Breast Cancer Risk Prediction Using Clinical Models and 77 Independent Risk-Associated SNPs for Women Aged Under 50 Years: Australian Breast Cancer Family Registry.

Background: The extent to which clinical breast cancer risk prediction models can be improved by including information on known susceptibility SNPs is not known.

Methods: Using 750 cases and 405 controls from the population-based Australian Breast Cancer Family Registry who were younger than 50 years at diagnosis and recruitment, respectively, Caucasian and not BRCA1 or BRCA2 mutation carriers, we derived absolute 5-year risks of breast cancer using the BOADICEA, BRCAPRO, BCRAT, and IBIS risk prediction models and combined these with a risk score based on 77 independent risk-associated SNPs. We used logistic regression to estimate the OR per adjusted SD for log-transformed age-adjusted 5-year risks.

Sources of polycyclic aromatic hydrocarbons are associated with gene-specific promoter methylation in women with breast cancer.

Background: Tobacco smoke, diet and indoor/outdoor air pollution, all major sources of polycyclic aromatic hydrocarbons (PAHs), have been associated with breast cancer. Aberrant methylation may be an early event in carcinogenesis, but whether PAHs influence the epigenome is unclear, particularly in breast tissue where methylation may be most relevant. We aimed to evaluate the role of methylation in the association between PAHs and breast cancer.

BRCA2 Polymorphic Stop Codon K3326X and the Risk of Breast, Prostate, and Ovarian Cancers.

Background: The K3326X variant in BRCA2 (BRCA2*c.9976A>T; p.Lys3326*; rs11571833) has been found to be associated with small increased risks of breast cancer.

Latent class analysis suggests four distinct classes of complementary medicine users among women with breast cancer.

Background: Breast cancer patients commonly report using >1 form of complementary and alternative medicine (CAM). However, few studies have attempted to analyze predictors and outcomes of multiple CAM modalities. We sought to group breast cancer patients by clusters of type and intensity of complementary and alternative medicine (CAM) use following diagnosis.

Psychosocial Adjustment in School-age Girls With a Family History of Breast Cancer.

Objective: Understanding how young girls respond to growing up with breast cancer family histories is critical given expansion of genetic testing and breast cancer messaging. We examined the impact of breast cancer family history on psychosocial adjustment and health behaviors among >800 girls in the multicenter LEGACY Girls Study.

Methods: Girls aged 6 to 13 years with a family history of breast cancer or familial BRCA1/2 mutation (BCFH+), peers without a family history (BCFH-), and their biological mothers completed assessments of psychosocial adjustment (maternal report for 6- to 13-year-olds, self-report for 10- to 13-year-olds), breast cancer-specific distress, perceived risk of breast cancer, and health behaviors (10- to 13-year-olds).

Polyunsaturated fatty acid interactions and breast cancer incidence: a population-based case-control study on Long Island, New York.

Purpose: Experimental studies demonstrate that ω-3 polyunsaturated fatty acids (PUFAs) inhibit inflammatory eicosanoids generated by ω-6 PUFAs. Epidemiologic studies on dietary ω-3 PUFA intake show consistent inverse associations with breast cancer incidence among Asian populations, where ω-3, relative to ω-6, intake is high. In contrast, associations are inconsistent among Western populations, where intake of ω-3, relative to ω-6, is low.

Polycyclic aromatic hydrocarbon (PAH)-DNA adducts and breast cancer: modification by gene promoter methylation in a population-based study.

Purpose: Polycyclic aromatic hydrocarbon (PAH)-DNA adducts have been associated with breast cancer incidence. Aberrant changes in DNA methylation may be an early event in carcinogenesis. However, possible relations between PAH-DNA adducts, methylation, and breast cancer are unknown.

The metabolic syndrome and mammographic breast density in a racially diverse and predominantly immigrant sample of women.

Purpose: The metabolic syndrome [MetS, clustering of elevated blood pressure, triglycerides and glucose, reduced high-density lipoprotein cholesterol (HDL-C), abdominal obesity] has been associated with increased breast cancer risk, but less is known about its association with mammographic breast density, a strong risk factor for breast cancer.

Methods: We collected data on risk factors, body size, and blood pressure via in-person interviews and examinations and measured glucose, triglycerides, and HDL-C from dried blood spots from women recruited through a mammography screening clinic (n = 373; 68 % Hispanic, 17 % African-American, 63 % foreign born). We performed linear regression models to examine the associations of each MetS component and the MetS cluster (≥3 components) with percent density and dense breast area, measured using a computer-assisted technique and Cumulus software.

microRNA Expression in Prospectively Collected Blood as a Potential Biomarker of Breast Cancer Risk in the BCFR.

