Elevated Breast Cancer Risk Research Articles

Change in risk of breast cancer after receiving hormone replacement therapy by considering effect-modifiers: a systematic review and dose-response meta-analysis of prospective studies.

We synthesize the current literatures and use the power of meta-analysis to examine trends on association between hormone replacement therapy (HRT) and the risk of breast cancer (BC). We performed a comprehensive literature search using PubMed, EMBASE, and Web of Science from their inception until Jan 2017. Prospective studies that provided adjusted risk estimates of HRT and BC risk were eligible. Categorical and dose-response meta-analyses followed the PRISMA were conducted using random effects model and restricted cubic spline model, respectively. Forty-seven publications from thirty-five unique studies were included, involving 3,898,376 of participants and 87,845 of BC cases. Compared with non-users, RR for current estrogen-only therapy (ET) users was 1.14 (95% confidence interval (CI) = 1.05–1.22), and for per year increases was 1.02 (95% CI = 1.02–1.02). Moreover, RR for current estrogen plus progestin therapy (EPT) users was 1.76, (95% CI = 1.56–1.96), and for per year increases was 1.08 (95% CI = 1.08–1.08). Dose-response analyses revealed 8–10 years’ onset peaks, and indicated residual increased BC risk remained after stopping use of ET regimen rather than for EPT. Effect-modifiers like BMI, duration of use, race/ethnicity, routes of administration were recognized. In Conclusions, current use of EP or EPT and ever use of tibolone are associated with an elevated risk of BC. Compared with slim HRT users and non-users, lower BC risks were found among overweight/obese HRT users and former EPT users, respectively. Both ET and EPT users are associated with higher risk of lobular BC than ductal BC, and more ER-positive than negative BC cases were detected among EPT users.

The Addition of Automated Breast Ultrasound to Mammography in Breast Cancer Screening Decreases Stage at Diagnosis

This study aimed to determine the best screening strategy using automated whole-breast ultrasound and mammography in women with increased breast density or an elevated risk of breast cancer. After an institutional review board waiver was obtained, a retrospective review of 122 cancer cases diagnosed in 3435 women with increased breast density or an elevated risk of breast cancer, screened with mammography and supplemental automated whole-breast ultrasound, was performed. The imaging modality on which each cancer was seen was noted. Screening strategies were postulated. For each screening strategy, rates of advanced cancer diagnosis, with 95% confidence limits, are calculated using the Clopper-Pearson method. Differences in outcomes were calculated using Cochrane Q test and McNemar test for paired observations. Results were expressed for all stages of cancer and for invasive cancers only. When all cancer stages are considered, mammographic screening reduces advanced cancers by 31% over no screening. Ultrasound-only screening results in a 32% reduction. The combination of mammographic and ultrasound screening reduces advanced cancers by 40% (P < .05). Compared to mammographic screening, mammographic plus ultrasound screening reduces advanced-stage cancers by 5.7% (P = 0.03) for all stages and 10.8% (P = 0.02) for invasive cancers. For women with increased breast density or who are at high risk of developing breast cancer, a combination of screening mammography and whole-breast automated ultrasound is superior to mammographic screening. Screening ultrasound alone is also an effective screening strategy.

Abstract 4269: Risk of different cancers among first-degree relatives of pancreatic cancer patients and impact of probands’ germline mutation on sibling cancer risk

Abstract Background: There have been varying reports on risk of different cancers, other than pancreatic cancer (PC), among first-degree relatives (FDRs) of PC patients. Because the pattern and scope of aggregation of PC with other malignancies in families of PC patients are not entirely clear, we investigated risk of 15 common malignancies among FDRs of unselected PC probands. Methods: The study included 17,181 FDRs with more than 336,000 person-years at risk. The FDRs were identified through sequentially enrolled PC probands (n=2,305) in the Mayo Clinic prospective pancreatic cancer patient registry from 2000-2016. Data on family history of cancer were provided by the probands at the time of enrollment in structured risk factor questionnaires. Standardized incidence ratios (SIRs) and 95% confidence intervals (CIs) were calculated by comparing cases of each cancer type observed among the FDRs with those expected using data from the Surveillance Epidemiology and End Results Program (SEER). Stratified analyses were performed among siblings of the probands based on whether the related proband tested positive for a mutation in ATM, BARD1, BRCA1, BRCA2, CDKN2A, CHEK2, MUTYH, NBN, PALB2, or PMS2; or tested negative for mutation in a total of 25 sequenced cancer susceptibility genes. Results: Compared to the SEER reference population, risk of PC was two-fold higher than expected among the FDRs (SIR=2.04, 95% CI: 1.78-2.31) and 12-fold higher than expected among FDRs with history of PC in at least two blood relatives (SIR=11.99, 95% CI: 10.48-13.64). Siblings of mutation-positive probands had higher risk of PC (SIR=13.57, 95% CI: 6.19-25.76) than siblings of mutation-negative probands (SIR=8.91, 95% CI=6.73-11.57). For other cancer types, primary liver cancer was elevated among female FDRs (SIR=2.10, 95% CI: 1.34-3.12), whereas breast (SIR=3.16, 95% CI: 1.63-5.52) and ovarian (SIR =6.61, 95% CI: 1.33-19.31) cancers were elevated only among siblings of the mutation-positive probands. There also were suggestions of lower than expected risk of other malignancies, such as bladder, colorectal and prostate cancers, among the FDRs as compared with the SEER population. Conclusions: These findings confirm familial aggregation of PC with breast and ovarian cancers, and further suggest a potential aggregation of PC and primary liver cancer among female FDRs of PC probands. The elevated risks of breast cancer and ovarian cancer among siblings of the mutation-positive probands suggests a strong influence of genetic susceptibility shared with the related proband, possibly due to an inherited mutation in BRCA1, BRCA2, or PALB2. These findings lend support to genetic counseling and targeted screening of certain cancers in high-risk families. Citation Format: Samuel O. Antwi, Sarah E. Fagan, Kari G. Chaffee, William R. Bamlet, McWilliams R. Robert, Ann L. Oberg, Gloria M. Petersen. Risk of different cancers among first-degree relatives of pancreatic cancer patients and impact of probands’ germline mutation on sibling cancer risk [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4269. doi:10.1158/1538-7445.AM2017-4269

