Menopausal symptoms have been suggested to be an indicator of better prognosis among patients treated for breast cancer, because women who experience these symptoms usually have a lower level of estrogen. We tested this hypothesis in a population-based, prospective cohort study involving 4,842 women with stage 0 to III primary breast cancer who were enrolled in the Shanghai Breast Cancer Survival Study between March 2002 and April 2006, were aged 20 to 75 years, and were recruited 6 months post-diagnosis. They were followed-up by in-person surveys and record linkages with the vital statistics registry. Cox regression analysis was used to evaluate the association of menopausal symptoms at baseline with breast cancer recurrence. Approximately 56% of patients experienced at least one menopausal symptom, including hot flashes, night sweats, and/or vaginal dryness at baseline. During a median follow-up period of 5.3 years, 720 women had a recurrence. Experiencing hot flashes or having ≥2 menopausal symptoms was associated with lower risk of recurrence among premenopausal women . Lower recurrence risk in relation to hot flashes was also observed among women who were not overweight/obese , those with relatively low waist-to-hip ratio (WHR) , and those who used tamoxifen . Consistently experiencing multiple menopausal symptoms was associated with lower recurrence risk among women with low WHR or who used tamoxifen. This large, population-based cohort study of women with breast cancer confirms that experiencing menopausal symptoms is an indicator of favorable breast cancer prognosis. Breast cancer is the most common malignancy among women worldwide. Approximately 14% of all female cancer deaths are caused by breast cancer, and it is the second leading cause of cancer-related deaths among women . In ChinWomen with breast cancer, particularly those who are younger, commonly experience menopausal symptoms after initial cancer treatment –6, incluMenopausal symptoms have serious effects on women’s quality of life, and medical intervention may be required to alleviate them . This isThe SBCSS was approved by the institutional review boards of Vanderbilt University and the Shanghai Municipal Center for Disease Control and Prevention. Before interviews were conducted, written informed consent was obtained from all patients.The SBCSS is a large, longitudinal, population-based study that recruited women aged 20-75 years who were diagnosed with primary breast cancer between March 2002 and April 2006. Breast cancer patients were identified from the population-based Shanghai Cancer Registry and recruited into the study approximately six months after cancer diagnosis. The inclusion criteria were: 1) diagnosis of primary breast cancer, 2) being a local resident and having a permanent household registration in Shanghai, China, and 3) alive at study recruitment. Initially, 6,299 patients were identified, of which 5,042 completed the baseline survey. Reasons for non-participation included: refusal (n=757), absence during study enrollment (n=258), unable to contact (n=83), and other miscellaneous reasons, such as health or communication problems (n=159). We excluded patients with distant metastases (TNM stage IV: n=28), because their treatment, clinical condition, and disease outcomes could affect their assessment of menopausal symptoms. Patients taking hormone replacement therapy (n=175) were excluded as well, since this therapy may affect the occurrence of menopausal symptoms. A total of 4,842 breast cancer patients remained for analysis.In-person interviews were conducted by trained interviewers at 6 months after breast cancer diagnosis by using structured questionnaires to collect information on demographic characteristics, reproductive and medical history, lifestyle, diet, use of complementary and alternative medicine, and quality of life. Clinical information such as cancer stage at diagnosis, tumor estrogen receptor (ER) and progesterone receptor (PR) status, and primary treatments, including surgery, radiation therapy, chemotherapy, immune therapy, and tamoxifen use, were also collected. The medical record of each patient was reviewed to verify clinical and treatment information. Anthropometric measurements such as height, weight, and waist and hip circumferences were taken according to a standard protocol. Body-mass index (BMI) and waist-to-hip ratio (WHR) were calculated based on these measurements. History of chronic disease before breast cancer diagnosis was collected and coded according to the International Classification of Diseases Ninth Revision, Clinical Modification (ICD-9-CM) ; and a CThe demographic, clinical, and lifestyle characteristics of breast cancer patients with or without any of the three major menopausal symptoms were compared using the Cochran-Mantel-Haenszel test for categorical variables and analysis of variance for continuous variables. Breast cancer recurrence was the main outcome of this study. Recurrence included local/regional recurrence, distant recurrence/metastasis, or development of new primary breast cancer . Diseasevs. no), soy isoflavone intake , and overweight/obesity status  with breast cancer recurrence. Women who reported no menopausal symptoms or who had high BMI, high WHR, no use of tamoxifen, or low isoflavone intake were used as the reference group in these analyses. Multiplicative interactions between menopausal symptoms and these exposures were examined using the log likelihood ratio test, which compared the model including only the main effects with the model that included both the main effects and the interactive terms. The statistical significance level was set at P < 0.05 and all tests were two-sided. SAS software, version 9.2  was used to perform the statistical tests.We used Cox proportional hazards models to evaluate associations of menopausal symptoms  with the risk of breast cancer recurrence by estimating hazard ratios (HRs) and 95% confidence intervals (CIs) using age as the time scale. Entry time was defined as age at diagnosis, and exit time was defined as age at recurrence or censoring at non-breast cancer death or last survey. Models were adjusted for demographic, lifestyle, and clinical prognostic factors, which included age at diagnosis (continuous); educational level (categories); number of pregnancies ; marital status (currently married/not married); history of chronic disease expressed as Charlson co-morbidity index (0/≥1); self-reported quality of life ; received radiotherapy, chemotherapy, tamoxifen (where appropriate) or immunotherapy (yes/no); TNM stage ; and tumor hormone receptor status (ER+/- and/or PR+/-). We examined associations of menopausal symptoms and risk of recurrence in relation to menopausal status . Further, we examined joint associations for menopausal symptoms and tamoxifen use . Menopausal symptoms did not appear to vary by level of regular exercise, vitamin supplement use, drinking tea or alcohol, cigarette smoking, surgical treatment or radiotherapy, disease stage (TNM stage), or family history of breast cancer.During a median follow-up time of 5.3 years, 676 total deaths and 720 recurrences were reported. About 56% of all patients reported one or more menopausal symptom at baseline. Prevalence for hot flashes was 44.2%, for night sweats was 35.4%, and for vaginal dryness was 8.8%. Among patients with TNM 0-I breast cancer: 808 had hot flashes, 611 had night sweats, and 165 had vaginal dryness; among patients with TNM II breast cancer: 1058 had hot flashes, 870 had night sweats, and 205 had vaginal dryness; and among patients with TNM III breast cancer: 188 had hot flashes, 153 had night sweats, and 36 had vaginal dryness. Demographic, clinical, and lifestyle characteristics in relation to the presence or absence of any of the three major menopausal symptoms are presented in P interactions >0.05 for all). Kaplan-Meier Curves describing the association of hot flashes and number of menopausal symptoms with recurrence is shown in Associations of breast cancer recurrence with menopausal symptoms according to menopausal status are presented in P-interaction=0.05), but not for BMI (P-interaction=0.24). Similarly, experiencing ≥2 menopausal symptoms was associated with a lower risk of recurrence among women with low BMI  or low WHR , but not among women with high body or abdominal fatness and without menopausal symptoms. Interaction tests between the number of menopausal symptoms and BMI or WHR were not statistically significant .The joint effects of menopausal symptoms, BMI, and WHR on breast cancer recurrence are presented in P-interaction=0.30). Similarly, patients who experienced ≥2 menopausal symptoms and used tamoxifen had a lower risk of recurrence  than those with no tamoxifen use and no menopausal symptoms. Associations between menopausal symptoms and breast cancer recurrence did not differ by soy-isoflavone intake.We also examined joint associations between menopausal symptoms and tamoxifen use or soy-isoflavone intake and breast cancer recurrence 6. TamoxIn this large population-based cohort study of 4,842 breast cancer patients aged 20-75 years, experiencing menopausal symptoms, especially hot flashes, as well as experiencing multiple symptoms during the first 6 months post-diagnosis, were associated with a lower risk of recurrence. These associations were predominantly seen among premenopausal women, women with low BMI or WHR, and those who used tamoxifen. To our knowledge, this study is the first large-scale, prospective investigation to provide evidence for an inverse association between menopausal symptoms, particularly hot flashes, shortly after breast cancer diagnosis and during the initial cancer treatment period, and breast cancer recurrence in Chinese women. Vaginal dryness and night sweats were less common among our study participants and were not associated with recurrence risk in our population, as has been previously reported for women in North America .Although the biological mechanisms underlying vasomotor symptoms such as hot flashes and night sweats are not very clear, it has been reported that these symptoms may be related to the acute drop in estrogen levels during natural and medically induced menopause ,29. WomeN-desmethyl tamoxifen (endoxifen), have potent anticancer effects, because of their anti-estrogenic properties [P=0.01) [Tamoxifen is one of the most widely used drugs for breast cancer patients ,32 and eoperties . In the [P=0.01) . The aut[P=0.01) . ConsistWe also observed that patients with lower BMI or WHR had a lower risk of recurrence, if they had hot flashes or reported multiple symptoms. Higher BMI and WHR, indicators for overall and central obesity, have been associated with high circulating estrogen levels ,34, whicSoy-isoflavone is known to have anti-estrogenic