Risk Of Invasive Breast Cancer Research Articles

Exposure to hazardous air pollutants and risk of incident breast cancer in the Nurses\u2019 Health Study II

BackgroundFindings from a recent prospective cohort study in California suggested increased risk of breast cancer associated with higher exposure to certain carcinogenic and estrogen-disrupting hazardous air pollutants (HAPs). However, to date, no nationwide studies have evaluated these possible associations. Our objective was to examine the impacts of mammary carcinogen and estrogen disrupting HAPs on risk of invasive breast cancer in a nationwide cohort.MethodsWe assigned HAPs from the US Environmental Protection Agency’s 2002 National Air Toxics Assessment to 109,239 members of the nationwide, prospective Nurses’ Health Study II (NHSII). Risk of overall invasive, estrogen receptor (ER)-positive (ER+), and ER-negative (ER-) breast cancer with increasing quartiles of exposure were assessed in time-varying multivariable proportional hazards models, adjusted for traditional breast cancer risk factors.ResultsA total of 3321 invasive cases occurred (2160 ER+, 558 ER-) during follow-up 1989–2011. Overall, there was no consistent pattern of elevated risk of the HAPs with risk of breast cancer. Suggestive elevations were only seen with increasing 1,2-dibromo-3-chloropropane exposures (multivariable adjusted HR of overall breast cancer = 1.12, 95% CI: 0.98–1.29; ER+ breast cancer HR = 1.09; 95% CI: 0.92, 1.30; ER- breast cancer HR = 1.14; 95% CI: 0.81, 1.61; each in the top exposure quartile compared to the lowest).ConclusionsExposures to HAPs during adulthood were not consistently associated with an increased risk of overall or estrogen-receptor subtypes of invasive breast cancer in this nationwide cohort of women.

Does mammographic density mediate risk factor associations with breast cancer? An analysis by tumor characteristics.

Though mammographic density (MD) has been proposed as an intermediate marker of breast cancer risk, few studies have examined whether the associations between breast cancer risk factors and risk are mediated by MD, particularly by tumor characteristics. Our study population included 3392 cases (1105 premenopausal) and 8882 (3192 premenopausal) controls from four case-control studies. For established risk factors, we estimated the percent of the total risk factor association with breast cancer that was mediated by percent MD (secondarily, by dense area and non-dense area) for invasive breast cancer as well as for subtypes defined by the estrogen receptor (ER+/ER-), progesterone receptor (PR+/PR-), and HER2 (HER2+/HER2-). Analyses were conducted separately in pre- and postmenopausal women. Positive associations between prior breast biopsy and risk of invasive breast cancer as well as all subtypes were partially mediated by percent MD in pre- and postmenopausal women (percent mediated = 11-27%, p ≤ 0.02). In postmenopausal women, nulliparity and hormone therapy use were positively associated with invasive, ER+ , PR+ , and HER2- breast cancer; percent MD partially mediated these associations (percent mediated ≥ 31%, p ≤ 0.02). Further, among postmenopausal women, percent MD partially mediated the positive association between later age at first birth and invasive as well as ER+ breast cancer (percent mediated = 16%, p ≤ 0.05). Percent MD partially mediated the associations between breast biopsy, nulliparity, age at first birth, and hormone therapy with risk of breast cancer, particularly among postmenopausal women, suggesting that these risk factors at least partially influence breast cancer risk through changes in breast tissue composition.

Breast Density and Risk of Invasive Breast Cancer among Older Women Undergoing Mammography: The Breast Cancer Surveillance Consortium Cohort Study

Abstract This study examined whether breast density is associated with risk of breast cancer in women age ≥65 years undergoing screening mammography in community practice. Methods: We used prospective cohort data between 1996 and 2012 from the Breast Cancer Surveillance Consortium (BCSC). We calculated separate cumulative incidence models for breast cancer incidence according to Breast Imaging Reporting and Data System (BI-RADS) breast density for women ages 65–74 and ages ≥75. Multivariable Cox proportional hazards regression models were fitted to determine the risk of invasive breast cancer adjusted for BCSC registry, race/ethnicity, BMI, hormone therapy use and benign breast disease. Results: Among the 403,268 women included in the study, approximately 40% were ages ≥75. The annual incidence rate of invasive breast cancer increased with increasing breast density among women ages 65–74 [BI- RADS fatty breasts: 2.2% (95% CI, 2.1%–2.4%) vs. heterogeneously or extremely dense breasts: 4.7% (95% CI, 4.6%–4.9%)] and women ages 75+ [BI-RADS fatty breasts: 2.3% (95% CI, 2.1%–2.5%) vs. heterogeneously or extremely dense: 4.3% (95% CI, 4.1%–4.5%)]. Women with BI-RADS fatty breasts had a decreased risk of breast cancer among women ages 65–74 [HR: 0.66 (95% CI: 0.58%–0.78%) and women ages ≥75 [HR: 0.73 (95% CI: 0.62%–0.87%). Women with BI-RADS heterogeneously or extremely dense breasts were found to have increased risk of breast cancer among women ages 65–74 [HR: 1.39 (95% CI: 1.28%–1.51%)] and women ages ≥75 [HR: 1.23 (95% CI: 1.10%–1.37%)]. Conclusions: Older women with higher BI-RADS density had a significantly increased risk of breast cancer. These findings add further evidence that breast density continues to be associated with an increased risk of breast cancer, even among women age ≥75 years.

