Unaffected Women Research Articles

Pregnancy after Endometriosis: Maternal and Neonatal Outcomes according to the Location of the Disease.

To systematically evaluate pregnancy and labor course, obstetrical complications, and maternal and neonatal outcomes in women with endometriosis, stratifying according to the specific location of the disease. We retrospectively analyzed our prospectively maintained obstetrical database from January 2011 to August 2014 to identify all women with a previous histological diagnosis of endometriosis who delivered at our institution (cases). We divided the cases according to the specific location of the disease (deep infiltrating endometriosis, ovarian endometriosis, and peritoneal endometriosis). As controls, we identified all unaffected women who delivered in the year 2013. To avoid the confounding effect of parity, we limited our analysis to nulliparous women. A total of 118 nulliparous women with endometriosis and 1,690 nulliparous controls were identified. Women with endometriosis were significantly older, had a lower body mass index, and had a higher incidence of assisted reproductive technology. The duration of pregnancy was significantly shorter among women with endometriosis. A higher incidence of placenta previa (3.4 vs. 0.5%; p = 0.006), hypertension (11 vs. 5.9%; p = 0.04), cesarean section (41.5 vs. 24.2%; p < 0.0001), and vacuum delivery (10.1 vs. 2.9%; p = 0.006) was found in women with endometriosis. Neonatal outcomes were similar between groups. The incidence of placenta previa in patients with deep endometriosis was 11.7 versus 0.5% among controls (p < 0.0001), whereas in women with ovarian and peritoneal endometriosis, it was similar to the controls. Women with endometriosis have a higher incidence of vacuum delivery, cesarean section, and placenta previa compared with unaffected women. The higher risk of placenta previa is attributable exclusively to women with deep endometriosis. Neonatal outcomes are unaffected by the presence of the disease.

Previving: How Unaffected Women with a BRCA1/2 Mutation Navigate Previvor Identity

ABSTRACT Receiving a positive result for a BRCA1/2 (BRCA) mutation – indicating a high lifetime risk to develop hereditary breast and ovarian cancer – can significantly alter a woman’s identity. BRCA-positive women who have not been diagnosed with cancer may be labeled “previvors,” which distinguishes those at-risk for developing cancer, but have not had cancer. Using semi-structured interviews (N = 25), this study explored how unaffected BRCA-positive women navigate the previvor identity. Women in this sample differed on their definitions of previvor, views of acceptance, rejection, or ambivalence toward the label, and identification as a previvor. Understanding how women interpret and embrace the previvor identity may help inform communication for those with BRCA genetic mutations, but whom have not been diagnosed with cancer.

Pan-Cancer Panel Testing: Variation in Testing and Results by Ancestry [27O

INTRODUCTION: Multi-gene panels and reduced costs have allowed for greater access to hereditary cancer genetic testing. Here we assess ancestry-based differences in testing practices for individuals with and without a personal history. METHODS: Clinical information was obtained from provider-completed test request forms for women who had pan-cancer panel testing from 2013 to 2018 (N=427,864). The proportion of patients with a pathogenic variant (PV), family cancer history, and age at testing were evaluated for the four most common ancestries in this cohort (White/non-Hispanic, Hispanic/Latino American, Black/African, Asian). Analyses were performed separately based on personal cancer history (affected, unaffected). RESULTS: 65.5% of individuals were unaffected (White, 64.2%; Black, 65.6%; Hispanic, 67.4%; Asian, 54.7%). Although positive rates were higher among affected individuals (9.2% to 11.5%), a substantial proportion of unaffected individuals had a PV (White, 5.2%; Black, 3.7%; Hispanic, 4.6%; Asian, 4.9%). Regardless of ancestry, family history of cancer was more common among unaffected individuals (99.0 to 99.4%) compared to affected individuals (71.2 to 91.0%). Affected women were older than unaffected women at the time of testing in the full cohort (53.2 vs 41.9 years, P<.0001) and among PV carriers (51.9 vs. 40.0 years, P<.0001). Affected, Hispanic women were the youngest at testing. CONCLUSION: These data demonstrate that obtaining a family cancer history for unaffected women is critical to identifying those at increased risk of carrying a PV in a cancer-predisposition gene, regardless of ancestry. The older age at testing observed for affected women may also suggest missed opportunities for earlier testing and subsequent intervention.

Risk-reducing medications for primary breast cancer: a network meta-analysis.