properties . The assMenopausal symptoms are known to negatively affect women’s quality of life (QoL), including breast cancer survivors –40. Our Several potential limitations should be considered in this study. First, data on menopausal symptoms were collected through in-person interviews by self-reports. Some Chinese women may not report certain symptoms, such as vaginal dryness, considering it too private. Thus, misreporting and under-reporting are likely, which would have biased our results towards null. Second, we did not collect information on the severity, frequency, or duration of symptoms. Third, although the results were adjusted for a wide range of covariates, the possibility of residual confounding still exists. Fourth, the lack of direct measurement of estrogen hormone levels prevented us from investigating the underlying mechanisms for the associations between menopausal symptoms and breast cancer recurrence. Our study also has several strengths. This is a large, population-based, prospective study specifically designed to investigate the association of menopausal symptoms with breast cancer recurrence among Chinese women. The high response rates, as well as the detailed information on socio-demographic, anthropometric, clinical, and lifestyle characteristics, collected using a well-validated questionnaire, minimized selection bias and allowed us to account for confounding from multiple factors and to evaluate potential interactions.In summary, we found that the occurrence of menopausal symptoms, including hot flashes, night sweats, and/or vaginal dryness during the first 6 months post-diagnosis and post- treatment, were associated with a lower risk of breast cancer recurrence among Chinese women. Although experience of menopausal symptoms is a subjective feeling from patients, the link between low estrogen exposure and menopausal symptoms has been well established . Thus, e


In this large population-based case-control study, we found no conclusive evidence of breast cancer risk associated with the use of SSRIs even after assessing the degree of serotonin reuptake inhibition and duration of use. Our results do not support the serotonin-mediated pathway for the prolactin-breast cancer hypothesis.Selective serotonin reuptake inhibitors (SSRIs) are a widely prescribed class of antidepressants. Laboratory and epidemiologic evidence suggests that a prolactin-mediated mechanism secondary to increased serotonin levels at neuronal synapses could lead to a potentially carcinogenic effect of SSRIs. In this population-based case-control study, we evaluated the association between SSRI use and breast cancer risk as a function of their relative degree of inhibition of serotonin reuptake as a proxy for their impact on prolactin levels. Cases were 2,129 women with primary invasive breast cancer diagnosed from 2003 to 2007, and controls were 21,297 women randomly selected from the population registry. Detailed information for each SSRI prescription dispensed was compiled using the Saskatchewan prescription database. Logistic regression was used to evaluate the impact of use of high and lower inhibitors of serotonin reuptake and duration of use, as well as to assess the effect of individual high inhibitors on the risk of breast cancer. Exclusive users of high or lower inhibitors of serotonin reuptake were not at increased risk for breast cancer compared with non-users of SSRIs , regardless of their duration of use or menopausal status. While we cannot rule out the possibility of a clinically important risk increase  for long-term users of sertraline (≥24 prescriptions), given the small number of exposed cases ( Selective serotonin reuptake inhibitors (SSRIs) are prescribed widely for the treatment of depression as well as for the management of chronic pain, menopausal symptoms, and migraine headache prophylaxis , such as vasoactive intestinal peptide (VIP) and oxytocin (OT), from the hypothalamus. In turn, these substances stimulate lactotrophs in the pituitary gland to release prolactin   , Canada were linked to conduct this study: (1) the population registry for socio-demographic information and dates of insurance coverage; (2) the Saskatchewan prescription drug plan database for outpatient prescriptions filled since the mid-1970s that are eligible for coverage by the drug plan for all Saskatchewan residents with the exception of approximately 9% of the population (primarily registered Indians); and, (3) the Saskatchewan Cancer Agency (SCA) cancer registry database for detailed information on cancer diagnoses since 1970  sampling approach  primary invasive cancers and 11 (0.5%) carcinomas For each case and control, we obtained detailed information for each SSRI prescription dispensed between either the start of their drug plan coverage or July 1, 1989 (when the first SSRI was listed on the SK Formulary), whichever was later, and their index date. Information available included drug name, strength, quantity dispensed, and dispensing date but did not include dosage prescribed , duration of the prescription, and indication for the SSRI prescription. SSRIs covered by the provincial drug plan during the study period and available without prescribing restrictions included citalopram, fluoxetine, fluvoxamine, paroxetine, and sertraline. SSRI use within a 2-year period preceding the index date was not considered to be causally associated with breast cancer development and therefore excluded from the analysis. This 2-year latency period between SSRI use and breast cancer diagnosis is supported by mathematical models of tumor growth by Moolgavkar et al.  and postParoxetine, sertraline, and fluoxetine were classified as “high” inhibitors based on their greater serotonin transporter binding potency relative to citalopram and fluvoxamine  , marital status , place of residence status , and income support status  using yearly demographic data available  and duration of use, as well as to assess the effect of individual high inhibitors on the risk of breast cancer using non-users of SSRIs as the comparator group for all analyses. To evaluate potential confounders, the “change in estimate” method was used with covariates retained in the final model if they changed the main exposure estimate by 10% or more  presented as stage one, 36.2% stage two, 13.0% stage three, 4.6% stage four, 0.5% Cases and controls were similar with regard to age, duration of follow-up, receipt of income support (a marker of socio-economic status), and place of residence Table . HoweverTable We did not observe an increase in breast cancer risk according to duration of SSRI use, regardless of the degree of serotonin reuptake inhibition . However, the number of long-term users  was very small Table .p = 0.24 for test of interaction) or lower inhibitors  , the borderline statistical significance and the wide confidence interval, these results need to be interpreted cautiously.In this large population-based case-control study, we found no evidence of increased risk of breast cancer associated with the use of high inhibitor SSRI antidepressants regardless of their duration of use or menopausal status. While we cannot rule out the possibility of a clinically important risk increase for long-term users of sertraline (≥24 prescriptions), given the small number of exposed cases  appear to be different, any comparisons between results for these three drugs are limited due to overlapping 95% confidence intervals and small numbers of exposed cases . Other studies that assessed risk of breast cancer according to duration of sertraline use did not observe a statistically significant increase in risk associated with longer durations of use  (Rosholm et al., In conclusion, we found no evidence of an increased risk of breast cancer associated with the use of SSRIs even after accounting for their degree of serotonin reuptake inhibition and their duration of use in women aged 28–79. Our results do not support the serotonin-mediated pathway for the prolactin-breast cancer hypothesis.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


There are many differences in culture, community identity, community participation, and ownership between communities in Western and Asian countries; thus, it is difficult to adopt the results of community intervention studies from Western countries. In this study, we conducted a multicity, multicomponent community intervention trial to correct breast cancer myths and promote screening mammography for women living in an urban community in Korea.A 6-month, 2-city community intervention trial was conducted. In the intervention city, 480 women were surveyed at baseline and 7 months later to evaluate the effects of the intervention program. Strategies implemented in the intervention city included community outreach and clinic and pharmacy-based in-reach strategies.This study showed a 20.4-percentage-point decrease in myths about the link between cancer and breast size, a 19.2-percentage-point decrease in myths concerning mammography costs, and a 14.1-percentage-point increase in intention to undergo screening mammography. We also saw a 23.4-percentage-point increase in the proportion of women at the action stage of the transtheoretical model in the intervention city. In the comparison city, smaller decreases and increases were observed.Our study showed the value of an intervention study aimed at reducing belief in breast cancer myths in an urban community in Korea. The invention also made women more likely to undergo mammography in future. Cancer has been the leading cause of death in the Republic of Korea since 1983. Approximately 140,000 people develop cancer annually with 65,000 annual fatalities. Cancer control is an important issue because of the country's rapidly aging society and the subsequent increased burden of cancer. The National Cancer Screening Program (NCSP) offers Medical Aid users and those National Health Insurance (NHI) beneficiaries who fall within the lower 50 percent income bracket free screening for 5 common cancers--cancer of the stomach, liver, colorectum, breast, and cervix uteri. For NHI beneficiaries in the upper 50 percent income bracket, the maximum cost of a mammogram is 6 dollars. The NCSP recommends biennial mammograms for women over 40 years of age. However, only 49.5% of women act in accordance with these guidelines.Although mass media health communication strategies can effectively promote health education, and influence health awareness, decisions, practices, and care , interpeThere are more than 250 Public Health Centers (PHCs) in Korea. These organizations are part of the National Health System and are operated by local governments to prevent and control diseases or tackle hygiene problems at the county/district level. Despite the presence of this strong