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Summary Purpose.Mammography (MG), breast (BU) and axillary ultrasound (AU), and clinical examination (CE) are commonly used for clinical staging. These different methods were compared in order to assess the accuracy of clinical tumor staging (cT). [ABSTRACT FROM AUTHOR]

Purpose: The receptor activator of nuclear factor kappa B (RANK) and its ligand (RANKL) have been shown to promote proliferation of the breast and breast carcinogenesis. The objective of this analysis was to investigate whether tumor-specific RANK and RANKL expression in patients with primary breast cancer is associated with high percentage mammographic density (PMD), which is a known breast cancer risk factor., Methods: Immunohistochemical staining of RANK and RANKL was performed in tissue microarrays (TMAs) from primary breast cancer samples of the Bavarian Breast Cancer Cases and Controls (BBCC) study. For RANK and RANKL expression, histochemical scores (H scores) with a cut-off value of > 0 vs 0 were established. PMD was measured in the contralateral, non-diseased breast. Linear regression models with PMD as outcome were calculated using common predictors of PMD (age at breast cancer diagnosis, body mass index (BMI) and parity) and RANK and RANKL H scores. Additionally, Spearman rank correlations (ρ) between PMD and RANK and RANKL H score were performed., Results: In the final cohort of 412 patients, breast cancer-specific RANK and RANKL expression was not associated with PMD (P = 0.68). There was no correlation between PMD and RANK H score (Spearman's ρ = 0.01, P = 0.87) or RANKL H score (Spearman's ρ = 0.04, P = 0.41). RANK expression was highest in triple-negative tumors, followed by HER2-positive, luminal B-like and luminal A-like tumors, while no subtype-specific expression of RANKL was found., Conclusion: Results do not provide evidence for an association of RANK and RANKL expression in primary breast cancer with PMD., (© 2024. The Author(s).)

Background: High mammographic density (MD) is a risk factor for the development of breast cancer (BC). Changes in MD are influenced by multiple factors such as age, BMI, number of full-term pregnancies and lactating periods. To learn more about MD, it is important to establish non-radiation-based, alternative examination methods to mammography such as ultrasound assessments., Methods: We analyzed data from 168 patients who underwent standard-of-care mammography and performed additional ultrasound assessment of the breast using a high-frequency (12 MHz) linear probe of the VOLUSON ® 730 Expert system (GE Medical Systems Kretztechnik GmbH & Co OHG, Austria). Gray level bins were calculated from ultrasound images to characterize mammographic density. Percentage mammographic density (PMD) was predicted by gray level bins using various regression models., Results: Gray level bins and PMD correlated to a certain extent. Spearman's ρ ranged from - 0.18 to 0.32. The random forest model turned out to be the most accurate prediction model (cross-validated R 2 , 0.255). Overall, ultrasound images from the VOLUSON ® 730 Expert device in this study showed limited predictive power for PMD when correlated with the corresponding mammograms., Conclusions: In our present work, no reliable prediction of PMD using ultrasound imaging could be observed. As previous studies showed a reasonable correlation, predictive power seems to be highly dependent on the device used. Identifying feasible non-radiation imaging methods of the breast and their predictive power remains an important topic and warrants further evaluation. Trial registration 325-19 B (Ethics Committee of the medical faculty at Friedrich Alexander University of Erlangen-Nuremberg, Erlangen, Germany)., (© 2023. The Author(s).)

Purpose: In many diseases, it is possible to classify a heterogeneous group into subgroups relative to tumor biology, genetic variations, or clinical and pathological features. No such classification is available for endometriosis. In our retrospective case-case analysis we defined subgroups of endometriosis patients relative to the type and location of the endometriosis lesion and relative to basic patient characteristics., Methods: From June 2013 to July 2017, a total of 1576 patients with endometriosis diagnosed at surgery were included in this study. The patients' history and clinical data were documented using a web-based remote data entry system. To build subgroups, all possible combinations of endometriosis locations/types (peritoneal; ovarian endometriosis; deeply infiltrating endometriosis; adenomyosis) were used. Due to the variation in group sizes, they were combined into five substantial larger groups., Results: Age, pregnancy rate, and live birth rate were identified as characteristics that significantly differed between the five patient groups that were defined. No significant differences were noted in relation to body mass index, length of menstrual cycle, age at menarche, reason for presentation, or educational level., Conclusion: This study describes basic patient characteristics in relation to common clinical subgroups in a large clinical cohort of endometriosis patients. Epidemiological information about different clinical groups may be helpful in identifying groups with specific clinical courses, potentially suggesting novel approaches to early detection and to surgical and systemic treatment., (© 2021. The Author(s).)