Abstract 3691: Analysis of germline BRCA1/2 mutation associated breast and ovarian tumors reveals distinct pathways of immunosuppression

Abstract BRCA1 and BRCA2 are essential homologous recombination (HR) repair proteins; germline mutations confer elevated risk for breast and ovarian cancer. Defects in BRCA can lead to immune-related effects including depletion of peripheral T-cell pools and increased somatic mutational burden. We investigated the immunophenotypic properties of breast and ovarian cancers associated with germline BRCA1/2 mutations. We determined neoantigen load in 16 breast and 26 ovarian tumors with germline BRCA1/2 mutations and 50 non-BRCA tumors for each disease using whole exome sequencing data from the TCGA. Although neoantigen load (IC50 &amp;lt;500 nM) was variable across tumors, it did not differ between BRCA1/2 mutant and non-BRCA tumors. Leveraging RNAseq data from the TCGA, we investigated immune-related transcriptomic features within each disease. Cytolytic index, a measure of PRF1 and GZMA expression, was higher in non-BRCA tumors than BRCA1/2 mutant for breast (p&amp;lt;0.01) tumors and correlated more closely with neoantigen load than in non-BRCA tumors (Breast: BRCA r2=-0.15, non-BRCA r2=0.237). Class I HLA expression also correlated with cytolytic index (p&amp;lt;0.05) in non-BRCA tumors but not BRCA1/2 mutation associated tumors for both breast and ovarian cancers, suggesting more robust antigen-driven adaptive immunity in non-BRCA tumors. HLA expression was significantly lower (p&amp;lt;0.01) among BRCA mutant breast tumors, indicating immune escape by HLA down-regulation. We classified non-BRCA breast tumors by their level of HR deficiency (HRD score), as HRD by both BRCA and non-BRCA mediated mechanisms can lead to increased somatic mutational burden. Non-BRCA breast tumors irrespective of HRD score exhibited evidence of a more inflamed phenotype than BRCA1/2 mutant tumors, indicated by higher inferred immune cell infiltration, immune checkpoint expression, and chemokine expression (all p&amp;lt;0.01). To investigate potential mechanisms of immune escape in BRCA1/2 vs non-BRCA tumors, we compared canonical gene sets (MsigDb) across the two cohorts. Expression of extracellular matrix (ECM) proteins was higher in BRCA1/2 breast and ovarian tumors (q&amp;lt;0.02), suggesting that BRCA1/2 tumors may exclude immune cells via a dense ECM as observed for colorectal cancer and melanoma. Among Penn BRCA1/2 tumors (19 breast, 20 ovarian), neoantigen load did not differ from TCGA BRCA1/2 tumors. We directly measured immune cell infiltration via tumor immunohistochemistry in 12 breast and 14 ovarian Penn BRCA1/2 tumors. We found that CD3+ and CD8+ T cell infiltration was significantly lower in BRCA1/2 tumors with PTEN deletion (p&amp;lt;0.05), a known correlate of ECM remodeling in breast and ovarian cancer. Our work provides early evidence that BRCA1/2 breast and ovarian tumors mitigate intratumoral adaptive immunity by T-cell exclusion, so that despite higher mutational burden, they may not respond to checkpoint blockade. Citation Format: Adam Kraya, Kara N. Maxwell, Brandon M. Wenz, Bradley Wubbenhorst, Nicole Lunceford, Amanda Barrett, Jennifer J. Morrissette, Michael D. Feldman, Susan M. Domchek, Robert H. Vonderheide, Katherine L. Nathanson. Analysis of germline BRCA1/2 mutation associated breast and ovarian tumors reveals distinct pathways of immunosuppression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3691. doi:10.1158/1538-7445.AM2017-3691

Abstract 2285: Menopausal hormone therapy (MHT) use and breast cancer risk by receptor subtypes: results from the New South Wales Cancer Lifestyle and EvAluation of Risk (CLEAR) study

