Unaffected Women Research Articles

11-oxygenated C19 steroids as circulating androgens in women with polycystic ovary syndrome.

11-oxygenated C19 steroids (11oxC19s) are newly specified human androgens. Although median serum levels of 11oxC19 were reported to be higher in patients with polycystic ovary syndrome (PCOS) than in unaffected women, inter-individual variations in androgen levels among PCOS patients have poorly been investigated. Here, we quantified four 11oxC19s, i.e., 11-ketotestosterone (11KT), 11β-hydroxytestosterone (11OHT), 11β-hydroxyandrostenedione (11OHΔ4A), and 11-ketoandrostenedione (11KΔ4A), in blood samples of 28 PCOS patients and 31 eumenorrheic women using liquid chromatography-tandem mass spectrometry. We referred to our previous data of classic androgens in these individuals. We found that 11OHT levels were higher in the PCOS group than in the eumenorrheic group. Moreover, although the median values of 11KT, 11KΔ4A, and 11OHΔ4A were comparable between the two groups, these steroids were markedly increased in some patients. Of the 28 patients, 8 had high levels of both 11oxC19s and classic androgens, whereas 4 had an increase only in 11oxC19 levels, and 12 had an increase only in classic androgen levels. Intragroup variations in androgen levels were relatively large in the PCOS group. Levels of 11OHT and 11KT were significantly higher in overweight/obese patients than in normal weight patients and correlated with body mass indexes. These results highlight the clinical significance of 11oxC19s as circulating androgens in PCOS patients and indicate that the accumulation of 11oxC19s and/or classic androgens is an essential feature of PCOS. The profiles of circulating androgens appear to vary among patients. In particular, overweight/obesity likely enhances the 11oxC19s accumulation in PCOS, although this notion awaits further validation.

Setting the Threshold for Surgical Prevention in Women at Increased Risk of Ovarian Cancer.

The number of ovarian cancer cases is predicted to rise by 14% in Europe and 55% worldwide over the next 2 decades. The current absence of a screening program, rising drug/treatment costs, and only marginal improvements in survival seen over the past 30 years suggest the need for maximizing primary surgical prevention to reduce the burden of ovarian cancer. Primary surgical prevention through risk-reducing salpingo-oophorectomy (RRSO) is well established as the most effective method for preventing ovarian cancer. In the UK, it has traditionally been offered to high-risk women (>10% lifetime risk of ovarian cancer) who have completed their family. The cost-effectiveness of RRSO in BRCA1/BRCA2 carriers older than 35 years is well established. Recently, RRSO has been shown to be cost-effective in postmenopausal women at lifetime ovarian cancer risks of 5% or greater and in premenopausal women at lifetime risks greater than 4%. The acceptability, uptake, and satisfaction with RRSO at these intermediate-risk levels remain to be established. Prospective outcome data on risk-reducing salpingectomy and delayed-oophorectomy for preventing ovarian cancer is lacking, and hence, this is best offered for primary prevention within the context and safe environment of a clinical trial. An estimated 63% of ovarian cancers occur in women with greater than 4% lifetime risk and 53% in those with 5% or greater lifetime-risk. Risk-reducing salpingo-oophorectomy can be offered for primary surgical prevention to women at intermediate risk levels (4%-5% to 10%). This includes unaffected women who have completed their family and have RAD51C, RAD51D, or BRIP1 gene mutations; first-degree relatives of women with invasive epithelial ovarian cancer; BRCA mutation-negative women from high-risk breast-and-ovarian cancer or ovarian-cancer-only families. In those with BRCA1, RAD51C/RAD51D/MMR mutations and the occasional families with a history of ovarian cancer in their 40s, surgery needs to be considered at younger than 45. In other moderate-risk gene mutation carriers and those with polygenic risk, RRSO needs be considered at 50. There is need for establishment/expansion of well-defined pathways to increase clinical access to RRSO. It is time to lower the risk threshold for RRSO to enable introduction of a targeted primary prevention approach, which could significantly impact the future burden of ovarian cancer.

A plasma telomeric cell-free DNA level in unaffected women with BRCA1 or/and BRCA2 mutations: a pilot study.