Depression, Antidepressant Use, and Breast Cancer Risk in Pre- and Postmenopausal Women: A Prospective Cohort Study.

Background: Depression and antidepressant use is highly prevalent among U.S. women and may be related to increased breast cancer risk. However, prior studies are not in agreement regarding an increase in risk.Methods: We conducted a prospective cohort study within the Nurses' Health Study (NHS) and NHSII among females age 25 and older. Over more than 10 years of follow-up in each cohort, 4,014 incident invasive breast cancers were diagnosed. We used Cox proportional hazards regressions with updating of exposures and covariates throughout follow-up to estimate HRs and 95% confidence intervals (CIs) for associations between clinical depression and antidepressant use with invasive breast cancer risk. Analyses were repeated separately for in situ disease, as well as stratified by estrogen receptor (ER) subtype and menopausal status at diagnosis.Results: No statistically significant associations were observed between clinical depression (HR for reporting ≥3 times vs. 0, 1.13; 95% CI, 0.85-1.49) or antidepressant use (HR for reporting ≥3 times vs. 0, 0.92; 95% CI, 0.80-1.05) and invasive breast cancer risk in multivariable analyses. Likewise, we observed no significant associations between clinical depression or antidepressant use and risk of in situ, ER+, ER-, premenopausal, or postmenopausal breast cancer.Conclusions: In the largest prospective study to date, we find no evidence that either depression or antidepressant use increase risk of breast cancer.Impact: The results of this study are reassuring in that neither depression nor antidepressant use appear to be related to subsequent breast cancer risk. Cancer Epidemiol Biomarkers Prev; 27(3); 306-14. ©2017 AACR.

Population-based study of factors influencing invasive breast cancer risk after screen-detected ductal carcinoma in situ: First results from the non-invasive breast cancer in England (NINBE) study

Population-based study of factors influencing invasive breast cancer risk after screen-detected ductal carcinoma in situ: First results from the non-invasive breast cancer in England (NINBE) study

Abstract P5-12-01: The joint effect of modifiable risk factors on risk of invasive breast cancer among Canadian women

Abstract Background Although several studies have suggested that obesity and other modifiable factors influence breast carcinogenesis, there is limited evidence on the combined effect of these exposures on risk of breast cancer. Thus, to gain further insight into whether modifiable risk factors may operate collectively to alter risk of breast cancer, we assessed the association of a healthy lifestyle index (HLI) score (a combination of diet, physical activity, smoking, alcohol consumption and anthropometry) with risk of invasive breast cancer among women in the Canadian Study of Diet, Lifestyle, and Health (CSDLH). Method We performed a case-cohort study using a cohort of 39,532 female participants in the CSDLH who were recruited between 1995 and 1998. The study included an age-stratified subcohort of 3,027 women and 1,018 incident invasive breast cancer cases. Lifestyle and dietary information was collected at baseline using self-administered questionnaires. We estimated hazard ratios (HR) and 95 % confidence intervals (CI) for the association of the HLI score and the individual HLI components with risk of breast cancer using Cox proportional hazards regression modified for the case cohort design. Results: Every unit increase in the HLI score was associated with a 3% reduced risk of breast cancer (HR: 0.97; 95% CI: 0.95-1.00). When considering quintiles of the HLI score, those in the highest quintile had a 26% lower risk for breast cancer compared to those with HLI score in the lowest quintile (HRq5 vs q1: 0.74; 95% CI: 0.59-0.93). In analyses stratified by menopausal status, there was a similar inverse association between the HLI score and risk of breast cancer among postmenopausal women (HR: 0.97; 95% CI: 0.94-1.00) and a tendency towards an inverse association among premenopausal women (HR per unit increase in the HLI score: 0.98; 95% CI: 0.95-1.01). Among the individual components of the HLI score, there was some suggestion of a reduction in risk of breast cancer in association with a relatively high physical activity level in the overall study population (HRq5 vs. q1: 0.81: 95% CI: 0.63-1.04, p trend: 0.08), but consuming a healthy diet, smoking, having high alcohol consumption and being obese were not associated with altered risk of breast cancer. Conclusion: Our findings indicate that adherence to a healthy lifestyle may be associated with reduced risk of breast cancer. These findings suggest the need to further investigate how modifiable risk factors may act jointly to contribute to the development of breast cancer. Such knowledge may have important implications for the development of interventions designed to promote a healthy lifestyle to aid in the primary prevention of breast cancer. Citation Format: Arthur R, Kirsh V, Kreiger N, Rohan T. The joint effect of modifiable risk factors on risk of invasive breast cancer among Canadian women [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P5-12-01.

