Breast Cancer Risk Evaluation Research Articles

Prevalence of mammographically dense breasts in the United States.

National legislation is under consideration that would require women with mammographically dense breasts to be informed of their breast density and encouraged to discuss supplemental breast cancer screening with their health care providers. The number of US women potentially affected by this legislation is unknown. We determined the mammographic breast density distribution by age and body mass index (BMI) using data from 1518 599 mammograms conducted from 2007 through 2010 at mammography facilities in the Breast Cancer Surveillance Consortium (BCSC). We applied these breast density distributions to age- and BMI-specific counts of the US female population derived from the 2010 US Census and the National Health and Nutrition Examination Survey (NHANES) to estimate the number of US women with dense breasts. Overall, 43.3% (95% confidence interval [CI] = 43.1% to 43.4%) of women 40 to 74 years of age had heterogeneously or extremely dense breasts, and this proportion was inversely associated with age and BMI. Based on the age and BMI distribution of US women, we estimated that 27.6 million women (95% CI = 27.5 to 27.7 million) aged 40 to 74 years in the United States have heterogeneously or extremely dense breasts. Women aged 40 to 49 years (N = 12.3 million) accounted for 44.3% of this group. The prevalence of dense breasts among US women of common breast cancer screening ages exceeds 25 million. Policymakers and healthcare providers should consider this large prevalence when debating breast density notification legislation and designing strategies to ensure that women who are notified have opportunities to evaluate breast cancer risk and discuss and pursue supplemental screening options if deemed appropriate.

Volumetric quantification of the effect of aging and hormone replacement therapy on breast composition from digital mammograms

ObjectiveTo assess the physiological changes in breast composition with aging using volumetric breast composition measurement from digital mammograms and to assess the effect of hormone replacement therapy (HRT). MethodsA total of 764 consecutive mammograms of 208 non-HRT using women and 508 mammograms of 134 HRT-using women were analyzed using a volumetric breast composition assessment software (Quantra™, Hologic Inc.). Fibroglandular tissue volume (FTV), breast volume (BV), and percent density (PD) were measured. For statistical analysis, women were divided into a premenopausal (<46 years), a perimenopausal (46–55 years), and a postmenopausal (>55 years) age group. More detailed graphical analysis was performed using smaller age brackets. Women using HRT were compared to age-matched controls not using HRT. ResultsWomen in the postmenopausal age group had a significantly lower FTV and PD and a significantly higher BV than women in the premenopausal age group (FTV: 77 vs. 120cm3, respectively; PD: 16% vs. 28%, respectively; BV 478 vs. 406cm3, respectively; p<0.01 for all). Median FTV was nearly stable in consecutive mammograms in the premenopausal and postmenopausal age groups, but declined at a rate of 3.9% per year in the perimenopausal period. Median PD was constant in the premenopausal and postmenopausal age groups and declined at a rate of 0.57% per year in the perimenopausal age group. BV continuously increased with age. Women using HRT throughout the study had a 5% higher PD than women not using HRT (22% vs. 17%, respectively; p<0.001). ConclusionsAccurate knowledge of normal changes in breast composition are of particular interest nowadays due to the importance of breast density for breast cancer risk evaluation. FTV and PD change significantly during the perimenopausal period but remain relatively constant before and thereafter. Median total breast volume consistently increases with age and further contributes to changes in breast density. HRT use is associated with a significantly higher PD.

Providing access to risk prediction tools via the HL7 XML-formatted risk web service

Cancer risk prediction tools provide valuable information to clinicians but remain computationally challenging. Many clinics find that CaGene or HughesRiskApps fit their needs for easy- and ready-to-use software to obtain cancer risks; however, these resources may not fit all clinics' needs. The HughesRiskApps Group and BayesMendel Lab therefore developed a web service, called "Risk Service", which may be integrated into any client software to quickly obtain standardized and up-to-date risk predictions for BayesMendel tools (BRCAPRO, MMRpro, PancPRO, and MelaPRO), the Tyrer-Cuzick IBIS Breast Cancer Risk Evaluation Tool, and the Colorectal Cancer Risk Assessment Tool. Software clients that can convert their local structured data into the HL7 XML-formatted family and clinical patient history (Pedigree model) may integrate with the Risk Service. The Risk Service uses Apache Tomcat and Apache Axis2 technologies to provide an all Java web service. The software client sends HL7 XML information containing anonymized family and clinical history to a Dana-Farber Cancer Institute (DFCI) server, where it is parsed, interpreted, and processed by multiple risk tools. The Risk Service then formats the results into an HL7 style message and returns the risk predictions to the originating software client. Upon consent, users may allow DFCI to maintain the data for future research. The Risk Service implementation is exemplified through HughesRiskApps. The Risk Service broadens the availability of valuable, up-to-date cancer risk tools and allows clinics and researchers to integrate risk prediction tools into their own software interface designed for their needs. Each software package can collect risk data using its own interface, and display the results using its own interface, while using a central, up-to-date risk calculator. This allows users to choose from multiple interfaces while always getting the latest risk calculations. Consenting users contribute their data for future research, thus building a rich multicenter resource.