community-based health service network, most PHCs have struggled to use theory or evidence-based approaches to promote cancer screening. However, with the new emphasis on community-based health communication in the Second Term (2006-2015) of the 10-year Comprehensive Plan for Cancer Control, these PHCs are now looking at ways to gather evidence. One difficulty they face is that most of the research on community campaigns for promoting cancer screening has been conducted in Western countries or in non-Asian populations. As there are many differences in culture, community identities, community participation, and ownership between communities in Western and Asian countries, it is not possible to directly adopt the results of studies from Western countries.In this study, we conducted a community-based intervention study to correct myths related to breast cancer and promote screening mammography for women living in an urban community in Korea, Gunpo. The theoretical framework for the community-based interventions included the PRECEDE/PROCEED model for planning  as well We chose the social marketing strategy approach to promoting health behavior. We did not merely try to inform people or persuade them to change their behavior, but attempted to sell our services as products. We analyzed the target population using segmentation by age and TTM stage of change, and developed intervention activities according to results of the analysis. Because breast screening with the NCSP is free for Korean women aged 40 years and over and because community health education is also free, we regarded "place" and "promotion" as the main elements of the marketing mix  needing to be addressed. Therefore, we adopted an outreach education program and direct mailing as campaign activities.The Gunpo Cancer Screening Project (GCSP) aimed to identify barriers to breast cancer screening and address these barriers in a multicomponent program designed to improve beliefs, attitudes, and screening behaviors for breast cancer.We used the HBM and the TTM to develop the questionnaire for our quantitative research into health behaviors. A cross-sectional face-to-face survey using structured questionnaires was conducted with randomly selected sample of 503 women aged 30-69 years who were permanent residents in the intervention city. Self-administered questionnaires were used to collect sociodemographic data. Survey was conducted to assess predisposing factors such as perceived risk of breast cancer, knowledge on breast cancer and breast screening, perceived severity of breast cancer, awareness of breast cancer screening, perceived barriers to breast cancer screening, satisfaction with recent breast cancer screening, and self-efficacy, and reinforcing factors which are recommendations from physician or pharmacist, past history of cancer and other chronic diseases, past history of benign breast diseases, and family history of breast cancer, and finally enabling factors, for example, perceived cues to action and factors affecting hospital choice for breast cancer screening.This study was approved by the Institutional Review Board of the National Cancer Center.Health workers from the health promotion and cancer control program department in the PHC were interviewed in their role as key administrative and policy informants. We explored their current health promotion activities including their cancer control program, policy, enabling factors for the regional cancer control program, perceived barriers to the regional cancer control program, and characteristics of the PHC organization and those staff conducting health promotion. We conducted eleven focus group interviews; questions were based on stages of mammography adoption using the TTM and the HBM constructs. The results of both qualitative and quantitative research were used to develop educational materials for small group education sessions. Since this study represents only the quantitative data, we do not report the findings of qualitative research.The main message of the community campaign was that screening mammography can detect masses which are not palpable. We brainstormed messages that matched our communication campaign goal of correcting myths about breast cancer and screening mammography. These were pretested and we revised the message with the members of the Community Advisory Committee. Posters were then drawn up.Gunpo was selected for the intervention for several reasons. First, the screening rate for breast cancer was about average for Korean PHCs. Second, physical accessibility to clinics or hospitals was not a significant barrier for cancer screening. Third, its geographic and demographic characteristics allowed for generalizability for urban Korea, which is where approximately half of all Koreans live. Fourth, Gunpo is neither too large nor too small to implement a community-based intervention trial with a limited budget.2, Gunpo is located in the metropolitan area near Seoul. As of December 2007, it had a total population of 275,351 . Gwang Myeong was selected as a comparison region. We selected it because it has similar geographic and sociodemographic characteristics and because it is far enough away from the intervention city to ensure the presence of a buffer zone should the intervention "contaminate" beyond the intervention city's boundaries. Gwang Myeong is also located in the metropolitan area around Seoul with a total population of 311,700  and a land area of 38.50 km2.With a land area of 36.38 kmTo develop effective interventions, we used results from the formative research, additional focus interviews, and input from the Community Advisory Committee. Interventions implemented in Gunpo over 6 months included: (a) posters on apartment billboards; (b) posters in clinic waiting rooms; (c) posters on pharmacy walls; (d) leaflets distributed at street events; (e) direct mailing to promote breast cancer screening; (f) street promotion; (g) outbound calls to women who signed application forms at the street promotions, monthly neighborhood meetings, or small group educational sessions; (h) small group educational sessions; and (i) a blog on breast cancer screening.We obtained informed consent from all the participants who were contacted by the study team.We conducted pre-intervention baseline surveys in June 2008. This cross-sectional face-to-face survey using structured questionnaires was conducted with a random sample of 240 women aged 30-69 years from the intervention city and another 240 from the comparison city. Phase 2 began at the conclusion of the intervention delivery, approximately 7 months after the baseline survey was concluded, and involved a follow-up survey of women. The post-intervention survey was conducted with an independent sample of 240 women from each city.For campaign and non-campaign exposure, we included items for measuring possible non-GCSP campaign activities in the questionnaire. This was done in order to control the confounding effect of those extrinsic activities, which could act as "noise," and make it more difficult to assess the effectiveness of the main GCSP campaign. For dose-exposure questions, participants were asked 3 questions with a 7-point Likert-type scale for each communication activity. The questions asked: (a) if they had been exposed to the campaign activity for breast cancer screening, ranging from "never seen" to "seen very frequently;" (b) if they had been able to see the activity in detail, ranging from "never could see it in detail" to "could see very detailed information;" and (c) if it was easy to remember the activity, ranging from "could not remember the activity at all" to "could remember the activity very clearly." Overall media exposure was measured as the average of each respondent's scores across this 3-item, 7-point Likert-type scale. There was no prompting for these questions. The instrument for measuring campaign exposure modified the framework used by a top advertising agency in Korea.Respondents responded to the following 7 statements or questions: (a) most lumps suspicious of breast cancer are painful; (b) women whose breast size is bigger are more likely to get breast cancer; (c) the best time to get a mammogram is when there are breast symptoms; (d) we do not need to get a mammogram when no abnormal signs or symptoms are found in breast self examination; (e) mammograms are expensive; (f) women older than 60 do not need a mammogram; (g) do you intend to get a mammogram within 2 years? These questions were based upon formative research conducted in the first phase. The myth assessment items were included in the questionnaire because they had received lower scores in the formative quantitative survey on breast cancer awareness, health status, lifestyle, health consciousness, health behavior, knowledge on breast cancer, perceived barriers toward cancer screening, and self efficacy.Stage of mammography adoption by TTM was assessed using women's responses to the questionnaire on their intention of obtaining a mammogram in the coming 2 years, asking whether they had been screened in the previous 2 years, and looking at their reported history of mammography use in the previous 2 years.2 tests. We used t-tests to compare campaign recall scores between baseline and follow-up for each city. To assess whether the intervention was related to a beneficial change in myths with respect to breast cancer and screening mammography, χ2 tests were used. The intervention's myth busting effect was assessed using unadjusted logistic regression models. Model factors included TIME (baseline/follow-up), CITY (intervention/comparison), and a TIME by CITY interaction term. This interaction term tested the differential effect of the intervention. To determine which intervention activity was related to correct answers (correct understanding) for 6 questions related to screening mammography, a series of logistic models was fitted. We developed models using forward stepwise logistic regression for the following: subjects' characteristics; CITY, TIME, CITY by TIME interaction; all of the intervention activities listed in Table The basic characteristics on demography and past history of mammography . Most components relied on volunteers, low-cost media, and participation in community events. In this community intervention study, the combination of community outreach  and clinic and pharmacy-based in-reach (posters in clinic waiting rooms or pharmacies and physician or pharmacist recommendations) strategies was related to improve in campaign outcomes.The level of penetration of the intervention was weak to modest. Measurement was complicated by a background effect represented by baseline scores; this was because many agencies and health professionals may promote cancer screening. Also, the possible presence of concurrent