active was not related to any variable other than attitudes. Attitude toward physical activity was, however, positively correlated with both breast cancer and heart disease message involvement and explicit believability, again supporting relationships reported by O’Cass and Griffin . Even thParticipants, regardless of their self-reported activity level, were equally involved with the breast cancer and heart disease messages and expressed equally high explicit believability of the messages. There was also no difference in belief confidence that women ‘like me’ are at risk for breast cancer comparted to heart disease. These results do not support the hypothesis that more active women will have higher scores for these constructs. However, active participants had higher heart disease compared to breast cancer physical activity BCI scores. This indicates that active participants were more likely confident in their belief that being physically active will help reduce risk of heart disease compared to breast cancer. There is likely greater internalization of the message that physical activity can help prevent heart disease by already active women and the messages may reinforce already held beliefs. However, it is not known if the participants are active because they are, in part, aware that being active will reduce risk of heart disease.There was also greater belief of being at risk of breast cancer compared to heart disease, and of perceptions of blame, regardless of LTPA group. Although the effect was small, women felt more at risk for breast cancer, supporting previous research that explicitly assessed risk perceptions of these diseases . RegardiIn support of the fourth hypotheses, there were stronger relationships between heart disease message constructs and LTPA group than there were for breast cancer. None of the breast cancer related BCIs increased prediction of activity group. Conversely, confidence in the belief that being active can reduce risk of heart disease was positively related to physical activity behavior. Also, greater confidence that women with heart disease are ‘like me’ was related to being more active, compared to inactive. The differences between the two disease-specific multinomial regression models may be a function of how the diseases are discussed in the media: heart disease is presented as avoidable through preventive behaviors whereas breast cancer is something one survives . ResearcThis research has several strengths including a randomized within-subject experimental design with strong measures. However, although less error variance existed between messages because participants responded to both disease messages, the within subjects’ design may also have resulted in carryover effects from one reading to the next, such that reading about one disease may have influenced responses to the subsequently read message. This was somewhat mitigated by counterbalancing the reading order. Another limitation is that although efforts were made to recruit a diverse sample of women, participants were younger and for the most part highly educated. These demographic factors might influence perceptions of disease risk and message processing and the results of this study should be replicated with a more diverse sample of women. An additional consideration is the labelling of the task developed by Huang and Hutchinson  as an imThis research is an important contribution that highlights that active women hold stronger beliefs that physical activity is preventive of heart disease compared to breast cancer. It seems likely that prevention messages created by health promoters are processed differently by already active women who may have internalized the messages, making them more readily available within memory. Further, the more participants indicated that women with heart disease are ‘like me’ the more likely they were to be active. This may demonstrate internalization of the idea that one is at risk for heart disease and that this may be related to decisions to be active. These results highlight that health promoters may be at risk of reaching those already engaged in prevention behaviors. Finding innovative ways of reaching those who are not interested in physical activity is needed. For example, investigating if inactive women find prevention information threatening is warranted. Other researchers have reported that healthy women who were moderate alcohol drinkers automatically avoided cancer-related words after being informed that alcohol is a risk factor for breast cancer, but self-affirmation moderated this relationship . It is l


Cardiovascular disease (CVD) is the leading cause of morbidity and mortality among older postmenopausal women. The impact of postmenopausal breast cancer on CVD for older women is uncertain. We hypothesized that older postmenopausal women with breast cancer would be at a higher risk of CVD than similar aged women without breast cancer and that CVD would be a major contributor to the subsequent morbidity and mortality.In a prospective Women’s Health Initiative study, incident CVD events and total and cause-specific death rates were compared between postmenopausal women with  and without  incident invasive breast cancer over 10 years post-diagnosis, stratified by 3 age groups .Postmenopausal women, regardless of breast cancer diagnosis, had similar and high levels of CVD risk factors  at baseline prior to breast cancer, which were strong predictors of CVD and total mortality over time. CVD affected mostly women age 70–79 with localized breast cancer (79% of breast cancer cases in 70–79 age group): only 17% died from breast cancer and CVD was the leading cause of death (22%) over the average 10 years follow up. Compared to age-matched women without breast cancer, women age 70–79 at diagnosis of localized breast cancer had a similar multivariate-adjusted hazard ratio (HR) of 1.01  for coronary heart disease, a lower risk of composite CVD , and a higher risk of total mortality .CVD was a major contributor to mortality in women with localized breast cancer at age 70–79. Further studies are needed to evaluate both screening and treatment of localized breast cancer tailored to the specific health issues of older women. With the aging US population and the favorable long term survival following breast cancer –4, greatCVD and breast cancer share multiple risk factors, such as age, postmenopausal obesity and physical inactivity –14. ManyPrevious studies compared some CVD outcomes over relatively short time period within breast cancer drug trials by intervention arms , but ageDetails of the design and conduct of the WHI clinical trials (CTs) and observational study (OS) have been published –35. In bIncident CVD events and breast cancer cases were initially ascertained by self-report and documented by medical record review. Potential cases were sent to local WHI-physician adjudicators for evaluation and classification. Locally adjudicated cases were then sent to the WHI CCC for central adjudication of selected outcomes . Cases rOf 115,407 WHI Extension Study participants, we excluded 9,181 with CVD history at baseline. Of the remaining 106,226 participants, 7,065 developed invasive breast cancer. Of these, only breast cancer cases that occurred within the first 10 years of follow up in the WHI were included because there was very little follow up time for CVD outcomes after diagnosis of breast cancer beyond 10 years from baseline. There were 4,518 incident invasive breast cancer cases. After excluding 178 with incident CVD prior to breast cancer diagnosis, 4,340 invasive breast cancer cases were available for the primary analyses. Of the 99,161 participants with no invasive breast cancer, 1,585 with incident non-invasive breast cancer  were excluded, resulting in 97,576 comparisons .Breast cancer stages were classified as localized or not localized