Family history: Breast cancer risk evaluation tools

Family history: Breast cancer risk evaluation tools

Hormonal Risk Factors for Breast Cancer and DNA Methylation

Abstract Epigenetic modifications influence gene expression and have been implicated in the development of breast cancer. Few studies have evaluated breast cancer risk factors in relation to DNA methylation. We examined known reproductive and hormonal risk factors for breast cancer and epigenome-wide methylation patterns. Participants included 612 women enrolled in the Sister Study prospective cohort who did not have breast cancer. DNA methylation profiling was performed using an Illumina array at the NIH Center for Inherited Disease (CIDR) on DNA extracted from whole blood. Methylation data was obtained at single CpG site resolution for 27,578 CpG sites covering &amp;gt;14,000 genes across 23 chromosomes. Statistical analyses were performed using normalized methylation residuals from a linear model adjusting for age and experimental variables. Controlling for a false discovery rate of 5% (q &amp;lt; 0.05), 1,452 methylation sites (1,220 in CpG islands) were differentially methylated in postmenopausal women compared to premenopausal women. Average methylation was increased at 1,040 sites and decreased at 412 sites. Gene ontology (GO) analysis suggested enrichment of several biological pathways including lobular involution. Among parous women, only 2 sites (1 CpG island) were differentially methylated among women with older versus younger ages at first birth. A single CpG site demonstrated lower average methylation values among long-term users of postmenopausal hormones compared to short-term users. No further statistically significant differences in methylation patterns (q &amp;lt; 0.05) were observed according to age at menarche, parity, breastfeeding history, or postmenopausal hormone use. These data support the menopausal transition as an influential period for epigenetic modifications; few associations between DNA methylation and other classical reproductive and hormonal breast cancer risk factors were observed.

Abstract P4-12-06: A mammographic density prediction model using environmental factors, endogenous hormones and growth factors in Japanese women

Abstract The incidence of breast cancer in Japanese women has doubled in all age groups over the past two decades, making it important to evaluate breast cancer risk factors in Japanese women. It is well known that mammographic density is positively associated with breast cancer risk in Western countries, and mammographic density is known to be affected by some environmental factors, serum hormones, and growth factors. We performed stepwise variable selection in a multiple regression model with fifteen independent variables as described below, based on the Akaike information criteria (AIC) to build a mammographic density prediction model using a dataset of 1191 women (913 women with breast cancer and 278 disease-free controls). The variables included were: environmental risk factors (body-mass index (BMI), age at menarche, pregnancy, age at first birth, breastfeeding, family history of breast cancer, age at menopause, use of hormone replacement therapy, alcohol intake and smoking), serum hormones and growth factors (estradiol, testosterone, prolactin, insulin-like growth factor 1 (IGF1) and IGF binding protein 3 (IGFBP3)) and mammographic density. The resulting prediction model is: Mammographic density = + 0.000476 (IGF1) −0.0605 (testosterone) − 0.0508 (IGFBP3) − 0.00683 (age) − 0.0175 (BMI) + 0.00883 (age at menarche) − 0.0153 (breast feeding), (R2 = 0.336). In this model, IGF1, testosterone, IGFBP3, age, BMI, age at menarche, and breastfeeding were considered to be important factors. IGF1 and age at menarche were positively associated with mammographic density, while on the other hand testosterone, IGFBP3, age, BMI, and breast feeding were negatively associated with mammographic density. Further studies are required to build a modified model incorporating serial measurements of serum hormones and growth factors to take into account time-dependent changes of serum hormones and growth factors, and to assess its accuracy. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P4-12-06.

Determination of breast density by bioimpedance.

