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Introduction: Several common breast cancer genetic susceptibility variants have recently been identified. We aimed to determine how these variants combine with a subset of other known risk factors to influence breast cancer risk in white women of European ancestry using case-control studies participating in the Breast Cancer Association Consortium.Methods: We evaluated two-way interactions between each of age at menarche, ever having had a live birth, number of live births, age at first birth and body mass index (BMI) and each of 12 single nucleotide polymorphisms (SNPs) (10q26-rs2981582 (FGFR2), 8q24-rs13281615, 11p15-rs3817198 (LSP1), 5q11-rs889312 (MAP3K1), 16q12-rs3803662 (TOX3), 2q35-rs13387042, 5p12-rs10941679 (MRPS30), 17q23-rs6504950 (COX11), 3p24-rs4973768 (SLC4A7), CASP8-rs17468277, TGFB1-rs1982073 and ESR1-rs3020314). Interactions were tested for by fitting logistic regression models including per-allele and linear trend main effects for SNPs and risk factors, respectively, and single-parameter interaction terms for linear departure from independent multiplicative effects.Results: These analyses were applied to data for up to 26,349 invasive breast cancer cases and up to 32,208 controls from 21 case-control studies. No statistical evidence of interaction was observed beyond that expected by chance. Analyses were repeated using data from 11 population-based studies, and results were very similar.Conclusions: The relative risks for breast cancer associated with the common susceptibility variants identified to date do not appear to vary across women with different reproductive histories or body mass index (BMI). The assumption of multiplicative combined effects for these established genetic and other risk factors in risk prediction models appears justified. © 2010 Milne et al.; licensee BioMed Central Ltd.

Abstract: Background: Re-operations after breast conserving surgery (BCS) are necessary, when specimen margins are not free of breast cancer cells. This study explored the accuracy of preoperative tumour size assessment and its influence on the rate of re-excisions and mastectomies. Methods: The study included 1591 patients with invasive breast cancer, who were planned for BCS. Patient, staging and tumor characteristics were evaluated concerning their influence on re-excision and mastectomy rates. Patient and tumor characteristics comprised histopathological tumour size, HER2 status, multifocality, in situ component, grading (G), nodal status and hormone receptor (HR) status. Staging characteristics included deviation from pathological tumour size as measured by clinical examination, sonography and mammography. Results: In 1316 patients (83%) sufficient treatment was possible with one operation. 275 patients (17%) had to undergo at least one further surgery as a result of positive specimen margins. In 138 patients (9%) mastectomy was ultimately necessary. In patients with a positive HER2 status, a larger tumour size, underestimation by ultrasound, an in situ component and multifocality, the risk for a re-operation was about doubled. Tumour size deviation in the mammogram or the clinical tumour size assessment did not have significant influence to the re-excision rates. Conclusion: Tumour size and accurate presurgical assessment of the tumour size itself are independent predictors for the need of a second surgery or even a mastectomy in patients for whom a primary BCS was planned. [Copyright &y& Elsevier]

Objectives: Tumour size estimates using mammography (MG), conventional ultrasound (US), compound imaging (CI) and real-time elastography (RTE) were compared with histopathological specimen sizes.Methods: The largest diameters of 97 malignant breast lesions were measured. Two US and CI measurements were made: US1/CI1 (hypoechoic nucleus only) and US2/CI2 (hypoechoic nucleus plus hyperechoic halo). Measurements were compared with histopathological tumour sizes using linear regression and Bland-Altman plots.Results: Size prediction was best with ultrasound (US/CI/RTE: R (2) 0.31-0.36); mammography was poorer (R(2) = 0.19). The most accurate method was US2, while US1 and CI1 were poorest. Bland-Altman plots showed better size estimation with US2, CI2 and RTE, with low variation, while mammography showed greatest variability. Smaller tumours were better assessed than larger ones. CI2 and US2 performed best for ductal tumours and RTE for lobular cancers. Tumour size prediction accuracy did not correlate significantly with breast density, but on MG tumours were more difficult to detect in high-density tissue.Conclusions: The size of ductal tumours is best predicted with US2 and CI2, while for lobular cancers RTE is best. Hyperechoic tumour surroundings should be included in US and CI measurements and RTE used as an additional technique in the clinical staging process. [ABSTRACT FROM AUTHOR]