based on the absence or presence of lymph node metastasis at the time of diagnosis. There were 466 localized breast cancer  cases diagnosed at age 50–59, 1,479 at age 60–69, and 1,164 at age 70–79. Breast cancer cases were also further classified by grade from well differentiated to anaplastic, presence of estrogen or progesterone receptors, and expression of human epidermal growth factor receptor 2 (HER2). The number of women in the WHI Hormone Trials in this study was too small for further separate analysis and included in the overall results, noting no effect on the overall results of the study ,39.The primary study outcomes were incident CVD events and mortality outcomes directly attributed to CVD and CHD, and all-causes. Composite CVD was defined as the first occurrence of any events of CHD, angina, coronary revascularization, heart failure, PAD, and stroke. CHD was defined as acute MI that required overnight hospitalization or coronary death. The diagnosis of nonfatal MI was confirmed if data in the hospital record met standardized criteria of diagnostic electrocardiographic changes, elevated cardiac-enzyme levels, or both. The presence of angina was confirmed by hospitalization and confirmatory evidence on angiography, diagnostic stress test, or diagnosis by a physician and medical treatment. Coronary revascularization was confirmed by documentation of coronary artery bypass graft, coronary angioplasty, stent, or artherectomy procedures in the medical record. Stroke was confirmed by documentation in the medical record of the rapid onset of a neurologic deficit consistent with stroke and lasting at least 24 hours or until death. The presence of heart failure was confirmed by hospitalization and diagnostic confirmatory tests. We also used the end points of CHD, angina, coronary revascularization, PAD, and stroke as individual outcomes ,40.Deaths were categorized as total death, CVD death, and CHD death and were determined by trained physician adjudicators at the CCC based on medical record or death certificate review. CVD mortality included deaths from CHD, cerebrovascular disease, pulmonary embolism, heart failure, and other cardiovascular causes. CHD mortality was defined as death consistent with CHD as the underlying cause plus one or more of the following: hospitalization for MI within 28 days before death, previous angina or MI, death due to a procedure related to CHD or a death certificate consistent with the underlying cause as atherosclerotic CHD ,40.2) based on baseline physical assessment. Waist circumference (cm) was measured after normal expiration over nonbinding undergarments. Blood pressure was measured with standard protocols. Hypertension was defined as either a blood pressure of at least 140/90 mm Hg or hypertension medication use and categorized as not hypertensive, untreated hypertensive, or treated hypertensive. Diabetes status was determined by self-report of treated diabetes or high blood sugar when not pregnant. Hypercholesterolemia was determined by history of cholesterol medication use. Physical activity was defined as a total metabolic equivalent score (MET-hours/week) [Baseline characteristics were obtained from self-administered questionnaires on demographics, health behaviors, medical history, and physical examination . Race/etrs/week) .Categorical variables were presented as frequency and percentage, and continuous variables were presented as mean ± standard deviation (SD) or median and inter-quartiles, if the distribution was skewed. Chi-square tests were conducted to compare categorical variables. Age-specific incidence or mortality rates per 1,000 person-years and their 95% confidence intervals (CIs) were calculated. Cox models were conducted to estimate hazard ratios (HRs) and 95% CIs for assessing the association of breast cancer status and CVD risk factors with outcomes. The starting points for time-to-event analyses were the WHI study entry for women with and without breast cancer as well as the date of invasive breast cancer for women with breast cancer. The ending point for all participants was the date of the initial CVD event or the end of follow up. Participants were censored at the time of death or the date of last information available. All analyses were 2-sided at alpha = 0.05 and performed with SAS version 9.3 .For women with breast cancer, the analyses were based on age at breast cancer diagnosis and person-years follow up limited to time after the breast cancer diagnosis. To handle the average difference of 5 years between age at entry to WHI and age at diagnosis of breast cancer in breast cancer cases , severalThe second approach was to adjust for both age at diagnosis and length of follow up. Women with breast cancer were categorized into 3 age groups based on the age at diagnosis of breast cancer but not the age at study entry, and follow up began at the time of breast cancer diagnosis. For the no breast cancer comparisons, length of follow up and baseline age began approximately 5 years after entry to WHI, and all CVD and mortality events that occurred during the first 5 years were excluded. Based on this approach, the age of women at diagnosis of breast cancer and the age at baseline of women in the comparisons were similar. Also, the length of follow up for both breast cancer cases and comparisons became the same. Furthermore, direct age adjustment within the 10-year age groups was done for both groups to further control for any age differences between the groups. These 2 approaches together controlled for both age and length of follow up to avoid potential survivor bias.Of a total of 4,518 incident invasive breast cancer cases, 4,340 had no history of CVD prior to their breast cancer. After excluding breast cancer cases after age 80+, 4,066 cases were available with detailed staging data , includiThe mean time to breast cancer diagnosis for the 4,340 women without CVD at baseline and prior to breast cancer was 5.0 ± 2.8 years . There wThe CVD risk factors were measured only at baseline entry to WHI. The relationships of risk factors to breast cancer cases with and without subsequent CVD were analyzed in several ways. First, we compared risk factors for CVD that occurred prior to incident breast cancer vs. for CVD events that occurred after breast cancer diagnosis . Among bAmong 627 women age 50–59 at diagnosis of breast cancer, 63 (10%) had died, including 35 of 446 (8%) with localized disease. Breast cancer was the leading cause of death accounting for 36 (57%) of the 63 deaths and CVD for 7 (11%) of the deaths in the group of age 50–59 at the time of breast cancer diagnosis . There wThe situation for women who developed breast cancer at age 70–79 was somewhat different in that 328 (22%) had died and 86 of 328 deaths (26%) were due to breast cancer and 63 (19%) to CVD . As noteThe number of CVD events was very low among breast cancer cases under the age of 70 regardless of stages of breast cancer at diagnosis . There wKaplan Meier survival analysis using analytical approaches similar to A supplementary analysis was conducted to further compare events rates using age at entry rather than age at diagnosis of breast cancer for both localized breast cancer and all invasive breast cancer stratified by ages 50–59, 60–69, and 70–79 . Person-Because mortality follow up was available for the total sample of WHI, we conducted a sensitivity analysis for the mortality results in In both groups, presence of more baseline CVD risk factors was significantly associated with higher risks of subsequent MI and CHD death at p values ≤ .0001 . Women wThe majority (79%) of older women age 70–79 had localized breast cancer at the time of diagnosis. There was a small but significant increase in total mortality HR = 1.20) among women age 70–79 who developed localized breast cancer than no breast cancer comparisons. A crude