56 Background: Mammographic breast density is a significant risk factor for breast cancer. Women with extremely dense breasts are at 4-to-6 times the risk of developing breast cancer than women with primarily fatty breast tissue. Electrical Breast Densitometry (EBD) is a new technique that assesses breast density. EBD is non-ionizing, fast, has low cost per test ($20-$30) and may help in breast cancer risk assessment in the primary care setting. Methods: This study evaluated the feasibility of the EBD in an IRB-approved pilot study of 20 patients. The study used a custom-made self-adhesive electrode (SenoSENSE Medical Systems, Toronto, Canada) interfaced to an off-the-shelf impedance meter (Bodystat 1500, Bodystat, Isle of Man, UK) with a customized cable. On the same day as the subject’s scheduled mammogram, impedance measurements were acquired for each breast. Mammogram densities were scored by a trained radiologist using standard BiRADS breast density categories 1 to 4. Results: A high correlation coefficient was observed (Pearson correlation coefficient &gt;0.80) between breast density determined by the EBD and the BiRADS breast density score. In addition a statistically significant difference was observed between dense categories (BiRADS 3,4) and fatty categories (BiRADS 1,2) (p&lt;0.01), as well as between extremely dense breasts (BiRADS 4) and all other categories (p&lt;0.01). Very high correlation (Pearson correlation coefficient &gt;0.95) was observed between EBD measurements on the left and right breasts. Previous studies have reported a left/right correlation of 0.89 for blinded mammography readers. Conclusions: These results suggests that the EBD measure may be less variable than mammographic estimates of density. The results of the study suggest that Electrical Breast Densitometry is a promising technique for the assessment of breast density and the ability to aid in evaluation of breast cancer risk. It can be reasonably deployed at primary care facilities.

An Essay on Sexual Frustration as the Cause of Breast Cancer in Women: How Correlations and Cultural Blind Spots Conceal Causal Effects

The main premise of this hypothesis is that breast cancer is caused by sexual frustration. Sexual frustration is triggered by multiple forms of dissonance between the absence or lack of sexual reward and the (un)conscious motivation to obtain these sexual rewards. I assume that neural and hormonal processes are capable of adjusting or distorting biologically active forms of specific sex hormones depending on experienced sexual stimuli. I hypothesize that prolonged sexual frustration will ultimately lead via aberrantly metabolized sex hormones to the development of breast cancer. Human female sexual behavior research links sexual frustration with breast cancer risk. The distinction between human female sexual behavior and reproduction is crucial to understand breast cancer risk. Current explanations are focused on reproduction. However, human female sexual behavior is causal in breast cancer development and androgens rather than estrogens are crucial for sexual behaviors in women. Social learning is the main determinant of human sexual behaviors that is why cultural and social processes are very important to understand breast cancer risk. Epidemiologists should evaluate breast cancer risk based on cultural female attitudes towards sexually related issues. Female mate choices should be examined for (un)conscious cultural, ethnic, religious, and socio-economic pressure to make a thorough assessment of breast cancer risk. Closer examination of (un)conscious female copulation strategies reveal that they are potential sources of sexual frustration in specific groups of women. Postmenopausal women seem vulnerable for self-fulfilling prophecies about post reproductive sexuality, body image, and negative perceptions of menopause which may cause sexual frustrations.

S4-4: Clarifying the Risk of Breast Cancer in Women with Atypical Breast Lesions.