communication activities by other projects in a control city may limit the effect of a campaign . BesidesIt is strange that there were also increases or decreases in myths in the comparison city. However, it is possible that there is a secular trend toward change in the control city. When such a trend exists, the effect of a campaign may be attenuated . SpecifiEven though the use of mass media, such as posters or leaflets, can convey simple information and increase knowledge, it can only change behavior if there are facilitating factors . TherefoAs part of this study, we also conducted fifteen group education sessions; these were held in nearly all apartment complexes in the intervention city over 6 months. The education session consists of following parts; OX quizzes to break the myths related to breast cancer and screening mammography, personified story to raise breast cancer awareness, statistics on breast cancer, symptoms of breast cancer, animation that shows how a mammogram is performed, and discussion on fear related to cancer screening. The education evaluation conducted in the pilot test of sampled residents showed that these education sessions improved the participants' knowledge level about both breast cancer and breast cancer screening. However, the limited number of education sessions might be insufficient to generate the critical mass necessary to impact the whole community. Group education by private hospitals (non-campaign) was negatively related to some outcome variables. This finding might be due to negative attitude toward private hospitals that provide the education sessions with intention to promote their hospitals to recruit more patients.Interestingly, personal stories of cancer patients were inversely associated with intention regarding screening mammography. The literature on cancer-related fear, worry, or anxiety, emotion regulation, and screening behavior is increasing. However, a recent review on this subject reported that the findings of the studies were contradictory . DiffereSeveral limitations need to be kept in mind when interpreting our data. This study used only 2 cities and, thus, could not guarantee the internal validity expected of randomized multi-city community intervention trials. Therefore, the results cannot be used to estimate true intervention effects or actual screening rates over time. Even though there are curvilinear functions between campaign effectiveness and campaign length, the duration of our campaign could have been too short to sufficiently impact the community. The inclusion of more cities and longer study duration were not possible because our resources were limited. Another limitation of this study is that baseline exposure scores were lower on every activity in the intervention city. A possible explanation is the inclusion of the comparison city in the World Health Organization Korean Healthy City Network in April 2008. A third limitation is that despite some sociodemographic similarities, such as age and education, at both baseline and follow-up in the intervention and comparison cities, the proportion of employed women and women with a history of mammography was different at baseline and follow-up. This suggests some differences in the baseline and follow-up survey populations in the 2 cities. However, those sociodemographic variables were statistically controlled by multivariate logistic regression including CITY, TIME, and CITY by TIME interaction to see whether the campaign activities in the intervention city had an independent influence on the city when we analyzed the effect of each campaign activity. Therefore, any statistically significant campaign activities can be regarded as independent of other variables, including sociodemographic variables.Because differences in goals, priorities, and values have been frequently found between researchers and communities -19, and The data presented here indicate a significant decrease in myths about breast size and the cost of mammography. There was also an increase in intention concerning screening mammography and in the proportion of women at the TTM action stage. These findings suggest that the combination of community outreach and clinic and pharmacy-based in-reach strategies could effectively correct myths related to breast cancer and screening mammography. They could also improve intention toward screening mammography and the stage of adoption for screening mammography for women living in urban Asian communities. Even though evaluation of community-based health interventions involving a comparison city as a control region can be laborious and difficult, such approaches are necessary to garner future support from policy-makers and other key stakeholders.The authors declare that they have no competing interests.KP participated in the conception and design of the study and drafted the manuscript. WHH and SYK participated in the conception and design of the study. EJ participated in the conception and design of the study. MK and HGP participated in design and analysis of the study. All authors gave final approval for the manuscript submitted for publication.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2458/11/468/prepub


Recently, several genome-wide association studies (GWAS) have identified novel single nucleotide polymorphisms (SNPs) associated with breast cancer risk. However, most of the studies were conducted among Caucasians and only one from Chinese.In the current study, we first tested whether 15 SNPs identified by previous GWAS were also breast cancer marker SNPs in this Chinese population. Then, we grouped the marker SNPs, and modeled them with clinical risk factors, to see the usage of these factors in breast cancer risk assessment. Two methods (risk factors counting and odds ratio (OR) weighted risk scoring) were used to evaluate the cumulative effects of the five significant SNPs and two clinical risk factors (age at menarche and age at first live birth).P = 0.006; 3q24.1, rs2307032: adjusted OR = 1.24, P = 0.005; 6q22.33, rs2180341: adjusted OR = 1.22, P = 0.006; 6q25.1, rs2046210: adjusted OR = 1.51, P = 2.40 × 10-8; 10q26.13, rs2981582: adjusted OR = 1.31, P = 1.96 × 10-4). Risk score analyses (area under the curve (AUC): 0.649, 95% confidence interval (CI): 0.631 to 0.667; sensitivity = 62.60%, specificity = 57.05%) presented better discrimination than that by risk factors counting  (P < 0.0001). Absolute risk was then calculated by the modified Gail model and an AUC of 0.658 (95% CI = 0.640 to 0.676)  was obtained for the combination of five marker SNPs, age at menarche and age at first live birth.Five SNPs located at 2q35, 3p24, 6q22, 6q25 and 10q26 were consistently associated with breast cancer risk in both testing set (878 cases and 900 controls) and validation set (914 cases and 967 controls) samples. Overall, all of the five SNPs contributed to breast cancer susceptibility in a dominant genetic model (2q35, rs13387042: adjusted OR = 1.26, This study shows that five GWAS identified variants were also consistently validated in this Chinese population and combining these genetic variants with other risk factors can improve the risk predictive ability of breast cancer. However, more breast cancer associated risk variants should be incorporated to optimize the risk assessment. BRCA1, BRCA2, PTEN and TP53) have been identified to be associated with familiar breast cancer [Breast cancer is one of the most common cancers among women worldwide . Althougt cancer . Howevert cancer .Recently, several genome-wide association studies (GWAS) reported many novel breast cancer predisposing single nucleotide polymorphisms (SNPs) -14. HoweIn the current study, a two-stage case-control study of 1,792 breast cancer cases and 1,867 cancer-free controls was conducted among Chinese women to replicate 15 selected SNPs identified from previous GWAS. Then, risk models were constructed and absolute risk was calculated to evaluate the combined effects of the significant SNPs and clinical risk factors.This study was approved by the institutional review board of Nanjing Medical University. The hospital-based case-control study included 1,792 breast cancer cases and 1,867 cancer-free controls, and the detail process of subjects recruitment was described previously -25. In bAfter providing informed consent, each woman was personally interviewed face-to-face by trained interviewers using a pre-tested questionnaire to obtain information on demographic data, menstrual and reproductive history, and environmental exposure history. After the interview, each subject provided 5 ml of venous blood. The estrogen receptor (ER) and progesterone receptor (PR) status of breast cancer was determined by immunohistochemistry examinations which were obtained from the medical records of the hospitals.2 < 0.8) if multiple SNPs can be found at the same region. Overall, 15 SNPs  reported marker SNP in previous GWAS (last search in November 2009); (b) minor allele frequency (MAF) ≥ 0.05 in Chinese Han Beijing (CHB) based on the HapMap database ; (c) only SNPs with low linkage disequilibrium (LD) were included  (for continuous variables). Hardy-Weinberg equilibrium was evaluated by exact test among the controls [Differences between breast cancer cases and controls in demographic characteristics, risk factors and frequencies of SNPs were evaluated by Fisher's exact tests  or Student controls .et al. [As shown in Additional file et al. . FurtherP < 0.001) and age at first live birth (P < 0.001) were consistently, differentially distributed between the cases and the controls in all samples. Among 1,437 breast cancer cases with known ER and PR status, 662 (46.07%) were both ER and PR positive, and 498 (34.66%) were both negative.A total of 1,792 breast cancer cases and 1,867 cancer-free controls were included in the final analysis, and the characteristics of these subjects were summarized in Table P = 0.039; 3p21.4: rs2307032, P = 0.017; 6q22.33: rs2180341, P = 0.040; 6q25.1: rs2046210, P = 1.26 × 10-5; 10q26.13: rs2981582, P = 0.037). Therefore, these five SNPs were included in the further validation analyses.The results of the selected 15 SNPs and the breast cancer risk in testing set samples were presented in Table P-values. Overall, after adjustment for age, age at menarche, menopausal status and age at first live birth, the five SNPs showed significant associations with breast cancer susceptibility .The call rates of the five SNPs in the validation stage were all above 95% Table . ConsistP for trend: 5.60 × 10-10). Similarly, a 4.73-fold increased risk was illustrated when taking age at menarche and age at first live birth into consideration . We then assessed the performance of the two risk prediction methods in discriminating cases and controls by ROC curves analyses. The AUC for