estimate showed about 60 excess deaths including 39 (65%) breast cancer deaths among women with localized breast cancer at age 70–79 than the no breast cancer comparisons. CVD incidence was significantly lower for breast cancer cases than comparisons primarily due to much lower incidence of coronary revascularization, the most common CVD diagnosis among older women. The lower rate of coronary revascularization in older women with localized breast cancer could be due to under-diagnosis of CHD symptoms that may mimic side effects of surgical treatment and radiotherapy for breast cancer . Indeed,.20 amongCVD was the leading cause of death over 10 years of follow up for women with localized breast cancer diagnosed at 70 years and older based on a strict formal adjudication process of the WHI study by thorough medical record review to determine breast cancer and CVD outcomes. Deaths due to breast cancer in the WHI included only those adjudicated to breast cancer, which provide more accurate data compared to studies that use all deaths after the diagnosis of breast cancer or death certificate classification with possible overestimation of breast cancer deaths . A retroFew studies have compared predictive performance of CVD risk factors on CVD outcomes in women with breast cancer . TraditiThese new results on the prospective evaluation of CVD risk factors prior to breast cancer extend findings of Haque and colleagues  who founThis study also provides clinical implications for the screening and management of breast cancer as well as CVD and other comorbidities for older women age 70+ at diagnosis of breast cancer. Mortality remains very high for women with non-localized or advanced  breast cancer. The goal of mammography is to increase the percentage of early detected breast cancer so that the treatment will effectively reduce mortality from breast cancer. In the WHI, mammographic examinations were required annually for women in the hormone therapy arm of the trial, every other year for those in the dietary modification arm, but were not required for participants in the WHI-OS. There are no clinical guidelines and trials specifically focusing on breast cancer screening among older women ,44. An eThe strengths of this study include the prospective study design, the large, well-characterized diverse WHI population of postmenopausal women with and without breast cancer, breast cancer and CVD outcomes formally adjudicated by medical record review, comprehensive data on CVD risk factors, and a follow-up period of more than a decade for the breast cancer cases. Our study has, however, a few limitations. First, some of the baseline CVD risk factors were based on self-report. However, a validation study revealed high concordance of self-report of diabetes with medical record review ,48. SecoIn conclusion, the majority of older postmenopausal women had localized breast cancer (79%) with good long term survival. Mostly affecting women of age 70+, CVD was the leading cause of death and a major contributor to total mortality in women age 70–79 with localized breast cancer. High prevalence of CVD risk factors prior to breast cancer was associated with CVD and total mortality over time. Optimal efforts to prevent and treat CVD and other diseases after localized breast cancer may have a bigger effect on survival of these older women than treatment that only focus on breast cancer ,49–51. AS1 Tablea n = 212 for age 70–74.9, and n = 406 for age 75–79.9 at breast cancer diagnosis.(PDF)Click here for additional data file.S2 TableMET indicates metabolic equivalent score.(PDF)Click here for additional data file.S3 TableaChi-square test included missing category. bChi-square test did not include missing category.HER2 indicates human epidermal growth factor receptor 2. (PDF)Click here for additional data file.S4 TableCVD indicates cardiovascular disease.(PDF)Click here for additional data file.S5 Table(PDF)Click here for additional data file.S6 Table(PDF)Click here for additional data file.S7 TableCHD indicates coronary heart disease; MI, myocardial infarction; REVASC, revascularization; and PAD, peripheral arterial disease.(PDF)Click here for additional data file.S8 TableHR indicates hazard ratio; CI, confidential interval; and MET, metabolic equivalent score.(PDF)Click here for additional data file.S1 FigBC indicates breast cancer; and FU, follow up.(PPTX)Click here for additional data file.S2 FigBC indicates breast cancer; and FU, follow up.(PPTX)Click here for additional data file.S3 FigBC indicates breast cancer; and FU, follow up.(PPTX)Click here for additional data file.


FTO), interleukin 6 (IL-6), and heat shock protein 60 (HSPD1), with breast cancer risk and survival in a Chinese Han population. The information on the history of diabetes was collected from 1551 incident breast cancer cases and 1605 age-frequency matched controls in Guangzhou, China. In total, 1168 cases were followed up. Diabetes was associated with both an increased risk of breast cancer [OR (95%CI): 1.67 ] and a poor overall survival and progression free survival for breast cancer patients . IL-6 rs1800796 and HSPD1 rs2605039 had interactions with diabetes on breast cancer risk. Among women with CC genotype of IL-6 rs1800796 or GG genotype of HSPD1 rs2605039, diabetic individuals had a remarkably increased risk of breast cancer compared to non-diabetic women with ORs and 95%CIs of 2.53  and 6.40 , respectively. GT/TT genotypes of HSPD1 rs2605039 was also associated with a better progression free survival for breast cancer patients [HR (95%CI): 0.70 ]. Our results suggest that the contribution of diabetes to breast cancer risk might be modified by IL-6 rs1800796 and HSPD1 rs2605039. Diabetes and HSPD1 rs2605039 might also influence breast cancer prognosis.The contribution of diabetes to breast cancer remains uncertain among Chinese females, which may result from different genetic factors. We evaluated the associations of diabetes, combined with the polymorphisms in the genes of fat mass and obesity-associated gene ( Diabetes is characterized by sustained hyperglycemia and is associated with increased cancer risk in many settings, possibly through proliferative, anti-apoptotic, and metastatic activity . TherefoIL-6)   cases and 1508 (94.0%) controls. After adjustment for potential breast cancer risk factors, diabetes mellitus was significantly associated with an elevated risk of breast cancer, with OR (95%CI) of 1.67  . This poctively] , and thectively] . We alsot cancer .FTO, IL-6, HSPD1 polymorphisms with diabetes on breast cancer risk. Compared to non-diabetic women, diabetic women had an increased risk of breast cancer among the women with the GG genotype of FTO rs3751812 [OR (95%CI): 2.05 ] but not among those with GT/TT genotypes [0.90 ], but the interaction was not significant (P > 0.05)  : 6.40 ] but not the women with the GT/TT genotypes [1.16 ], and the interaction was significant in a multiplicative model but not in an additive model   . Comparectively) . For HSPctively) .FTO rs3751812, and IL-6 rs1800796 were associated with neither OS nor PFS of breast cancer patients  (HSPD1 rs2605039 was significantly associated with PFS (P = 0.031) (P = 0.061). Except for age at diagnosis, other clinical factors  were all significantly associated with OS and PFS in a univariate Cox regression model (HSPD1 rs2605039 had a better PFS but not OS than those with GG genotype with HR (95%CI) of 0.70 (0.49 .99)   Figs, wh= 0.031)  but not on model . After aon model , Fig 2. .49 .99) , Fig 1B.t cancer . Due to IL-6 rs1800796 and HSPD1 rs2605039. Diabetes and HSPD1 rs2605039 might also influence breast cancer survival.In the present study, we confirmed the positive association of diabetes with breast cancer risk and prognosis. We further found that the risk association might be modified by polymorphisms of IL-6 rs1800796. The G and