Abstract Background: Women diagnosed with atypical ductal hyperplasia (ADH), atypical lobular hyperplasia (ALH), lobular carcinoma in situ (LCIS), and borderline ADH/DCIS are at increased risk for breast cancer, but the precise degree of risk varies widely in the literature. Information from prior studies is limited by grouping ADH and ALH together and by small cohort sizes. Objectives: To identify women with a pathologic diagnosis of ADH, ALH, LCIS, and borderline ADH/DCIS using Natural Language Processing. To evaluate breast cancer risk based on atypia type. Methods: Using Natural Language Processing, we reviewed all electronically available pathology reports from Massachusetts General Hospital, Brigham and Women's Hospital, and Newton-Wellesley Hospital (members of Partners HealthCare System) from 1987–2010. We identified all women with a diagnosis of ADH, ALH, LCIS, and borderline ADH/DCIS with no prior or concurrent diagnosis of breast cancer. We determined the incidence of subsequent invasive and noninvasive breast cancer, the side of cancer diagnosis compared to original atypia side, and the time to cancer diagnosis for each atypia type. Results: We reviewed 76,333 path reports in 42,950 unique individuals and identified 3049 women who were diagnosed with atypical breast lesions over this 14-year period; 1233 (40.4%) had ADH, 851 (27.9%) had ALH, 595 (19.5%) had LCIS, and 370 (12.1%) had borderline ADH/DCIS. The mean age for atypia diagnosis was 51 years (range: 18–93). At a mean follow-up of 66 months, cancer occurred in 7.0% of women with ADH, 11.3% of women with ALH, 11.1% of women with LCIS, and 8.4% of women with borderline ADH/DCIS. The median time to breast cancer diagnosis was 48 months with ADH, 50 months with ALH, 47 months with LCIS, and 60 months with borderline ADH/DCIS. Significantly more ipsilateral cancers developed than contralateral cancers for all types of atypia combined (p=0.027). The development of invasive versus noninvasive breast cancer was not significantly affected by atypia type. Subsequent cancers were DCIS in 121 patients (43.4%) and invasive in 158 patients (56.6%). Kaplan Meier curves for time to cancer diagnosis based on atypia type were created. The curves for ADH and borderline ADH/DCIS were similar and significantly different than the curves for ALH and LCIS (p&amp;lt;0.001). The estimated 5 and 10-year breast cancer risks for each atypia type are presented in Table 1. Conclusion: A diagnosis of ADH, ALH, LCIS, or borderline ADH/DCIS increases a woman's risk of invasive and noninvasive breast cancer in either breast. The breast cancer risk at 5 and 10 years is significantly higher in those with ALH or LCIS compared to those with ADH or borderline ADH/DCIS, but there is little difference in risk between ADH and borderline ADH/DCIS or between LCIS and ALH. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr S4-4.

Evaluating breast cancer risk projections for Hispanic women

For Hispanic women, the Breast Cancer Risk Assessment Tool (BCRAT; "Gail Model") combines 1990-1996 breast cancer incidence for Hispanic women with relative risks for breast cancer risk factors from non-Hispanic white (NHW) women. BCRAT risk projections have never been comprehensively evaluated for Hispanic women. We compared the relative risks and calibration of BCRAT risk projections for 6,353 Hispanic to 128,976 NHW postmenopausal participants aged 50 and older in the Women's Health Initiative (WHI). Calibration was assessed by the ratio of the number of breast cancers observed with that expected by the BCRAT (O/E). We re-evaluated calibration for an updated BCRAT that combined BCRAT relative risks with 1993-2007 breast cancer incidence that is contemporaneous with the WHI. Cox regression was used to estimate relative risks. Discriminatory accuracy was assessed using the concordance statistic (AUC). In the WHI Main Study, the BCRAT underestimated the number of breast cancers by 18% in both Hispanics (O/E = 1.18, P = 0.06) and NHWs (O/E = 1.18, P < 0.001). Updating the BCRAT improved calibration for Hispanic women (O/E = 1.08, P = 0.4) and NHW women (O/E = 0.98, P = 0.2). For Hispanic women, relative risks for number of breast biopsies (1.71 vs. 1.27, P = 0.03) and age at first birth (0.97 vs. 1.24, P = 0.02) differed between the WHI and BCRAT. The AUC was higher for Hispanic women than NHW women (0.63 vs. 0.58, P = 0.03). Updating the BCRAT with contemporaneous breast cancer incidence rates improved calibration in the WHI. The modest discriminatory accuracy of the BCRAT for Hispanic women might improve by using risk factor relative risks specific to Hispanic women.