Abstract P5-13-02: Chemoprevention utilization in patients with a history of atypical hyperplasia, atypical lobular hyperplasia, or lobular carcinoma in-situ: A retrospective chart review of patients diagnosed at an urban hospital with a large minority patient population

Abstract Background: The Breast Cancer Prevention Trial (BCPT) and the Study of Tamoxifen and Raloxifene (STAR) trial showed that chemoprevention can reduce the risk of invasive breast cancer by nearly 50%. Despite these results, studies have shown that while an estimated 2 million women in the United States are eligible for chemoprevention, actual acceptance of these medications is low. Improving chemoprevention utilization rates hinges on better understanding current rates of utilization and factors affecting patient acceptance. Reported rates and barriers to chemoprevention use may not accurately reflect true utilization patterns in lower socioeconomic, minority patient populations. The aim of this IRB approved retrospective study was to characterize the rate and factors associated with chemoprevention use in patients with a diagnosis of atypical ductal hyperplasia (ADH), atypical lobular hyperplasia (ALH), or lobular carcinoma in-situ (LCIS) at an urban hospital with a high minority population. Methods – A retrospective chart review was performed for all diagnoses of ADH, ALH, and LCIS made at the University of Maryland Medical Center between the years 2005-2015. Concurrent DCIS or invasive cancer were excluded. Demographic and clinical information including age, race, education, GAIL score, BMI, and use of chemoprevention was recorded. Univariable and multivariable logistic regression were performed to identify factors associated with chemoprevention discussion and use. Results – 301 diagnoses of ADH/ALH/or LCIS were obtained and 127 women were eligible for analysis. The median age was 53 years old with 47% of patients being premenopausal. The majority were African-American (65%) and 51% had a high school degree or less. The median 5 year risk for developing breast cancer based on the GAIL model was 2.4%. The chemoprevention utilization rate for our patient population was 28% (n=34). Race, menopausal status, and breast density were not associated with chemoprevention discussion or use. We found that patients were more likely to have a chemoprevention discussion with their provider if they were older (p=0.03) or if they were referred to medical oncology (p<0.001, Fisher's exact test). Conclusions - Our study evaluated chemoprevention use in an understudied predominantly African-American patient population. We found a higher rate of chemoprevention utilization (28%) compared to previously reported rates. Age and medical oncology referral had a significant impact on provider-patient chemoprevention discussion. Though limited due to small sample size, our study nonetheless provided thought provoking results. Older patients may be at higher risk for developing breast cancer, however, it is important to consider that younger patients with risk factors may have a more favorable endocrine therapy benefit-risk ratio. In addition, our results highlight the importance of encouraging all physicians who are involved in women's' breast health to have a chemoprevention discussion with eligible patients, or for these physicians to refer patients to a medical oncologist for further discussion. Citation Format: DeRidder A, Mainor C, Goloubeva O, Ioffe O, Bellavance E, Tkaczuk K, Rosenblatt P. Chemoprevention utilization in patients with a history of atypical hyperplasia, atypical lobular hyperplasia, or lobular carcinoma in-situ: A retrospective chart review of patients diagnosed at an urban hospital with a large minority patient population [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P5-13-02.

Abstract GS5-07: Weight change in postmenopausal women and breast cancer risk in the women's health initiative observational study

Abstract Purpose While obesity is an established breast cancer risk factor, information about the influence of weight loss on breast cancer risk in postmenopausal women is mixed precluding generation of a strong public health message regarding potential benefits of weight loss with respect to cancer risk. Therefore, we evaluated associations between weight change and invasive breast cancer risk in postmenopausal women participating in the Women's Health Initiative (WHI) Observational Study. Patients and Methods Postmenopausal women (n=61,335) with no prior breast cancer and normal mammogram who were not underweight (body mass index [BMI] ≥ 18.5 kg/m2), ages 50-79 years at WHI enrollment between 1993 and 1998 at 40 US clinical centers, had body weight and height measured and BMI calculated at the clinical centers at baseline and at year 3. Weight change over 3 years was categorized as: stable (no change ≤ 5%), loss (change ≥ 5%), or gain (change ≥ 5%) with weight lost intentionality determined by self-report response to direct query at year 3. Breast cancers were initially ascertained through annual survey and were centrally confirmed by medical record review. Multi-variable Cox proportional hazards regression models incorporating breast cancer risk factors and baseline BMI were used to evaluate relationships between weight change and breast cancer incidence. Results During 11.4 years (mean) of follow-up, 3,061 women developed invasive breast cancer. In multi-variable analyses, compared with women with stable weight (n=41,139), women with weight loss (≥ 5%) (n=8,175) had a significantly lower breast cancer risk (hazard ratio [HR] 0.88 95% confidence interval [CI] 0.78-0.98). Adjustment for mammography did not alter findings (HR 0.88 95% CI 0.78-0.99). There was no significant interaction for breast cancer effect by weight loss intentionality. Women with weight loss ≥ 15% had even lower breast cancer risk (HR 0.63 95% CI 0.45-0.90). While weight gain (≥ 5%) (n=12,021) was not associated with higher overall breast cancer risk, women with weight gain had a significantly higher risk of triple negative breast cancer (HR 1.54 95% CI 1.16-2.05). Weight change association with breast cancer incidence was examined in four subgroups: by tumor subtype (hormone receptor and HER2 status based), baseline BMI (normal, overweight, obese), race/ethnicity, and age group (50, -<70 years). Effects in all subgroups was similar with no evidence of heterogeneity as no interaction term test in these analyses was significant. Conclusion Weight loss in postmenopausal women is associated with lower breast cancer risk. These findings suggest that postmenopausal women who lose weight may reduce their breast cancer risk. Citation Format: Chlebowski RT, Luo J, Anderson GL, Simon M, Barrington W, Reding K, Manson JE, Rohan T, Wactawki-Wende J, Lane D, Strickler H, Mossavar-Rahmani Y, Freudenheim J, Saquib ATN, Stefanick M. Weight change in postmenopausal women and breast cancer risk in the women's health initiative observational study [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr GS5-07.