C alleles were reported to be associated with low and high serum levels of IL-6, respectively . On the other hand, a high level of IL-6 by C allele may be dominant in tumor-promoting effects, deteriorate the chronic inflammatory state in diabetes, and synergically increase breast cancer risk, implying that the contribution to breast cancer by diabetes may be varied by different IL-6 levels.We found that the increased risk of breast cancer by diabetes was more obvious among women with the CC genotype than those with CG/GG genotypes of ectively . For breectively ,28. Furtectively ,29. ThesHSPD1 rs2605039 had a better PFS than those with GG genotype, indicating that the T and G alleles are likely to be associated with low and high levels of hsp60, respectively. It has been found that up-regulation (high level) of hsp60 resulted in anti-apoptosis and promoting carcinogenesis [HSPD1 rs2605039 might increase the hsp60 level high enough to make the host’s anti-apoptotic effect, inflammatory and insulin resistant states more apparent while the co-existence of diabetes and the T allele might keep hsp60 at a certain low level to exert a pro-apoptosis effect. However, the exact mechanisms in which diabetes and hsp60 interact on breast cancer risk remain to be studied. Nevertheless, the finding suggested that HSPD1 may be a potential target gene to be interfered for a better prognosis of breast cancer, particularly for the breast cancer patients with diabetes.Hsp60 was supposed to be positively correlated with tumor growth and proliferation . In the ogenesis ,32. It hogenesis . Similarogenesis , the co-IL-6 rs1800796 and HSPD1 rs2605039 is a reason for the race difference of the association between diabetes and breast cancer risk, although the possibility can’t be excluded as it is only an ecological relationship between allele frequencies and the association strength. It would be interesting that a similar study could be conducted among Caucasians: A same result would suggest a general phenomenon; a different result may be explained by the interaction between genes and environments [The above modification effects in the present study may provide a possible explanation for the previous findings that the association between diabetes and breast cancer risk was more obvious in European populations than in Asians ,7–9. We ronments . It is aronments , while tronments ,37 as weP = 0.003), whereas chemotherapy was associated with a poor prognosis in the present study  have been reported to be associated with an increased risk of cancer . On the Several limitations should be considered when interpreting the results of the present study. First of all, the hospital-based design in our case-control study might lead to selection bias . HoweverIL-6 rs1800796 and HSPD1 rs2605039. Diabetes and HSPD1 rs2605039 were also associated with breast cancer survival. Whether the genetic variations contribute to the different strengths of the association between diabetes and breast cancer risk, however, can’t be confirmed and remains to be further studied.In summary, our results suggested that diabetes was associated with breast cancer risk in the Chinese population, which may be modified by genetic variations of S1 Table(DOC)Click here for additional data file.S2 Table(DOC)Click here for additional data file.S3 Table(DOC)Click here for additional data file.S4 Table(DOC)Click here for additional data file.S1 Fig(A) Kaplan—Meier estimates on overall survival for breast cancer patients according to genotypes of FTO rs3751812. (B) Kaplan—Meier estimates on overall survival for breast cancer patients according to genotypes of IL-6 rs1800796. (C) Kaplan—Meier estimates on overall survival for breast cancer patients according to diabetes.(DOC)Click here for additional data file.S2 Fig(A) Kaplan—Meier estimates on progression free survival for breast cancer patients according to genotypes of FTO rs3751812. (B) Kaplan—Meier estimates on progression free survival for breast cancer patients according to genotypes of IL-6 rs1800796. (C) Kaplan—Meier estimates on progression free survival for breast cancer patients according to diabetes.(DOC)Click here for additional data file.


Background: This study investigated the association of vitamin D3 levels with breast cancer risk and progression in African-Americans and Hispanics. Methods: A total of 237 African-American  and 423 Hispanic women  were recruited in the study. Blood samples were collected at the time of breast cancer screening and prior to cancer treatment for 4 weeks on average for the cases. The serum 25-hydroxyvitamin D (25(OH)D3) was measured at a Quest-Diagnostics™ facility. Results: The results showed that 69.2% of African-Americans and 37.8% of Hispanics had 25(OH)D3 levels below 20 ng/mL. The 25(OH)D3 level below 20 ng/mL was significantly associated with breast cancer in both African-Americans  and Hispanics . However, the predicted probabilities of breast cancer in African-Americans were significantly higher than in Hispanics (p < 0.001). The 25(OH)D3 below 20 ng/mL was significantly associated with triple negative breast cancer (TNBC) in African-Americans , but not in Hispanics in our cohort of participants. Levels of 25(OH)D3 below 26 ng/mL predicts a decrease in disease-free survival, but it was not an independent predictor. Conclusions: Our data shows an association between 25(OH)D3 levels and the risk of breast cancer. Further studies on the relationship between 25(OH)D3 level and breast cancer risk are warranted. Breast cancer is the most common cancer and the second leading cause of cancer death in women in the US. African-American women with breast cancer have the highest mortality rates compared to other ethnic groups and for all age groups . LaboratMost of these studies reported data on Caucasians. Only few of these studies were on Hispanic/Latino populations, and the results were contradictory ,11,12. EIt has been reported that African-Americans and Hispanic-Americans tend to have lower circulating vitamin D levels compared to Caucasians . Hence ip = 0.005). Overall, the age of Hispanic women was younger than African-American women in this study. As shown in A total of 660 women participated in our study, divided into two groups: “case” and “control”. The case group had 243 (36.8%) women diagnosed with breast cancer and the control group had 417 (63.1%) women who did not have cancer. The self-identified ethnic distribution of the subjects is shown in p < 0.001). In this study we did not find an association between the level of 25(OH)D3 and BMI in both African-Americans and Hispanics.The mean level of 25(OH)D3 and the frequency of 25(OH)D3 deficiency (<20 ng/mL) between African-American and Hispanic women are shown in p-value < 0.001)  and Hispanics . A linearized inverse association between the predicted probabilities of breast cancer with the serum 25(OH)D3 levels was seen in both African-Americans  and Hispanics . However, the predicted probability of breast cancer increased rapidly in African-Americans than in Hispanics at each percentile (p < 0.001) . Furthermore, the significant association of 25(OH)D3 deficiency with breast cancer was confirmed by multivariate analysis in both African-Americans  and Hispanics .Utilizing univariate analysis we were able to demonstrate that there was a significant association between 25(OH)D3 deficiency and breast cancer in the total cohort  . Further< 0.001) B. As shop = 0.02) (In  = 0.02) .The level of 25(OH)D3 had no association with either ER/PR+/HER2− tumor or ER/PR−/HER2− tumor. There were no significant differences in the 25(OH)D3 levels among the different ER/PR, HER2 status, tumor size, lymph node involvement, and tumor stages in both African-Americans and Hispanics groups . As showThe Cox regression with univariate and multivariate analysis adjusted for ethnicity, ER/PR/HER2 receptors, tumor