the risk score analysis .The cumulative effects of the five SNPs and the two risk factors (age at menarche and age at first live birth) on breast cancer risk were examined by two methods Table . One metAbsolute risk was also calculated to evaluate the combined effects of the five SNPs and the two risk factors by a modified Gail model and a 65-year absolute risk for breast cancer among women aged 20 to 85 years was estimated for each subject. From Table The stratified analyses by ER or PR status of the five SNPs were summarized in Additional file In our study involving 1,792 breast cancer cases and 1,867 cancer-free controls, 5 of the 15 variants, identified in previous GWAS studies , were coet al. [et al. reported marker SNPs rs4973768 and rs1357245 in a four-stage GWAS study, and then located the strongest marker rs2307032 in this region [ESR1 gene on chromosome 6q25.1, was the only one reported by Zheng et al. (2009) in a GWAS conducted among Chinese women [et al. in the first large-scale breast cancer GWAS [We summarized associations of the 15 SNPs of breast cancer identified by previous GWAS studies and following replication studies , rs889312 (5p11.2) and rs3803662 (16q12.1) in Korean women with breast cancer [For the other SNPs, Han t cancer . Howevert cancer ,24,38,39et al. conducted a validation study with 3,039 breast cancer cases and 3,082 controls for 12 GWAS identified SNPs (nine regions) in Asian women [Traditional approaches to assessing patients' disease risk are primarily achieved through non-genetic risk factors with apparent limitations, and it is expected that a better prediction can be reached if we can incorporate genetic determinants. Recently, several studies on these efforts were published -22. Zhenan women , and buiOverall, risk model prediction is not a diagnostic tool but provides an estimate of likelihood of developing disease in the future. A well-evaluated risk model, taking genetic and clinical risk factors together, can be used as a screening tool for high risk individuals among the general population. Women at high risk for breast cancer can be focused on by choosing an optimal cutoff , and these women should perform regular breast cancer screening ,49. ResuOverall, five GWAS identified variants were also consistently validated in this Chinese population. Risk assessment models that incorporate both a genetic risk score based on these SNPs and the established risk factors for breast cancer may be useful for identifying high-risk women for targeted cancer prevention. More genetic risk variants and other risk factors should be well evaluated and incorporated into the risk-predicting models to improve the ability of personalized risk assessment.AR: absolute risk; AUC: area under the curve; CHB: Chinese Han Beijing; CI: confidence intervals; ER: estrogen receptor; GWAS: genome-wide association studies; LD: linkage disequilibrium; MAF: minor allele frequency; ORs: odds ratios; PR: progesterone receptor; ROC curves: receiver-operator characteristic curves; SNPs: single nucleotide polymorphismsThe authors declare that they have no competing interests.HS directed the study, obtained financial support, and was responsible for study design, interpretation of results and manuscript writing. JD performed data management, statistical analyses and drafted the initial manuscript. ZH performed overall project management and manuscript writing. YJ, HS, JD and HM were responsible for samples processing and managed the genotyping data. All authors read and approved the final manuscript.Supplementary Figure Click here for fileSupplementary Figure Click here for fileSupplementary Figure Click here for fileSupplementary Table Click here for file


IFN-γ may modify the association of febrile infection with breast cancer risk.There is an inverse relationship between febrile infection and the risk of malignancies. Interferon gamma (IFN-γ) plays an important role in fever induction and its expression increases with incubation at fever-range temperatures. Therefore, the genetic polymorphism of IFN-γ (rs2069705) was genotyped using a matrix-assisted laser desorption/ionization time-of-flight mass spectrometry platform. Odds ratios (OR) and 95% confidence intervals (CIs) were calculated using multivariate logistic regression. We found that women who had experienced ≥1 fever per year had a decreased risk of breast cancer [ORs and 95% CI: 0.77 (0.61–0.99)] compared to those with less than one fever a year. This association only occurred in women with CT/TT genotypes [0.54 (0.37–0.77)] but not in those with the CC genotype [1.09 (0.77–1.55)]. The association of IFN-γ rs2069705 with the risk of breast cancer was not significant among all participants, while the CT/TT genotypes were significantly related to an elevated risk of breast cancer [1.32 (1.03–1.70)] among the women with <1 fever per year and to a reduced risk of breast cancer [0.63 (0.40–0.99)] among women with ≥1 fever per year compared to the CC genotype. A marked interaction between fever frequencies and the IFN-γ genotypes was observed .Information on potential breast cancer risk factors, history of fever during the last 10 years, and blood specimens were collected from 839 incident breast cancer cases and 863 age-matched controls between October 2008 and June 2010 in Guangzhou, China. IFN-γ rs2069705.Our findings indicate a possible link between febrile acute infection and a decreased risk of breast cancer, and this association was modified by  They were comparable in terms of marital status, body mass index (BMI), age at menarche, parity, and family history of breast cancer . The proIFN-γ rs2069705 were equally distributed in cases and controls and, consequently, were not significantly associated with breast cancer risk  and 0.79 (0.47–1.32), respectively . The noncer risk .IFN-γ genotypes were not significantly associated with the risk of breast cancer in each stratum and no interaction between them on breast cancer risk occurred .Finally, the joint effects of fever frequency and IFN-γ genotypes on breast cancer risk were analyzed. Compared to women who had experienced a fever below once a year, the reduced risk of one fever or above per year was more evident among women with the CT/TT genotypes than among those with the CC genotype with ORs and 95% CIs of 0.54 (0.37–0.77) and 1.09 (0.77–1.55), respectively . Comparein vitro and in vivo that dendritic cells  treated with fever-like heat (41°C) were significantly superior compared to non-heat-treated DC in stimulating T cells and activating NF-κB  Acute infections are often accompanied by inflammatory reactions including fever, which is a cytokine-mediated rise in core temperature, and other immunologic, endocrinologic, neurologic, and physiologic changes IFN-γ gene, mainly rs2069705 (−1615 C/T) and rs2430561 (+874 T/A), with the risk of breast cancer IFN-γ rs2069705 with the risk of breast cancer among the study participants as a whole. However, we observed a positive association among the women with <1 fever per year but an inverse association among women with ≥1 fever per year for the CT/TT genotypes and breast cancer risk. These phenomena may explain the previously mentioned inconsistent results to some extent, and suggest that IFN-γ plays a role in tumorigenesis depending on certain environments, such as febrile infections.IFN-γ is one of the main products of Th1-specific proinflammatory cytokines and has an effect on host defense and immune regulation, such as antivirus, antimicrobe, and antitumor activities IFN-γ rs2069705 might increase the IFN-γ level high enough to make the host's anticancer defense more effective while the co-existence of less fever and the T allele might keep IFN-γ at a certain low level to promote tumourgenesis, supporting our results to some extent that women with CT/TT genotypes and ≥1 fever per year have a decreased breast cancer risk and women with CT/TT genotypes and <1 fever per year have an increased breast cancer risk. Nevertheless, the exact mechanisms in which fever and IFN-γ interact on breast cancer risk remain to be studied.The evidence of interplay between fevers and IFN-γ has been noted in previous experimental studies that show how fever can induce IFN-γ and be induced by IFN-γ IFN-γ rs2069705 C allele among the healthy controls was 0.73 in our study, which was similar to that found in other populations within Asia . Information about these infections was successfully collected from 731 cases (87.1% of those eligible) and 777 controls (90.0% of those eligible). The interviewers did not know the hypotheses of this study.Blood samples were collected immediately after admission to the hospital for patients or after the interview for controls and were stored at −80°C. The clinical characteristics of the breast cancer patients were collected from medical records. The statuses of oestrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) for the breast cancer were determined by pathologists using immunohistochemistry tests. The definitions of statuses of ER, PR and HER2 statuses were described in detail in our previous study IFN-γ rs2069705. No deviation from the Hardy-Weinberg equilibrium was observed (P = 0.350 in control group).Genomic DNA was extracted from the buffy coats of the participants using the TIANamp Genomic DNA Kit  and genotyped using a matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry platform , according to the manufacturer's instructions. The details of the primers are described elsewhere 2 test  or Student's t-test (for continuous variables). Differences in fever frequency between cases and controls were tested using the Mann-Whitney U test. The Hardy–Weinberg equilibrium for IFN-γ rs2069705 was evaluated using a goodness-of-fit χ2 test to compare the observed genotype frequency with the expected one among the controls. Multivariate logistic regression models were used to assess the effects of fever history and genotype on breast cancer risk, controlling for age and for the potential risk factors of breast cancer , which were defined categorically with the exception of age (IFN-γ rs2069705 and the mutant homozygotes and heterozygotes were combined because the effects' directions of the CT and TT genotypes were the same (OR>1).The differences in demographic characteristics and common risk factors for breast cancer between the cases and controls were tested using the χn of age . Models The interaction between fever frequency and genotype on breast cancer risk was evaluated by multiplicative and additive models. We tested for multiplicative interaction by including the product term in multivariate logistic regression. Additive interaction was assessed using a method proposed by Rothman