Abstract Background: Prior observational studies have identified an elevated breast cancer risk associated with current MHT use for ER+ (Estrogen Receptor positive), and for ER+ / PR+ (Estrogen and Progesterone Receptor positive) breast cancers than for ER- and ER-/PR- subtypes respectively. We have previously reported, from a large case-control study for all cancer types (the NSW CLEAR study) that current MHT use was associated with a doubling of the odds of breast cancer. Here, we describe further analyses investigating the MHT-breast cancer association for the breast cancer tumor receptor subtypes defined by ER expression, by ER and PR expression and by the joint expression of ER, PR, and HER-2 (Human Epidermal growth factor Receptor-2). Methods: Analyses were carried out for a subset of registry-verified CLEAR breast cancer cases with hormone receptor status data (n=410) and CLEAR (cancer-free) controls recruited over the same period (n=324). We used a multinomial logistic regression model to estimate Odds Ratios (ORs) adjusted for other breast cancer risk factors and 95% Confidence Intervals (CI) for current and past MHT use in subgroups defined by tumor receptor subtypes. Never users comprised the reference group. Findings: In a multinomial model, current MHT use was associated with an elevated risk of ER+ breast cancer (aOR= 2.04, 95%CI: 1.28 -3.24). When breast cancers were categorised by ER and PR status, current use was associated with an elevated risk of developing ER+PR+ breast cancer (aOR= 2.29, 1.41-3.72). Current MHT use was associated with the surrogate luminal A breast cancer characterized by ER+/PR+/HER2- phenotype (aOR= 2.30, 1.42-3.73). None of the other subtypes of breast cancer (ER+/PR+/HER2+, ER-/PR-/HER2+, and ER-/PR-/HER2-) were significantly associated with current MHT use. A significant difference in the odds of developing breast cancer for current MHT users was detected between the surrogate luminal A and luminal B (ER+/PR+/HER2+) subtypes only (aOR= 0.28, 0.09-0.88, p=0.029). None of the other groups were significantly differently associated with MHT use, although this may be due to lack of power. Past MHT use was not associated with an increased risk of breast cancer for any breast cancer subtype. Conclusion: The findings from this contemporary Australian study are consistent with findings from other studies that current, but not past, use of MHT is associated with increased risk of breast cancer, with higher risks reported for ER+, ER+ and PR+ and ER+/PR+/HER2- (surrogate luminal A) subtypes. Our findings are consistent with the hypothesis that breast cancers induced by MHT may occur through receptor-mediated mechanisms. Citation Format: Usha G. Salagame, Emily Banks, Dianne O’Connell, Sam Egger, Karen Canfell. Menopausal hormone therapy (MHT) use and breast cancer risk by receptor subtypes: results from the New South Wales Cancer Lifestyle and EvAluation of Risk (CLEAR) study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2285. doi:10.1158/1538-7445.AM2017-2285

PTEN, DICER1, FH, and Their Associated Tumor Susceptibility Syndromes: Clinical Features, Genetics, and Surveillance Recommendations in Childhood.

PTEN hamartoma tumor syndrome (PHTS), DICER1 syndrome, and hereditary leiomyomatosis and renal cell cancer (HLRCC) syndrome are pleiotropic tumor predisposition syndromes that include benign and malignant neoplasms affecting adults and children. PHTS includes several disorders with shared and distinct clinical features. These are associated with elevated lifetime risk of breast, thyroid, endometrial, colorectal, and renal cancers as well as melanoma. Thyroid cancer represents the predominant cancer risk under age 20 years. DICER1 syndrome includes risk for pleuropulmonary blastoma, cystic nephroma, ovarian sex cord-stromal tumors, and multinodular goiter and thyroid carcinoma as well as brain tumors including pineoblastoma and pituitary blastoma. Individuals with HLRCC may develop multiple cutaneous and uterine leiomyomas, and they have an elevated risk of renal cell carcinoma. For each of these syndromes, a summary of the key syndromic features is provided, the underlying genetic events are discussed, and specific screening is recommended. Clin Cancer Res; 23(12); e76-e82. ©2017 AACRSee all articles in the online-only CCR Pediatric Oncology Series.

Risk of breast or ovarian cancer in family members who do not carry the BRCA1 or BRCA2 family mutation: Findings from the EMBRACE study.

1558 Background: BRCA1/BRCA2 true-negatives are proven non-carriers of the BRCA mutation segregating within their family. Currently, there is no conclusive evidence on the risk of developing breast or ovarian cancer in these individuals, potentially leading to non-uniform clinical practices. The purpose of this study was to estimate breast and ovarian cancer risks for true-negatives from the EMBRACE prospective cohort study. Methods: Risks were calculated separately for incident invasive breast cancer and epithelial ovarian cancer (EOC). We used cohort analysis to estimate incidences, cumulative risks and standardised incidence ratios (SIRs). Results: A total of 1895 unaffected women were eligible for inclusion in the breast cancer analysis and 1736 for the ovarian cancer analysis. There were 23 incident invasive breast cancers and 2 EOCs diagnosed during follow-up. The cumulative risk of invasive breast cancer was 9.4% (95% CI 5.9%-15%) by the age of 85-years, whilst the corresponding risk of EOC was 0.6% (95% CI 0.2%-2.6%). The SIR for breast cancer was 0.93 (95% CI 0.62-1.40) in the overall cohort, 0.85 (95% CI 0.48-1.50) in non-carriers from BRCA1 families and 1.03 (95% CI 0.57-1.87) in non-carriers from BRCA2 families. The SIR for EOC was 0.79 (95% CI 0.20-3.17) in the overall cohort and 1.74 (95% CI 0.44-6.98) in non-carriers from BRCA2 families. Conclusions: This is the largest cohort to date of prospectively ascertained true-negatives from BRCA1/ BRCA2 families. Our results did not provide evidence for elevated risks of invasive breast cancer or EOC in proven non-carriers. Risk-reducing bilateral mastectomy and risk-reducing salpingo-oophorectomy may not be appropriate for these individuals. Female relatives of a known BRCA1/BRCA2 mutation carrier should be advised towards genetic testing to avoid unnecessary surgical procedures. However, we were not able to investigate variation in risks by cancer family history. Therefore, we cannot rule out that risks may be slightly higher for close relatives of affected mutation carriers. In such cases, model-based estimates incorporating family history, such as those given by BOADICEA, can be used in the counselling process.