size, node involvement, BMI, age at the time of diagnosis and the seasons of blood draw were performed to assess the relative risk (RR) for reducing disease-free survival (DFS) and overall survival (OS).p ≤ 0.03). Patients with 25(OH)D3 level ≤ 12 ng/mL also increase RR to 1.7, however, it was not statistically significant and this may be due to less number of patients in this quartile. Similar trend was seen in RR for overall survival (OS) (The relative risk (RR) for DFS increases with decrease in the levels of 25(OH)D3 per quartile. Univariate analysis  showed tval (OS) . Multivaval (OS) . HoweverThe vitamin D deficiency has been defined as a serum 25 (OH)D3 level less than 20 ng/mL and the 25(OH)D3 level of 21 ng/mL to 29 ng/mL is considered insufficiency for vitamin D . Based oIn this study we examined the association between serum 25(OH)D3 levels and breast cancer using pre-cancer treatment serum from African-American and Hispanic women patients at the breast clinic at the Martin Luther King (MLK) Medical Center in South Los Angeles . Both the African-American and Hispanic women in this study have similar socio-economic status and access to health care. In our study cohort Hispanic women were self-reported mostly of Mexican-Hispanic origin. Our data showed that both African-American and Hispanic women had low serum 25(OH)D3 levels. The mean levels of 25(OH)D3 were in the range of insufficiency for the Hispanic women and in the range of deficiency for the African-Americans in both groups “case” and “control”. This trend was consistent with the data from National Health and Nutrition Examination Survey (NHANES) ,27. MeatVitamin D is a steroid hormone and the mechanisms underlying for vitamin D in cancer development are not well understood. Some evidence suggest that vitamin D is involved in the regulation of cell growth, apoptosis and cell differentiation ,31,32,33Several studies have shown that the low level of vitamin D was more likely to be associated with women with obesity ,23,42,43It has been reported that vitamin D deficiency is inversely associated with histological grade and tumor stage in breast cancer ,45. The p < 0.03). After adjustment for ethnicity, tumor size, node stage, ER/PR/HER2 status, seasons of blood draw, BMI and age at the time of diagnosis the RR of reducing DFS was still remaining at 1.9 to 2.2 when the level of 25(OH)D3 below 20 ng/mL. The RR for reducing OS was also increased per quartile with decreasing level of 25(OH)D3 in our study. However, once the analysis was performed by stratifying ethnicity the RR lost statistical significance in both univariate and multivariate analyses. In this study we were not able to adjust other potential confounders, such as alcohol usage, smoking, oral contraceptives using and physical activities since this information was not collected for all of subjects. Further study with an enlarged sample size or by adjustment for all of those potential confounders need to be conducted to verify the significant association between the level of 25(OH)D3 and the disease-outcome of breast cancer in African-American and Hispanics.Our study is one of the few studies that compares the association between serum 25(OH)D3 level and incidence of breast cancer between African-American and Hispanic living in south Los Angeles with similar lower social-economic status. South Los Angeles and/or SPA6 area had 31% of population that lives in poverty ) and median household income is $36,400  . The finIn summary, data from this study showed a significant inverse association between serum 25(OH)D3 levels and breast cancer risk in African-American and Hispanic women. The predicted probability of breast cancer was significantly higher in African-American women with 25(OH)D3 level below to 26 ng/mL compared to that in Hispanic women with same level of 25(OH)D3. A significant association of 25(OH)D3 level (below 20 ng/mL) with TNBC tumor was seen in African-American patients. The 25(OH)D3 level below 13 ng/mL predicts reduced DFS, but it was not an independent predictor. The significance was lost after adjustment for tumor characteristics, age, BMI and the seasons of blood draw. The data suggests that the benefits of vitamin D may be included in reducing the risk of breast cancer and perhaps in reducing the risk of TNBC. Further studies are also warranted to understand the influence of SNPs in the vitamin D induced VDR pathway. Assessment of serum vitamin D levels could provide a positive benefit toward identification of at risk populations for breast cancer, and subsequently provide better intervention strategies for prevention of breast cancer.The study population was recruited from SPA6 region of South Los Angeles County in California. The population by race/ethnicity in SPA6 are 28% African-American, 68% Hispanic/Latino, and 4% others that include Caucasian, Asian, Native-American and Pacific-islander. The cohort comprised of women examined in the Mammography Clinic or the Hematology/Oncology Clinic at the Martin Luther King Ambulatory Care Center  between 1995 and 2007. Women were consented for an ongoing breast cancer study conducted in the Division of Cancer Research and Training at Charles R. Drew University of Medicine and Science and MACC. The study was approved by the Institutional Review Board. For follow up data, we conducted post-hoc medical records abstraction.n = 1400). Those women were consented for the breast cancer study. The inclusion/exclusion criteria were the following: (a) Self-identified race/ethnicity: from self-report, 30% were African-American, 65% were Hispanic, and the remaining 5% were Caucasian or Asian subjects. Considering the subjects from Caucasian and Asian were relative small that will not generate meaningful analysis we only included African-American and Hispanic women in this study. When the African-American and Hispanic ethnicity criteria were applied, n = 1330 women met the criteria; (b) Confirmation of breast cancer: For cases, breast cancer status was determined by biopsy/pathology confirmed neoplasm of the breast, and only subjects who had documentation of this information were included in the study (n = 368). For controls, normal was determined by normal mammogram results, and benign was determined by mammogram and biopsy confirmed non-cancer  (n = 962); (c) Baseline blood sample (serum sample collected at the time of diagnosis and prior to any cancer treatment for cases), documentation of age at the time of sample collection. A total 940 samples were available (330 cases and 610 controls); We selected (d) cases with documented disease follow-up information and controls with benign disease having 2-years follow-up mammography information for assessing level of 25(OH)D2, 25(OH)D3 and total vitamin D. .To measure circulating 25-hydroxyvitamin D levels a total 150 µL of serum samples prior to any cancer treatment (average 4 weeks prior treatment) was sent to a Quest-Diagnostics™ laboratory. The serum 25(OH)D2, 25(OH)D3 and total level of 25(OH)D were measured using a Liquid Chromatography/Tandem Mass Spectrometry (LC/MS/MS) method. The 25(OH)D3 indicates both endogenous production and supplementation. The 25(OH)D2 is an indicator of exogenous sources such as diet or supplementation. The total vitamin D is a combination of 25(OH)D2 and 25(OH)D3. The level of 25(OH)D2 was lower than 4 ng/mL (out of range for determination) in 88% of the subjects from our cohort. To obtain the meaningful statistical analysis the level of 25(OH)D3 was used for the study analysis. The level of vitamin D was considered “deficiency” if the 25(OH)D3 level < 20 ng/mL, “insufficiency” if the 25(OH)D3 level at range from 20 ng/mL to 29 ng/mL, or sufficiency if otherwise for this study. The 25(OH)D3 levels were also calculated according to the quantiles  for assessing predicted probability of breast cancer and for