Breast cancer is the most frequently occurring malignancy and the second cause of death for cancer in women. Cancer prevention agents (CPAs) are a promising approach to reduce the burden of breast cancer. Currently, two main types of CPAs are available: selective estrogen receptor modulators (SERMs, such as tamoxifen and raloxifene) and aromatase inhibitors (AIs, such as exemestane and anastrozole). To assess the efficacy and acceptability of single CPAs for the prevention of primary breast cancer, in unaffected women, at an above-average risk of developing breast cancer.Using a network meta-analysis, to rank single CPAs, based on their efficacy and acceptability (an endpoint that is defined as the inverse of CPA-related toxicity). We searched the Cochrane Breast Cancer Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, World Health Organization's International Clinical Trials Registry Platform (WHO ICTRP), and ClinicalTrials.gov on 17 August 2018. We handsearched reference lists to identify additional relevant studies. We included randomized controlled trials (RCTs) that enrolled women without a personal history of breast cancer but with an above-average risk of developing a tumor. Women had to be treated with a CPA and followed up to record the occurrence of breast cancer and adverse events. Two review authors independently extracted data and conducted risk of bias assessments of the included studies, and assessed the certainty of the evidence using GRADE. Outcome data included incidence of breast carcinoma (both invasive and in situ carcinoma) and adverse events (both overall and severe toxicity). We performed a conventional meta-analysis (for direct comparisons of a single CPA with placebo or a different CPA) and network meta-analysis (for indirect comparisons). We included six studies enrolling 50,927 women randomized to receive one CPA (SERMs: tamoxifen or raloxifene, or AIs: exemestane or anastrozole) or placebo. Three studies compared tamoxifen and placebo, two studies compared AIs (exemestane or anastrozole) versus placebo, and one study compared tamoxifen versus raloxifene. The risk of bias was low for all RCTs.For the tamoxifen versus placebo comparison, tamoxifen likely resulted in a lower risk of developing breast cancer compared to placebo (risk ratio (RR) 0.68, 95% confidence interval (CI) 0.62 to 0.76; 3 studies, 22,832 women; moderate-certainty evidence). In terms of adverse events, tamoxifen likely increased the risk of severe toxicity compared to placebo (RR 1.28, 95% CI 1.12 to 1.47; 2 studies, 20,361 women; moderate-certainty evidence). In particular, women randomized to receive tamoxifen experienced a higher incidence of both endometrial carcinoma (RR 2.26, 95% CI 1.52 to 3.38; high-certainty evidence) and thromboembolism (RR 2.10, 95% CI 1.14 to 3.89; high-certainty evidence) compared to women who received placebo.For the AIs versus placebo comparison, AIs (exemestane or anastrozole) reduced the risk of breast cancer by 53% (RR 0.47, 95% CI 0.35 to 0.63; 2 studies, 8424 women; high-certainty evidence). In terms of adverse events, AIs increased the risk of severe toxicity by 18% (RR 1.18, 95% CI 1.09 to 1.28; 2 studies, 8352 women; high-certainty evidence). These differences were sustained especially by endocrine (e.g. hot flashes), gastrointestinal (e.g. diarrhea), and musculoskeletal (e.g. arthralgia) adverse events, while there were no differences in endometrial cancer or thromboembolism rates between AIs and placebo.For the tamoxifen versus raloxifene comparison, raloxifene probably performed worse than tamoxifen in terms of breast cancer incidence reduction (RR 1.25, 95% CI 1.09 to 1.43; 1 study, 19,490 women; moderate-certainty evidence), but its use was associated with lower toxicity rates (RR 0.87, 95% CI 0.80 to 0.95; 1 study, 19,490 women; moderate-certainty evidence), particularly relating to incidence of endometrial cancer and thromboembolism.An indirect comparison of treatment effects allowed us to compare the SERMs and AIs in this review. In terms of efficacy, AIs (exemestane or anastrozole) may have reduced breast cancer incidence slightly compared to tamoxifen (RR 0.67, 95% CI 0.46 to 0.98; 5 RCTs, 31,256 women); however, the certainty of evidence was low. A lack of model convergence did not allow us to analyze toxicity data. For women with an above-average risk of developing breast cancer, CPAs can reduce the incidence of this disease. AIs appear to be more effective than SERMs (tamoxifen) in reducing the risk of developing breast cancer. AIs are not associated with an increased risk of endometrial cancer and thromboembolic events. However, long-term data on toxicities from tamoxifen are available while the follow-up toxicity data on unaffected women taking AIs is relatively short. Additional data from direct comparisons are needed to fully address the issues of breast cancer prevention by risk-reducing medications, with special regards to acceptability (i.e. the benefit/harm ratio).

Intersections of health and gender imperatives: stratified decision-making among women with a BRCA mutation

Receiving a positive test result for a BRCA mutation is a life-altering event. Thrust into a biomedical category of “high-risk” for developing breast and ovarian cancer, unaffected BRCA-positive women confront decisions about how to manage their risk. The knowledge provided through the use of genetic testing burdens women with having to make crucial decisions in a context of great uncertainty. Using 25 semi-structured interviews, this paper examines how women make decisions about how to manage their health after learning about a BRCA mutation. We situate the biographies of these women in the context of neoliberal expectations about personal responsibility for health and gender norms, and argue that the intersection of these imperatives plays out in unique ways depending on an individual’s life-stage, resulting in stratified decision-making. For older women who are married and have children, gender and health expectations neatly align. However, for younger, single women without children, the normative expectations about gender and health management often conflict, resulting in the prioritization of gender imperatives over health expectations, albeit temporarily. The analysis concludes with a discussion of the implications of BRCA testing for women and their experiences of choice and decision-making as well as their resistance to preventative surgeries.

Pregnancy outcome of Japanese patients with glucokinase-maturity-onset diabetes of the young.