Abstract GS5-08: A validation of DCIS biological risk profile in a randomised study for radiation therapy with 20 year follow-up (SweDCIS)

Abstract Background: Women diagnosed with ductal carcinoma in situ (DCIS) and their physicians need tools that assess individualized risk and predict treatment benefit. A DCIS biologic signature was previously validated in an observational study at Kaiser Permanente NW. We evaluated the results of the signature for predictive utility in a national randomized clinical trial (SweDCIS) by assessing the 10-year benefit of adjuvant radiotherapy (RT) on ipsilateral breast event (IBE) and invasive breast cancer (IBC) risks. Methods: The signature was validated in a prospective-retrospective study in women from the SweDCIS trial (n=1046) performed by the Swedish Breast Cancer Group. Women were treated with breast conserving surgery (BCS) between 1987-1999 and randomized to RT or no RT. A central pathology review of paraffin embedded tissue blocks (n=873) was performed at Uppsala University (UU). Freshly cut slides were provided to PreludeDx for biomarker testing. Extended follow-up of SweDCIS was published in 2014. A panel of biomarkers (HER2, PR, Ki67, COX2, p16/INK4A, FOXA1 and SIAH2) were assayed and scored in PreludeDx's CLIA lab by board-certified pathologists. Continuous Decision Scores (DS) were calculated with the biologic signature using the biomarker and clinical factors (age, size, margin, and palpability) blinded to patient outcome. The DS results were provided to the Uppsala Regional Cancer Center for analysis. A predefined and co-developed statistical analysis plan was executed. Absolute 10-year RT benefit was assessed using Kaplan-Meier survival analysis. Hazard ratios (HR) were determined using Cox proportional hazards analysis and the interaction of the DS and RT benefit was assessed. Results: Complete biomarker and clinical information was available in 584 women. In women with clear margins (n=506), 78 IBEs, including 31 IBCs, were recorded within 10 years of diagnosis. The multivariate analysis of DS (0-10 unit scale) and the RT interaction was significant for risk of IBC (p=0.048) and IBE (p<0.001) at 10 years. The DS defined an elevated risk group (>3) for which there was pronounced 10-year benefit of RT (p=0.01) with an absolute risk reduction of 9% for IBC (Table 1). The corresponding low risk group (≤3), which included 48% of all patients, demonstrated no significant RT benefit (p=0.70) with an absolute risk reduction of 1%. The continuous DS variable was correlated with IBE risk, HR 1.49/per 5 units 95%CI[1.02,2.18] (p=0.038), in addition to the RT benefit for IBE in low (p=0.04) and elevated (p<0.001) risk groups. Table 1. 10-year RT benefit in women from the SweDCIS trial.DS Risk GroupsIBC eventsIn Situ or IBC eventsnAbsolute RT-benefitHR [95%CI] Absolute RT-benefit HR [95%CI]Low Risk Group (DS≤3)2431%0.83 [0.32, 2.16]9%0.48 [0.24-0.97]Elevated Risk Group (DS>3)2639%0.24 [0.08, 0.73]17%0.31 [0.17-0.59] Discussion: Evaluation of the SweDCIS trial validated prognostic and RT predictive utility of the biologic signature. Women diagnosed with DCIS and treated with BCS±RT were stratified into clinically relevant low and elevated risk groups (≤3 vs >3). Women in the elevated risk group had twice the treatment benefit for IBC from RT compared to prior randomized trials, while the low risk group had no benefit from RT. Citation Format: Wärnberg F, Garmo H, Folkvaljon Y, Holmberg L, Karlsson P, Sandelin K, Linke S, Lyle S, Simin K, Leesman G, Barry T, Savala J, Whitworth P, Bremer T. A validation of DCIS biological risk profile in a randomised study for radiation therapy with 20 year follow-up (SweDCIS) [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr GS5-08.