assessing RR of reducing DFS and OS for breast cancer patients.Tumor size, lymph node status and TNM staging were all determined according to AJCC definitions. Tumor subtype was categorized according to the status of receptors and as follows: (i) ER/PR+/HER2−; (ii) HER2+ (ER/PR− or ER/PR+); (iii) Triple negative (ER/PR−/HER2−).The information on ethnicity was based on self-report and age at the diagnosis/recruitment, Body Mass Index (BMI) and clinical information were obtained through medical chart extraction. Estrogen and progestogen receptors (ER/PR) status was considered “Positive” if > 5% of tumor cell nuclei immunoreactive, or “Negative” if otherwise. HER2 (HER2/nu) status was considered “Positive” if HER2 = 3+, “Negative” if HER2 = 0, 1+, 2+, determined by immunohistochemistry or assigned using in situ hybridization to assess HER2 gene amplification. Survival and disease outcome in the study were assessed by 5 year DFS and 5 year OS. DFS was assessed based on screening tests such as mammography, CT scan, Ultrasounds, Bone-scans that the patient underwent after treatment and resolution of the primary cancer. DFS for a patient was defined as not having any of the following: (1) Reoccurrence; (2) Metastatic disease; (3) New primary tumor formation at another organ site. OS was calculated from the time of diagnosis to death from breast cancer.2-test and the p-values from χ2-test were adjusted with Bonferroni correction. Logistic regression with univariate and multivariate analysis were used to assess the association of deficiency in 25(OH)D3 level with breast cancer in the total and ethnically sub-categorized cohort. The multivariate analysis for the association between deficiency of 25(OH)D3 and breast cancer in the total cohort was adjusted for age, ethnicity, BMI and the seasons of blood draw. The association for ethnically sub-categorized cohort was adjusted for age, BMI and the seasons of blood draw. The level of 25(OH)D3 was also categorized by percentiles based on the distribution of 25(OH)D3 in controls. The probability of breast cancer in African-American and Hispanic was predicted by Logistic Regression according to the percentiles of 25(OH)D3 and the linear trends of the predicted probability was estimated using Regression Curve estimation. The significant differences of the trends of predicted probability between African-American and Hispanic was determined by Wilcoxon signed-rank test.Statistical analysis was performed using SPSS software . The level of 25(OH)D3 was analyzed as both continuous variable (median and mean ± SD) and categorical variable (<20 ng/mL or ≥20 ng/mL). The statistical differences of 25(OH)D3 level among different ethnic, age group (categorised as 10 years group), BMI . The statistical significance was evaluated by using ANOVA for mean, Mann-Whitney U test for median age and median BMI. The associations of the deficiency of 25(OH)D3 with ethnicity, age group and BMI were assessed throughout using the χp < 0.05 was considered statistically significant.The associations of 25(OH)D3 levels with breast cancer subtypes were also determined by Logistic regression with multivariate analysis adjusted for age, BMI and the seasons of blood draw. Relative Risk (RR) of 25(OH)D3 levels for reducing DFS and OS was assessed by Cox regression with multivariate analysis adjusted for ER/PR/HER2 status, tumor size, node involvement, tumor stages, BMI, the seasons of blood draw and the age at the time of diagnosis. The 25(OH)D3 levels were categorized by quartiles based on the distribution of 25(OH)D3 level in cases and the RRs were evaluated with the level of 25(OH)D3 per quartile. Throughout all analyses, only the Data from our study supports the hypothesis that the 25(OH)D3 level below 20 ng/mL was significantly associated with risk of breast cancer. The level of 25(OH)D3 below 26 ng/mL predicts a decrease in disease-free survival, but it was not an independent predictor. The level of 25(OH)D3 below 20 ng/mL was fund to be associated with TNBC in African-Americans. Further studies on the relationship between 25(OH)D3 level and breast cancer risk are warranted.


Several randomized controlled trials of anti-estrogens, such as tamoxifen and aromatase inhibitors, have demonstrated up to a 50–65% decrease in breast cancerincidence among high-risk women. Approximately 15% of women, age 35–79 years, in the U.S. meet criteria for breast cancer preventive therapies, but uptake of these medications remain low. Explanations for this low uptake includelack of awareness of breast cancer risk status, insufficient knowledge about breast cancer preventive therapies among patients and physicians, and toxicity concerns. Increasing acceptance of pharmacologic breast cancer prevention will require effective communication of breast cancer risk, accurate representation about the potential benefits and side effects of anti-estrogens, targeting-specific high-risk populations most likely to benefit from preventive therapy, and minimizing the side effects of current anti-estrogens with novel administration and dosing options. One strategy to improve the uptake of chemoprevention strategies is to consider lessons learned from the use of drugs to prevent other chronic conditions, such as cardiovascular disease. Enhancing uptake and adherence to anti-estrogens for primary prevention holds promise for significantly reducing breast cancer incidence, however, this will require a significant change in our current clinical practice and stronger advocacy and awareness at the national level. Based upon results from several randomized controlled trials  and aromatase inhibitors (AIs), have been associated with a 50–65% relative risk reduction in invasive breast cancer among high-risk women.9 Due to the strength of this evidence, the U.S. Preventive Services Task Force (USPSTF), American Society for Clinical Oncology (ASCO), National Comprehensive Cancer Network (NCCN), and the National Institute for Health and Care Excellence (NICE) recommend that clinicians discuss preventive therapy with high-risk women.13 About 10 million women in the U.S. are eligible for breast cancer preventive therapy,14 but fewer than 10% of high-risk women offered an anti-estrogen for primary prevention agree to take it.16 Because breast cancer risk assessment is not routinely conducted in the primary care setting, many women and their physicians may be unaware of their risk of developing breast cancer and that preventive options are available. These options include lifestyle modifications, such as reduction of alcohol consumption, increasing exercise, and maintaining a healthy body weight, and pharmacologic options. Many primary care providers (PCPs) may feel uncomfortable prescribing a medication that is commonly prescribed by cancer specialists. The perception is that since these medications are used to treat cancer, they may have significant side effects.17 The commonly used phrase of “chemoprevention” for the use of anti-estrogens for primary prevention often has negative connotations, however, “preventive therapy” may be more acceptable.18 Further research is needed to determine how to better educate and communicate with physicians and women about breast cancer risk, healthy lifestyle, and preventive therapy options available.Breast cancer is the most common malignancy among women in the U.S. and worldwide.19 easily accessible at no cost on-line, is the most commonly used tool to estimate a woman’s risk of developing breast cancer. This tool was used to determine eligibility for breast cancer preventive therapy in the North American prevention trials. It incorporates current age, age at menarche, age at first live birth, race/ethnicity, first-degree family history of breast cancer, and the presence of benign breast disease, including atypical hyperplasia. Eligibility for chemoprevention included women