MMP1 (9 SNPs), MMP2 (8 SNPs), MMP3 (4 SNPs), and MMP9 (3 SNPs) and breast cancer risk among Hispanic  and non-Hispanic white (NHW)  women in the Breast Cancer Health Disparities Study. Ancestral informative markers (n = 104) were assessed to determine Native American (NA) ancestry. MMP1 [4 single nucleotide polymorphisms (SNPs)] and MMP2 (2 SNPs) were associated with breast cancer overall. MMP1 rs996999 had strongest associations among women with the most NA ancestry  as did MMP3 rs650108  and MMP9 rs3787268 . The adaptive rank truncated product (ARTP) showed a significant pathway partp value of 0.04, with a stronger association among women with the most NA ancestry (partp = 0.02). Significant pathway genes using the ARTP were MMP1 for all women (partp = 0.02) and MMP9 for women with the most NA ancestry (partp = 0.024); MMP2 was borderline significant overall (partp = 0.06) and MMP1 and MMP3 were borderline significant for women with the most NA ancestry (partp = 0.07 and 0.06 respectively). MMP1 and MMP2 were associated with ER+/PR+ and ER+/PR-tumors; MMP3 and MMP9 were associated with ER−/PR− tumors. The pathway was highly significant with survival (partp = 0.0041) with MMP2 having the strongest gene association (partp = 0.0007). Our findings suggest that genetic variation in MMP genes influence breast cancer development and survival in this genetically admixed population.Matrix metalloproteinases (MMPs) contribute to cancer through their involvement in cancer invasion and metastasis. We evaluated genetic variation in  Matrix metalloproteinase (MMP) plays an important role in cancer progression by degrading extracellular matrix and basement membrane and are the main proteolytic enzymes involved in cancer invasion and metastasis MMP1, MMP2, MMP3, and MMP9 genes have been examined in studies evaluating cancer metastasis MMP1 −1607, MMP3 −1171 and MMP9 −1562 have been associated with general cancer metastasis in a large meta-analysis MMP1 −1607 has shown stronger associations among individuals with more European ancestry MMP2 −1306 was not associated with overall cancer metastasis in that study, other studies have shown this polymorphism to be associated with tumor size, estrogen receptor status and survival MMP2 have been associated with breast cancer risk specifically in the Shanghai Breast Cancer Study, a large case-control study of over 6000 Chinese women MMP1 and MMP3 were not associated with breast cancer risk in the Shanghai Breast Cancer Study Polymorphisms in the MMP1, MMP2, MMP3, and MMP9 using data from a large collaborative case-control study of breast cancer in Hispanic and non-Hispanic white women (NHW) from the United States and Mexico. It is of interest to evaluate these genes and their association with breast cancer among these populations because of the observed ethnic differences in breast cancer incidence and survival rates MMP polymorphisms in breast cancer risk and survival taking into account tumor characteristics. In this study we used a comprehensive tagSNP approach to evaluate associations with breast cancer risk and survival, taking into account genetic admixture, menopausal status, estrogen receptor (ER) and progesterone receptor (PR) tumor status, tumor grade, and disease stage.In this study we evaluated genetic variation in in situ (n = 341) or invasive (n = 1492) cancer between October 1999 and May 2004; controls were selected from the target populations of cases living in Arizona, Colorado, New Mexico, and Utah and were frequency matched to cases on ethnicity and 5-year age distribution in situ or invasive breast cancer between January 2004 and December 2007 at 12 participating hospitals from three main health care systems; controls were randomly selected from the catchment area of the 12 participating hospitals using a probabilistic multi-stage design. The San Francisco Bay Area Breast Cancer Study included women aged 35 to 79 years from the San Francisco Bay Area diagnosed with a first primary histologically confirmed invasive breast cancer between April 1995 and April 2002; controls were identified by random-digit dialing (RDD) and frequency-matched to cases based on the expected race/ethnicity and 5-year age distribution in situ cases, the results presented include both. All participants signed informed written consent prior to participation; this study was approved by the Institutional Review Board for Human Subjects at the University of Utah, Comisión de ética, and Institutional Review Board of the Cancer Prevention Institute of California.The Breast Cancer Health Disparities Study includes participants from three population-based case-control studies, the 4-Corner's Breast Cancer Study, the Mexico Breast Cancer Study, and the San Francisco Bay Area Breast Cancer Study Data were harmonized across all study centers and questionnaires as previously described 2 = 0.8; minor allele frequency (MAF) >0.1; range = −1500 bps from the initiation codon to +1500 bps from the termination codon; and 1 SNP/LD bin. Additionally, 104 Ancestral Informative Markers (AIMs) were used to distinguish European and Native American ancestry in the study population MMP1 (9 SNPs), MMP2 (8 SNPs), MMP3 (4 SNPs), and MMP9 (3 SNPs). A description of these genes and all SNPs is shown in DNA was extracted from either whole blood or mouthwash samples; 7287 blood-derived and 634 mouthwash-derived samples were available. Whole Genome Amplification (WGA) was applied to the mouthwash-derived DNA samples prior to genotyping. A tagSNP approach was used to characterize variation across candidate genes. TagSNPs were selected using the following parameters: linkage disequilibrium (LD) blocks were defined using a Caucasian LD map and an rCancer registries in Utah, Colorado, Arizona, New Mexico, and California provided information on stage at diagnosis, months of survival after diagnosis, cause of death, and estrogen receptor (ER) and progesterone receptor (PR) status. Information on ER and PR status of tumors was available for 1019 (69%) NHW and 977 (75%) Hispanic cases. Survival information, tumor grade, and stage at diagnosis were not available for cases from Mexico.The program STRUCTURE was used to compute individual ancestry for each study participant assuming two founding populations All statistical analyses were performed using SAS version 9.3 . Genes and SNPs were assessed for their association with breast cancer risk for all women and by strata of genetic ancestry, ER/PR status, and menopausal status. Logistic regression models were used to estimate odds ratios (OR) and 95% confidence intervals (CI) for breast cancer risk associated with SNPs, adjusting for age, study center, genetic ancestry, reference year BMI, and parity. Associations with SNPs were assessed assuming a co-dominant model. Based on the initial assessment, SNPs which appeared to have a dominant or recessive mode of inheritance were evaluated with those inheritance models in subsequent analyses.The p values used to adjust for multiple comparisons were based on Wald chi-square test statistics comparing the homozygote variant to the wildtype for additive/co-dominant models, the homozygote variant/heterozygote to the wildtype for dominant models, and the homozygote variant to the wildtype/heterozygote for recessive models. They were adjusted for multiple comparisons taking into account tagSNPs within the gene using the step-down Bonferroni correction . This method of correction for multiple comparisons is very conservative, especially for correlated variables such as SNPs within a gene. To take into account the correlated nature of the data, we determined the effective number of independent SNPs using the SNP spectral decomposition method proposed by Nyholt Survival months were calculated based on month and year of diagnosis and month and year of death or date of last contact. Associations between SNPs and risk of dying of breast cancer among primary invasive cases were evaluated using Cox proportional hazards models to obtain multivariate hazard ratios (HR) and 95% CI for all women and by admixture strata. Since survival data were not available for the Mexico study site, the upper two admixture strata were combined to evaluate survival. Individuals were censored when they died of causes other than breast cancer or were lost to follow-up. In addition to the minimal adjustments for age, study center, genetic ancestry, referent year BMI, and parity, models were also adjusted for SEER summary stage to estimate HRs. Generalized logit models were used to assess associations between SNPs and both tumor stage and grade. In these models, the comparison group for calculation of ORs for tumor stage was localized/in situ while associations with grade were well differentiated tumors.Interactions between genetic variants and genetic ancestry and genetic variants and menopausal status were assessed using one degree of freedom (1-df) Wald chi-square tests. Differences in risk by ER/PR status were estimated using Wald chi-square tests from generalized logit model. Interactions between genetic variants and genetic ancestry with survival were assessed using p values from Wald chi-square tests.Haplotypes were developed to help define risk associated with genes. SNPs were selected based on their individual significance overall or within a genetic ancestry group. Haplotypes were estimated using the expectation maximization algorithm. Per-copy and copy number haplotype risk estimates were obtained using logistic regression and adjusted for age, study center, genetic admixture, BMI in referent year, and parity. We focused on haplotypes with a frequency of ≥0.05 in reporting results since those with lower frequency were generally imprecise.artp)We used the adaptive rank truncated product (ARTP) method that utilizes a highly efficient permutation algorithm to determine the significance of association of each gene and of the MMP pathway with breast cancer overall, by admixture, and by ER/PR strata. To estimate the ARTP for survival we categorized the outcome as death from breast cancer versus alive to approximate the associations using the proportional hazard models. The gene p values were generated using the ARTP package in R, permuting case-control status 10,000 times while adjusting for age, reference year BMI, and genetic admixture The majority of breast cancer cases were Hispanic, under 60 years of age, and post-menopausal . Among UMMP1 and MMP2 were associated with breast cancer risk  (MMP pathway was significantly associated with breast cancer risk (partp = 0.04) with the strongest association observed for women with the most Native American ancestry (partp = 0.02). MMP1 was significant overall (partp = 0.02) and MMP2 was borderline significant (partp = 0.06). Among women with the most Native American ancestry, MMP1 and MMP3 were of borderline significance (partp = 0.07 and 0.06 respectively) whereas MMP9 was statistically