Alcohol Intake and Breast Cancer Risk in African American Women from the AMBER Consortium.

Background: Alcohol is a recognized risk factor for invasive breast cancer, but few studies involve African American women.Methods: The current analysis included 22,338 women (5,108 cases of invasive breast cancer) from the African American Breast Cancer Epidemiology and Risk (AMBER) Consortium. The association between number of alcoholic drinks per week (dpw) and breast cancer was estimated using logistic regression, adjusting for potential confounders, and stratifying by breast cancer subtype.Results: Approximately 35% of controls were current drinkers at interview. Women who reported current drinking of ≥14 dpw had an elevated risk of breast cancer compared with light drinkers (>0-<4 dpw) [adjusted OR (ORadj), 1.33; 95% confidence interval (CI), 1.07-1.64]. We observed elevated risk among women drinking ≥7 dpw for ER - [ORadj, 1.31; 95% CI, 1.00-1.72], PR - [ORadj, 1.28; 95% CI, 1.00-1.63], HER2 - [ORadj, 1.36; 95% CI, 1.09-1.70], and triple-negative [ORadj, 1.39; 95% CI, 0.98-2.00] molecular subtype. Among receptor-positive cases, ORs remained elevated but attenuated relative to receptor-negative cases. Sensitivity analysis of age-defined windows of exposure (<30 years, 30-49, 50+ years of age) did not reveal variation in patterns of association. Risk associated with alcohol intake did not vary significantly by oral contraceptive use, smoking status, or menopausal status.Conclusions: Among African American women, similar to women of European descent, drinking ≥7 alcoholic dpw was associated with an increased risk of breast cancer regardless of subtype.Impact: Alcohol intake is a modifiable risk factor for breast cancer, and reduced intake among African American women should be encouraged. Cancer Epidemiol Biomarkers Prev; 26(5); 787-94. ©2017 AACR.

Abstract B12: The effect of physical activity and body size on mammographic density in high-risk, BRCA mutation-negative women

Abstract Purpose: Mammographic density (MD) reflects the proportion of dense tissue in relation to non-dense tissue in the breast and is the strongest biological marker of breast cancer risk. MD is known to be higher among women with a family history compared to women in the general population. We have previously demonstrated that women with a strong family history of breast cancer but no BRCA mutation face an elevated lifetime risk of breast cancer estimated at 40% compared to 11% in the general population. Various lifestyle factors, such as physical activity and body mass index (BMI), have been shown to modify MD in the general population. It is of interest to determine if such an association exists among high-risk women. Objective: To evaluate the relationship between physical activity, BMI and MD in high-risk women. Methods: This study included 100 women enrolled in an on-going prospective study of high-risk women with a strong family history of breast cancer (two first-degree relatives with breast cancer under age 50 or three cases at any age) and no identified BRCA mutations in their families. Current physical activity levels and BMI were collected using self-reported questionnaires. Physical activity was defined as moderate to vigorous physical activity (MVPA). Two dichotomous variables were created to define high vs. low MVPA levels: 1) based on the Canadian Society for Exercise Physiology guideline of 2.5 hours of MVPA per week and 2) the 75th percentile of MVPA in the sample (3.5 hours per week). A BMI of 25 or more was defined as high using the World Health Organization criteria of overweight. Mammograms were assigned a percentage of density (0 - 100%) using a computer-assisted method (Cumulus 6). Multivariate linear regression modelling was used to evaluate the relationships between both MVPA and BMI with MD while adjusting for age, menopausal status, and parity. BMI models also adjusted for MVPA (continuous) and MVPA models adjusted for BMI (continuous). Results: Among all women, those with a high BMI had significantly lower mean percent density compared to women with a low BMI (13% vs. 23%; P = 0.01). This association was stronger for premenopausal (27% vs. 37%; P = 0.06) vs. postmenopausal (12% vs. 20%; P = 0.10) women. Women who engaged in MVPA for 2.5 hours per week or more had significantly greater mean percent density compared to women who were less physically active (29% vs. 22%; P = 0.04). This relationship did not vary by menopausal status (P ≥ 0.15). Based on the 75th percentile of MVPA, women with high MVPA levels had significantly greater mean percent density compared to women with low MVPA levels (31% vs. 22%; P = 0.02). This relationship was significant for postmenopausal (26% vs. 13%; P = 0.04) but not premenopausal (31% vs. 25%; P = 0.27) women. Conclusion: In this cohort of high-risk women, high BMI was associated with lower MD that was suggestively stronger for premenopausal women. Although preliminary, these findings suggest a possible mechanism by which a lifestyle factor may influence MD, and possibly breast cancer risk, in high-risk women. Further evaluation with a larger sample size is needed to elucidate the relationships between physical activity, as well as other modifiable factors, and MD in this cohort of women. This study adds to the growing evidence supporting the inclusion of MD into breast cancer risk prediction models, in order to improve individualized treatments and prevention strategies for women at an increased risk for disease. Citation Format: Olivia M. Moran, Dina Nikitina, Anoma Gunasekara, Martin J. Yaffe, Kelly A. Metcalfe, Steven A. Narod, Joanne Kotsopoulos. The effect of physical activity and body size on mammographic density in high-risk, BRCA mutation-negative women. [abstract]. In: Proceedings of the AACR Special Conference: Improving Cancer Risk Prediction for Prevention and Early Detection; Nov 16-19, 2016; Orlando, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2017;26(5 Suppl):Abstract nr B12.