Purpose: Mammographic density (MD) is one of the strongest risk factors for breast cancer (BC). However, the influence of MD on the BC prognosis is unclear. The objective of this study was therefore to investigate whether percentage MD (PMD) is associated with a difference in disease-free or overall survival in primary BC patients., Methods: A total of 2525 patients with primary, metastasis-free BC were followed up retrospectively for this analysis. For all patients, PMD was evaluated by two readers using a semi-automated method. The association between PMD and prognosis was evaluated using Cox regression models with disease-free survival (DFS) and overall survival (OS) as the outcome, and the following adjustments: age at diagnosis, year of diagnosis, body mass index, tumor stage, grading, lymph node status, hormone receptor and HER2 status., Results: After median observation periods of 9.5 and 10.0 years, no influence of PMD on DFS (p = 0.46, likelihood ratio test (LRT)) or OS (p = 0.22, LRT), respectively, was found. In the initial unadjusted analysis higher PMD was associated with longer DFS and OS. The effect of PMD on DFS and OS disappeared after adjustment for age and was caused by the underlying age effect., Conclusions: Although MD is one of the strongest independent risk factors for BC, in our collective PMD is not associated with disease-free and overall survival in patients with BC., Competing Interests: Declaration of competing interest Peter A. Fasching reports research grants from Novartis and BioNTech and personal fees from Novartis, Roche, Pfizer, Celgene, Daiichi-Sankyo, TEVA, AstraZeneca, Puma, Eisai, Merck Sharp & Dohme, and Myelo Therapeutics. Carolin C. Hack reports personal fees from Roche and Novartis. Julius Emons reports personal fees from Novartis, Pfizer and Eisai. Arndt Hartmann has received honoraria from BMS, MSD, Roche, AstraZeneca, Boehringer Ingelheim, Abbvie, Jansen-Cilag, Diaceutics, Cepheid, Lilly, Agilent, and Ipsen. Ramona Erber has received honoraria from Roche, Eisai, Pfizer, and Novartis and travel grants from BioNTech. The institution of Arndt Hartmann and Ramona Erber conducts research for AstraZeneca, Roche, Janssen-Cilag, NanoString Technologies, Novartis, Cepheid, and BioNTech. All the other authors declare that they have no conflicts of interest., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Endometriosis is one of the most common benign gynecological diseases. The extremely heterogeneous complex of symptoms complicates the diagnosis and treatment of this disease. In most patients, there is a latency period of several years between the first occurrence of symptoms and the definitive diagnosis. This paper aims (1) to evaluate standards for the diagnosis and treatment of patients with (symptoms suspicious for) endometriosis in terms of feasibility, and (2) to assess the potential use of data collected by a certified clinical and scientific endometriosis center to answer scientific questions. Standards for outpatient consultations were developed for a special endometriosis outpatient clinic. Between January 2014 and December 2017, a total of 1715 outpatients with a suspicion of endometriosis presented to this special endometriosis outpatient clinic; the diagnosis and treatment of patients was carried out in accordance with the developed standards. Data of this patient cohort obtained from patient records created during outpatient consultations and from a questionnaire recorded in an Oracle-based database was analyzed. The patient cohort was also compared with another patient cohort who had attended different outpatient clinics and had been diagnosed intraoperatively with endometriosis. 41.8% of patients examined during special outpatient consultations had surgery for suspicion or recurrence of endometriosis. Endometriosis was confirmed in 81.5% of cases. Pain symptoms were the main indication for surgery in 70.1% of cases compared to 45.1% of cases in the comparison group. The structured approach used in the special endometriosis outpatient clinic is a key aspect of the care provided by the certified clinical and scientific endometriosis center. It ensures that patients are diagnosed and treated in accordance with guideline recommendations, that diagnosis and treatment comply with certification requirements, and that the collected data can be used to answer scientific questions.

Introduction Would adolescent girls in Germany choose a different method of contraception to the combined oral contraceptive if provided with the appropriate information? Is there a need for long-acting contraception among our adolescent girls? How satisfied are female patients with the information they receive at their respective gynaecology practices, and how much do the girls know about different methods of contraception? Materials and Methods In the study "Thinking About Needs in COntraception" (TANCO), not only female patients, but also their respective gynaecologists were surveyed online about current methods of contraception, their satisfaction with these methods, and also their level of knowledge concerning the individual methods of contraception, the situation related to advice about different contraceptive options and their general satisfaction with gynaecological care. This article presents the data from the subset of adolescent girls aged 14 to 19 years (n = 2699) out of the total of 18 521 women surveyed. Results The girls surveyed were familiar with at least the name of more than five different methods of contraception (average 5.3). The doctors assumed that the respondents would know only 4.2 different methods. When asked explicitly about how the individual methods of contraception work, clear deficits became evident. This applies not only to the entire population of respondents, but also the users of the respective contraceptive method. In addition, a strong interest in long-acting contraception emerged from the survey, particularly among young women. Discussion The data from the TANCO study reveal a clear discrepancy between the existing contraception almost exclusively in the form of the contraceptive pill and the contraceptive options considered by adolescent girls if they are thoroughly informed. The need for education into alternatives to the pill is high, as is the willingness to use such alternatives after receiving information - much higher than the figures suggested by the gynaecologists.