EVALUATION OF BREAST CANCER RISK IN RELATION TO NIGHT SHIFT WORK IN A CASE-CONTROL STUDY IN A SPANISH POPULATION

Background and Aims: Recent epidemiologic and animal data indicate that night work may increase the risk for breast cancer. We evaluated breast cancer risk in female night shift workers in a population based case-control study in Spain, the Multi Case-Control study (MCC-Spain). Methods: Incident breast cancer cases (n=795) and randomly selected population controls (n=849) were enrolled in 7 regions of Spain. Lifetime occupational history including questions on shift work and information on reproductive and lifestyle factors were assessed by face-to-face interviews. We estimated the risk of different shift profiles using unconditional logistic regression models adjusting for a wide range of potential confounders. Results: Among 1644 female subjects, 14 controls and 16 cases had ever worked in permanent night shift and 49 controls and 52 cases in rotating night shift for ≥1 year. Having ever worked in permanent night work was associated with an increased risk for breast cancer (Odds Ratio (OR) 1.36 (95% Confidence Interval (CI) 0.62-2.97), compared to permanent day workers, after adjusting for confounders. The corresponding OR for rotating night workers was 1.17 (95%CI 0.71-1.92). Women who had worked in night work for more than 10 years during lifetime, had an OR=1.43, (95%CI 0.79-2.57). This risk was higher in postmenopausal women (OR=1.67, 95%CI 0.79-3.53) as compared to premenopausal women (OR=1.09, 95%CI 0.41-2.89). Conclusions: A moderate increased risk for breast cancer was associated with having ever worked in night shift, but results were not statistically significant. Risk estimates tended to increase among permanent night workers, among workers with long-term exposure to night work and in postmenopausal women. These estimates were based on small numbers due to the low prevalence of night shift in this population. The study is ongoing and, at the conference, results will be presented for a much larger population sample.

Evaluation of breast cancer risk in relation to night shift work in a case-control study in a Spanish population

ObjectivesRecent epidemiologic and animal data indicate that night work may increase the risk for breast cancer. We evaluated breast cancer risk in female night shift workers in a population based...

Age at Menopause: Imputing Age at Menopause for Women With a Hysterectomy With Application to Risk of Postmenopausal Breast Cancer

Age at menopause, a major marker in the reproductive life, may bias results for evaluation of breast cancer risk after menopause. We followed 38,948 premenopausal women in 1980 and identified 2,586 who reported hysterectomy without bilateral oophorectomy and 31,626 who reported natural menopause during 22 years of follow-up. We evaluated risk factors for natural menopause, imputed age at natural menopause for women reporting a hysterectomy without bilateral oophorectomy, and estimated the hazard of reaching natural menopause in the next 2 years. We applied this imputed age at menopause to both increase sample size and to evaluate the relation between postmenopausal exposures and risk of breast cancer. Age, cigarette smoking, age at menarche, pregnancy history, body mass index, history of benign breast disease, and history of breast cancer were each significantly related to age at natural menopause; duration of oral contraceptive use and family history of breast cancer were not. The imputation increased sample size substantially, and although some risk factors after menopause were weaker in the expanded model (height, and alcohol use), use of hormone therapy is less biased. Imputing age at menopause increases sample size, broadens generalizability making it applicable to women with hysterectomy, and reduces bias.

Abstract B83: Breast cancer risk evaluation and action using the OncoVue Risk Tool in self-referred and targeted minority populations

Abstract The Breast Cancer RE-ACT (Risk Evaluation and Action) Program at Trinity Clinic provides medical genetics evaluation and personalized recommendations for breast cancer prevention and early detection. The RE-ACT Program has received funding from Komen for the Cure to reach medically underserved and minority women in Tyler, Texas, and our surrounding rural communities. As part of this project, use of the OncoVue breast cancer risk tool was compared between a self-referred population and a population targeted as medically underserved with at least two risk factors for breast cancer. Risk factors considered included affected first degree relative, early age of menarche, nulliparity or first liveborn delivery over age 30, and obesity. The OncoVue test incorporates a woman's personal and family history with a panel of her genetic variants associated with breast cancer risk. The OncoVue test was free to all participants in both of the populations studied. Women in the targeted population were more likely to have a first-degree relative with breast cancer than the self-referred population (48% versus 35%). Hispanic and African American women made up the majority of the targeted group (46% and 20%, respectively) compared to the self-referred population which was 91% Caucasian. Women in the targeted group were younger than the self-referred group (72% versus 45% under age 50). Interestingly, the stratification of results was similar in the two populations despite efforts to reach higher risk women in the targeted group. “Standard” risk was found in 77% and 76% of the self-referred and targeted populations, respectively. “Moderate” risk was identified in 16% and 20% of the self-referred and targeted populations, respectively. Only 7% of the self-referred and 4% of the targeted population of women was classified as “high” risk by the OncoVue. Citation Information: Cancer Epidemiol Biomarkers Prev 2010;19(10 Suppl):B83.