Multi-institutional Evaluation of Women at High Risk of Developing Breast Cancer

IntroductionWe performed the present study to better understand the practices and preferences of women with an elevated risk of breast cancer by merging the registries from 2 separate institutions and comparing the clinical characteristics and outcomes. Materials and MethodsThe data from women enrolled in institutional review board-approved registries from 2003 to 2015 at the New York University Langone Medical Center and University of Vermont Medical Center were evaluated. We compared patient characteristics, risk factors, uptake of prevention methods, and cancer rates between the 2 registries. ResultsA total of 1035 women were included in the present analysis. We found a 99% concordance of variables collected between the 2 registries. Significant differences were found in age, risk characteristics, uptake of prevention methods, and cancer rates between the 2 registries. The uptake of chemoprevention was low (8% for all women), with greater uptake among women with atypia found on biopsy examination (66%) than among those with a strong family history or BRCA mutations. Women with BRCA mutations accounted for 76% of those undergoing risk-reducing surgery. Of the 1035 women, 43 (4%) developed breast cancer. Of these, 86% were diagnosed with American Joint Committee on Cancer stage 0 or 1 disease, 95% with tumors < 2 cm, and 70% with poor to moderately differentiated pathologic features. Only 1 of the women who developed breast cancer had been undergoing chemoprevention, and none had undergone previous prophylactic surgery. ConclusionWe found a high degree of concordance between registries, suggesting no barriers exist to multi-institutional collaboration. Overall, a low uptake of prevention opportunities was found in this high-risk population. Women developing breast cancer had predominantly low-stage but higher grade disease, which might suggest a benefit to participation in surveillance (or high-risk) programs.

Patient Reactions to Surgeon Recommendations About Contralateral Prophylactic Mastectomy for Treatment of Breast Cancer

Guidelines assert that contralateral prophylactic mastectomy (CPM) should be discouraged in patients without an elevated risk for a second primary breast cancer. However, little is known about the impact of surgeons discouraging CPM on patient care satisfaction or decisions to seek treatment from another clinician. To examine the association between patient report of first-surgeon recommendation against CPM and the extent of discussion about it with 3 outcomes: patient satisfaction with surgery decisions, receipt of a second opinion, and receipt of surgery by a second surgeon. This population-based survey study was conducted in Georgia and California. We identified 3880 women with stages 0 to II breast cancer treated in 2013-2014 through the Surveillance, Epidemiology, and End Results registries of Georgia and Los Angeles County. Surveys were sent approximately 2 months after surgery (71% response rate, n = 2578). In this analysis conducted from February to May 2016, we included patients with unilateral breast cancer who considered CPM (n = 1140). Patients were selected between July 2013 and September 2014. We examined report of surgeon recommendations, level of discussion about CPM, satisfaction with surgical decision making, receipt of second surgical opinion, and surgery from a second surgeon. The mean (SD) age of patients included in this study was 56 (10.6) years. About one-quarter of patients (26.7%; n = 304) reported that their first surgeon recommended against CPM and 30.1% (n = 343) reported no substantial discussion about CPM. Dissatisfaction with surgery decision was uncommon (7.6%; n = 130), controlling for clinical and demographic characteristics. One-fifth of patients (20.6%; n = 304) had a second opinion about surgical options and 9.8% (n = 158) had surgery performed by a second surgeon. Dissatisfaction was very low (3.9%; n = 42) among patients who reported that their surgeon did not recommend against CPM but discussed it. Dissatisfaction was substantively higher for those whose surgeon recommended against CPM with no substantive discussion (14.5%; n = 37). Women who received a recommendation against CPM were not more likely to seek a second opinion (17.1% among patients with recommendation against CPM vs 15.1% of others; P = .52) nor to receive surgery by a second surgeon (7.9% among patients with recommendation against CPM vs 8.3% of others; P = .88). Most patients are satisfied with surgical decision making. First-surgeon recommendation against CPM does not appear to substantively increase patient dissatisfaction, use of second opinions, or loss of the patient to a second surgeon.

Breast Cancer Risk and Progressive Histology in Serial Benign Biopsies.

Background: More than 1 million women per year in the United States with benign breast biopsies are known to be at elevated risk for breast cancer (BC), with risk stratified on histologic categories of epithelial proliferation. Here we assessed women who had serial benign biopsies over time and how changes in the histologic classification affected BC risk.Methods: In the Mayo Clinic Benign Breast Disease Cohort of 13 466 women, 1414 women had multiple metachronous benign biopsies (10.5%). Both initial and subsequent biopsies were assessed histologically. BC risk for clinical and prognostic factors was assessed using subdistribution models to account for competing risks, and logistic regression/Wilcoxon/chi-square tests to assess covariates. All statistical tests were two-sided.Results: Breast cancer risk for women with serial biopsies, stratified by histologic category in the later biopsies, was similar to women with a single biopsy. We found that changes in histological category between initial and subsequent biopsy statistically significantly impacted BC risk. Women with nonproliferative initial findings and subsequent proliferative findings had an increased risk (hazard ratio [HR] = 1.77, 95% confidence interval [CI] = 1.06 to 2.94, P = .03) compared with no change. Among women with proliferative disease without atypia at initial biopsy, risk decreased if later biopsy regressed to nonproliferative (HR = 0.49, 95% CI = 0.25 to 0.98) and increased if later biopsy showed progression to atypical hyperplasia (HR = 1.49, 95% CI = 0.73 to 3.05) compared with no change (P = .04).Conclusions: We found that breast cancer risk increases in women with progressive epithelial proliferation over time and decreases in women whose biopsies show less proliferation. This finding has important implications for effective clinical management of the 100 000 women per year who have multiple benign breast biopsies.