significant among this group of women (partp = 0.024).Among all women combined, cer risk . When st= 0.002) . UtilizaMMP2 rs243845 showed significant differences in associations by menopausal status (data not shown). MMP2 rs243845 was significantly associated with breast cancer risk among post-menopausal women only .Only MMP1 and MMP2 showed statistically significant haplotype associations using both the additive model  for the entire population , and with the strongest association found in women with the highest Native American ancestry . Similarly, the converse of the haplotype MMP1 TCTC was inversely associated with breast cancer risk when looking at copy number for all women  and among women with the least Native American ancestry specifically .Evaluation of haplotypes for ve model  and the MMP genes were associated with ER/PR tumor status prior to adjustment for multiple comparisons  and rs1144393 remained significant after multiple comparison adjustment. MMP1 rs5854 and MMP2 rs1477017 and rs243836 also were associated with ER+/PR− tumors . Only MMP1 rs7125062 was associated with ER−/PR+ tumors prior to multiple comparison adjustment. MMP2 rs243839 and MMP3 rs650108 and MMP9 rs3918261 and rs3918249 were associated with ER−/PR− tumors prior to multiple comparison adjustment. Assessment of haplotypes for MMP1, MMP2, and MMP9 showed several statistically significant associations ; MMP1 was most significantly associated with ER+/PR+ tumors (partp = 0.013), while both MMP3 and MMP9 were associated with ER−/PR− tumors (partp = 0.04 and 0.046 respectively).Polymorphisms in all of the parisons . MMP1 rsions see . The TTCMMP3 was significantly associated with more advanced tumor stage. The AA genotype of MMP3 rs650108 and the GG genotype of rs522616 were associated with almost a four-fold increased risk of having a distant tumor versus a tumor staged as localized or in situ  relative to the major allele genotype. Evaluation of tumor grade showed that women with the MMP1 rs17293761 TT genotype were less likely to have a poorly differentiated tumor than a well differentiated tumor .Other tumor characteristics, i.e. stage and grade, that could indicate metastatic potential also were evaluated (data not shown in table). Only MMP1 (2 of 9 SNPs) and MMP2 (6 of 8 SNPs) were associated with survival after adjusting for disease stage . Specifically, the GA/AA genotypes of rs17293823 were associated with a reduced risk of death among those with the least Native American ancestry whereas a non-significant increased risk of death was found among those with most Native American ancestry. Evaluation of haplotypes . ARTP supported the independent SNP assessment with an overall pathway p value of 0.0041and for MMP2 specifically (partp = 0.0007).Both se stage . Only MMplotypes  showed tMMP1 and MMP2 were associated with breast cancer risk overall and with ER+ tumors. MMP3 and MMP9 were associated with breast cancer risk among those with most Native American ancestry and those with ER−/PR− tumors. Only MMP1 and MMP2 were associated with survival after diagnosis with breast cancer. We observed minimal differences in risk by menopausal status. Overall the MMP pathway was associated with both breast cancer risk and survival as indicated by a significant p value using the ARTP statistic.Our findings suggest that MMP genes are associated with breast cancer risk and survival after diagnosis in this genetically admixed population  was associated with significantly higher risk of breast cancer in a study of 90 breast cancer cases from Mexico , especially among women younger than 50 years of age Although other studies of the MMP1 was associated with node- negative breast cancer, whereas MMP9 was associated with ER−/PR− tumors, greater lymph node involvement, and larger tumor size. However, Grieu et al. observed that the MMP9 −1562 polymorphism was associated with better survival and ER positive tumors whereas survival associated with the MMP2 rs243865 polymorphism was dependent on ER tumor status MMP genes MMP1 (−1607) was associated with over a two-fold increased risk of breast cancer metastasis especially among those with more European background. Reduced risk of breast cancer metastasis was observed for MMP3 −1171 5A/6A polymorphism; MMP9 −1562 was associated with increased metastatic potential; and no associations were observed for MMP2 −1306.Most studies of MMPs have focused on metastatic potential given the underlying biology of MMPs and cancer. Metastatic potential has been determined by evaluating tumor stage at time of diagnosis, tumor grade and histology. One study hypothesized that MMP-1 was involved in local invasion and that MMP-9 was involved in tumor growth and malignancy MMP3 and MMP9 were associated with ER−/PR− tumors. Additionally, we observed that MMP3 polymorphisms were associated with tumor grade, with women having a much higher risk of a non-differentiated tumor if they had the rare variant of the MMP3 polymorphisms. We observed few differences by tumor stage at diagnosis; however, stage is also associated with screening practices and could not be examined in this population. Our data suggest that both MMP1 and MMP2 influence survival. Two of nine MMP1 SNPs were associated with survival and six of eight MMP2 SNPs were associated with survival. Our data provide support for the hypothesis that MMP genes influence metastatic potential and survival. Utilization of the ARTP allowed us to focus on the significance of the pathway and of the genes. This was important given that multiple SNPs in several genes that were associated and the importance missed by multiple comparison adjustment that does not consider the overall gene importance when a high proportion of SNP are significant at the 0.02 or even 0.01 prior to multiple comparison adjustment.In our study, both MMP1 was associated with tumor differentiation, MMP3 and MMP9 were associated with ER−/PR− tumors. MMP1 and MMP2 were associated with many aspects of breast cancer prognosis including unique associations with ER/PR tumor status as well as with survival. Six of the eight MMP2s evaluated were associated with survival independent of genetic ancestry, suggesting the importance of that gene in tumor progression and invasiveness for both NHW and Latina women with a wide range of Native American ancestry. These findings were confirmed by the ARTP analysis.Most of the literature on the biology of MMPs points to their role in maintaining cell integrity and their role in cancer invasion and metastasis. MMPs are proteolytic enzymes that degrade extracellular matrix and basement membrane. MMP-1 is one of the most widely expressed MMPs and degrades interstitial connective tissue. MMP-2 and MMP-9 play a key role in angiogenesis and MMP-3 is produced by connective tissue that activates other MMPs. Our findings suggest that all of the MMPs are involved in various aspects of breast cancer development and progression. While only MMP9 being different by ancestry group. Additionally we did observe a statistically significant pathway partp for women with the highest Native American ancestry but not for the other two groups, suggesting that this pathway is more important for women with greater Native American ancestry. One would hypothesize that given the biological role of MMPs that women with greater Native American ancestry could also have poorer survival associated with genes in this pathway. We did not detect differences in survival by ancestry. This lack of an association is most likely from the narrower range of Native American ancestry available for study given that the Mexico City sample did not have survival information. The highest Native American ancestry group used to evaluate breast cancer risk was comprised of mainly from women in Mexico City.Ours is the largest study to date to report on MMP genes in an admixed population of U.S. and Mexican women with breast cancer and population-based controls. While we stratified the population to maximize our ability to examine the risk associated within strata of Native American ancestry, it should be recognized that cutpoints chosen were arbitrary based on this population distribution. However, we observed few differences in breast cancer risk by Native American ancestry, with only Whereas the populations in the U.S. had information on tumor characteristics such as ER and PR status and tumor grade and survival, this information was not available from Mexico. This limited our ability to evaluate these characteristics in as much detail by admixture since most women in the high Native American ancestry group were from Mexico. We hypothesized associations with specific genes and for some candidate SNPs that had previously been associated with cancer. However, in general we invoked a tagSNP approach to characterize genetic variation across the genes of interest. We acknowledge that associations could be spurious. Adjustment for multiple comparisons was made, although given the number of SNPs evaluated; some associations could be from chance. However, the study was one of candidate genes that were hypothesized to be associated with breast cancer development and progression and therefore too conservative interpretation of multiple comparison adjustments could lead to rejecting findings that may actually be true; thus replication of these findings in other studies is needed. Since information on the functionality of most of the SNPs examined is limited, our interpretation of findings is greatly guided by the literature on MMPs and their association with cancer in general. Additionally, we had limited power to evaluate variants with low minor allele frequency, and thus could have missed associations for both SNPs and haplotypes.MMP3 and MMP9 being associated with ER−/PR− tumors. MMP1 and MMP2 were associated with survival after diagnosis with breast cancer. The composite of data suggest that MMPs are associated with breast cancer progression. Replication of these findings by other large studies and work to determine the functionality of the polymorphisms examined will help determine the role of MMPs in breast cancer carcinogenesis.In this study of breast cancer in an admixed population of Hispanic and non-Hispanic white women, MMPs were associated both with breast cancer development and prognosis. Several polymorphisms were uniquely associated with ER and PR status of tumors, with Table S1MMP gene haplotypes for all women and by genetic admixture.Breast cancer risk associated with (DOCX)Click here for additional data file.Table S2MMP gene haplotypes and ER/PR status of tumorsBreast cancer risk associated with (DOCX)Click here for additional data file.Table S3MMP gene haplotypes for all women and by Native American ancestry.Associations between survival and (DOCX)Click here for additional data file.