Purpose: Percentage mammographic density (PMD) is a major risk factor for breast cancer (BC). It is strongly associated with body mass index (BMI) and age, which are themselves risk factors for breast cancer. This analysis investigated the association between the number of full-term pregnancies and PMD in different subgroups relative to age and BMI., Methods: Patients were identified in the breast cancer database of the University Breast Center for Franconia. A total of 2410 patients were identified, for whom information on parity, age, and BMI, and a mammogram from the time of first diagnosis were available for assessing PMD. Linear regression analyses were conducted to investigate the influence on PMD of the number of full-term pregnancies (FTPs), age, BMI, and interaction terms between them., Results: As in previous studies, age, number of FTPs, and BMI were found to be associated with PMD in the expected direction. However, including the respective interaction terms improved the prediction of PMD even further. Specifically, the association between PMD and the number of FTPs differed in young patients under the age of 45 (mean decrease of 0.37 PMD units per pregnancy) from the association in older age groups (mean decrease between 2.29 and 2.39 PMD units). BMI did not alter the association between PMD and the number of FTPs., Conclusions: The effect of pregnancies on mammographic density does not appear to become apparent before the age of menopause. The mechanism that drives the effect of pregnancies on mammographic density appears to be counter-regulated by other influences on mammographic density in younger patients.

Background: Tumors in radiologically dense breast were overlooked on mammograms more often than tumors in low-density breasts. A fast reproducible and automated method of assessing percentage mammographic density (PMD) would be desirable to support decisions whether ultrasonography should be provided for women in addition to mammography in diagnostic mammography units. PMD assessment has still not been included in clinical routine work, as there are issues of interobserver variability and the procedure is quite time consuming. This study investigated whether fully automatically generated texture features of mammograms can replace time-consuming semi-automatic PMD assessment to predict a patient's risk of having an invasive breast tumor that is visible on ultrasound but masked on mammography (mammography failure)., Methods: This observational study included 1334 women with invasive breast cancer treated at a hospital-based diagnostic mammography unit. Ultrasound was available for the entire cohort as part of routine diagnosis. Computer-based threshold PMD assessments ("observed PMD") were carried out and 363 texture features were obtained from each mammogram. Several variable selection and regression techniques (univariate selection, lasso, boosting, random forest) were applied to predict PMD from the texture features. The predicted PMD values were each used as new predictor for masking in logistic regression models together with clinical predictors. These four logistic regression models with predicted PMD were compared among themselves and with a logistic regression model with observed PMD. The most accurate masking prediction was determined by cross-validation., Results: About 120 of the 363 texture features were selected for predicting PMD. Density predictions with boosting were the best substitute for observed PMD to predict masking. Overall, the corresponding logistic regression model performed better (cross-validated AUC, 0.747) than one without mammographic density (0.734), but less well than the one with the observed PMD (0.753). However, in patients with an assigned mammography failure risk >10%, covering about half of all masked tumors, the boosting-based model performed at least as accurately as the original PMD model., Conclusion: Automatically generated texture features can replace semi-automatically determined PMD in a prediction model for mammography failure, such that more than 50% of masked tumors could be discovered.

Purpose: The aim of this study was to determine the extent to which women's choice of contraceptive method depends on the advice received from their gynecologist and whether more intensive counseling might lead to more frequent use of long-acting reversible contraception (LARC)., Methods: A total of 1089 physicians and 18,521 women responded to 32 or 37 questions, respectively, using an online questionnaire. The women were asked about their current use of contraceptive methods, the extent of their satisfaction with them, their satisfaction with the counseling they had received, and whether they wanted to have more information about contraception. The physicians were similarly asked which contraceptive methods were being used, how satisfied with them they were, how they would assess their patients' satisfaction with them, and whether the women wanted to have more information., Result: The results showed that 61% of the women were using oral contraceptives, and a total of only 9% were using behavior-independent long-term contraceptive methods. However, 60% of the women stated that long-term contraception would be an option for them if they had more information about it. Gynecologists underestimated this figure, at only 18%. Whereas 66% of the gynecologists believed that their patients never forgot to take the pill, nearly, half of the women stated that they had forgotten it at least once during the previous 3 months., Conclusion: The small number of women who use long-term contraception is in clear contrast to the fact that many women want to have a very safe but also behavior-independent method.