Breast and ovarian cancer risk evaluation in families with a disease-causing mutation in BRCA1/2

Germline mutations in BRCA1 and BRCA2 confer high risks of breast and ovarian cancer, and their identification allows genetic testing of at-risk relatives. However, estimates of these risks illustrate controversies, depending on the published series. The penetrance, the earlier onset of the disease and the effect of mutations on the risk of developing breast and ovarian cancer were evaluated in 344 females belonging to 34 families from the Basque Country in Spain, in which BRCA1 or BRCA2 mutations were transmitted. Kaplan-Meier survival curves were used to derive cumulative probability curves for breast and ovarian cancer by mutation status, birth cohort and mutation position, and significance of the differences was assessed using the log-rank test. The estimated probability for breast cancer by age 70 is about 64% in BRCA1 and 69% in BRCA2, whereas the probability of developing ovarian cancer is about 37% and 25% for BRCA1 and BRCA2, respectively. There is a marginally significant higher risk of developing ovarian cancer in BRCA1 families than in BRCA2 families. The effect of birth cohort on breast cancer cumulative incidence presents an increased risk for females born after 1966 and a decreased risk for those born before 1940. There is no association between mutation position and breast cancer; however, ovarian cancer is associated to BRCA1, presenting exon 11 as an ovarian cluster. These results are important for the breast and ovarian cancer diagnosis and prevention in at-risk families.

Nipple discharge and the efficacy of duct cytology in evaluating breast cancer risk

Background Nipple discharge accounts for up to 5% of referrals to breast surgical services. With the vast majority of breast carcinomas originating in the ductal system, symptomatic dysfunction of this system often raises disproportionate clinical concern. The aim of this study is firstly, to evaluate the clinical importance of nipple discharge as an indicator of underlying malignancy and secondly, to assess the diagnostic application of duct cytology in patients presenting with nipple discharge. Study design We performed a retrospective analysis of all patients presenting with nipple discharge as their primary symptom to the symptomatic breast unit at a tertiary referral center over a 30-month period ( n = 313). The Hospital Inpatient Enquiry (HIPE) System and BreastHealth database were used to identify our study cohort. Parameters evaluated included patient demographics, clinical presentation, clinical evaluation, radiological assessment and histological/cytological analysis. Results Three-hundred and thirteen patients presented with nipple discharge as their primary complaint. Invasive breast carcinoma was diagnosed by Triple Assessment in 5% of patients. 24% of patients presenting with nipple discharge underwent nipple aspiration and cytological analysis. Duct cytology was diagnostic of the underlying breast carcinoma in 50% of triple assessment diagnosed carcinoma. Four risk factors were identified as having a significant association with breast carcinoma, these included (a) age >50 years ( p < 0.0001), (b) bloody nipple discharge ( p < 0.008), (c) presence of a breast lump ( p < 0.0001) and (d) single duct discharge ( p < 0.006). Conclusions Nipple discharge is a poor indicator of an underlying malignancy. Use of nipple aspiration and duct cytology for the assessment of nipple discharge is of limited diagnostic benefit. However, by utilizing the systematic, gold standard approach of Triple Assessment (clinical, radiological and cytological evaluation), the risk of underlying carcinoma can be accurately defined.

Comparative analysis of breast cancer risk factors among hispanic and non‐hispanic white women

Hispanic and non-Hispanic white (NHW) populations within the United States have different breast cancer incidence rates, yet there is limited research on how ethnic differences in the prevalence of established risk factors and their associations with breast cancer contribute to the observed differences. Odds ratios and population-attributable risk estimates for breast cancer were determined for Hispanic and NHW women in the population-based, case-control 4-Corners Breast Cancer Study. When comparing NHW and Hispanic women, the authors observed differences in the prevalence of certain risk factors and in the magnitude and direction of their associations with breast cancer. Hispanic women were more likely to have characteristics associated with lower breast cancer risk, such as younger age at first birth, having more children, shorter height, less hormone use, and less alcohol consumption. Among premenopausal women, ethnic differences in risk were observed with taller height and positive family history, which were not associated with breast cancer among Hispanic women. Among postmenopausal women, associations for certain risk factors were either weaker or were not observed in Hispanics, such as recent estrogen plus progestin hormone therapy use and younger age at menarche. Among NHW women, an estimated 62% to 75% of breast cancers were attributed to the evaluated risk factors compared with 7% to 36% in Hispanic women. Breast cancer risk factors established in NHW populations had less influence on breast cancer risk in Hispanic women. These findings reflect the need to further evaluate breast cancer risk factors among different ethnic and racial populations.