MEN1-Dependent Breast Cancer: Indication for Early Screening? Results From the Dutch MEN1 Study Group.

Multiple endocrine neoplasia type 1 (MEN1) is associated with an early-onset elevated breast cancer risk. This finding potentially has implications for breast cancer screening for women with MEN1, and therefore it is necessary to assess whether other risk factors are involved to identify those at greatest risk. A cross-sectional case control study was performed using the Dutch MEN1 cohort, including >90% of the adult Dutch MEN1 population. All women with a confirmed MEN1 mutation received a questionnaire regarding cancer family history and breast cancer-related endocrine and general cancer risk factors. A total of 138 of 165 (84%) eligible women with MEN1 completed the questionnaire. Eleven of the 138 women had breast cancer. Another 34 relatives with breast cancer were identified in the families of the included women, of whom 11 were obligate MEN1 carriers, 14 had no MEN1 mutation, and 9 had an unknown MEN1 status. The median age at breast cancer diagnosis of women with MEN1 (n = 22) was 45 years (range, 30 to 80 years), in comparison with 57.5 years (range, 40 to 85 years) in female relatives without MEN1 (n = 14; P = 0.03) and 61.2 years in the Dutch reference population. Known endocrine risk factors and general risk factors were not different for women with and without breast cancer. The increased breast cancer risk in MEN1 carriers was not related to other known breast cancer risk factors or familial cancer history, and therefore breast cancer surveillance from the age of 40 years for all women with MEN1 is justifiable.

History of Gestational Diabetes Mellitus and Risk of Incident Invasive Breast Cancer among Parous Women in the Nurses' Health Study II Prospective Cohort.

Background: Type II diabetes is associated with breast cancer in epidemiologic studies. Pregnancy also modifies breast cancer risk. We hypothesized that women with a history of gestational diabetes mellitus (GDM), which shares pathogenesis and risk factors with type II diabetes, would have greater invasive breast cancer risk than parous women without a history of GDM.Methods: We conducted a prospective analysis among parous women in the Nurses' Health Study II, with mean age 35 years in 1989. Multivariate Cox proportional hazards models were used to compare risks of incident invasive breast cancer in women with and without a history of GDM.Results: Among 86,972 women studied, 5,188 women reported a history of GDM and 2,377 developed invasive breast cancer (100 with history of GDM, 2,277 without GDM) over 22 years of prospective follow-up. History of GDM was inversely associated with incident invasive breast cancer [HR, 0.68; 95% confidence interval (CI), 0.55-0.84; P = 0.0004], compared with no history of GDM, after adjustment for body mass index, reproductive history, and other breast cancer risk factors. Findings were similar by menopausal status, although observed person-time was predominantly premenopausal (premenopausal: HR, 0.73; 95% CI, 0.56-0.96; P = 0.03; postmenopausal: HR, 0.63; 95% CI, 0.43-0.92; P = 0.02). Restricting to women undergoing mammography screening modestly attenuated the relationship (HR, 0.74; 95% CI, 0.57-0.96; P = 0.02).Conclusions: Among a large cohort of U.S. women, history of GDM was not associated with an elevated risk of subsequent invasive breast cancer.Impact: Our findings highlight the need to further investigate GDM's role in breast cancer development. Cancer Epidemiol Biomarkers Prev; 26(3); 321-7. ©2016 AACR.

ESR1 single nucleotide polymorphism rs1062577 (c.*3804T > A) alters the susceptibility of breast cancer risk in Iranian population

ObjectivesAlbeit single nucleotide polymorphisms related to ESR1 gene have been studied, only a number of them have been reported to be associated with breast cancer risk. rs1062577 is one of the most recent microRNA-related ESR1 SNPs; however, no study has been conducted to investigate the significance this polymorphism in Iranian population. In this study, we aimed to investigate the frequency and also the association between rs1062577 and breast cancer. Materials and methodsrs1062577 position was genotyped by Tetra-primer ARMS-PCR in totally 182 blood specimens obtained from breast cancer patients (n=86), and healthy blood donors (n=96). The distribution of different genotypes was statistically analyzed in terms of the potential association between rs1062577 different alleles, breast cancer risk and clinicopathological criteria of breast cancer patients. ResultsThe statistical analyses confidently indicated that rs1062577 A allele is associated with the increased breast cancer risk in both univariate and multivariate regression models (Odds Ratio=8.403 and 32.602 respectively). rs1062577 T allele was statistically associated with stage I of breast cancer patients (p-value=0.025). In silico studies implied that rs1062577 A allele can alter the binding capacity of ESR1 mRNA and miRNAs via either breakage or formation of hydrogen bonds. Conclusionrs1062577 A allele is significantly and dramatically associated with the elevated risk and greater stages of breast cancer.