Aims/IntroductionGlucokinase–maturity‐onset diabetes of the young (GCK‐MODY; also known as MODY2) is a benign hyperglycemic condition, which generally does not require medical interventions. The only known exception is increased birthweight and related perinatal complications in unaffected offspring of affected women. As previous data were obtained mostly from white Europeans, the present study analyzed the pregnancy outcomes of Japanese women with GCK‐MODY to better formulate the management plan for this population.Materials and MethodsThe study participants were 34 GCK‐MODY families whose members were diagnosed at Osaka City General Hospital during 2010–2017. A total of 53 pregnancies (40 from 23 affected women, 13 from 11 unaffected women) were retrospectively analyzed by chart review.ResultsBirthweights of unaffected offspring born to affected women were significantly greater as compared with those of affected offspring (P = 0.003). The risk of >4,000 g birthweight (16%), however, was lower as compared with that previously reported for white Europeans, and none of the offspring had complications related to large birthweight. Insulin treatment of the affected women resulted in a significant reduction in the birthweights of unaffected offspring. Perinatal complications including small‐for‐gestational age birthweight were found only in affected offspring born to insulin‐treated women.ConclusionsIn Japanese GCK‐MODY families, unaffected offspring born to affected women were heavier than affected offspring. However, insulin treatment of affected women might not be advisable because of the lower risk of macrosomic birth injury, and an increased risk of perinatal complications in affected offspring.

SAT-049 Growth Hormone Treatment in Mexican Turner's Syndrome

INTRODUCTION: Turner syndrome(TS) is a chromosomal disorder that occurs in one of every 2500 live births, characterized by the complete or partial absence of a chromosome X (the complete monosomy [45,X] accounts for more than 50% of cases), although some studies have found evidence of a high prevalence of mosaicism. It is associated with a range of phenotypic characteristics, chief of which are short stature, gonadal dysgenesis, hand and foot lymphoedema, pterygium colli, cubitus valgus and cardiovascular malformations, among others. Growth failure is a cardinal feature of TS, which may impair their quality of life, and adult patients have a mean height approximately 20 cm lower than that of unaffected women of the same ethnic group. METHODOLOGY: A study performed in the outpatient clinic of pediatric endocrinology of the National Institute for Pediatrics, descriptive, retrospective in 19 patients with Turner syndrome confirmed with karyotype, was followed up for 1 year in growth hormone treatment, size, weight was determined , Body mass index, growth rate at the beginning and at the end of the treatment. In addition, serum glucose, glycosylated hemoglobin was determined at the beginning and end of treatment. Statistical analysis was performed in the SPSS version program. RESULTS: We evaluated 19 patients with mean age 9 years +3.51, the average of the dose of growth hormone was of 1.43mg / day the size before treatment was an average of 114.73 with a SD:-3.06, showing improvement in the posterior size to treatment with an average of 119.25 SD:-2.7. In addition, the Body Mass Index was assessed with an average of 24.63 + 9.9 and at the end of treatment 27.98 +10.4. Regarding the growth rate, it is observed prior to the treatment Media 4.3 DE: 1.66 and the growth rate after the average treatment: 17.5 DE: 3.42 Levels of glycosylated hemoglobin (HBA1C) were assessed at the start of treatment with a mean of 5.3 (4.2- 5.7) and at the end of treatment the average of HBA1C 5.59 (4-6). DISCUSSION AND CONCLUSIONS: The short stature in TS is the fundamental finding and may be present in the absence of other clinical manifestations.The use of rhGH to increase the speed of growth and final height in patients with TS is an accepted and endorsed by different study. It has been observed in international studies that gains of 5-10cm are obtained with respect to the final size. It should start when the size is below -2 SDS with respect to the population mean or when the growth rate is lower than the 10th percentile for their bone age.The study that is presented is 12 months after the start of the treatment, an increase in the speed of growth as well.

The Vaginal and Urinary Microbiomes in Premenopausal Women With Interstitial Cystitis/Bladder Pain Syndrome as Compared to Unaffected Controls: A Pilot Cross-Sectional Study.

Interstitial cystitis/bladder pain syndrome (ICBPS) may be related to an altered genitourinary microbiome. Our aim was to compare the vaginal and urinary microbiomes between premenopausal women with ICBPS and unaffected controls. This cross-sectional study screened premenopausal women with an O'Leary-Sant questionnaire (ICBPS if score ≥6 on either index; controls <6 on both). Women completed questionnaires on health characteristics, pelvic floor symptoms (OABq, PFDI-20), body image (mBIS), and sexual function (PISQ-IR). Bacterial genomic DNA was isolated from vaginal and clean-catch urinary specimens; the bacterial 16 rRNA gene was sequenced and analyzed using the QIIME pipeline. We performed UniFrac analysis (β-diversity) and generated Chao1 estimator (richness) and Simpson index (richness and evenness) values. We analyzed 23 ICBPS and 18 non-ICBPS patients. ICBPS patients had increased vaginal deliveries, BMI, and public insurance as well as worsened OAB-q, PFDI-20, mBIS, and PISQ-IR domain scores. Lactobacilli was the most abundant genus in both cohorts, and anaerobic or fastidious predominance was similar between groups (p = 0.99). For both the urine and vagina specimens, Chao1 and Simpson indices were similar between ICBPS and unaffected women. Weighted and unweighted UniFrac analyses showed no differences between groups. A significant correlation existed between the urinary and vaginal Simpson indices in ICBPS women, but not in unaffected women. Premenopausal women with ICBPS, despite worsened socioeconomic indicators and pelvic floor function, were not found to have significantly different urinary and vaginal microbiomes compared to women without ICBPS.