Percentage mammographic breast density (PMD) is one of the most important risk factors for breast cancer (BC). Calcium, vitamin D, bisphosphonates, and denosumab have been considered and partly confirmed as factors potentially influencing the risk of BC. This retrospective observational study investigated the association between serum calcium level and PMD. A total of 982 BC patients identified in the research database at the University Breast Center for Franconia with unilateral BC, calcium and albumin values, and mammogram at the time of first diagnosis were included. PMD was assessed, using a semiautomated method by two readers. Linear regression analyses were conducted to investigate the impact on PMD of the parameters of serum calcium level adjusted for albumin level, and well-known clinical predictors such as age, body mass index (BMI), menopausal status and confounder for serum calcium like season in which the BC was diagnosed. Increased calcium levels were associated with reduced PMD (P = 0.024). Furthermore, PMD was inversely associated with BMI (P < 0.001) and age (P < 0.001). There was also an association between PMD and menopausal status (P < 0.001). The goodness-of-fit of the regression model was moderate. This is the first study assessing the association between serum calcium level and PMD. An inverse association with adjusted serum calcium levels was observed. These findings add to previously published data relating to vitamin D, bisphosphonates, denosumab, and the RANK/RANKL signaling pathway in breast cancer risk and prevention., (© 2017 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Purpose: Extracting ovarian tissue before oncologic therapy and transplanting it afterwards are increasingly being used to preserve fertility in women. This study describes standardized and safe operative procedures, with few complications, and reports the resulting ovarian function and pregnancy rates., Methods: The standardized operative techniques for removing and transplanting ovarian tissue used at the Erlangen center are: for tissue removal, one-third to half of the tissue from one ovary is excised with scissors, without tissue coagulation; for subsequent transplantation, pieces of ovarian tissue are placed in a retroperitoneal pocket without closure of the pocket., Results: Between January 2007 and December 2015, ovarian tissue was extracted in 399 women and transplanted following cancer therapy in 38. No surgical complications were observed within 28 days. To date, there have been ten pregnancies and nine live births after transplantation in seven different women; 26 of the 38 women developed hormonal activity, confirmed by a menstrual cycle or raised serum estradiol levels., Conclusions: The techniques for laparoscopic removal and transplantation of ovarian tissue described here provide a standardized method with a very low risk of complications. The pregnancy rate after ovarian tissue transplantation, currently 15-30%, can be expected to rise further in the near future.

Introduction The placement of intramammary marker clips has proven to be helpful for tumor localization in patients undergoing neoadjuvant chemotherapy and breast-conserving surgery. The purpose of our study was to investigate the feasibility of using a clip marker system for breast cancer localization and its influence on the imaging assessment of treatment responses after neoadjuvant chemotherapy. Patients and Methods Between March and June 2015, a total of 25 patients (n = 25), with a suspicion of invasive breast cancer with diameters of at least 2 cm (cT2), underwent preoperative sonographically guided core needle biopsy using a single-use breast biopsy system (HistoCore™) and intramammary clip marking using a directly adapted clip system based on the established O-Twist Marker™, before their scheduled preoperative neoadjuvant chemotherapy. Localization of the intramammary marker clip was controlled by sonography and digital breast tomosynthesis. Results Sonography detected no dislocation of intrammammary marker clips in 20 of 25 patients (80 %), while digital breast tomosynthesis showed accurate placement without dislocation in 24 patients (96 %) (p < 0.05). There was no evidence of significant clip migration during preoperative follow-up imaging after neoadjuvant chemotherapy. No complication related to the clip marking was noted and there was no difficulty in evaluating the treatment response to neoadjuvant chemotherapy. Among the breast-conserving surgeries performed, no cases were identified in which intraoperative loss of the marker clip had occurred. Conclusion Our study underscores the importance of intramammary marking clip systems before neoadjuvant chemotherapy. Placement of marker clips is advised to facilitate accurate tumor bed localization. With regard to digital breast tomosynthesis, its development continues to improve the quality of diagnostics and the therapy of breast cancer particularly for small breast cancer tumors or in neoadjuvant chemotherapy setting.

Although mammography screening programs do not include ultrasound examinations, some diagnostic units do provide women with both mammography and ultrasonography. This article is concerned with estimating the risk of a breast cancer patient diagnosed in a hospital-based mammography unit having a tumor that is visible on ultrasound but not on mammography. A total of 1,399 women with invasive breast cancer from a hospital-based diagnostic mammography unit were included in this retrospective study. For inclusion, mammograms from the time of the primary diagnosis had to be available for computer-assisted assessment of percentage mammographic density (PMD), as well as Breast Imaging Reporting and Data System (BIRADS) assessment of mammography. In addition, ultrasound findings were available for the complete cohort as part of routine diagnostic procedures, regardless of any patient or imaging characteristics. Logistic regression analyses were conducted to identify predictors of mammography failure, defined as BIRADS assessment 1 or 2. The probability that the visibility of a tumor might be masked at diagnosis was estimated using a regression model with the identified predictors. Tumors were only visible on ultrasound in 107 cases (7.6%). PMD was the strongest predictor for mammography failure, but age, body mass index and previous breast surgery also influenced the risk, independently of the PMD. Risk probabilities ranged from 1% for a defined low-risk group up to 40% for a high-risk group. These findings might help identify women who should be offered ultrasound examinations in addition to mammography., (© 2016 UICC.)