Abstract P3-08-02: Multi-gene panel testing for hereditary cancer predisposition in unsolved high risk breast and ovarian cancer patients

Abstract Background Among women with an elevated risk of hereditary breast and ovarian cancer who previously tested negative for pathogenic mutations in BRCA1 and BRCA2, a subset remain at increased risk of having hereditary breast, ovarian or other cancers, and should be offered multi-gene panel testing. We tested three groups of women who were enrolled in the UCSF Cancer Genetics and Prevention Program: (i) 97 women with a personal history of bilateral breast cancer, (ii) 104 women with a personal history of breast cancer and a first-degree or second-degree relative with ovarian cancer, and (iii) 99 women with a personal history of ovarian, fallopian tube, or primary peritoneal cancer. All women previously tested negative for pathogenic BRCA1 and BRCA2 mutations by either limited or comprehensive testing. Methods We performed comprehensive next-generation sequencing using a panel of 19 genes developed by Color Genomics (a CLIA-certified laboratory) covering ATM, BARD1, BRCA1, BRCA2, BRIP1, CDH1, CHEK2, EPCAM, MLH1, MSH2, MSH6, NBN, PALB2, PMS2, PTEN, RAD51C, RAD51D, STK11, and TP53. Results Across the groups tested, 9% had pathogenic mutations in one or more of the genes analyzed (8% in genes other than BRCA1 and BRCA2). Among these women, Ashkenazi Jewish and Hispanic women had elevated mutation rates compared to those of other ethnicities. In addition, we identified two women with pathogenic mutations in two cancer susceptibility genes, which has significant implications for family testing. These results demonstrate the importance of genetic testing of genes other than BRCA1 and BRCA2. Conclusions Among women with an elevated risk of hereditary breast and ovarian cancer who have previously tested negative for BRCA1 and BRCA2 mutations, we propose that women with characteristics of any of the three groups above be considered for subsequent multi-gene panel testing. Additionally, ethnicity and the possibility of multiple mutations may be indications for additional testing in these women and in family members of carriers. Citation Format: Crawford BB, Adams SB, Sittler T, Van den Akker J, Chan SB, Leitner O, Ryan LN, Gil E, Van 't Veer LJ. Multi-gene panel testing for hereditary cancer predisposition in unsolved high risk breast and ovarian cancer patients [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P3-08-02.

Abstract P5-10-10: Predictors of breast density among Black and Hispanic women presenting for mammographic screening

Abstract Background: Increased breast density has been associated with elevated breast cancer risk and complicating mammographic interpretation. Although previous studies have investigated population variations in breast density, Black and Hispanic women are often underrepresented in these analyses. Moreover, it is unclear how breast density differs between these ethnicities. We report on the mammographic density distribution of Black and Hispanic women having breast cancer screening at the Capital Breast Care Center (CBCC) and analyze factors associated with high breast density. Methods: Retrospective data from electronic medical records at a population-based mammography screening center were abstracted. From 2010 to 2014, data from women undergoing their first breast cancer screening were reviewed. Patient demographics including race, age at screening, education and menopausal status were abstracted in addition to body mass index (BMI) and Breast Imaging-Reporting and Data System (BI-RADS) density category:1- “fatty”, 2- “scattered fibroglandular densities”, 3- “heterogeneously dense” and 4- “extremely dense”. Logistic regression was used to investigate factors associated with breast density. Results: Density categorization was recorded for 1747 women over the five-year period, with 855 (49%) Black and 892 (51%) Hispanic. Patient characteristics associated with high density (categories 3 and 4) were younger age, Hispanic ethnicity, nulliparity, premenopausal status, and BMI &amp;lt; 30 kg/m2. On multivariate logistic regression, Hispanic ethnicity, premenopausal status, and BMI &amp;lt; 30 kg/m2 were predictive of high mammographic density. Conclusion: In a sample of women presenting for mammographic screening at CBCC, Hispanic women were more likely to have higher breast density compared to Black women. After controlling for ethnicity, postmenopausal and obese women were less likely to have dense breasts. Additional investigation is needed to further study the impact of obesity on breast density in underserved minority women. Citation Format: Oppong BA, Dash C, Li Y, Makambi K, Coleman T, Adams-Campbell L. Predictors of breast density among Black and Hispanic women presenting for mammographic screening [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P5-10-10.

Abstract A52: Racial Differences in Prevention Decision Making among Women at High Risk of Breast Cancer

Abstract Background &amp; Objectives: Prior research has documented significant racial disparities in adherence to breast cancer screening recommendations, use of breast-conserving surgery by early stage breast cancer patients, and breast cancer mortality. Decision making about breast cancer prevention options among high risk women has been less thoroughly studied, and racial differences remain mostly unexplored in this arena. The current study employs semi-structured interviews and inductive analytic methods to explore prevention decision making among African American and White women. Its core objective is to investigate the degree to which decision-making processes and outcomes differ across racial groups, and the specific content of these differences, in order to support interventions and programs to facilitate empowered, preventive decision making. Methods: In-depth, semi-structured interviews were conducted with 20 African American and 30 non-Hispanic White women at elevated risk of breast cancer. Allowing women to speak in their own words, these interviews explore women's perception of their risk status; the sources and content of risk information they have obtained; their understanding and consideration of prevention options; decision-making processes; decision-making networks, psychosocial well-being; and women's use of financial, time, and energy resources in coping with risk and prevention. Interviews ranged in length from 30 to 140 minutes and were professionally transcribed. Transcribed data are analyzed through grounded theory methods, using the NVivo 10 software package for qualitative data. Results: High risk African American women's experiences are distinct from those of their White counterparts in a range of ways, including the following. (1) African American women are much less frequently aware of the existence of prophylactic surgeries and chemoprevention options are clinically recommended for women at their own level of risk. (2) Among women who do know about these prevention options, African American women are less likely to consider or undertake prophylactic surgeries or chemoprevention to lower their breast cancer risk. (3) A much higher proportion of African American women have experienced several different types of cancer among their loved ones. These women tend to perceive of themselves as at risk for cancer in general, and not to perceive a specific high risk for breast or ovarian cancer. (4) African American women experience considerably more financial limitations on their ability to access health care and engage in specific prevention activities. Most have been uninsured for some period, and have had at least one health care decision affected by financial constraints. (5) African American women are considerably more likely to reference faith, spirituality, and religion in discussing their perceived risk of cancer and their attitudes toward prevention behavior. Conclusions &amp; Implications: High risk women's narratives reveal substantial racial differences in perceptions, feelings, and choices related to breast cancer prevention. African American women who are clinically determined to be at high risk for breast and ovarian cancer are less likely than similar White women to understand this specific risk, to know about prevention options that could lower the risk, or to consider using these options even when they do know about them. The processes through which African American women navigate risk and prevention are also more heavily influenced by religious faith and financial constraint than those of White women. These distinctions merit further investigation, and confirmation with larger samples. Ultimately, knowledge of such inter-group differences may contribute to tailored interventions to support empowered and health-protective decision making among women at elevated risk. Citation Format: Tasleem J. Padamsee, Anna Muraveva, Electra D. Paskett. Racial Differences in Prevention Decision Making among Women at High Risk of Breast Cancer. [abstract]. In: Proceedings of the Ninth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2016 Sep 25-28; Fort Lauderdale, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2017;26(2 Suppl):Abstract nr A52.