Plasma cell-free DNA (cfDNA) is a small DNA fragment circulating in the bloodstream originating from both non-tumor- and tumor-derived cells. A previous study showed that a plasma telomeric cfDNA level decreases in sporadic breast cancer patients compared to controls. Tumor suppressor gene products including BRCA1 and BRCA2 (BRCA1&2) play an important role in telomere maintenance. In this study, we hypothesized that the plasma telomeric cfDNA level is associated with the mutation status of BRCA1&2 genes. To test this hypothesis, we performed plasma telomeric cfDNA quantitative PCR (qPCR)-based assays to compare 28 women carriers of the BRCA1&2 mutation with age-matched controls of 28 healthy women. The results showed that the plasma telomeric cfDNA level was lower in unaffected BRCA1&2 mutation carriers than in age-matched controls from non-obese women (BMI < 30), while there was no association between unaffected BRCA1&2 mutation carriers and age-matched controls in obese women (BMI > 30). Moreover, the plasma telomeric cfDNA level applied aptly to the Tyrer-Cuzick model in non-obese women. These findings suggest that circulating cfDNA may detect dysfunctional telomeres derived from cells with BRCA1&2 mutations and, therefore, its level is associated with breast cancer susceptibility. This pilot study warrants further investigation to elucidate the implication of plasma telomeric cfDNA levels in relation to cancer and obesity.

Prenatal testosterone and theory of mind development: Findings from disorders of sex development

Women on average perform better than men on the “Reading the Mind in the Eyes” test (RMET) which is a measure of Theory of Mind (ToM). The aim of this study was to assess whether these sex differences are influenced by differences in prenatal testosterone levels through a study on individuals with Disorders of Sex Development and matched controls. ToM performance was examined using the RMET in female-assigned-at-birth individuals with increased prenatal testosterone exposure (Congenital Adrenal Hyperplasia (CAH) and 5-alpha Reductase type-2 Deficiency (5α-RD-2)), female-assigned-at-birth individuals with testosterone insensitivity (Complete Androgen Insensitivity Syndrome (CAIS)), and their age-matched unaffected male and female relatives. A total number of 158 individuals participated in the study; 19 with 5α-RD-2, 17 with CAH, 18 women with CAIS, 52 matched unaffected men and 52 matched unaffected women. All subgroups were around 20 years of age. Women with CAH scored significantly lower on RMET than control women and CAIS individuals. CAIS individuals scored significantly higher than control men and participants with 5α-RD. Statistically, CAIS individuals' performance on RMET was similar to control women's, women with CAH did not differ significantly from control men and 5α-RD-2 individuals scored significantly lower than control men. These results, which are in line with previous theories, illustrate that performance on the RMET, as an index of ToM, may be influenced by variations in prenatal androgens levels.

Provider Discussions of Genetic Tests With U.S. Women at Risk for a BRCA Mutation

The U.S. Preventive Services Task Force recommends that primary care providers screen unaffected women with a family history of BRCA mutation-associated cancers, but without a personal history of BRCA-related cancer, for referral to genetic counseling and potential genetic testing. The 2015 National Health Interview Survey was analyzed in January 2017 to determine the rates at which unaffected adult women with a positive family history of BRCA-related cancers, assessed using the Family History Screen-7, reported discussing genetic testing with a provider, using genetic counseling services, and having genetic testing for increased cancer risk. Clinical correlates associated with these outcomes were assessed using multivariable logistic regression (AOR with 95% CI). Among unaffected Family History Screen-7 screen-positive women, 9.5% reported discussing genetic testing with a provider, 5.1% reported genetic counseling, and 2.7% reported uptake of genetic testing. Younger women (aged 18-39 and 40-49 years) were more likely to discuss genetic testing than women aged ≥60 years (AOR=1.50, 95% CI=1.09, 2.06 and AOR=1.64, 95% CI=1.15, 2.33, respectively). Women of black race (AOR=1.50, 95% CI=1.09, 2.07) and women with greater than a high school education (AOR=1.85, 95% CI=1.41, 2.43) were more likely to discuss genetic testing than women of white race and women with a high school education or less, respectively. Among a higher risk subgroup with an even stronger family history of BRCA-associated cancers, 18.5% of women reported discussions. Despite a decade-old U.S. Preventive Services Task Force recommendation, few unaffected women at risk for BRCA-associated cancer report discussing genetic testing with a provider.