Borderline ovarian tumours are semimalignant tumours occurring unilaterally or bilaterally with a peak incidence among women of reproductive age. Since the affected women often wish to preserve fertility, particular precautions must be taken when counselling the patient and obtaining consent prior to planning an individual treatment. Options for preserving fertility include an organ-sparing surgical procedure and cryopreservation of oocytes and/or ovarian tissue. In this article, we report on a 25-year-old patient with a bilateral seromucinous borderline tumour who desired all fertility-preserving options. In order to perform the procedure without delay, we opted to perform luteal phase stimulation prior to oocyte retrieval. We conclude by discussing the current literature on the state of fertility preservation in the treatment of borderline ovarian tumours.

Introduction: Endometriosis is a heterogeneous disease characterized by a range of different presentations. It is usually diagnosed when patients present with pain and/or infertility, but it has also been diagnosed in asymptomatic patients. Because of the different diagnostic approaches and diverse therapies, time to diagnosis can vary considerably and the definitive diagnosis may be delayed, with some cases not being diagnosed for several years. Endometriosis patients have many unmet needs. A systematic registration and follow-up of endometriosis patients could be useful to obtain an insight into the course of the disease. The validation of biomarkers could contribute to the development of diagnostic and predictive tests which could help select patients for surgical assessment earlier and offer better predictions about patients who might benefit from medical, surgical or other interventions. The aim is also to obtain a better understanding of the etiology, pathogenesis and progression of the disease., Material and Methods: To do this, an online multicenter documentation system was introduced to facilitate the establishment of a prospective multicenter case-control study, the IEEP (International Endometriosis Evaluation Program) study. We report here on the first 696 patients with endometriosis included in the program between June 2013 and June 2015., Results: A documentation system was created, and the structure and course of the study were mapped out with regard to data collection and the collection of biomaterials., Conclusion: The documentation system permits the history and clinical data of patients with endometriosis to be recorded. The IEEP combines this information with biomaterials and uses it for scientific studies. The recorded data can also be used to evaluate clinical quality control measures such as the certification parameters used by the EEL (European Endometriosis League) to assess certified endometriosis centers.

Protecting the fertility of patients with oncologic disease is becoming more and more important, as fulfilling the wish to have children is increasingly occurring at a later stage in life and long-term survival rates after cancer are continuing to improve. A number of fertility-preserving options exist. In addition to techniques which have been around for some time such as medical ovarian suppression, ovarian transposition, and organ-preserving surgery, there are other, more recent, innovative methods which have developed over the last few years such as cryopreservation of oocytes or ovarian tissue transplantation after completing cancer therapy. As every procedure has its specific advantages and disadvantages, informed patient consent is essential. The physician's aim must be to select the optimal procedure for each patient. The extent of patients' information about the options to preserve fertility in women with oncologic disease remains limited. One of the main reasons for this is that clinicians are not sure how to inform patients about existing procedures and methods. The aim of this review article is to provide help in clinical practice.

As breast cancer (BC) screening identifies many BCs with a good prognosis, which might be overdiagnosed and therefore overtreated, the identification of subgroups with a high risk for aggressive subtypes might be helpful. The aim of this case-case analysis was to investigate the association between epidemiological risk factors and molecular subtypes in a cohort of BC patients. Epidemiological risk factors for 2587 BC patients were obtained using a structured questionnaire and from the patients' charts. The histopathological information (estrogen and progesterone receptor, HER2 and Ki-67) used in the analysis was retrieved from the original pathology reports. Analyses using conditional inference regression trees were carried out on these data. The strongest influence factor on the distribution of the molecular subtypes was age at first diagnosis of BC. An influence of BMI was also identified in patients aged either more than 42 years or 49.6 years or less. Older patients aged more than 49.6 years and perimenopausal women with a BMI of 32.4 kg/m or less were most likely to develop luminal A-like BC. Young patients aged 42 years or less and perimenopausal patients with a BMI more than 32.4 kg/m more often developed triple-negative BC. The study confirmed that age at diagnosis is an important factor influencing the distribution of molecular subtypes. In the perimenopausal group, it may be postulated that BMI plays a critical role in the pathogenesis of BC, defining a subgroup that is more likely to develop triple-negative BC or luminal B-like disease and another group in which there is a more postmenopausal distribution pattern.