aged ≥ 60 years or those with a 5-year invasive breast cancer risk greater than1.67% or lifetime risk greater than 20%. The European prevention trials used the Tyrer-Cuzick model,20 which incorporates genetic and non-genetic breast cancer risk factors including a more extensive family history, to determine eligibility for pharmacologic prevention. For the International Breast cancer Intervention Studies of tamoxifen (IBIS-I) and anastrozole (IBIS-II), women who had a 10-year risk of breast cancer according to the Tyrer-Cuzick model of 5% or greater were eligible to enroll.9 Both the Gail and Tyrer-Cuzick models have been cited as inadequate for risk assessment. The Tyrer-Cuzick model overestimates risk of cancer in women with breast atypia.21 The Gail model has been well-validated at the population level,19 and has been updated for more sensitive risk estimates in African American22 and Asian American populations.23 However, few studies have used this model in Hispanic populations.25 Other breast cancer risk models, such as Tyrer-Cuzick, BRCAPRO, and BOADICEA , may be used to estimate risk in women with a strong family history of breast or ovarian cancer.26The Gail breast cancer risk assessment tool (BCRAT),27 Long-term studies indicate that women with atypical hyperplasia or LCIS have a greater than 30% lifetime risk of breast cancer.29 Due to the high estrogen receptor (ER) expression in benign breast disease,30 these women appear to derive a greater benefit from anti-estrogensin terms of breast cancer risk reduction compared to other high-risk populations. The subgroup of women with atypical hyperplasia enrolled in the chemoprevention trials had a 41–79% relative risk reduction in breast cancer incidence.32 Since uptake of breast cancer preventive therapy remains low among these women,33 this is an important high-risk population to specifically target for use of anti-estrogens for primary prevention.Women with high-risk benign breast lesions, such as atypical ductal hyperplasia, atypical lobular hyperplasia, and lobular carcinoma in situ (LCIS), have up to a 4- to 10-fold increased risk of breast cancer compared to women with non-proliferative breast disease.CHEK2, ATM, CDH1, NBN, NF1, PALB2, among others, are now being identified. It is unclear if chemoprevention would be efficacious in this population of women.A new and emerging group of women who are at increased risk of developing breast cancer are those with a gene mutation that is associated with a moderately increased risk of breast cancer. The ability to test for multiple genes (panel testing) has revealed a group of women who may be at moderately elevated risk of developing breast cancer. 38 Based upon long-term follow-up in the IBIS-I, the protective effect of tamoxifen for breast cancer risk reduction persisted after discontinuation of therapy.6 Another SERM, raloxifene, has been shown to reduce breast cancer incidence and improve bone health among postmenopausal women.40 Although initial results from the Study of Tamoxifen and Raloxifene (STAR) trial suggested that raloxifene may be inferior to tamoxifen in lowering noninvasive breast cancer risk among high-risk postmenopausal women,41 updated results demonstrated that raloxifene was 25% less effective than tamoxifen for lowering invasive breast cancer risk, but had a more favorable side effect profile with fewer uterine cancers and thromboembolic events.7 The results of these trials led to the approval by the U.S. Food and Drug Administration (FDA) of tamoxifen in 1998 and raloxifene in 2007 for the primary prevention of breast cancer among high-risk women.The Breast Cancer Prevention Trial (BCPT) showed that 5 years of tamoxifen reduced breast cancer incidence in high-risk women by 49% ref. . Other t8 Similar findings were observed in the IBIS-II trial in high-risk postmenopausal women with a lower incidence of invasive and non-invasive breast cancers seen with anastrozole for 5 years vs. placebo . Extended hormonal therapy in the adjuvant setting with the AI, letrozole, for up to 10 years compared to 5 years for women with early stage invasive breast cancer has been shown to be more effective at preventing contralateral breast cancers.42 This study also brings into question about the optimal duration of AI therapy for breast cancer prevention.MAP.3  confirmed the efficacy of AIs for the primary prevention of breast cancer among high-risk postmenopausal women. Five years of exemestane was associated with a 65% relative risk reduction in invasive breast cancer incidence compared to placebo.44 unclear duration of chemoprevention for optimal efficacy, and lack of evidence in reducing breast cancer-specific or overall mortality. The reason why none of the prevention studies have shown an improvement in overall survival is because the primary end point of the prevention studies has been breast cancer incidence. Without demonstrating an improvement in overall survival, some physicians may be reluctant to prescribe a long-term medication with potential for toxicity. Additionally, none of the prevention studies have demonstrated an improvement in quality of life (QOL) for women who choose chemoprevention. However, lowering breast cancer incidence may impact the rising costs of diagnosing, treating, and providing care for breast cancer patients, with annual costs for breast cancer care projected to surpass $20 billion by 2020  of new benign endometrial abnormalities on tamoxifen with up to 5 years of follow-up.59 Based on this study, a baseline normal endometrial sonogram could potentially provide some reassurance to women who might otherwise decline tamoxifen therapy due to fear of endometrial cancer. During tamoxifen therapy, women should undergo yearly examinations by a gynecologist with diagnostic work-ups for postmenopausal vaginal bleeding. Routine pelvic ultrasounds or endometrial biopsies during tamoxifen treatment in asymptomatic women is not recommended, because this has not been shown to be effective.60Concerns about rare but serious side effects of tamoxifen, such as endometrial cancer and thromboembolism, are the main reasons for reluctance among high-risk women to take this agent and reservations among physicians to prescribe it.61 Overall QOL was similar in women receiving tamoxifen and raloxifene in the STAR trial.61 Compared to placebo, the AIs are associated with in increased rate of vasomotor symptoms (57% vs. 49%), vaginal dryness (19% vs. 16%), arthralgias (51% vs. 46%), and hypertension (5% vs. 3%).9 Osteoporosis, decreased bone density and fractures are another concern with AI use; there was no significant difference in new-onset osteoporosis in the MAP-3 study of exemestane vs. placebo.7 In addition, there was no difference in cardiovascular events, second malignancies, or QOL in women receiving exemestane vs. placebo.8Raloxifene is associated with a lower rate of of thromboembolism, uterine complaints, and cataracts compared to tamoxifen.62 The first network meta-analysis of the efficacy and acceptability of preventive therapies for breast cancer from randomized controlled trials found that new-generation SERMs, such as raloxifene, had the best risk-benefit ratio, followed by AIs and tamoxifen.63 Therefore, high-risk postmenopausal women have more options for preventive therapy with raloxifene and AIs, which have fewer serious side effects compared to tamoxifen.To provide a more personalized risk-benefit profile of preventive therapy among high-risk postmenopausal women, a model was developed to weigh the potential risks and benefits of tamoxifen and raloxifene based upon age, race/ethnicity, absolute breast cancer risk, and prior hysterectomy.Of note, the side effects diminish after completing 5 years of anti-estrogens, but the beneficial aspect in preventing breast cancer endures after drug cessation. Unlike other pharmacologic