Long-term Risk of a Seizure Disorder After Eclampsia

To evaluate the incidence rate and relative risk of a seizure disorder after eclampsia. We evaluated 1,565,733 births in a retrospective data linkage cohort study in Ontario, Canada, from April 1, 2002, to March 31, 2014. We included females aged 15-50 years and excluded patients with epilepsy, conditions predisposing to seizure, and those who died within 30 days of the delivery discharge date. The exposure was defined as a hypertensive disorder of pregnancy, namely 1) eclampsia, 2) preeclampsia, or 3) gestational hypertension. The referent was an unaffected pregnancy. The primary outcome was the risk of seizure disorder starting 31 days after a hospital birth discharge. Risk was expressed as an incidence rate and a hazard ratio (HR) with 95% CI. The predefined study hypothesis was that women with eclampsia would have an increased risk of future seizure disorder. There were 1,615 (0.10%) pregnancies exclusively affected by eclampsia, 17,264 (1.1%) with preeclampsia, 60,863 (3.9%) with gestational hypertension, and 1,485,991 (94.9%) unaffected. A future seizure disorder was significantly more likely after a pregnancy with eclampsia (4.58/10,000 person-years) than a pregnancy without a hypertensive disorder of pregnancy (0.72/10,000 person-years; crude HR 6.09, 95% CI 2.73-13.60). The adjusted HR was minimally attenuated from 6.09 to 5.42 (95% CI 2.42-12.12) after multivariable adjustment for confounders at the index birth as well as adjusting for traumatic brain injury, stroke, cerebral tumor, aneurysm or hemorrhage, and multiple sclerosis. The risk of seizure disorder was doubled in pregnancies affected by preeclampsia (adjusted HR 1.96, 95% CI 1.21-3.17), but not by gestational hypertension (adjusted HR 1.01, 95% CI 0.71-1.43). Women with eclampsia should be reassured that, although the relative risk of a seizure disorder is higher than unaffected women, the absolute risk is extremely low (approximately one seizure/2,200 person-years).

Asthma is associated with endometriosis: A retrospective population-based cohort study.

Evidence regarding the association between asthma and endometriosis is limited and inconsistent. The goal of the study was to investigate whether women diagnosed as having asthma were at a greater risk of endometriosis than age-matched unaffected women. We conducted a nationwide population-based retrospective study by using data retrieved from the Taiwan National Health Insurance Research Database during the period of 2000-2005 with follow-up through 2013. The current analysis included 7337 women aged 12-50 years with newly diagnosed asthma and using asthma-related medications and 29,348 age-matched women without asthma. A Cox proportional hazards regression model was used to estimate the risks of endometriosis in women with asthma as compared with those without asthma. The overall risk of endometriosis in the asthma group was 1.50-fold higher (95% confidence interval=1.33-1.70) than that in the nonasthma group. A stratified analysis by age further revealed that patients with asthma were associated with a higher risk of endometriosis in age groups of 21-50 years. Compared with women without asthma, women with asthma of reproductive age are at a higher risk of endometriosis. Additional studies are warranted to elucidate the mechanism(s) underlying the association between asthma and a higher risk of endometriosis.

Moving In and Out of the What-Ifs: The Experiences of Unaffected Women Living in Families Where a Breast Cancer 1 or 2 Genetic Mutation Was Not Found.

In families where genetic testing for the breast cancer 1 and 2 genes (BRCA1/2) has not identified a deleterious mutation, the risk for hereditary breast cancer (HBC) can still be high when there is a strong family history. Little is known about how an awareness of risk for HBC impacts the everyday lives of unaffected women (no personal history for breast and/or ovarian cancer) in these families. The aim of this study is to explore how unaffected women, living in BRCA1/2-negative families, experience living with risk for HBC. van Manen's hermeneutic phenomenological approach guided this study. Unaffected at-risk women were recruited from a hereditary breast and ovarian cancer clinic in Western Canada. Nine women participated in 20 open-ended conversations. Phenomenological reflection on the 4 life existentials (lived space, body, time, and relations) revealed "Moving In and Out of the What-Ifs" as an overarching description that was communicated through the following themes: "Just Moving Along: Living a Normal Life," "Moving Into Those Dark Spaces," "Is there Something Wrong With Me"? "Markings in Time," "Living in the Moment," "Being Cared For," and "Keeping Me Grounded." The findings reveal how knowledge from predictive medicine impacts the lives of women and the importance of supportive relations and provides a foundation for future research into how health is perceived. The findings inform the practices of healthcare professionals as they engage in discussions with women living with risk for HBC and highlight the importance of a supportive relationship.

Telomere Length Is Predictive of Breast Cancer Risk in BRCA2 Mutation Carriers.