Abstract OT3-01-02: Randomized controlled trial of web-based decision support tools for high-risk women and primary care providers to increase breast cancer chemoprevention

Abstract Background: Breast cancer chemoprevention with selective estrogen receptor modulators (SERMs) and aromatase inhibitors (AIs) is under-utilized despite several randomized controlled trials demonstrating a 40-65% decrease in breast cancer incidence among high-risk women. Reasons for low chemoprevention uptake include inadequate time for counseling, insufficient knowledge about SERMs and AIs, and concerns about side effects. Intervention trials of clinical decision support tools designed to increase chemoprevention uptake have been met with limited success. We have developed web-based decision aids (DAs), RealRisks for high-risk women and BNAV for primary care providers (PCPs). Our intervention differs from the prior literature in that we are targeting both patients and PCPs with personalized risk reports and education about the risks and benefits of chemoprevention. Our patient-centered decision aid is available in English and Spanish and has been rigorously tested in multi-ethnic women with varying health literacy. We hypothesize that standard educational materials combined with RealRisks and BNAV will increase uptake of SERMs or AIs among high-risk women in the primary care setting. Trial Design: We are conducting a randomized controlled trial at Columbia University Medical Center (CUMC) in New York, NY, consisting of standard educational materials combined with RealRisks and BNAV or standard educational materials alone among 300 high-risk women stratified by Hispanic ethnicity and menopausal status. Women in the intervention arm are given access to the RealRisks DA, and, based on their responses, an action plan is generated summarizing their breast cancer risk profile, risks/benefits of SERMs and AIs, and personal preferences for chemoprevention. PCPs are given their patient's tailored risk report, which is the providers' view of the action plan, and are invited to access the BNAV tool. Eligibility Criteria: 1) Women, aged 35-75 years; 2) 5-year invasive breast cancer risk ≥1.67% or lifetime risk ≥20% according to the Gail model (Breast Cancer Risk Assessment Tool) or history of lobular carcinoma in situ; 3) No prior use of SERM or AI; 4) No prior history of breast cancer; 5) PCP at CUMC; 6) English- or Spanish-speaking. Specific Aims: The primary endpoint is chemoprevention uptake of a SERM or AI at 6 months based upon documentation in the electronic health record. Secondarily, we use validated surveys to assess breast cancer and chemoprevention knowledge, accuracy of perceived breast cancer risk and worry, decision self-efficacy, and informed choice at baseline, 1 month, 6 months, and post-clinical encounter with the patients' PCP. PCPs will complete a 1-time survey on personal and professional characteristics and practice patterns. Statistical Methods: With a total sample size of 300 (150 per arm), assuming a Type 1 error of 5% and a 10% drop-out rate (effective sample size of 270), we will have >80% power to detect a difference in chemoprevention uptake of 1% in the control arm and 10% in the active intervention arm. Target Accrual: 300. Seventy-eight participants accrued as of June 2017. Accrual completion expected November 2018. Contact: Katherine Crew, CUMC, kd59@cumc.columbia.edu Citation Format: Vanegas A, Vargas JM, Kukafka R, Crew KD. Randomized controlled trial of web-based decision support tools for high-risk women and primary care providers to increase breast cancer chemoprevention [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr OT3-01-02.

Family History and Breast Cancer Risk Among Older Women in the Breast Cancer Surveillance Consortium Cohort

First-degree family history is a strong risk factor for breast cancer, but controversy exists about the magnitude of the association among older women. To determine whether first-degree family history is associated with increased risk of breast cancer among older women, and identify whether the association varies by breast density. Prospective cohort study between 1996 and 2012 from 7 Breast Cancer Surveillance Consortium (BCSC) registries located in New Hampshire, North Carolina, San Francisco Bay area, western Washington state, New Mexico, Colorado, and Vermont. During a mean (SD) follow-up of 6.3 (3.2) years, 10 929 invasive breast cancers were diagnosed in a cohort of 403 268 women 65 years and older with data from 472 220 mammography examinations. We estimated the 5-year cumulative incidence of invasive breast cancer by first-degree family history, breast density, and age groups. Cox proportional hazards models were fit to estimate the association of first-degree family history with risk of invasive breast cancer (after adjustment for breast density, BCSC registry, race/ethnicity, body mass index, postmenopausal hormone therapy use, and benign breast disease for age groups 65 to 74 years and 75 years and older, separately). Data analyses were performed between June 2016 and June 2017. First-degree family history of breast cancer. Incident breast cancer. In 403 268 women 65 years and older, first-degree family history was associated with an increased risk of breast cancer among women ages 65 to 74 years (hazard ratio [HR], 1.48; 95% CI, 1.35-1.61) and 75 years and older (HR, 1.44; 95% CI, 1.28-1.62). Estimates were similar for women 65 to 74 years with first-degree relative's diagnosis age younger than 50 years (HR, 1.47; 95% CI, 1.25-1.73) vs 50 years and older (HR, 1.33; 95% CI, 1.17-1.51) and for women ages 75 years and older with the relative's diagnosis age younger than 50 years (HR, 1.31; 95% CI, 1.05-1.63) vs 50 years and older (HR, 1.55; 95% CI, 1.33-1.81). Among women ages 65 to 74 years, the risk associated with first-degree family history was highest among those with fatty breasts (HR, 1.67; 95% CI, 1.27-2.21), whereas in women 75 years and older the risk associated with family history was highest among those with dense breasts (HR, 1.55; 95% CI, 1.29-1.87). First-degree family history was associated with increased risk of invasive breast cancer in all subgroups of older women irrespective of a relative's age at diagnosis.