interventions for cardiovascular disease prevention that require chroniclife-long treatment, breast cancer chemoprevention may be limited to 5 years with long-standing benefits with adverse effects present only during active therapy. Table 16 Based upon data from 26 studies on uptake of preventive therapies, Smith et al.16 reported that uptake was 25.2% among women screened for clinical trials, but only 8.7% in the non-trial settings.16 After its FDA approval for primary prevention in 1999, tamoxifen use among women unaffected with breast cancer was 0.2% in 2000 and decreased to 0.08% in 2005  discontinued treatment within 4.5 years.65 Factors associated with poor drug adherence include lower socioeconomic class and members of ethnic minorities.67 Better understanding of the predictors for poor uptake and adherence will inform the development of targeted interventions that may improve utilization of chemoprevention for high-risk populations.The effectiveness of preventive therapy also depends on patient adherence. In the prevention trials, adherence varied from 64 to 85% refs , 61. Adh52 Strategies to minimize side effects of anti-estrogens include developing novel endocrine agents, novel administration including intermittent or lower drug dosing, and alternative drug delivery systems, such as topical chemoprevention agents. Novel SERMs used for osteoporosis, such as arzoxifene,68 bazedoxifene,69 and lasofoxifene,70 show evidence of reducing breast cancer risk with a better side effect profile compared to tamoxifen.63 Several studies of low-dose tamoxifen (1–10 mg daily) or intermittent dosing of 10–20 mg every other day or weekly have shown similar biologic effects to daily dosing of tamoxifen 20 mg with fewer adverse effects.78 Transdermal tamoxifen applied to the breasts, is another novel, and perhaps more acceptable prevention modality.79 Two presurgical window-of-opportunity trials in women with invasive and non-invasive breast cancer demonstrated that topical 4-hydroxytamoxifen (4-OHT) was comparable to oral tamoxifen for decreasing tumor proliferation with lower systemic drug levels.81 The long-term effects of these alternative strategies for breast cancer prevention are actively being investigated.Most patients and providers may believe that the risks of side effects of chemoprevention may outweigh the potential benefits for breast cancer risk reduction, therefore, use of these medications remains low. Concern about side effects has been associated with lower uptake for primary prevention.82 Different medical specialties vary widely in their use of the Gail model  and ever prescribing anti-estrogens .83 Additional barriers to routine breast cancer risk assessment include time constraints, lack of familiarity and comfort prescribing preventive therapy.84 Physician recommendation and effective communication strongly influence uptake of preventive therapy for breast cancer.85 Providers who were less informed about breast cancer risk-reducing options were less than half as likely to prescribe a SERM than those who felt sufficiently trained.86In addition to concerns about toxicities, another major barrier to uptake of anti-estrogens for preventive therapy is a robust risk assessment model that accurately estimates patient risk. The Gail model is the most widely used risk assessment model, but its accuracy may be limited by patient ethnicity and consideration of first-degree relatives only when evaluating family history of cancer. The Tyrer-Cuzick model, is not one that is familiar to most PCPs. Only 18% of PCPs report use of the on-line Gail model to estimate a patient’s breast cancer risk.87 What is needed even more is chemoprevention for the more difficult to cure ER-negative breast cancers. When diagnosed at an early stage, women with ER-positive breast cancer have an excellent prognosis.Critics of chemoprevention cite that ER-positive breast cancer is a curable condition; so why should we subject healthy women to a long-term treatment with potential for adverse effects. At 20 years, the number needed to treat to prevent 1 invasive breast cancer is 29; so that 28 women would unnecessarily undergo treatment to prevent 1 curable cancer.Guide to Decide, which informed high-risk postmenopausal women about potential benefits and side effects of chemoprevention yielded only 0.5% uptake of raloxifene and no tamoxifen use.88 The Ready, Set, GO GAIL! project involved systematic screening of over 5700 women by PCPs using the Gail model.89 Among 868 (15.2%) women who met high-risk criteria for breast cancer, 14.7% were referred for specialized risk counseling, 6.4% completed the consultation, and only 2% initiated chemoprevention. The BreastCARE intervention used a tablet-based patient intake tool in the primary care setting that produced a tailored breast cancer risk report for patients and their physicians.90 In a randomized controlled trial of the BreastCARE intervention in 1235 women (age 40–74 years), more women in the intervention arm compared to controls were referred for a high-risk consultation (18.8% vs. 4.1%), however, there was limited discussions about chemoprevention documented in the medical record (1% vs. 0%). Orlando et al.91 reported on an implementation trial of the MyTree family history screener, which generated tailored risk reports for patients and providers. Of 26 women found to be eligible for preventive therapy, none of them initiated an anti-estrogen for breast cancer prevention.Intervention trials of clinical decision support tools designed to increase uptake of breast cancer preventive therapy targeting both patients and providers have met with limited success. A web-based decision aid called Studies from specialized risk assessment and counseling clinics reported uptake of preventive therapy ranging from 11 to 58% refs , 92–94. Breast cancer preventive therapy with anti-estrogens is efficacious among high-risk women; however, acceptance remains low. Potential strategies to improve uptake of preventive therapy include: (1) Targeting-specific high-risk populations, such as younger women who are at lower risk of serious side effects and women with high-risk benign breast lesions who derive greater benefit from anti-estrogens; (2) Minimizing toxicities with alternative endocrine agents and novel drug administration schedules and drug delivery methods; (3) Enhancing breast cancer risk assessment and informed decision-making about preventive therapy in the primary care setting with decision support tools integrated into clinic workflow.95 Novel ways of conducting breast cancer risk assessment are needed. Screening mammography visits may represent such a “teachable moment”. As the majority of states in the U.S. now have legislation for mandatory breast density notification, when women receive information about high breast density, which also increases breast cancer risk, this may serve as an opportunity to discuss risk-reducing options with their PCP. Health information technologies such as electronic health records and patient health portals may be a method for collecting data on breast cancer risk and presenting information about chemoprevention, which is integrated into clinic workflow.4 Preventive therapy may also be integrated into broader strategies of cancer prevention, such as discussions about lifestyle factors, which influence breast cancer risk, such as obesity, physical activity, and alcohol consumption.Cancer prevention is not as well established as cardiovascular disease prevention.96 due to increasing costs of cancer care.99 Promoting breast cancer prevention should be a priority that involves novel risk assessment strategies, education of patients, and providers, advocacy, and awareness at the national level.Breast cancer incidence continues to increase and the economic burden of cancer in the U.S. is expected to increase significantly,