Background: Germline BRCA2 mutations increase risk of breast cancer and other malignancies. BRCA2 has been shown to play a role in telomere protection and maintenance. Telomere length (TL) has been studied as a modifying factor for various diseases, including breast cancer. Previous research on TL in BRCA mutation carriers has produced contradicting results.Methods: We measured blood TL, using a high-throughput monochrome multiplex qPCR method, in a well-defined Icelandic cohort of female BRCA2 mutation carriers (n = 169), sporadic breast cancer patients (n = 561), and healthy controls (n = 537).Results: Breast cancer cases had significantly shorter TL than unaffected women (P < 0.0001), both BRCA2 mutation carriers (P = 0.0097) and noncarriers (P = 0.00006). Using exclusively samples acquired before breast cancer diagnosis, we found that shorter telomeres were significantly associated with increased breast cancer risk in BRCA2 mutation carriers [HR, 3.60; 95% confidence interval (CI), 1.17-11.28; P, 0.025] but not in non-carriers (HR,1.40; 95% CI, 0.89-2.22; P, 0.15). We found no association between TL and breast cancer-specific survival.Conclusions: Blood TL is predictive of breast cancer risk in BRCA2 mutation carriers. Breast cancer cases have significantly shorter TL than unaffected women, regardless of BRCA2 status, indicating that samples taken after breast cancer diagnosis should not be included in evaluations of TL and breast cancer risk.Impact: Our study is built on a well-defined cohort, highly accurate methods, and long follow-up and can therefore help to clarify some previously published, contradictory results. Our findings also suggest that BRCA2 has an important role in telomere maintenance, even in normal blood cells. Cancer Epidemiol Biomarkers Prev; 26(8); 1248-54. ©2017 AACR.

Abstract LB-251: Development of a circulating microRNA risk signature predictive of breast cancer diagnosis among high-risk women

Abstract Introduction: Current models predicting short and long term risk of breast cancer based on clinical factors, such as family history, have significant limitations. Circulating microRNAs (c-miRNAs) have emerged as measurable ‘liquid biopsy’ biomarkers for cancer detection. However, the value of c-miRNAs, an epigenetic regulator of protein levels, as a novel prediction tool of breast cancer development years before detection has not been explored. Methods: Twenty-four breast cancer cases and matched were selected from a source population cohort of 584 unaffected women enrolled in the High Risk Breast Program at the UVM Cancer Center. Women with a mutation in BRCA1 or BRCA2 were excluded. Cases were women diagnosed with stage I-III breast cancer. One control was matched to each case on age (± 3.5 yrs) and reason for high-risk status (family history or benign breast disease). Clinical data and serum samples were collected at study enrollment and at subsequent cancer-free 4-year intervals. RNA was isolated from serum and over 2500 mature human miRNAs were profiled (Affymetrix microRNA v4.0 microarray). Two sets of candidate miRNAs were identified that distinguished cases from controls and a multivariate risk score for each set calculated using Cox regression models. Set 1: 20 miRNAs with greatest area under the receiver operating characteristic curve (AUC) after univariate regression. Set 2: 19 miRNAs with significantly different expression (ANOVA p &amp;lt; 0.05) between cases and controls. Candidate sets 1 and 2 included 25 c-miRNAs: 14 shared, 6 unique to set 1, and 5 unique to set 2. Results: We identified 2 panels of c-miRNAs that distinguish high-risk unaffected women who later develop breast cancer from those remaining cancer-free; the AUC values of 0.896 and 0.870, greatly exceed modeled risk based on clinical parameters (Gail model AUC = 0.497; Claus model AUC = 0.507; IBIS model AUC = 0.503). Panel 1: 6 model-selected c-miRNAs from set 1. Panel 2: 5 model-selected c-miRNAs from set 2. Panels 1 and 2 included 9 c-miRNAs; 2 shared, 4 unique to panel 1, and 3 unique to panel 2. Of these 9 c-miRNAs, 6 are detected at lower levels in serum from women going onto develop breast cancer while 3 are elevated in cases as compared to cancer-free women. Pathway analysis for modeled miRNAs revealed roles in many cancer-related pathways and biological functions including Regulation of EMT, Molecular Mechanisms of Cancer, and malignant solid tumor. Conclusions: In contrast to clinical breast cancer risk models, the identified miRNA panels perform well at distinguishing cases from controls, with AUCs approaching 0.9. While these data require validation, this non-invasive ‘risk signature’ of c-miRNAs will help identify high-risk women who will most benefit from enhanced screening and prevention strategies. Pathways targeted by ‘risk signature’ c-miRNAs may provide insight into mechanisms promoting breast cancer development. Citation Format: Nicholas H. Farina, Jon E. Ramsey, Melissa E. Sands, Tiffany J. Rounds, David J. Shirley, Thomas P. Ahern, Janet L. Stein, Gary S. Stein, Jane B. Lian, Marie E. Wood. Development of a circulating microRNA risk signature predictive of breast cancer diagnosis among high-risk women [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 LB-251. doi:10.1158/1538-7445.AM2017-LB-251

Gestational diabetes mellitus and first trimester pregnancy-associated plasma protein A: A case-control study in a Chinese population.