Background: No screening programs are available for ovarian or endometrial cancer. One reason for this is the low incidence of the conditions, resulting in low positive predictive values for tests, which are not very specific. One way of addressing this problem might be to use risk factors to define subpopulations with a higher incidence. The aim of this study was to investigate the extent to which a medical history of endometriosis can serve as a risk factor for ovarian or endometrial cancer., Methods: In a hospital-based case-control analysis, the cases represented patients with endometrial or ovarian cancer who were participating in studies aimed at assessing the risk for these diseases. The controls were women between the age of 40 and 85 who were invited to take part via a newspaper advertisement. A total of 289 cases and 1016 controls were included. Using logistic regression models, it was tested whether self-reported endometriosis is a predictor of case-control status in addition to age, body mass index (BMI), number of pregnancies and previous oral contraceptive (OC) use., Results: Endometriosis was reported in 2.1 % of the controls (n = 21) and 4.8 % of the cases (n = 14). Endometriosis was a relevant predictor for case-control status in addition to other predictive factors (OR 2.63; 95 % CI, 1.28 to 5.41)., Conclusion: This case-control study found that self-reported endometriosis may be a risk factor for endometrial or ovarian cancer in women between 40 and 85 years. There have been very few studies addressing this issue, and incorporating it into a clinical prediction model would require a more precise characterization of the risk factor of endometriosis.

Genome-wide association studies have identified SNPs near ZNF365 at 10q21.2 that are associated with both breast cancer risk and mammographic density. To identify the most likely causal SNPs, we fine mapped the association signal by genotyping 428 SNPs across the region in 89,050 European and 12,893 Asian case and control subjects from the Breast Cancer Association Consortium. We identified four independent sets of correlated, highly trait-associated variants (iCHAVs), three of which were located within ZNF365. The most strongly risk-associated SNP, rs10995201 in iCHAV1, showed clear evidence of association with both estrogen receptor (ER)-positive (OR = 0.85 [0.82-0.88]) and ER-negative (OR = 0.87 [0.82-0.91]) disease, and was also the SNP most strongly associated with percent mammographic density. iCHAV2 (lead SNP, chr10: 64,258,684:D) and iCHAV3 (lead SNP, rs7922449) were also associated with ER-positive (OR = 0.93 [0.91-0.95] and OR = 1.06 [1.03-1.09]) and ER-negative (OR = 0.95 [0.91-0.98] and OR = 1.08 [1.04-1.13]) disease. There was weaker evidence for iCHAV4, located 5' of ADO, associated only with ER-positive breast cancer (OR = 0.93 [0.90-0.96]). We found 12, 17, 18, and 2 candidate causal SNPs for breast cancer in iCHAVs 1-4, respectively. Chromosome conformation capture analysis showed that iCHAV2 interacts with the ZNF365 and NRBF2 (more than 600 kb away) promoters in normal and cancerous breast epithelial cells. Luciferase assays did not identify SNPs that affect transactivation of ZNF365, but identified a protective haplotype in iCHAV2, associated with silencing of the NRBF2 promoter, implicating this gene in the etiology of breast cancer., (Copyright © 2015 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Mammographic density measures adjusted for age and body mass index (BMI) are heritable predictors of breast cancer risk, but few mammographic density-associated genetic variants have been identified. Using data for 10,727 women from two international consortia, we estimated associations between 77 common breast cancer susceptibility variants and absolute dense area, percent dense area and absolute nondense area adjusted for study, age, and BMI using mixed linear modeling. We found strong support for established associations between rs10995190 (in the region of ZNF365), rs2046210 (ESR1), and rs3817198 (LSP1) and adjusted absolute and percent dense areas (all P < 10(-5)). Of 41 recently discovered breast cancer susceptibility variants, associations were found between rs1432679 (EBF1), rs17817449 (MIR1972-2: FTO), rs12710696 (2p24.1), and rs3757318 (ESR1) and adjusted absolute and percent dense areas, respectively. There were associations between rs6001930 (MKL1) and both adjusted absolute dense and nondense areas, and between rs17356907 (NTN4) and adjusted absolute nondense area. Trends in all but two associations were consistent with those for breast cancer risk. Results suggested that 18% of breast cancer susceptibility variants were associated with at least one mammographic density measure. Genetic variants at multiple loci were associated with both breast cancer risk and the mammographic density measures. Further understanding of the underlying mechanisms at these loci could help identify etiologic pathways implicated in how mammographic density predicts breast cancer risk., (©2015 American Association for Cancer Research.)