A case-comparison study of pregnant women with mitochondrial disease - what to expect?

ObjectiveMitochondrial disease is a disorder of energy metabolism that affects 1 in 4300 adults in the UK. Pregnancy is associated with physiological demands that have implications for energy metabolism. We were interested to know how pregnancy was affected in women with mitochondrial disease, particularly those with the most common pathogenic mutation m.3243A>G.DesignRetrospective case‐comparison study.Population/SettingSixty‐seven women with genetically confirmed mitochondrial disease from the UK Mitochondrial Diseases Cohort and 69 unaffected women participated.MethodsParticipants answered questionnaires regarding each of their pregnancies. Patients were divided into two groups according to genetic mutation, with those harbouring m.3243A>G comprising a single group.Main outcome measuresPregnancy‐related complications, mode of delivery, gestational age and birthweight of newborns.ResultsOf 139 live births in the comparison group, 62 were in the m.3243A>G group and 87 were in the ‘all other mutations’ group. Pregnancies of women with the m.3243A>G mutation had significantly more gestational diabetes (odds ratio [OR] = 8.2, 95% CI 1.3–50.1), breathing difficulties (OR = 7.8, 95% CI 1.0–59.1) and hypertension (OR = 8.2, 95% CI 3.1–21.5) than the comparison group. Only half of the pregnancies in the m.3243A>G group had normal vaginal delivery, with emergency caesarean section accounting for 24.2% of deliveries. Babies were born significantly earlier to mothers harbouring m.3243A>G with 53.3% of them preterm (<37 weeks). These babies were also more likely to require resuscitation and admission.ConclusionWomen who carried the m.3243A>G mutation appeared to be at higher risk of complications during pregnancies, caesarean section and preterm delivery than the unaffected women or those with other forms of mitochondrial disease.Tweetable abstractPregnant women with mitochondrial disease – m.3243A>G mutation – are at greatly increased risk of complications and preterm delivery.

The Relationship Between Sexual Functioning and Sexual Concordance in Women

Previous research using clinical samples has shown a positive relationship between women’s sexual functioning and sexual concordance (i.e., agreement between genital and subjective sexual arousal). We further examined this relationship using concurrent measures of vaginal, clitoral, and subjective sexual responses in a community sample of women (N = 64, with 59.4% and 34.1% reporting sexual desire and/or arousal difficulties, respectively). Contrary to studies using clinical samples, sexual desire and arousal difficulties were associated with stronger sexual concordance, specifically when changes in subjective arousal predicted changes in genital responses. The subjective experience of arousal may be particularly important in influencing genital responses in women with sexual desire and arousal difficulties compared to unaffected women.

Association of DUSP9 gene polymorphisms with gestational diabetes mellitus

To assess the association of single nucleotide polymorphisms (SNPs) of dual specificity phosphatase 9 (DUSP9) gene rs5945326 locus with gestational diabetes mellitus (GDM). Genotypes for the rs5945326 locus were determined for 206 pregnant women with GDM (GDM group) and 189 unaffected pregnant women (control group). Allelic and genotypic frequencies of the GDM and control groups were compared. For individuals with various genotypes, the level of blood glucose, serum lipids, and body mass index (BMI) were also compared. The frequencies of AA, AG and GG genotypes for the GDM group were 32.2%, 52.2% and 15.6%, respectively, and 41.2%, 43.9% and 15.0%, for the control group, respectively. No significant difference was detected in the distribution of above genotypes between the two groups (chi-square=3.601, P=0.165). The frequencies of alleles A and G were 58.3% and 41.7% in the GDM group, and 63.1% and 36.9% in the control group, respectively. No significant difference was detected between the two groups too (chi-square=1.894, P=0.188). The high density lipoprotein (HDL) levels of the GG genotype [(2.34×0.61) mmol/L] was significantly higher than that of the AG+AA genotype [(2.06×0.56) mmol/L] (t=2.993, P=0.003). No significant difference was detected in other clinical indexes between the two groups (P> 0.05). The SNP rs5945326 in DUSP9 gene may be not associated with the risk of GDM. However, there are correlated with HDL levels.

Abstract P5-10-02: Development and validation of a polygenic score to predict breast cancer risk in unaffected Hispanic women negative for mutations on a multi-gene hereditary cancer panel