Aims/IntroductionTo investigate the relationship between pregnancy‐associated plasma protein A (PAPP‐A) and gestational diabetes mellitus (GDM), and to determine whether PAPP‐A has improved value for predicting GDM in a Chinese population.Materials and MethodsClinical data for 599 GDM patients and 986 unaffected pregnant women undergoing both antenatal examinations and delivery were retrospectively analyzed. First‐trimester serum PAPP‐A levels were compared between the groups. Binary logistic regression analysis was used to explore the risk factors for GDM, and the area under the receiver operating characteristic curve was used to determine the value of PAPP‐A for predicting GDM.Results GDM‐affected and unaffected pregnant women were significantly different in terms of age (P < 0.001), BMI (P < 0.001), family history of diabetes (P = 0.002), α‐thalassemia trait (P < 0.01), parity (P < 0.001), conception methods (P < 0.001), gestational weeks at the time of labor (P < 0.001) and corrected PAPP‐A multiples of the median values (P < 0.001). Binary logistic regression analysis showed that PAPP‐A levels were negatively related to the subsequent development of GDM (odds ratio 0.798, 95% confidence interval 0.647–0.984). The area under the receiver operating characteristic curve for maternal factors was 0.684 (95% CI: 0.657–0.711), and did not significantly differ from that for the combination of maternal factors and serum PAPP‐A levels, which was 0.686 (95% CI: 0.660–0.713; χ2 = 0.625, P = 0.429).ConclusionsSerum PAPP‐A was an independent factor for the development of GDM in pregnant Chinese women. Serum‐PAPP‐A does not have improved value with respect to predicting GDM when combined with other maternal factors.

Development and validation of a residual risk score to predict breast cancer risk in unaffected women negative for mutations on a multi-gene hereditary cancer panel.

1579 Background: Women who are unaffected with cancer but have a significant family history of breast cancer (BC) are frequently referred for hereditary cancer testing with multi-gene panels; however, &lt; 10% test positive for clinically actionable mutations. Large-scale genotyping studies have identified common variants (primarily single-nucleotide polymorphisms) that individually confer modest BC risk, but together may explain the genetic susceptibility for BC in many women without monogenic mutations. Here, we describe the development and validation of a polygenic residual risk score in a large, consecutive cohort of women who tested negative for mutations in known BC susceptibility genes. Methods: This IRB-approved study includes women of European ancestry tested with a multi-gene hereditary cancer panel who were negative for mutations in 11 genes associated with BC ( BRCA1, BRCA2, TP53, PTEN, STK11, CDH1, PALB2, CHEK2, ATM, NBN, BARD1). Clinical information was collected from provider-completed test request forms. The dataset was divided into a training (July – November 2016) and validation cohort (November 2016 – April 2017). Multivariable logistic regression models were used to evaluate 94 common variants and develop candidate residual risk scores as predictors of personal BC history (invasive ductal carcinoma, IDC) in the training cohort. Independent variables included age, personal/family cancer history, and ancestry. An optimal subset of the 94 common variants and a residual risk score will be selected through cross-validation followed by independent validation. Results: The training cohort includes 11,838 women (median age 47 years), 18% of whom reported a personal history of IDC and 36% of whom reported BC in a first-degree relative. Results from validation of the residual risk score in an independent cohort of approximately 12,000 women will be completed at the time of presentation. Conclusions: The validation and clinical implementation of a residual risk score for women at risk for hereditary BC may offer significant potential for the management of high-risk, unaffected women who test negative for monogenic BC mutations.

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.

Association of baseline plasma levels of 25OH vitamin D and breast cancer risk in a chemoprevention trial.

1546 Background: Observational studies have shown a correlation of higher serum 25-hydroxyvitamin D (25OHD) concentrations and reduced cancer risk, including breast cancer (BC). We assessed the association of 25OHD and Vitamin D Receptor (VDR) polymorphisms (SNPs) with breast cancer events within a chemoprevention trial in premenopausal women at risk for BC. Methods: Premenopausal women with history of intraepithelial neoplasia (IEN) or at risk women according to the Gail model were included in a 4 arm phase II prevention trial (low dose tamoxifen vs fenrerinide vs their combination vs placebo). Level of 25OHD were measured at baseline. VDR SNPs ( FokI, BsmI, TaqI, ApaI, and Cdx2) were determined using the Applied Biosystems’ Taqman Allelic Discrimination Assay according to manufacturer’s instructions. Survival analysis for breast cancer events was performed using competing risk models, adjusted for BMI, age, season and risk strata. Results: Plasma samples were available for 228 subjects. At baseline the median plasma 25OHD concentrations were slightly higher in 53 unaffected women, 19.6 ng/ml (IQR 12.7-27.3 ng/mL) than in 175 women with IEN, 18.8 ng/ml (11.7-25.8). After a median follow up of 15 years, 79 women developed a breast cancer event, 12 had different neoplastic events. The median level of 25OHD was 19.7 ng/ml (IQR 12.8-26.1) in subjects free from oncological events and 17.8 ng/ml (9.7-23.9) in subjects with breast events. Women in the lowest 25OHD quartile (≤12 ng/ml) had an increased risk of breast cancer events: HR = 1.79 (95%CI, 1.07-2.99, p = 0.03). Considering all cancer events, the associations with 25OHD were confirmed (P = 0.005). Among the VDR SNPs the ApaI variant in homozygote or heterozygote versus wild type showed an HR of 1.83 (95%CI, 1.04-3.21 p = 0.03). Conclusions: Our results support a role of plasma vitamin D levels in breast cancer risk. Subjects in the lowest quartile had a two-fold increased risk of a cancer event. Our findings support trials of 25OHD supplementation to prevent breast cancer in 25OHD insufficient subjects.