Abstract C24: Interplay between ECM stiffness, miR-203 and mammographic density

Abstract High mammographic density (MD) is associated with a greater risk of breast cancer and is characterized by high extracellular matrix (ECM) collagen. Elevated collagen increases ECM stiffness and can promote the malignant transformation of oncogenically-primed mammary epithelial cells in culture and in vivo. Whether or not high MD reflects a breast stroma that is stiff and if ECM stiffness accounts for the elevated breast cancer risk in high MD tissue and how has yet to be resolved. To address this question we are conducting a comprehensive biophysical and molecular analysis of BIRADS status in prophylactic mastectomies in women with low (BIRADS 1) versus high MD (BIRADS 4). Data revealed that the intra-lobular ECM associated with the terminal end-buds contains anisotropic compliant and relaxed collagen fibrils. By contrast, the inter-lobular ECM contains stiff, oriented collagen fibrils. Preliminary data suggest that the ECM associated with the terminal end-buds in the upper outer quadrant may be stiffer in women with high MD as compared to low MD. These same tissues also expressed lower levels of the microRNA miR-203, which has been implicated in epithelial-to-mesenchymal transition (EMT) inhibition. Consistently, in vitro studies revealed that miR-203 was repressed in MECs cultured on a stiff ECM. We also found that a stiffened mammary ECM decreases miR-203 expression and promotes an EMT. Additionally, inhibiting ECM stiffening restored miR-203 levels and reduced an EMT. Moreover and importantly, we showed that triple negative breast tumors that often express EMT markers have reduced miR-203 levels. Studies are underway to elaborate these preliminary findings and to assess their clinical relevance. (This work is supported by the: NIH NSRA T32 CA 108462-11 to Ivory Dean, Susan G Komen PDF12230246 to Irene Acerbi, W81XWH-13-1-0216, USMRAA DOD-BCRP BC122990, NIH R01 CA138818-01A1 and NIH R01 CA192914-01 to Valerie Weaver.) Citation Format: Ivory Dean, Irene Acerbi, Janna Mouw, Quanming Shi, Yunn-Yi Chen, Jan Liphardt, Shelley Hwang, Valerie Weaver. Interplay between ECM stiffness, miR-203 and mammographic density. [abstract]. In: Proceedings of the Ninth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2016 Sep 25-28; Fort Lauderdale, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2017;26(2 Suppl):Abstract nr C24.

Relationship between crown-like structures and sex-steroid hormones in breast adipose tissue and serum among postmenopausal breast cancer patients

BackgroundPostmenopausal obesity is associated with increased circulating levels of androgens and estrogens and elevated breast cancer risk. Crown-like structures (CLS; microscopic foci of dying adipocytes surrounded by macrophages) are proposed to represent sites of increased aromatization of androgens to estrogens. Accordingly, we examined relationships between CLS and sex-steroid hormones in breast adipose tissue and serum from postmenopausal breast cancer patients.MethodsFormalin-fixed paraffin embedded benign breast tissues collected for research from postmenopausal women (n = 83) diagnosed with invasive breast cancer in the Polish Breast Cancer Study (PBCS) were evaluated. Tissues were immunohistochemically stained for CD68 to determine the presence of CLS per unit area of adipose tissue. Relationships were assessed between CD68 density and CLS and previously reported sex-steroid hormones quantified using radioimmunoassays in serum taken at the time of diagnosis and in fresh frozen adipose tissue taken at the time of surgery. Logistic regression analysis was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for the relationships between hormones (in tertiles) and CLS.ResultsCLS were observed in 36% of benign breast tissues, with a higher frequency among obese versus lean women (54% versus 17%, p = 0.03). Detection of CLS was not related to individual hormone levels or breast tumor pathology characteristics. However, detection of CLS was associated with hormone ratios. Compared with women in the highest tertile of estrone:androstenedione ratio in fat, those in the lowest tertile were less likely to have CLS (OR 0.12, 95% CI 0.03–0.59). A similar pattern was observed with estradiol:testosterone ratio in serum and CLS (lowest versus highest tertile, OR 0.18, 95% CI 0.04–0.72).ConclusionsCLS were more frequently identified in the breast fat of obese women and were associated with increased ratios of select estrogens:androgens in the blood and tissues, but not with individual hormones. Additional studies on CLS, tissue and blood hormone levels, and breast cancer risk are needed to understand and confirm these findings.