Abstract Background: Breast cancer (BC) is the most commonly diagnosed cancer and the leading cause of cancer-related death among Hispanic women in the United States. For women of European ancestry, genome-wide association studies (GWAS) have identified common variants, primarily single-nucleotide polymorphisms (SNPs), that individually confer modest risk but together explain a significant proportion of genetic BC predisposition. For Hispanic women, the genetic contribution of SNPs to BC risk is not well understood. In these studies, we aim to develop and validate a polygenic score to improve risk assessment for Hispanic women who test negative for mutations in known BC susceptibility genes. Methods: Genotypes and clinical histories were collected from consecutive development and validation cohorts of patients referred for hereditary cancer testing. Study subjects include women who report strictly Hispanic or Latin American ancestry, and who test negative for mutations in 11 genes associated with breast cancer (BRCA1, BRCA2, TP53, PTEN, STK11, CDH1, PALB2, CHEK2, ATM, NBN, BARD1). Based on a development cohort ascertained through June 2017, we evaluated an 86-SNP Residual Risk Score (RRS) that was previously developed and validated for women of European ancestry. In the same cohort we are developing a Hispanic Residual Risk Score (HRRS) optimized for women of Hispanic ancestry. BC associations of individual SNPs are being established through meta-analysis of the development cohort and published Hispanic studies. Multivariate logistic regression models were used to evaluate the 86-SNP RRS, and were the primary statistical tool for evaluation of individual SNPs and candidate polygenic scores. All models included personal/family cancer history and age as independent variables. P-values are based on likelihood ratio test statistics, and reported as two-sided. The development and validation studies are being conducted according to a protocol approved by the Quorum Institutional Review Board. Results: The development cohort included 5,454 Hispanic women, 24% of whom reported a personal history of BC. The 86-SNP RRS was significantly associated with a personal history of BC after accounting for personal and family cancer history (p&amp;lt;10-19) with odds ratio per unit standard deviation 1.39 (95% CI = 1.30-1.50). To date, more than 5,000 Hispanic women have been ascertained for inclusion in the validation cohort. Results comparing discriminatory accuracy of the RRS and the HRRS will be presented. Conclusions: The implementation of a clinically validated polygenic score may improve risk assessment and medical management of Hispanic women who test negative for monogenic BC mutations. The HRRS will be validated in an independent study population according to a pre-specified statistical analysis plan. Citation Format: Hughes ER, Wagner S, Pruss D, Gallagher SK, Swedlund B, Bulka K, Hoff R, Jammulapati S, Morris B, Perry T, Lanchbury JS, Gutin A. Development and validation of a polygenic score to predict breast cancer risk in unaffected Hispanic women negative for mutations on a multi-gene hereditary cancer panel [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P5-10-02.

Abstract P5-05-02: Thyroid hormone replacement therapy shortens survival in hormone receptor positive early stage breast cancers

Abstract Purpose A majority of breast cancer (BC) patients have clinical or subclinical thyroid disease as compared to a minority of unaffected women. This comorbidity has been recognized for over a century. We hypothesized that thyroid hormone (TH) promotes breast carcinogenesis and growth, and may reduce survival for patients on long term TH replacement therapy (THRT). We sought to validate these findings in a study of BC patients and investigate mechanisms of hormonal interaction using model systems. Methods Over 800 consecutively diagnosed lymph node (LN) negative, mostly chemo-naïve invasive BC patients from 1976 to 1993 at were evaluated. Clinical and outcomes data were derived from medical records (10.2 year median follow up). Primary tumors from surgery (typically mastectomy with node dissection) were analyzed for receptors and biomarkers. Univariate and multivariate statistical methods were used. In vivo and in vitro studies were performed using immortalized human BC cell lines and patient derived xenograft(PDX) models. Results LN- THRTvs. non-THRT BC patients showed nosignificantdifferencesinclinical,histologic or prognosticdata. THRT was significantly associated with a higher relativerisk(RR)ofrecurrence2.376fold(p&amp;lt;0.0001)anddisease specific survival (DSS), 2.02fold (p=0.0183). Subset analyses showed only steroid receptor (SR) positive patients had a deleterious interaction with THRT (mean RFS 68mo.,RR3.431,p&amp;lt;0.0001), mean disease specific survival (DSS)81mo.,RR3.960,p=0.0001)ascomparedtonon-THRTpatients(mean RFS206mo.,meanDSS223mo.). Tamoxifen (Tam) treated patients on THRT had an especially poor outcome, DFS p=0.0004. Usinginvitromethods we showedpotent induction of cell proliferation by estrogen (E2)and/or thyroidhormone (TH) acrossawiderange of concentrations in SR+, but not SR- BC (P&amp;lt;0.0001). Fulvestrant (ICI) significantly inhibited these interactions, whereas Tam failed to provide an equivalent antagonistic effect. In some SR+ cells, Tam further increased cell proliferation. In vivo studies showed co-localization of ER and THRα were upregulated by co-administration of E2 + TH. Tam further induced co-localization, whereas ICI lowered receptor expression and co-localization. ER+ PDXtumors in mice with continuous E2 showed enhanced tumorigenesis with TH (tumorgrowth(p&amp;lt;0.0001),tumorweight(mg)(p=0.0052)and Ki67labeling(p=0.001)). Mice on E2 + TH with PDX tumors treated with Tam showed enhanced tumor growth and proliferation (p&amp;lt;0.0001), whereas ICI inhibited and in some cases eliminated tumors. RNA-seq data performed on our ER+ PDX tumors treated with hormone combinations +/- Tam show that E2 + TH potently upregulates numerous cell cycle and hormone regulated genes. Conclusion We show statistically significant interactions between THRT at the time of BC diagnosis, early relapse and shortened survival in SR+ (but not SR-) Stage I BC patients. In vitro and in vivo BC models confirm these deleterious interactions. Mechanistically we observe co-localization of the cognate receptors and activation of ER, with downstream upregulation of cell cycle and hormone regulated genes. These interactions are blocked by ICI, whereas Tam fails to block and may in fact enhance tumorigenesis. Citation Format: Wahdan-Alaswad RS, Edgerton SM, Salem HS, Liu B, Thor AD. Thyroid hormone replacement therapy shortens survival in hormone receptor positive early stage breast cancers [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P5-05-02.