MicroRNA expression in benign breast tissue and risk of subsequent invasive breast cancer.

MicroRNAs are endogenous, small non-coding RNAs that control gene expression by directing their target mRNAs for degradation and/or posttranscriptional repression. Abnormal expression of microRNAs is thought to contribute to the development and progression of cancer. A history of benign breast disease (BBD) is associated with increased risk of subsequent breast cancer. However, no large-scale study has examined the association between microRNA expression in BBD tissue and risk of subsequent invasive breast cancer (IBC). We conducted discovery and validation case-control studies nested in a cohort of 15,395 women diagnosed with BBD in a large health plan between 1971 and 2006 and followed to mid-2015. Cases were women with BBD who developed subsequent IBC; controls were matched 1:1 to cases on age, age at diagnosis of BBD, and duration of plan membership. The discovery stage (316 case-control pairs) entailed use of the Illumina MicroRNA Expression Profiling Assay (in duplicate) to identify breast cancer-associated microRNAs. MicroRNAs identified at this stage were ranked by the strength of the correlation between Illumina array and quantitative PCR results for 15 case-control pairs. The top ranked 14 microRNAs entered the validation stage (165 case-control pairs) which was conducted using quantitative PCR (in triplicate). In both stages, linear regression was used to evaluate the association between the mean expression level of each microRNA (response variable) and case-control status (independent variable); paired t-tests were also used in the validation stage. None of the 14 validation stage microRNAs was associated with breast cancer risk. The results of this study suggest that microRNA expression in benign breast tissue does not influence the risk of subsequent IBC.

A Metabolomics Analysis of Body Mass Index and Postmenopausal Breast Cancer Risk.

Elevated body mass index (BMI) is associated with increased risk of postmenopausal breast cancer. The underlying mechanisms, however, remain elusive. In a nested case-control study of 621 postmenopausal breast cancer case participants and 621 matched control participants, we measured 617 metabolites in prediagnostic serum. We calculated partial Pearson correlations between metabolites and BMI, and then evaluated BMI-associated metabolites (Bonferroni-corrected α level for 617 statistical tests = P < 8.10 × 10-5) in relation to invasive breast cancer. Odds ratios (ORs) of breast cancer comparing the 90th vs 10th percentile (modeled on a continuous basis) were estimated using conditional logistic regression while controlling for breast cancer risk factors, including BMI. Metabolites with the lowest P values (false discovery rate < 0.2) were mutually adjusted for one another to determine those independently associated with breast cancer risk. Of 67 BMI-associated metabolites, two were independently associated with invasive breast cancer risk: 16a-hydroxy-DHEA-3-sulfate (OR = 1.65, 95% confidence interval [CI] = 1.22 to 2.22) and 3-methylglutarylcarnitine (OR = 1.67, 95% CI = 1.21 to 2.30). Four metabolites were independently associated with estrogen receptor-positive (ER+) breast cancer risk: 16a-hydroxy-DHEA-3-sulfate (OR = 1.84, 95% CI = 1.27 to 2.67), 3-methylglutarylcarnitine (OR = 1.91, 95% CI = 1.23 to 2.96), allo-isoleucine (OR = 1.76, 95% CI = 1.23 to 2.51), and 2-methylbutyrylcarnitine (OR = 1.89, 95% CI = 1.22 to 2.91). In a model without metabolites, each 5 kg/m2 increase in BMI was associated with a 14% higher risk of breast cancer (OR = 1.14, 95% CI = 1.01 to 1.28), but adding 16a-hydroxy-DHEA-3-sulfate and 3-methylglutarylcarnitine weakened this association (OR = 1.06, 95% CI = 0.93 to 1.20), with the logOR attenuating by 57.6% (95% CI = 21.8% to 100.0+%). These four metabolites may signal metabolic pathways that contribute to breast carcinogenesis and that underlie the association of BMI with increased postmenopausal breast cancer risk. These findings warrant further replication efforts.