Head circumference in the clinical detection of PTEN hamartoma tumor syndrome in a clinic population at high-risk of breast cancer

PTEN Hamartoma Tumor Syndrome (PHTS) is often recognized by the presence of macrocephaly and associated mucocutaneous features, and is notable for a profound predisposition to breast and thyroid cancers. Head circumference (HC) is rarely measured when evaluating women at high risk for breast cancer, but may offer insight into characterizing cancer risk. Patients enrolled in the University of Michigan Cancer Genetics registry for breast cancer evaluation were analyzed for personal and family history of cancer and features of PHTS. This group of women was compared to all women who had undergone PTEN testing and whether or not they met clinical criteria for PHTS. Among the 164 women referred for breast cancer risk evaluation, a statistically significant difference in mean HC was found between women who did (57.3 cm) and did not (55.4 cm) meet clinical criteria for PHTS with both values below the established threshold for macrocephaly (58 cm). The sensitivity and specificity of macrocephaly for the presence of a PTEN mutation were 100 and 53%, respectively, among the 28 women tested. The positive predictive value was 14%. PTEN mutation positive and PTEN mutation negative women were not well differentiated by PHTS clinical criteria (P = 0.2348). The high sensitivity of HC suggests that this simple measure can improve the detection of unrecognized patients with PHTS. Measuring HC is a useful clinical feature, but is insufficient as a singular screening tool for PHTS. Even in a high risk population, the PPV of this test is low. Diagnosis of this important genetic syndrome still relies heavily on detailed history and full physical exam.

Evaluation of Breast Cancer Risk in a Multigenic Model Including Low Penetrance Genes Involved in Xenobiotic and Estrogen Metabolisms

Breast cancer has become the most frequent cancer among women in Westernized countries. The majority of breast cancers are due to low penetrance genes, which can act with environmental factors, particularly nutrition. Polymorphisms in gene coding for xenobiotic and estrogen metabolic pathways could increase individual cancer susceptibility and lead to the indication of individuals at higher cancer risk. A population-based, case-control study consisting of 911 breast cancer cases and 1,000 healthy control cases was performed. The association between 11 single nucleotide polymorphisms (SNP) in 7 genes and breast cancer risk was investigated in a multigenic model. The CYP1B1-432 Leu-Val and Val-Val genotypes significantly increased risk [odds ratio (OR) = 1.23, 95% confidence interval (CI) = 1.08–1.39; OR = 1.51, 95% CI = 1.17–1.94, respectively] similarly as observed with CYP1B1-453 (Asn-Ser genotype: OR = 1.17, 95% CI = 1.00–1.37; Ser-Ser genotype: OR = 1.38, 95% CI = 1.00–1.89). We showed that catechol-O-methyltransferase (COMT) could modulate the risk conferred by CYP1B1, ESR, GSTP1, and NAT2 acetylation phenotype. Additionally, a higher risk conferred by the variant for COMT was noted only for individuals presenting a high waist-to-hip ratio (COMT Val-Met, OR = 1.60, 95% CI = 1.04–2.44; COMT Met-Met, OR = 1.57, 95% CI = 0.98–2.53), suggesting a relationship with abdominal adiposity. In conclusion, COMT constitutes a crucial element in estrogen metabolism by regulating carcinogen metabolites elimination and, consequently, is a major factor in breast cancer risk.

DNA repair genes XRCC1 and XRCC3 polymorphisms and their relationship with the level of micronuclei in breast cancer patients

Breast cancer (BC) is the most prevalent type worldwide, besides being one of the most common causes of death among women. It has been suggested that sporadic BC is most likely caused by low-penetrance genes, including those involved in DNA repair mechanisms. Furthermore, the accumulation of DNA damage may contribute to breast carcinogenesis. In the present study, the relationship between two DNA repair genes, viz., XRCC1 (Arg399Gln) and XRCC3 (Thr241Met) polymorphisms, and the levels of chromosome damage detected in 65 untreated BC women and 85 healthy controls, was investigated. Chromosome damage was evaluated through micronucleus assaying, and genotypes determined by PCR-RFLP methodology. The results showed no alteration in the risk of BC and DNA damage brought about by either XRCC1 (Arg399Gln) or XRCC3 (Thr241Met) action in either of the two groups. Nevertheless, on evaluating BC risk in women presenting levels of chromosome damage above the mean, the XRCC3Thr241Met polymorphism was found to be more frequent in the BC group than in the control, thereby leading to the conclusion that there is a slight association between XRCC3 (241 C/T) genotypes and BC risk in the subgroups with higher levels of chromosome damage.