Abstract GS3-01: A randomized placebo controlled phase III trial of low dose tamoxifen for the prevention of recurrence in women with operated hormone sensitive breast ductal or lobular carcinoma in situ

Abstract Background: Tamoxifen is an effective drug for breast cancer prevention and treatment, but the risk of endometrial cancer and venous thromboembolism has limited its broader use. We have repeatedly shown in biomarker trials that the minimal effective dose of tamoxifen is lower than 20 mg/day, but a definitive answer on efficacy and safety required a phase III trial. The optimal treatment of ductal carcinoma in situ (DCIS) is still controversial. Methods: We conducted a phase III trial of tamoxifen (T), 5 mg/day versus placebo (P) in women with operated hormone sensitive breast intraepithelial neoplasia (DCIS or LCIS). Women with G3, positive margins or comedo/necrosis DCIS received radiotherapy. Women were seen every 6 months with an annual mammography for at last 5 years after randomization. Initial statistical calculations were revised according to the lower than expected accrual, and the Independent Data Safety Monitoring Board recommended the disclosure of results as 80% of the originally expected events were observed. Results: Between November 1, 2008 and March 31, 2015 a total of 500 women were randomized to either T, 5 mg/day or P for 3 years. A total of 10 patients are not assessable becuse of consent withdrawal or drop out. The main subject characteristics were well balanced between arms. As of May 31, 2018, after a median follow-up of 5.1 years (interquartile range, 3.9-6.3), there were 14 recurrences in the T arm and 29 in the P arm (hazard ratio=0.48, 95% CI, 0.25-0.89, p=0.02). The incidence rate of events was 11.8/1000 py in the T arm and 24.9/1000 py in the P arm. Most recurrences were invasive breast cancers: 11/14 (78%) in the T arm and 16/29 (55%) in the P arm. There were 8 serious adverse events in the T arm and 12 in the P arm, including 2 arterial events in each arm, 2 superficial phlebitis in the T arm and 1 endometrial cancer (annual rate 0.85/1000 py) in the T arm. There were 6 versus 4 second primary cancers in the T and P arm, respectively, and 2 deaths in the P arm. Menopausal symptoms were more frequent in the T arm and will be reported in details at the conference. Baseline characteristics Tamoxifen (n=246)Placebo (n=244) mean (SD)mean (SD)Age (yrs) 54.0 (9.4)53.7 (9.1)Body Mass Index (kg/m2) 25.7 (4.8)25.3 (4.2) n (%)n (%)Menopausal statusPre-110 (45)107 (44) Post-136 (55)137 (56)Type of lesionDCIS221 (89)220 (90) LCIS25 (10)24 (10)Type of surgeryConservative (Q/L)206 (84)200 (82) Mastectomy39 (16)44 (18) Axillary dissection1 (0)-SD=standard deviation; DCIS=ductal carcinoma in situ; LCIS=lobular carcinoma in situ; Q=quadrantectomy; L=lumpectomy Conclusions: Tamoxifen at the dose of 5 mg/day can halve the incidence of recurrence in women with operated hormone sensitive DCIS or LCIS with a limited toxicity, providing a valid treatment option in women with disease. In addition, this study has important implications for the preventive therapy of high risk unaffected women. ClinicalTrials.gov Identifier: NCT01357772; Supported by the Italian Ministry of Health - RFPS-2006-1-339898 and the Italian Association for Cancer Research (AIRC) - IG 2008 Grant no. 5611. Citation Format: DeCensi A, Puntoni M, Guerrieri Gonzaga A, Avino F, Cortesi L, Donadio M, Pacquola M, Falcini F, Gulisano M, Digennaro M, Tienghi A, Cagossi K, Pinotti G, Varicchio C, Caviglia S, Boni L, Bonanni B. A randomized placebo controlled phase III trial of low dose tamoxifen for the prevention of recurrence in women with operated hormone sensitive breast ductal or lobular carcinoma in situ [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr GS3-01.

Abstract P4-09-04: Associations between clinical factors in v7.02 of the Tyrer-Cuzick model and a SNP-based residual risk score