Alcohol Consumption as a Risk Factor for Breast Cancer Development: A Case-Control Study in Brazil

Background:Alcohol consumption is a well-established risk factor for breast cancer, but the evidence is mostly from developed countries. Brazil is going through a rapid demographic expansion, and studies of this relationship are also needed in such unexplored settings.Methods:We assessed the relationship between alcohol consumption and breast cancer risk among 1,506 Brazilian women (406 cases and 1,100 controls). Regression models were used to calculate odds ratios (OR) and 95% confidence intervals (CI). All statistical tests were two-tailed.Results:The mean age of the 1,506 women was 42.0 (standard deviation, ±15.0) years. There was a significant association between breast cancer and age, body mass index, age at menarche, menstrual flow and menstrual cycle. Multivariate analysis showed an increased risk of invasive breast cancer in regular alcohol consumers (<50 years old: OR 4.7; 95% CI 1.4–16.2; ≥50 years old: OR 3.9; 95% CI 1.2–13.4) compared with abstainers or occasional drinkers. Women with a regular alcohol intake for 10 years or more who were less than 50 years old had a threefold higher risk of developing breast cancer (OR 3.0; 95% CI 1.2–7.6).Conclusion:Regular alcohol consumption increases the risk of breast cancer mainly among women less than 50 years old.

Contemporary Hormonal Contraception and the Risk of Breast Cancer

BackgroundLittle is known about whether contemporary hormonal contraception is associated with an increased risk of breast cancer.MethodsWe assessed associations between the use of hormonal contraception and the risk of invasive breast cancer in a nationwide prospective cohort study involving all women in Denmark between 15 and 49 years of age who had not had cancer or venous thromboembolism and who had not received treatment for infertility. Nationwide registries provided individually updated information about the use of hormonal contraception, breast-cancer diagnoses, and potential confounders.ResultsAmong 1.8 million women who were followed on average for 10.9 years (a total of 19.6 million person-years), 11,517 cases of breast cancer occurred. As compared with women who had never used hormonal contraception, the relative risk of breast cancer among all current and recent users of hormonal contraception was 1.20 (95% confidence interval [CI], 1.14 to 1.26). This risk increased from 1.09 (95% CI, 0.96 to 1.23) with less than 1 year of use to 1.38 (95% CI, 1.26 to 1.51) with more than 10 years of use (P=0.002). After discontinuation of hormonal contraception, the risk of breast cancer was still higher among the women who had used hormonal contraceptives for 5 years or more than among women who had not used hormonal contraceptives. Risk estimates associated with current or recent use of various oral combination (estrogen–progestin) contraceptives varied between 1.0 and 1.6. Women who currently or recently used the progestin-only intrauterine system also had a higher risk of breast cancer than women who had never used hormonal contraceptives (relative risk, 1.21; 95% CI, 1.11 to 1.33). The overall absolute increase in breast cancers diagnosed among current and recent users of any hormonal contraceptive was 13 (95% CI, 10 to 16) per 100,000 person-years, or approximately 1 extra breast cancer for every 7690 women using hormonal contraception for 1 year.ConclusionsThe risk of breast cancer was higher among women who currently or recently used contemporary hormonal contraceptives than among women who had never used hormonal contraceptives, and this risk increased with longer durations of use; however, absolute increases in risk were small. (Funded by the Novo Nordisk Foundation.)

Self-Assembling Raloxifene Loaded Mixed Micelles: Formulation Optimization, In Vitro Cytotoxicity and In Vivo Pharmacokinetics.

Raloxifene (RLX) has been strongly recommended for postmenopausal women at high risk of invasive breast cancer and for prevention of osteoporosis. However, low aqueous solubility and reduced bioavailability hinder its clinical application. The objective of this study was to explore the potential of RLX loaded mixed micelles (RLX-MM) using Pluronic F68 and Gelucire 44/14 for enhanced bioavailability and improved anticancer activity on human breast cancer cell line (MCF-7). RLX-MM were prepared by solvent evaporation method and optimized using 32 factorial design. The average size, entrapment efficiency and zeta potential of the optimized formulation were found to be 190 ± 3.3nm, 79 ± 1.3%, 13 ± 0.8mV, respectively. In vitro study demonstrated 74.68% drug release from RLX-MM in comparison to 42.49% drug release from RLX dispersion. According to the in vitro cytotoxicity assay, GI50 values on MCF-7 breast cancer cell line for RLX-MM and free RLX were found to be 22.5 and 94.71μg/mL, respectively. Significant improvement (P < 0.05) in the anticancer activity on MCF-7 cell line was observed in RLX-MM over RLX pure drug. Additionally, oral bioavailability of RLX-MM was improved by 1.5-fold over free RLX when administered in female Wistar rats. Incorporation of RLX in the hydrophobic core and improved solubility of the drug due to hydrophilic shell attributed to the enhanced cytotoxicity and bioavailability of RLX-MM. This research establishes the potential of RLX loaded mixed micelles of Pluronic F68 and Gelucire 44/14 for improved bioavailability and anticancer activity on MCF-7 cell line.