We evaluated whether a 76-locus polygenic risk score (PRS) and Breast Imaging Reporting and Data System (BI-RADS) breast density were independent risk factors within three studies (1643 case patients, 2397 control patients) using logistic regression models. We incorporated the PRS odds ratio (OR) into the Breast Cancer Surveillance Consortium (BCSC) risk-prediction model while accounting for its attributable risk and compared five-year absolute risk predictions between models using area under the curve (AUC) statistics. All statistical tests were two-sided. BI-RADS density and PRS were independent risk factors across all three studies (P interaction = .23). Relative to those with scattered fibroglandular densities and average PRS (2(nd) quartile), women with extreme density and highest quartile PRS had 2.7-fold (95% confidence interval [CI] = 1.74 to 4.12) increased risk, while those with low density and PRS had reduced risk (OR = 0.30, 95% CI = 0.18 to 0.51). PRS added independent information (P < .001) to the BCSC model and improved discriminatory accuracy from AUC = 0.66 to AUC = 0.69. Although the BCSC-PRS model was well calibrated in case-control data, independent cohort data are needed to test calibration in the general population., (© The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Introduction: This study aimed to compare the accuracy of sonography versus digital breast tomosynthesis to locate intramammary marker clips placed under ultrasound guidance. Patients and Methods: Fifty patients with suspicion of breast cancer (lesion diameter less than 2 cm [cT1]) had ultrasound-guided core needle biopsy with placement of a marker clip in the center of the tumor. Intramammary marker clips were subsequently located with both sonography and digital breast tomosynthesis. Results: Sonography detected no dislocation of intrammammary marker clips in 42 of 50 patients (84 %); dislocation was reported in 8 patients (16 %) with a maximum dislocation of 7 mm along the x-, y- or z-axis. Digital breast tomosynthesis showed accurate placement without dislocation of the intramammary marker clip in 48 patients (96 %); 2 patients (4 %) had a maximum clip dislocation of 3 mm along the x-, y- or z-axis (p < 0.05). Conclusion: The use of digital breast tomosynthesis could improve the accuracy when locating intramammary marker clips compared to sonography and could, in future, be used to complement or even completely replace sonography.

The receptor activator of NF-κB (RANK) pathway is involved in bone health as well as breast cancer (BC) pathogenesis and progression. Whereas the therapeutic implication of this pathway is established for the treatment of osteoporosis and bone metastases, the application in adjuvant BC is currently investigated. As genetic variants in this pathway have been described to influence bone health, aim of this study was the prognostic relevance of genetic variants in RANK and RANKL. Single nucleotide polymorphisms in RANK(L) (rs1054016/rs1805034/rs35211496) were genotyped and analyzed with regard to bone metastasis-free survival (BMFS), disease-free survival, and overall survival for a retrospective cohort of 1251 patients. Cox proportional hazard models were built to examine the prognostic influence in addition to commonly established prognostic factors. The SNP rs1054016 seems to influence BMFS. Patients with two minor alleles had a more favorable prognosis than patients with at least one common allele (HR 0.37 (95% CI: 0.17, 0.84)), whereas other outcome parameters remained unaffected. rs1805034 and rs35211496 had no prognostic relevance. The effect of rs1054016(RANKL) adds to the evidence that the RANK pathway plays a role in BC pathogenesis and progression with respect to BMFS, emphasizing the connection between BC and bone health.

Several advancements over the last decade have triggered the developments in the field of breast cancer risk research. One of them is the availability of the human genome sequence along with cheap genotyping possibilities. Another is the globalization of research, which has led to the growth of research collaboration into large international consortia that facilitate the pooling of clinical and genotype data of hundreds of thousands of patients and healthy control individuals. This review concerns with the recent developments in breast cancer risk research and focuses on the discovery of new genetic breast cancer risk factors and their meaning in the context of established non-genetic risk factors. Finally the clinical application is highly dependent on the accuracy of breast cancer risk prediction models, not only for all breast cancer patients, but also for molecular subtypes, preferably for those which are associated with an unfavorable prognosis. Recently risk prediction incorporates all possible risk factors, which include epidemiological risk factors, mammographic density and genetic risk factors.

Introduction: A newly adapted clip system for intramammary marking during ultrasound-guided core needle biopsy for suspicion of breast cancer is described and evaluated here. Material and Method: Fifty patients with suspicion of breast cancer (cT2) had ultrasound-guided core needle biopsy using a newly adapted clip marker system (HistoCore™ and O-Twist Marker™). Subsequently, ultrasound follow-up and tomosynthesis scans were done to determine the location of the marker clips. Results: No dislocation of the marker clip was detected on ultrasound in 45 of 50 patients (90 %), and 5 patients (10 %) had a maximum dislocation of 5 mm along the x-, y- or z-axis. Tomosynthesis scans demonstrated precise placement without dislocation of the clip markers in 48 patients (96 %); 2 patients (4 %) had a maximum dislocation of 3 mm along the x-, y- or z-axis. Conclusion: The newly developed clip marker system, a combination of a single-use breast biopsy needle and a precise, length-adapted intramammary marker clip, represents a further improvement in oncological therapy. This is of particular importance for patients requiring subsequent neoadjuvant chemotherapy, as in cases with complete tumour remission, there is no target point for preoperative, ultrasound-guided wire marking.