Background/aim: Current breast cancer risk assessment models have moderate discriminatory ability. We evaluated whether microRNA (miRNA) expression profiles in peripheral blood mononuclear cells (PBMC) could be a useful biomarker of risk in high-risk women.

Materials And Methods: Next-generation sequencing evaluated miR expression in PBMCs of 20 women who were unaffected at the time of recruitment and later diagnosed with breast cancer and 20 unaffected women.

Assessing absolute changes in breast cancer risk due to modifiable risk factors.

Clinical risk assessment involves absolute risk measures, but information on modifying risk and preventing cancer is often communicated in relative terms. To illustrate the potential impact of risk factor modification in model-based risk assessment, we evaluated the performance of the IBIS Breast Cancer Risk Evaluation Tool, with and without current body mass index (BMI), for predicting future breast cancer occurrence in a prospective cohort of 665 postmenopausal women. Overall, IBIS's accuracy (overall agreement between observed and assigned risks) and discrimination (AUC concordance between assigned risks and outcomes) were similar with and without the BMI information.

Gene-Specific Promoter Methylation Status in Hormone-Receptor-Positive Breast Cancer Associates with Postmenopausal Body Size and Recreational Physical Activity.

Introduction: Breast cancer, the leading cancer diagnosis among American women, is positively associated with postmenopausal obesity and little or no recreational physical activity (RPA). However, the underlying mechanisms of these associations remain unresolved. Aberrant changes in DNA methylation may represent an early event in carcinogenesis, but few studies have investigated associations between obesity/RPA and gene methylation, particularly in postmenopausal breast tumors where these lifestyle factors are most relevant.

Global DNA Methylation, Measured by the Luminometric Methylation Assay (LUMA), Associates with Postmenopausal Breast Cancer in Non-Obese and Physically Active Women.

Introduction: Little is known about how modifiable lifestyle factors interact with the epigenome to influence disease. Body mass index (BMI, weight kg/height m2) and physical activity are associated with postmenopausal breast cancer, but the mechanisms are not well-understood. We hypothesized that BMI or physical activity may modify the association between markers of global DNA methylation and postmenopausal breast cancer risk.

Second primary breast cancer in BRCA1 and BRCA2 mutation carriers: 10-year cumulative incidence in the Breast Cancer Family Registry.

BReast CAncer genes 1 and 2 (BRCA1 and BRCA2) mutation carriers diagnosed with breast cancer are at increased risk of developing a second primary breast cancer. Data from high-risk clinics may be subject to different biases which can cause both over and underestimation of this risk. Using data from a large multi-institutional family registry we estimated the 10-year cumulative risk of second primary breast cancer including more complete testing information on family members.

Practical problems with clinical guidelines for breast cancer prevention based on remaining lifetime risk.

Background: Clinical guidelines for breast cancer chemoprevention and MRI screening involve estimates of remaining lifetime risk (RLR); in the United States, women with an RLR of 20% or higher meet "high-risk" criteria for MRI screening.

Methods: We prospectively followed 1764 women without breast cancer to compare the RLRs and 10-year risks assigned by the risk models International Breast Cancer Intervention Study (IBIS) and Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm (BOADICEA) and to compare both sets of model-assigned 10-year risks to subsequent incidence of breast cancer in the cohort. We used chi-square statistics to assess calibration and the area under the receiver operating characteristic curve (AUC) to assess discrimination.

No clinical utility of KRAS variant rs61764370 for ovarian or breast cancer.

Objective: Clinical genetic testing is commercially available for rs61764370, an inherited variant residing in a KRAS 3' UTR microRNA binding site, based on suggested associations with increased ovarian and breast cancer risk as well as with survival time. However, prior studies, emphasizing particular subgroups, were relatively small. Therefore, we comprehensively evaluated ovarian and breast cancer risks as well as clinical outcome associated with rs61764370.

An original phylogenetic approach identified mitochondrial haplogroup T1a1 as inversely associated with breast cancer risk in BRCA2 mutation carriers.

Introduction: Individuals carrying pathogenic mutations in the BRCA1 and BRCA2 genes have a high lifetime risk of breast cancer. BRCA1 and BRCA2 are involved in DNA double-strand break repair, DNA alterations that can be caused by exposure to reactive oxygen species, a main source of which are mitochondria. Mitochondrial genome variations affect electron transport chain efficiency and reactive oxygen species production.