Abstract Background: Genome-wide association studies (GWAS) have identified common variants, primarily single-nucleotide polymorphisms (SNPs), that individually confer modest risk but together explain a significant proportion of genetic breast cancer (BC) predisposition. GWAS have also demonstrated that SNPs cannot replace family history evaluation: familial BC assessment captures a large magnitude of risk information that is not captured by SNPs. Thus, improved BC risk stratification may be achieved by combining family history assessment with SNP markers. However, to avoid double-counting shared risk information, familial and/or SNP-based risks must be adjusted for confounding. Additional clinical and biological factors that contribute to BC risk are included in version 7.02 of the Tyrer-Cuzick model. These include height; weight; BMI; age of menarche; parity and age of first childbirth; menopausal status and age of onset; and use of hormonal replacement therapy (HRT). Confounding of SNPs with these factors is not well understood. Here we present an analysis of associations between an 86-SNP Residual Risk Score (RRS) and factors included in version 7.02 of the Tyrer-Cuzick model. Methods: De-identified clinical records and genotypes were collected from a consecutive series of patients referred for hereditary cancer testing with a multigene panel. Study subjects included unaffected women age 18-84 who reported European ancestry and tested negative for mutations in 11 genes associated with BC (BRCA1, BRCA2, TP53, PTEN, STK11, CDH1, PALB2, CHEK2, ATM, NBN, BARD1). For each risk factor, we constructed a univariate linear regression model with RRS as the dependent variable and the clinical factor as the independent variable. From these models, we examined regression coefficients, p-values based on F-statistics, and Pearson correlation coefficients. Scatterplots and boxplots were used to visually assess associations. All analyses were conducted using R version 3.4.4. P-values were reported as two-sided with no corrections for multiple testing. Results: 5,489 patients met the study selection criteria. The median age at hereditary cancer testing was 42 years. Nearly one third (33.1%) of women reported a BC diagnosis in a first degree relative. The RRS was significantly associated with familial BC (p&amp;lt;10-08). We observed marginal evidence of association between the RRS and HRT use (p=0.04). However, this association would not survive a multiple testing correction, and was not significant after multivariate adjustment for family cancer history. We found no evidence for association of the RRS with height, weight, BMI, menopausal stage, age of menarche, age of menopause, duration of menarche, parity, age of first live birth, HRT type, or HRT length of use. Conclusions: The RRS is largely independent from the non-familial risk factors in version 7.02 of the Tyrer-Cuzick model, but is significantly associated with BC family history. Risk assessment based on Tyrer-Cuzick and SNPs must be adjusted for confounding to avoid double-counting familial risk. Citation Format: Hughes ER, Rosenthal E, Morris B, Wagner S, Lanchbury JS, Gutin A. Associations between clinical factors in v7.02 of the Tyrer-Cuzick model and a SNP-based residual risk score [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P4-09-04.

Persistent breast pain in post-surgery breast cancer survivors and women with no history of breast surgery or cancer: associations with pain catastrophizing, perceived breast cancer risk, breast cancer worry, and emotional distress

Background: Persistent breast pain (PBP) is prevalent among breast cancer survivors and has powerful negative psychological consequences. The present study provided a first test of the hypothesis that: (a) pain catastrophizing, (b) heightened perceived risk of cancer, and (c) worry that pain indicates cancer may be independent mediating links between breast cancer survivors’ experiences of PBP and heightened emotional distress.Methodology: We assessed levels of PBP and psychological factors in breast cancer survivors (Survivor Group: n = 417; Stages I-IIIA; White = 88.7%; Age M = 59.4 years) at their first surveillance mammogram post-surgery (6–15 months). A comparison group of women without histories of breast surgery or cancer (Non-cancer Group: n = 587; White = 78.7%; Age M = 57.4 years) was similarly assessed at the time of a routine screening mammogram. All women completed measures of breast pain, pain catastrophizing, perceived breast cancer risk, and worry that breast pain indicates cancer, as well as measures of emotional distress (symptoms of anxiety, symptoms of depression, and mammography-specific distress). Analyses included race, age, BMI, education, and menopausal status as covariates, with significance set at 0.05.Results: As expected, PBP prevalence was significantly higher in the Survivor Group than in the Non-cancer Group (50.6% vs. 17.5%). PBP+ survivors also had significantly higher levels of emotional distress, pain catastrophizing, mammography-specific distress, and worry that breast pain indicates cancer, compared to PBP− survivors. Structural equation modeling results were significant for all hypothesized mediational pathways. Interestingly, comparisons of PBP+ to PBP− women in the Non-cancer Group showed similar results.Conclusion: These findings suggest the importance of (a) pain catastrophizing, (b) perceived breast cancer risk and, (c) worry that breast pain may indicate cancer, as potential targets for interventions aimed at reducing the negative psychological impact of PBP in post-surgery breast cancer survivors, as well as in unaffected women with PBP due to unknown reasons.

Risk of miscarriage in women with endometriosis undergoing IVF fresh cycles: a retrospective cohort study

BackgroundEndometriosis is thought to affect the effectiveness of ART by an increased risk of miscarriage. We aimed to investigate the impact of endometriosis in women achieving singleton pregnancies through IVF fresh cycles and risk of miscarriage.MethodsThis retrospective cohort study included all women undergoing a first IVF cycle and achieving singleton pregnancies after fresh embryo transfer in a tertiary university hospital reproductive medical center between January 2008 and June 2016. Women with endometriosis were compared with women with no endometriosis. Women in the endometriosis group were all with a history of laparoscopy or laparotomy for endometriosis and/or with ovarian endometrioma. The control group was matched 1:2 according to age and study period.ResultsAmong the cohort, we identified 1006 women with endometriosis as study group and 2012 unaffected women matched in a 1:2 ratios as control group. The miscarriage rate between women with and without endometriosis was similar (22.4 and 20.1%, P = 0.085). The odds ratio after adjusting for the risk factors for miscarriage was 1.14 (95% confidence interval 0.95–1.37). In the study group, the women with and without endometrioma did not show a significant risk of miscarriage, (19.8 and 23.8%, P = 0.152, OR 0.79, 95% CI 0.58–1.09). The miscarriage rate in women with endometrioma ≥30 mm (37.3 ± 7.1 mm) and < 30 mm (19.3 ± 5.5 mm) was not significantly different, (24.7 and 18.5%, P = 0.229, OR 1.44, 95% CI 0.79–2.63). After adjustment for risk factors for miscarriage, the presence of endometrioma and the size of endometrioma, regression model confirmed no significant increase for the risk of miscarriage in the subgroup analyses.ConclusionsThe risk of miscarriage did not statistically increase in women with endometriosis who achieved pregnancy through IVF fresh cycles.