Treatment decisions in oncology are based on a balance between the efficacy of therapy and its side effects. Patients with metastases and patients with a limited prognosis are a particular challenge, since communication about the disease situation and the expected therapeutic benefit is difficult not only for patients, but also for physicians. The aim of this study was therefore to compare the benefits expected of therapy by patients and physicians. Questionnaires were sent to 9,000 breast cancer patients and to 6,938 physicians. The questionnaires described 10 cases of breast cancer in the metastatic setting. The patients and physicians were asked to state the treatment benefit they would require to decide for the therapy options chemotherapy, endocrine therapy, antibody therapy, radiotherapy, and bisphosphonates. Additionally, the participants provided data on patient and physician characteristics. Expected treatment benefits were compared between patients and physicians, and influencing factors that modified the expected benefit were identified. Patients expected much greater benefits from the therapies offered than the physicians. For all treatment modalities, about 50 % or more of patients expected more than a 12-month increase in overall survival from all therapies. Among the doctors, this proportion ranged from 7 to 30 %. Among patients, previous experience of side effects and having young children in the family were the strongest influencing factors. Among the doctors, age and level of education had a strong influence on the expected prognostic improvement to indicate a therapy option. As expectations of treatment differ greatly between patients and doctors, a structured approach to solving this conflict is required. There appear to be some indicators that might help address the problem, such as the physicians' level of training and experience and the patients' specific social circumstances.

Aim: This prospective clinical study aimed to evaluate whether it would be possible to reduce the rate of re-excisions using CMOS technology, a specimen radiography system (SRS) or digital breast tomosynthesis (DBT) compared to a conventional full field digital mammography (FFDM) system. Material and Method: Between 12/2012 and 2/2013 50 patients were diagnosed with invasive breast cancer (BI-RADS™ 5). After histological verification, all patients underwent breast-conserving therapy with intraoperative imaging using 4 different systems and differing magnifications: 1. Inspiration™ (Siemens, Erlangen, Germany), amorphous selenium, tungsten source, focus 0.1 mm, resolution 85 µm pixel pitch, 8 lp/mm; 2. BioVision™ (Bioptics, Tucson, AZ, USA), CMOS technology, photodiode array, flat panel, tungsten source, focus 0.05, resolution 50 µm pixel pitch, 12 lp/mm; 3. the Trident™ specimen radiography system (SRS) (Hologic, Bedford, MA, USA), amorphous selenium, tungsten source, focus 0.05, resolution 70 µm pixel pitch, 7.1 lp/mm; 4. tomosynthesis (Siemens, Erlangen, Germany), amorphous selenium, tungsten source, focus 0.1 mm, resolution 85 µm pixel pitch, 8 lp/mm, angular range 50 degrees, 25 projections, scan time > 20 s, geometry: uniform scanning, reconstruction: filtered back projection. The 600 radiographs were prospectively shown to 3 radiologists. Results: Of the 50 patients with histologically proven breast cancer (BI-RADS™ 6), 39 patients required no further surgical therapy (re-excision) after breast-conserving surgery. A retrospective analysis (n = 11) showed a significant (p < 0.05) increase of sensitivity with the BioVision™, the Trident™ and tomosynthesis compared to the Inspiration™ at a magnification of 1.0 : 2.0 or 1.0 : 1.0 (tomosynthesis) (2.6, 3.3 or 3.6 %), i.e. re-excision would not have been necessary in 2, 3 or 4 patients, respectively, compared to findings obtained with a standard magnification of 1.0 : 1.0. Conclusion: The sensitivity of the BioVision™, the Trident™ and tomosynthesis was significantly (p < 0.05) higher and the rate of re-excisions was reduced compared to FFDM using a conventional detector at a magnification of 2.0 but without zooming.

Pregnancy and breastfeeding are major factors reducing breast cancer (BC) risk. A potential mechanism for this effect might be changes in mammographic density, but other factors might be involved. The aim of this study was to investigate factors influencing changes in breast size and breast stiffness after pregnancy. Of a consecutive cohort of 5991 women who gave birth between 1996 and 1999, 559 replied to a questionnaire including questions about breast changes. The women completed their own assessments of changes in breast size and stiffness since their last pregnancy. Factors being investigated regarding their predictive value for these changes were: BMI before pregnancy, weight gain, age at first full-term pregnancy (FFTP), number of pregnancies, breastfeeding, and BMI of the children's fathers. A decrease in breast size was reported in 21.8% of the participants and an increase in 35.1%. With regard to the breast stiffness, 66.4% reported a decrease and only 5% reported an increase. Independent predictors for increased breast size were age at FFTP, increase in BMI since last pregnancy, BMI before pregnancy, and time since FFTP. Factors predictive of greater breast stiffness included age at FFTP, BMI before FFTP, time since FFTP, breastfeeding status, and number of pregnancies. Breast changes after pregnancy depend on several variables, which are described as BC-risk factors. Individual reaction of the female breast to a pregnancy leads to different outcomes with regard to breast size and stiffness. Further studies are needed to clarify whether these individual responses interact with the effect of pregnancy on the BC risk.