Breast Cancer Chemoprevention among High-risk Women and those with Ductal Carcinoma In Situ.

Chemoprevention with the anti-estrogens, tamoxifen, raloxifene, and aromatase inhibitors, reduce breast cancer incidence in high-risk women; however, uptake has been poor (<5%) in the prevention setting. We assessed use of anti-estrogens for breast cancer prevention, among high-risk women seen at an academic breast center, to observe how uptake rates compare in this setting. We collected data on demographics, breast cancer risk factors, and health behaviors via self-administered questionnaires and medical chart abstraction.

Association of type and location of BRCA1 and BRCA2 mutations with risk of breast and ovarian cancer.

Importance: Limited information about the relationship between specific mutations in BRCA1 or BRCA2 (BRCA1/2) and cancer risk exists.

Objective: To identify mutation-specific cancer risks for carriers of BRCA1/2.

Design, Setting, And Participants: Observational study of women who were ascertained between 1937 and 2011 (median, 1999) and found to carry disease-associated BRCA1 or BRCA2 mutations.

Assessing associations between the AURKA-HMMR-TPX2-TUBG1 functional module and breast cancer risk in BRCA1/2 mutation carriers.

While interplay between BRCA1 and AURKA-RHAMM-TPX2-TUBG1 regulates mammary epithelial polarization, common genetic variation in HMMR (gene product RHAMM) may be associated with risk of breast cancer in BRCA1 mutation carriers. Following on these observations, we further assessed the link between the AURKA-HMMR-TPX2-TUBG1 functional module and risk of breast cancer in BRCA1 or BRCA2 mutation carriers. Forty-one single nucleotide polymorphisms (SNPs) were genotyped in 15,252 BRCA1 and 8,211 BRCA2 mutation carriers and subsequently analyzed using a retrospective likelihood approach.

Dietary intake of fish, polyunsaturated fatty acids, and survival after breast cancer: A population-based follow-up study on Long Island, New York.

Background: In laboratory experiments, ω-3 polyunsaturated fatty acids (PUFAs) have been found to reduce inflammatory eicosanoids resulting from ω-6 PUFA metabolism via competitive inhibition, and the ω-3-induced cytotoxic environment increases apoptosis and reduces cell growth in breast cancer cells. To the authors' knowledge, epidemiologic investigations regarding whether dietary ω-3 PUFA intake benefits survival after breast cancer are limited and inconsistent.

Methods: The authors used resources from a population-based follow-up study conducted on Long Island, New York, among 1463 women newly diagnosed with first primary breast cancer who were interviewed an average of approximately 3 months after diagnosis to assess risk and prognostic factors, including dietary intake (using a food frequency questionnaire).

Life course exposure to smoke and early menopause and menopausal transition.

Objective: Early age at menopause is associated with increased risk of cardiovascular disease, stroke, osteoporosis, and all-cause mortality. Cigarette smoke exposure in adulthood is an established risk factor for earlier age at natural menopause and may be related to age at the menopausal transition. Using data from two US birth cohorts, we examined the association between smoke exposure at various stages of the life course (prenatal exposure, childhood exposure to parental smoking, and adult smoke exposure) and menopause status in 1,001 women aged 39 to 49 years at follow-up.

The association of alcohol consumption with mammographic density in a multiethnic urban population.

Background: Alcohol consumption is associated with higher breast cancer risk. While studies suggest a modest association between alcohol intake and mammographic density, few studies have examined the association in racial/ethnic minority populations.

Methods: We assessed dense breast area and total breast area from digitized film mammograms in an urban cohort of African American (42%), African Caribbean (22%), white (22%), and Hispanic Caribbean (9%) women (n = 189, ages 40-61).

Genetic polymorphisms in DNA repair and oxidative stress pathways may modify the association between body size and postmenopausal breast cancer.

Purpose: Obesity is associated with increased bioavailability of estrogen, hyperinsulinemia, and chronic inflammation, all of which may promote tumor growth. Given DNA repair and oxidative stress pathways may work together with these mechanisms to influence carcinogenesis, we hypothesized that genetic variation in these pathways may modify the obesity-postmenopausal breast cancer (BC) association.

Methods: Resources from a population-based case-control study (990 cases and 970 controls) were used to construct logistic regression models.