Negative Valence Life Events Promote Breast Cancer Development

BackgroundThe influence of stress on breast cancer risk remains unknown. The goal of the present study was to determine the effect of stress in the form of salient positive and negative valence life events (LEs) on primary invasive breast cancer risk. We hypothesized that salient negative LEs would increase breast cancer risk and salient positive LEs would attenuate this increased risk. Patients and MethodsWe used a case-control design with 664 cases identified through the Cancer Surveillance Program of Orange County and 203 population-based controls. Participants completed a risk factor questionnaire, which included a LE section. Fourteen salient LEs of positive or negative valence were used to quantify stress exposure. A baseline model was constructed, and odds ratios (ORs) were calculated using multivariate unconditional logistic regression. ResultsNegative LEs were associated with increased breast cancer risk. The OR for ≥ 4 negative LEs showed a 2.81-fold increase in breast cancer risk (OR, 2.81; 95% confidence interval [CI], 1.47-5.36). A significant dose–response relationship between lifetime negative valence LEs and breast cancer risk was found. Previous personal illness increased breast cancer risk by 3.6-fold (OR, 3.60; 95% CI, 2.50-5.20). In contrast, abortion was associated with a 45% decrease in breast cancer risk (OR, 0.55; 95% CI, 0.34-0.89). Salient positive LEs did not have a significant effect on breast cancer risk. However, they seemed to buffer the adverse effect of salient negative LEs on breast cancer risk. ConclusionThe findings from the present study support the role of salient negative LEs in promoting breast cancer development, with a possible buffering effect of salient positive LEs.

1075. Population-based study of factors influencing invasive breast cancer risk after screen-detected ductal carcinoma in situ: First results from the non-invasive breast cancer in England (NINBE) study

1075. Population-based study of factors influencing invasive breast cancer risk after screen-detected ductal carcinoma in situ: First results from the non-invasive breast cancer in England (NINBE) study

Simple Decision-Analytic Functions of the AUC for Ruling Out a Risk Prediction Model and an Added Predictor.

When using risk prediction models, an important consideration is weighing performance against the cost (monetary and harms) of ascertaining predictors. The minimum test tradeoff (MTT) for ruling out a model is the minimum number of all-predictor ascertainments per correct prediction to yield a positive overall expected utility. The MTT for ruling out an added predictor is the minimum number of added-predictor ascertainments per correct prediction to yield a positive overall expected utility. An approximation to the MTT for ruling out a model is 1/[P (H(AUCmodel)], where H(AUC) = AUC - {½ (1-AUC)}½, AUC is the area under the receiver operating characteristic (ROC) curve, and P is the probability of the predicted event in the target population. An approximation to the MTT for ruling out an added predictor is 1 /[P {(H(AUCModel:2) - H(AUCModel:1 )], where Model 2 includes an added predictor relative to Model 1. The latter approximation requires the Tangent Condition that the true positive rate at the point on the ROC curve with a slope of 1 is larger for Model 2 than Model 1. These approximations are suitable for back-of-the-envelope calculations. For example, in a study predicting the risk of invasive breast cancer, Model 2 adds to the predictors in Model 1 a set of 7 single nucleotide polymorphisms (SNPs). Based on the AUCs and the Tangent Condition, an MTT of 7200 was computed, which indicates that 7200 sets of SNPs are needed for every correct prediction of breast cancer to yield a positive overall expected utility. If ascertaining the SNPs costs $500, this MTT suggests that SNP ascertainment is not likely worthwhile for this risk prediction.

Clinical trials in menopause.

Clinical trials in menopause have undergone much scrutiny over the years. This has led to significant shifts in the treatment of symptomatic menopause and a substantial impact on women. We aim to delineate the key studies contributing to this controversy and highlight new directions specifically related to menopausal hormone therapy (HT) and vascular disease risk. We performed a search of sentinel studies delineating the risks and benefits of HT in otherwise healthy postmenopausal women. Using PubMed we input the following search terms: hormone replacement therapy, cardiovascular disease, coronary artery disease, coronary atherosclerosis, myocardial infarction, angina, coronary heart calcification, carotid intimal thickness, lipids, and/or lipoproteins. We included studies of menopausal women (surgical or natural) using combined estrogen/progestogen therapy or estrogen-only therapy that looked at cardiovascular disease risk factors or outcomes. Studies were evaluated for inclusion by the authors; however, this is not intended to be a systematic or an exhaustive analysis. In women close to the time of menopause, there is a decreased risk of subclinical and clinical coronary heart disease with menopausal HT. Additionally, HT confers a significant benefit to vasomotor symptoms of menopause, bone health, and colorectal cancer. There is an increased risk of venous thromboembolism with oral formulations that appears mitigated with transdermal estradiol. Mixed data regarding breast cancer risk are available, with some studies suggesting an increased risk of invasive breast cancer with estrogen/progestogen therapy and a null effect with estrogen-only therapy. Other more long-term epidemiologic studies identify a decreased risk. The available literature suggests that HT is a viable option for the primary prevention of cardiovascular disease in postmenopausal women. Newer trials will likely verify this assessment. If this is enough to change clinical practice, however, remains to be seen given the general fear of HT by many with prescriptive authority, and also the women in our care.