Abstract PR07: Comparison of risk model recommendations for women at high-risk of breast cancer based on clinical thresholds using the Prospective Family Study Cohort (ProF-SC)

Abstract Background: Clinical guidelines for classifying women as high-risk for breast cancer when considering chemoprevention and/or MRI screening options include thresholds of remaining lifetime risk (RLR) of 20% or more and/or a fixed time interval (e.g., 5-year risk of 1.67 or higher, 10-year risk of 3.34 or higher). Although clinicians have noted differences in risk estimates from the existing risk models, there have been few prospective validations using large cohorts to describe the magnitude of the discordancies between these models. Methods: We prospectively followed 16,285 women without breast cancer at baseline for an average of 10.2 years to compare the RLR and 10-year risk assigned by two commonly used risk estimation models for high risk women: 1) The International Breast Cancer Intervention Study tool (IBIS); and 2) the Breast Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm (BOADICEA). We compared the model-assigned 10-year risks with 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. Results: We observed differences between risk models in terms of the proportion of women classified as high-risk based on 20% or more RLR (IBIS=56% vs BOADICEA=23%). Only 21% of women were classified as high risk by both models, 35% of women were classified as high risk by IBIS only and 2% of women were classified as high risk by BOADICEA only. The difference was not evident (IBIS=52% vs BOADICEA=51%) when using a 10-year risk threshold of 3.34%. Using this 10-year threshold, 43% of women were classified as high risk by both models, 9% of women were classified as high risk by IBIS only and 8% of women were classified as high risk by BOADICEA only. IBIS risk predictions (mean=4.9%) were better calibrated to observed breast cancer incidence (5.8%, 95% confidence interval (CI)=5.4% to 6.2%) than were those based on BOADICEA (mean=4.2%). When we compared the magnitude of the discordancy between IBIS and BOADICEA by age, race/ethnicity, and number of relatives affected, we observed the extent of discordancy (e.g. one model resulted in a woman being above the clinical threshold when the other did not) depended on age. Specifically, for women under the age of 40 years, only 3.1% of women were high risk with IBIS but not BOADICEA compared with 7.5% classified as high risk by BOADICEA but not IBIS. Both models gave similar predictions of high risk with same proportion discordant for women over 50, and the same proportion discordant by race/ethnicity. When we compared the discordancy by those unaffected and affected with breast cancer after ten years of follow-up, 51% of unaffected women were high risk by IBIS using the 10-year threshold and 50% by BOADICEA with only 8% discordant (high risk on only one model). For women who were diagnosed with breast cancer prospectively after baseline, 75% were classified as high risk at baseline by IBIS and 72% were classified by BOADICEA with 8% high risk by IBIS only and 5% high risk by BOADICEA only. Conclusion: These results suggest that there is a considerable discordancy between two commonly used risk models to determine high risk classification for MRI and chemoprevention. There is a greater concordancy between the two models when using a shorter time-horizon, especially for women over the age of 50 years. However, as MRI and chemoprevention for high-risk women often needs to start before the age of 50 years, there is a great need to enhance risk assessment for these younger high risk women. Citation Format: Mary Beth Terry, Kelly-Anne Phillips, Yuyan Liao, Robert J. MacInnis, Gillian S. Dite, Mary B. Daly, Esther M. John, Irene L. Andrulis, Saundra S. Buys, Richard Buchsbaum, John L. Hopper. Comparison of risk model recommendations for women at high-risk of breast cancer based on clinical thresholds using the Prospective Family Study Cohort (ProF-SC). [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 PR07.

Use of BRCA Mutation Test in the U.S., 2004-2014.