BRCA1/2 testing becomes more routine, questions remain about long-term satisfaction and quality of life following testing. Previously, we described long term distress and risk management outcomes among women with BRCA1/2 mutations. This study addresses positive psychological outcomes in BRCA1/2 carriers, describing decision satisfaction and quality of life in the years following testing.As BRCA1/2 carriers. Prior to genetic testing, we assessed family history, sociodemographics and distress. At a mean of 5.3 years post-testing, we assessed management decisions, satisfaction with decisions and, among women with cancer, quality of life.We evaluated satisfaction with testing and management decisions among 144 Overall, satisfaction with decision making was high. Women who had risk reducing mastectomy or oophorectomy were more satisfied with management decisions. Participants who obtained a risk reducing oophorectomy were more satisfied with their genetic testing decision. Among affected carriers, high pretest anxiety was associated with poorer quality of life and having had risk reducing mastectomy prior to testing was associated with better quality of life. The negative impact of pre-test anxiety was diminished among women who had mastectomies before testing.BRCA1/2 carriers are satisfied with their testing and risk management decisions and report good quality of life years after testing. Having risk reducing surgery predicts increased satisfaction and improved quality of life. BRCA1/2 testing has become routine, increasing numbers of women now face these decisions. Women who carry mutations in the BRCA1 or BRCA2 (BRCA1/2) gene have a lifetime risk of 40% to 75% of developing breast cancer and up to a 40% risk of developing ovarian cancer [Decisions about genetic testing and medical management among women at increased risk for breast and ovarian cancer are complex and driven by a combination of medical recommendations and patients’ value-based preferences. As n cancer .BRCA1/2 mutation carriers opt for RRO, RRM or both [BRCA1/2 carriers who did and did not opt for risk reducing surgery. One study, using single item assessments of satisfaction, found no difference in satisfaction associated with risk reducing mastectomy [BRCA1/2 mutation carriers) who had either undergone RRO or gynecologic screening a mean of four years following a high risk gynecology visit [Several recent studies document that the majority of  or both -10. Thus or both -15, few stectomy . Other istectomy ,13,16. Ogy visit . In thisBRCA1/2 carriers’ long-term quality of life. A short-term negative impact of surgery on physical functioning domains of quality of life has been noted, most likely related to recovery from surgery [Despite the apparent high rates of satisfaction with risk reducing surgery decisions, it remains unclear if such surgery significantly impacts  surgery , but mos surgery ,17,19-21BRCA1/2 mutation status, others make these decisions over time [BRCA1/2 testing and subsequent decision-making. Previous reports, including one from this cohort, have addressed long term distress outcomes and found that BRCA1/2 carriers experience distress related to their genetic status that is significantly greater, though not clinically significant, compared to those who do not carry BRCA1/2 mutations [BRCA1/2 carriers with and without a history of cancer. In this report, we describe decisional satisfaction over time and long-term quality of life, comparing women who have made different decisions regarding the management of their breast and ovarian cancer risk.While some high-risk women opt for surgery very soon after learning their ver time . As suchutations ,23. QuesThis study was approved by the Georgetown University Institutional Review Board  and the USAMRMC Office of Research Protections (Protocol #A-12074). Written informed consent was obtained from all participants on Institutional Review Board-approved consent documents.BRCA1/2 test results and had participated in one of four previous studies: two observational studies of the short-term outcomes of genetic counseling and testing [BRCA1/2 carriers, one of a psychosocial telephone counseling intervention [BRCA1/2 carriers in making decisions about managing their breast cancer risk [We recruited participants from the Lombardi Comprehensive Cancer Center (LCCC) familial cancer registry (FCR). All participants had received clinical genetic counseling and testing at LCCC, were at least 3 years post-disclosure of  testing ,24,25 anrvention  and one cer risk . All parBRCA1/2 mutation carriers. Of 206 potentially eligible BRCA1/2 carriers who were active in the FCR, we had incorrect contact information for 9. Of the remaining 197 eligible women, 38 (19.2%) declined participation and 15 (7.6%) could not be reached after repeated attempts. Our final sample (N = 144) represents 73.1% of those who were eligible and for whom we had correct contact information. Participants differed from eligible non-participants on three sociodemographic variables. Participants were more likely to be White (p = .03), Jewish (p < .001) and college graduates (p = .003). Participants and decliners did not differ on any psychosocial or personal/family history variables.The present report is limited to We mailed eligible participants study packets containing a study invitation, Institutional Review Board approved consent documents, a printed version of the survey, a stamped return-addressed card to decline participation, and a telephone number to call should they wish to provide their answers by phone, or decline by phone.We measured age, race/ethnicity, education, marital status, employment status and religion.BRCA1/2 result and the date they completed the current survey.We calculated the time elapsed between the date that participants received their We assessed participants’ personal history of breast and gynecologic cancer and time since diagnosis. For logistic regressions, we divided the time since diagnosis variable into 3 groups: unaffected women, those diagnosed less than 10 years ago and those diagnosed more than 10 years ago. We also assessed the number of first- and second-degree relatives with breast and/or ovarian cancer.Our measure of baseline anxiety is a composite of two anxiety measures we used in previous studies. Twenty-three participants completed the 20-item State Anxiety subscale of the State Trait Anxiety Inventory (STAI)  and 121 Using face-valid interview questions previously described , we asseAll participants completed modified versions of the reliable and valid Satisfaction with Decision Making (SWD) scale . We modiWe assessed quality of life among the affected women in our sample (N = 97) using the 36-item FACT-B  designed for use in breast cancer patients  .t-tests  to identify bivariate predictors of satisfaction with management decisions, satisfaction with genetic testing and, among women with a history of cancer, quality of life. Next, we used logistic (for satisfaction with management decisions and satisfaction with the genetic testing decision) and linear regression  with hierarchical variable entry in which we included all main effect variables with p < 0.10 bivariate associations with the outcome of interest on the first step. Because quality of life had multiple independent predictors, we conducted follow-up testing for interactions between the main effects by entering the interaction term on the second step of the linear regression model. For models of satisfaction with management decisions, we excluded women who had bilateral mastectomies or oophorectomies for reasons other than prevention. For all models, when testing variables with significant colinearity  we included only the variable with the stronger bivariate association.We characterized the sample in terms of sociodemographics, personal history of cancer, cancer treatment and prevention decisions, anxiety prior to genetic testing and time since genetic testing. We used chi-square and BRCA1/2 mutation carriers in this sample had a prior diagnosis of breast cancer, five had been diagnosed with ovarian cancer, one had both breast and ovarian cancer and one had breast and uterine cancer. On average it had been a mean of 5.2 (SD = 1.2) years since genetic testing. Among affected women, it had been a mean of 10.9 (SD = 7.9) years since their diagnosis. The majority of participants were white (94%), college educated (96%), and married (77%). The mean age of participants at long-term follow up was 49.6 (SD 10.0), and they had a mean of 2.8 first or second-degree relatives with breast or ovarian cancer.As displayed in Table As described in our previous report ,22, the BRCA1/2 testing and with their management decisions following receipt of a positive test result. Over 90% of participants scored a 20 or higher (out of 25) on both satisfaction scales and over 60% of participants scored a perfect 25 on both scales.Participants reported extremely high satisfaction with their decision to undergo Χ2  = 12.5, p < 0.001), having had RRM before testing  16.04, p < 0.001), and a shorter time since cancer diagnosis (r(94) = −0.26, p < 0.05).In bivariate analyses of satisfaction with the genetic testing decision Table , high saΧ2  = 6.44, p = 0.01) and having ever received an RRO  = 4.87, p = 0.03). Timing of RRM and RRO was also associated with satisfaction. Women who underwent RRM prior to testing were more likely to report high satisfaction with their management decisions  = 8.50, p = 0.01) and women who had RRO prior to testing were also more likely to report high satisfaction  = 6.89, p = 0.03). Notably, having had a diagnosis of cancer was not significantly associated with satisfaction with management decisions or with genetic testing satisfaction.High satisfaction with management decisions, also assessed as scoring a “very satisfied” across all items on the SWD scale, was associated with: having ever received an RRM (r(48) = 0.32, p = 0.03) and high pretest anxiety was associated with lower quality of life (r(96) = −0.31, p = .002). Although ever having received RRM or RRO was not associated with quality of life, timing of RRM was significantly associated. Women who underwent RRM prior to testing reported significantly higher quality of life at follow-up compared to those who had never undergone RRM (t(68) = −1.98, p = .05) and those who underwent RRM after testing (Satterthwaite t(39.8) = 2.11, p = 0.04).In terms of quality of life among women with a history of cancer, greater time since RRM (among affected women who had RRM) was associated with higher quality of life . Because RRM ever and RRM before testing were highly correlated, we included only RRM ever in the multivariate model due to its stronger bivariate association. In order to include unaffected women in the model, we created a dummy coded variable for time since diagnosis in which unaffected women were the referent generating comparisons with women diagnosed less than 10 years ago and with women diagnosed more than 10 years ago. Neither the omnibus time since diagnosis variable p = 0.31) nor the constituent comparisons . In each case we chose the variable with the stronger bivariate association with satisfaction. Given that our questions were anchored on management of ongoing cancer risk vs. decisions about cancer treatment, and the lack of significant association between cancer history and satisfaction, we included both unaffected women and women with a history of cancer in our model. Thus, our multivariate model included RRO ever and RRM ever. As displayed in Table We used linear regression to identify independent predictors of long-term quality of life among women with a personal history of cancer (n = 97). As above, we included variables with bivariate association of p < 0.1 with quality of life: baseline anxiety and RRM prior to testing, excluding time since mastectomy because of its overlap with RRM prior to testing. Higher baseline anxiety  independently predicted poorer long-term quality of life and RRM prior to genetic testing  independently predicted better long-term quality of life  and at long-term follow up and propose that difference in time between reference points  reflect progress of our outcomes over time. It is also possible that changes not measured or controlled for in the intervening time periods  could confound the interaction effect between time since testing and satisfaction with management decisions. We modified the Satisfaction with Decision scale for this study, to make it more appropriate for the risk management decisions addressed in this study. Additionally, there may be other differences in variables not assessed in this study between the group of women who underwent RRM and those who did not that might contribute to the differences in outcomes between these groups. Though our outcomes did not differ with regard to women’s cancer history, and the focus of this paper is on risk management, rather than disease management, we were underpowered to do subgroup analyses of affected and unaffected women, and cannot rule out cancer treatment variables as potential confounders. Finally, as testing has become more routine, there are likely to be fewer women who opt for risk reducing surgery prior to genetic testing – making our results regarding timing of surgery less relevant to the current clinical setting.BRCA1/2 carriers. We provide evidence to support long-term impacts of the decision to undergo mastectomy and oophorectomy, and the lasting effects these decisions have as time increases. It is clear, from this study and others, that receiving a positive test result is not an isolated stressor, and that there are many ongoing stressors and decisions to be faced over time. As such, long-term outcomes reflect the combined impact of these multifaceted experiences. Indeed, in our previous study from this population, RRM and RRO were associated with decreased perceived risk for breast and ovarian cancer [This study is the largest prospective report of long-term outcomes related to surgical decision making in affected and unaffected n cancer . Furthern cancer . Though The authors declare that they have no competing interests.GWH performed statistical analysis and oversaw drafting of the manuscript. LK and LV performed literature reviews and assisted in the drafting of the manuscript. KH, BNP and EP provide project management and oversight in participant recruitment and data management. EP conducted interviews and coordinated survey collection. KG, BNP, CI, KT participated in the design of the study and clinical recruitment of the original cohorts of participants. MDS conceived of the study, participated in design and coordination, oversaw the statistical analysis and helped to draft the manuscript. All authors read and approved the final manuscript.