High-risk breast cancer surveillance with MRI: 10-year experience from the German consortium for hereditary breast and ovarian cancer.

To report on 10years of high-risk service screening with annual MRI in the German Consortium for Hereditary Breast and Ovarian Cancer (GC-HBOC). A cohort of 4,573 high-risk, previously unaffected women (954 BRCA1 carriers, 598 BRCA2 carriers, 3021 BRCA1/2 non-carriers) participating in the GC-HBOC surveillance program was prospectively followed. Screening outcomes for 14,142 screening rounds with MRI between 2006 and 2015 were analyzed and stratified by risk group, type of screening round, and age. A total of 221 primary breast cancers (185 invasive, 36 in situ) were diagnosed within 12months of an annual screening round with MRI. Of all cancers, 84.5% (174/206, 15 unknown) were stage 0 or I. In BRCA1 carriers, 16.9% (10/59, 5 unknown) of all incident cancers (screen-detected and interval cancers combined) and in BRCA2 carriers 12.5% (3/24, 4 unknown) were stage IIA or higher, compared to only 4.8% (2/42, 2 unknown) in high-risk BRCA1/2 non-carriers. Program sensitivity was 89.6% (95% CI 84.9-93.0) with no significant differences in sensitivity between risk groups or by age. Specificity was significantly lower in the first screening round (84.6%, 95% CI 83.6-85.7) than in subsequent screening rounds (91.1%, 95% CI 90.6-91.7), p < 0.001. Cancer detection rates (CDRs) and as a result positive predictive values were strongly dependent on type of screening round, risk group and patient age. CDRs ranged from 43.5‰ (95% CI 29.8-62.9) for the first screening round in BRCA2 carriers to 2.9‰ (95% CI 1.3-6.3) for subsequent screening rounds in high-risk non-carriers in the age group 30 to 39years. High-risk screening with MRI was successfully implemented in the GC-HBOC with high sensitivity and specificity. Risk prediction and inclusion criteria in high-risk non-carriers need to be adjusted to improve CDRs and thus screening efficacy in these patients.

Evaluation of National Comprehensive Cancer Network guideline-based Tool for Risk Assessment for breast and ovarian Cancer (N-TRAC): A patient-reported survey for genetic high-risk assessment for breast and ovarian cancers in women.

Identification of mutations that increase lifetime risk of breast and ovarian cancer is critical to improving women's health. Because these mutations are relatively rare in the general population, there is a need for efficient methods to identify appropriate women to undergo genetic testing. The objective of this study was to assess the feasibility, accuracy, and performance of the NCCN guideline-based Tool for Risk Assessment for breast and ovarian Cancer (N-TRAC)-a patient-facing assessment for those affected and unaffected by cancer. This study enrolled a prospective cohort of 100 affected and 100 unaffected women that used N-TRAC in a clinical setting. Recommendations for referral to genetic counseling based on N-TRAC and other standard risk assessment methods were compared.Seventy-seven of the 100 affected women and 35 of the 100 unaffected women were identified as high risk by N-TRAC. The average completion time was approximately 2min for both groups. N-TRAC accuracy for family history was exceptional in both groups (kappa>0.96). N-TRAC and other risk assessment methods do not always identify the same high risk population. N-TRAC is an accurate and feasible tool that can assist in identifying women at increased risk for hereditary breast and ovarian cancer and may lead to more informed decision-making.

Development and Testing of a Decision Aid for Unaffected Women with a BRCA1 or BRCA2 Mutation.

For women who are unaffected carriers of a pathogenic BRCA mutation, cancer risk management requires ongoing education, counseling, and support from an interdisciplinary team of medical specialists, genetic counselors, and nurses specializing in genomics. The purpose of this study was to develop and pilot test an educational, patient-focused decision aid to facilitate shared decision making. A steering committee developed the prototype aid after an extensive review of the literature. The aid was designed at the ninth-grade reading level, to be consistent with internationally accepted clinical guidelines and inclusive of all risk management options and psychosocial issues important to cancer risk management decision making. The aid was tested with 23 participants: eight experts and 15 end users. Eleven survey items were asked related to organization, clarity, usefulness, comprehensiveness, ease of understanding, and relevance to the cancer risk management decision-making process. Mean scores were 3 or higher on Likert scales of 1-4 (high) for each of the 11 items. Two open-ended questions elicited general comments and suggestions for additions, deletions, or revisions to the decision aid. The steering committee made final revisions to the aid based on participant feedback and committee consensus.