BRCA mutation testing has been used for screening women at high risk of breast and ovarian cancer and for selecting the best treatment for those with breast cancer. To optimize the infrastructure and medical resources allocation for genetic testing, it is important to understand the use of BRCA mutation testing in the U.S. health system. This retrospective cohort study included 53,254 adult women with insurance claims for BRCA mutation testing between 2004 and 2014 from ClinformaticsTM Data Mart Database. Data analysis was performed in 2016. This study assessed trends in the use of BRCA mutation testing in women with previously diagnosed breast or ovarian cancer and those without (unaffected women). Between 2004 and 2014, of those receiving BRCA testing, the proportion of BRCA tests performed in unaffected women increased significantly (p<0.001), from 24.3% in 2004 to 61.5% in 2014. An increase in the proportion of BRCA tests used in unaffected women was found in each characteristic subgroup. In 2014, most subgroups had a proportion surpassing 50%, except for those aged 51-65 years and those without a family history of breast cancer. There was a much lower proportion of those aged 20-40 years among tested women with previously diagnosed breast or ovarian cancer than in unaffected women (17.6% vs 41.7%, p<0.001). During the past decade, the role of BRCA testing has gradually shifted from being used primarily in cancer patients to being used in unaffected women in the U.S.

Characterization of BRCA1 and BRCA2 variants in multi-ethnic Asian cohort from a Malaysian case-control study

BackgroundGenetic testing for BRCA1 and BRCA2 has led to the accurate identification of individuals at higher risk of cancer and the development of new therapies. Approximately 10-20% of the genetic testing for BRCA1 and BRCA2 leads to the identification of variants of uncertain significance (VUS), with higher proportions in Asians. We investigated the functional significance of 7 BRCA1 and 25 BRCA2 variants in a multi-ethnic Asian cohort using a case-control approach.MethodsThe MassARRAY genotyping was conducted in 1,394 Chinese, 406 Malay and 310 Indian breast cancer cases and 1,071 Chinese, 167 Malay and 255 Indian healthy controls. The association of individual variant with breast cancer risk was analyzed using logistic regression model adjusted for ethnicity, age and family history.ResultsOur study confirmed BRCA2 p.Ile3412Val is presented in >2% of unaffected women and is likely benign, and BRCA2 p.Ala1996Thr which is predicted to be likely pathogenic by in-silico models is presented in 2% of healthy Indian women suggesting that it may not be associated with breast cancer risk. Single-variant analysis suggests that BRCA1 p.Arg762Ser may be associated with breast cancer risk (OR = 7.4; 95% CI, 0.9–62.3; p = 0.06).ConclusionsOur study shows that BRCA2 p.Ile3412Val and p.Ala1996Thr are likely benign and highlights the need for population-specific studies to determine the likely functional significance of population-specific variants. Our study also suggests that BRCA1 p.Arg762Ser may be associated with increased risk of breast cancer but other methods or larger studies are required to determine a more precise estimate of breast cancer risk.

Abstract P4-12-05: Extracellular vesicles from young women's and postpartum breast cancer display unique proteomic content, alter breast cancer aggressive behavior, and influence immune cell function

Abstract Background: Young women's breast cancer[YWBC] affects 27,000 US women age ≤45 annually. Half of these cancers occur within 5-10 years of a prior childbirth, a postpartum breast cancer[PPBC], incurring a 3 fold increased risk for metastasis and death. Recently, extracellular vesicles[EV] have been identified in human circulation, released from cancer cells, that have paracrine and autocrine effects, alter the tumor microenvironment and establish metastatic niches. EVs isolated from breast cancer lines increase proliferation and invasion of other breast cancer cells in vitro. However, the impact of EVs isolated from primary breast cancer patients on tumor invasion, metastasis and their role in tumor immune suppression is largely unknown. We hypothesized that EVs from YWBC/PPBC patients may contain unique pro-metastatic cargo, influence aggressive breast cancer cell behavior and may demonstrate the ability to alter immune cell function. Method: We isolated EVs using size-exclusion chromatography [SEC] from the plasma of 10 unaffected young women and 20 YWBC patients balanced for parity, age, subtype and stage. We compared the breast cancer-specific EV proteins within various clinical groups of YWBC and PPBC to identify significant proteomic differences by parity, sub-type, stage, and disease recurrence. We determined the functional impact of these EVs on tumor cell motility and proliferation, and analyzed the effect of breast cancer derived EVs on immune cell phenotype, function, and T cell proliferation assays. Results: Of the 582 proteins, 22 proteins are significantly increased in the EVs of YWBC compared to unaffected donors. The protein set includes breast cancer antigens [MUC 1, 2, 5b], transcriptional regulators [Myc target protein], enzymes [catalase, MMP inhibitor 1], and signaling molecules [Annexin 1, latent TGFb binding protein 1], among others. Several identified proteins specifically track with those YWBC cases with subsequent metastases. Furthermore, 8 unique proteins track with PPBC, including cartilage oligomeric matrix protein, a novel breast cancer biomarker that correlates with increased invasiveness, and decreased recurrence-free survival. EVs isolated from the plasma of newly diagnosed YWBC increase breast cancer invasion and EVs derived from breast cancer are engulfed by the majority of monocytic immune cells, including dendritic cells, classical and activated monocytes, but not by lymphocytes. Specifically, CD14+ monocytic myeloid derived suppressor cells engulfed the EVs while the CD15+ granulocytic subset did not. Once engulfed, phenotypic changes occurr in the EV containing monocytes and a significantly reduction in T cell stimulation in standard mixed-lymphocyte reactions is observed. Conclusion: EVs isolated from YWBC &amp; PPBC cases have unique protein content and increase breast cancer invasiveness, which suggests potential mechanistic roles for EVs as increasing metastatic risk and provides novel candidate biomarkers. We identified an immunomodulatory effect of breast cancer EVs on human monocytes that may contribute to immunosuppression in breast cancer and a role for EVs as directly modulating the host and tumor microenvironment. Citation Format: Borges VF, Jordan KR, Hall JK, Schedin T, Hansen K, Schedin P. Extracellular vesicles from young women's and postpartum breast cancer display unique proteomic content, alter breast cancer aggressive behavior, and influence immune cell function [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 P4-12-05.

We Need to Talk: Disclosure of Sexual Problems Is Associated With Depression, Sexual Functioning, and Relationship Satisfaction in Women

Women with sexual problems (e.g., difficulties with desire, arousal, lubrication, orgasm, and pain during sexual activity) experience more depressive symptoms, and poorer sexual functioning and relationship satisfaction compared with unaffected women. A robust literature highlights the importance of sexual communication, and sexual self-disclosures in particular, for the well-being of individuals in romantic relationships. However, little is known about the disclosure of sexual problems to romantic partners and its association with women's psychological, sexual, and relationship well-being. This study examined the proportion of women (N = 277) who disclose (vs. do not disclose) sexual problems to their partner, and the consequences of disclosure. Women (Mage = 29.79, SD = 6.54) completed online validated measures assessing sexual problems, relationship satisfaction, sexual functioning, and depressive symptoms. The majority (69.3%) reported disclosing sexual problems to their current romantic partner. Disclosers reported fewer depressive symptoms, and greater sexual functioning and relationship satisfaction compared to nondisclosers. Disclosing sexual problems may benefit women's well-being by enhancing intimacy or allowing couples to adapt sexual activities to accommodate sexual problems. Clinicians might use cognitive-behavioral strategies to assist women in disclosing sexual problems to partners to maximize the potential psychological, sexual, and relationship benefits.

Impact of social disadvantage and parental offending on rates of criminal offending among offspring of women with severe mental illness.

Children of parents with severe mental illness have an increased risk of offending. Studies suggest that risk factors such as parental offending and social disadvantage may be associated with the increased risk. This paper assesses the impact of these risk factors on offending rates in the offspring of women with severe mental illness compared to offspring of unaffected women. This is part of a longitudinal record-linked whole-population study of 467,945 children born in Western Australia from 1980 to 2001 to mothers with severe mental illness and mothers with no recorded psychiatric illness. These data were linked to Western Australia corrective services data producing a dataset of 12,999 people with at least one offence (3.7% of birth cohort). Cox proportional hazard was used to calculate incidence rate ratios of offspring offending. The offending rate for offspring of mothers with severe mental illness (cases) was almost three times the rate for offspring of unaffected mothers (comparison) with an unadjusted incidence rate ratio of 2.75 (95% confidence interval: [2.58, 2.93]). Adjusting for sex, indigenous status, socio-economic status and geographical remoteness reduced the rate ratio by 24% to incidence rate ratio 2.10, 95% confidence interval: [1.97, 2.23]. Adjusting for parental offending further reduced the rate ratio by 23% to incidence rate ratio 1.62, 95% confidence interval: [1.52, 1.72]. The mean age at first recorded offence was significantly lower for cases compared to comparison offspring. Children of mothers with a severe mental illness have a higher rate of offending than children of unaffected mothers, and social disadvantage and parental offending have a major impact on this rate. Services supporting these vulnerable children need to focus on improving the social environment in which they and their families live in.