Abstract: Aim: The aim of this study was to evaluate factors affecting the risk for reexcision following breast-conserving surgery. Positive tumor margins are critical for local disease control following surgery for breast cancer. Several factors, including tumor size, multifocality, and an extensive in situ component, may be associated with a higher rate of repeat operations due to positive margins. This study included mammographic density in the analysis. Methods: A total of 565 breast cancer patients were considered eligible for breast-conserving therapy after a core biopsy had confirmed malignancy. The patients’ mammographic findings were reviewed, and mammographic density was documented in addition to the histopathological features of the lesions. Associations between these factors and the risk for a second operation were analyzed using the chi-squared test, and a model was developed for multivariate analysis. Results: At least one repeat operation was necessary in 121 patients (21.4%), and mastectomy was ultimately necessary in 54 patients (9.6%). Tumor size, multifocality, and the presence of an in situ component were identified as risk factors. A mammographic density of category 4 was associated with a need for further surgery (OR 3.2; 95% CI, 1.2–11). Conclusions: Mammographic density is an additional risk factor for a second operation following breast-conserving procedures, and it may make radiographic and intraoperative localization of the tumor technically difficult. Using mammographic density to define a group of patients with a higher risk of reexcision might allow these patients to benefit from more sophisticated methods of localization and margin assessment. [Copyright &y& Elsevier]

Abstract Background The pathological complete response (pCR) after neoadjuvant chemotherapy is a surrogate marker for a favorable prognosis in breast cancer patients. Factors capable of predicting a pCR, such as the proliferation marker Ki67, may therefore help improve our understanding of the drug response and its effect on the prognosis. This study investigated the predictive and prognostic value of Ki67 in patients with invasive breast cancer receiving neoadjuvant treatment for breast cancer. Methods Ki67 was stained routinely from core biopsies in 552 patients directly after the fixation and embedding process. HER2/neu, estrogen and progesterone receptors, and grading were also assessed before treatment. These data were used to construct univariate and multivariate models for predicting pCR and prognosis. The tumors were also classified by molecular phenotype to identify subgroups in which predicting pCR and prognosis with Ki67 might be feasible. Results Using a cut-off value of > 13% positively stained cancer cells, Ki67 was found to be an independent predictor for pCR (OR 3.5; 95% CI, 1.4, 10.1) and for overall survival (HR 8.1; 95% CI, 3.3 to 20.4) and distant disease-free survival (HR 3.2; 95% CI, 1.8 to 5.9). The mean Ki67 value was 50.6 ± 23.4% in patients with pCR. Patients without a pCR had an average of 26.7 ± 22.9% positively stained cancer cells. Conclusions Ki67 has predictive and prognostic value and is a feasible marker for clinical practice. It independently improved the prediction of treatment response and prognosis in a group of breast cancer patients receiving neoadjuvant treatment. As mean Ki67 values in patients with a pCR were very high, cut-off values in a high range above which the prognosis may be better than in patients with lower Ki67 values may be hypothesized. Larger studies will be needed in order to investigate these findings further.

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.

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.)

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.

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.

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.

Prediction of the prognosis for metastatic breast cancer patients depends on molecular subtypes similar to those found in patients with primary breast cancer. Several studies have shown that estrogen receptor (ER) and progesterone receptor (PR) status determine the course of the disease and the prognosis. As Ki-67 helps to differentiate molecular subtypes in patients with primary breast cancer, the aim of this study was to assess the prognostic relevance of Ki-67 in the primary tumor in relation to its prognostic relevance for patients with metastatic breast cancer. A total of 467 patients with invasive breast cancer were identified in the database of a single breast cancer center, in whom Ki-67 had been assessed in tumor material from the breast at the time of the primary diagnosis and who had developed a metastasis at any time during the subsequent course. For these patients, tumor and patient characteristics were used to determine prognostic factors relative to overall survival after the diagnosis of distant metastases. Ki-67 was added to this model to investigate whether this might improve the prediction of overall survival. In the multivariate Cox model, age at diagnosis, body mass index, nodal status, tumor size, ER and PR status, and time from diagnosis to metastasis were identified as relevant prognostic factors. Adding Ki-67 to the model improved the prediction of overall survival. There was also a significant and relevant interaction with the PR status. In patients with a low-proliferation primary tumor, a high level of PR expression would indicate an extraordinarily good prognosis (HR 0.39; 95 % CI, 0.23-0.66). In patients with higher-proliferation primary tumors, PR status was not capable of differentiating prognostic groups. Ki-67 is useful in addition to known prognostic factors for breast cancer. It is able to indicate a group of women with a poorer prognosis, specifically in the group of patients with PR-positive breast cancer.

Aim: Nodal status remains one of the most important prognostic factors in breast cancer. The cellular and molecular reasons for the spread of tumor cells to the lymph nodes are not well understood and there are only few predictors in addition to tumor size and multifocality that give an insight into additional mechanisms of lymphatic spread. Aim of our study was therefore to investigate whether breast characteristics such as mammographic density (MD) add to the predictive value of the presence of lymph node metastases in patients with primary breast cancer. Methods: In this retrospective study we analyzed primary, metastasis-free breast cancer patients from one breast center for whom data on MD and staging information were available. A total of 1831 patients were included into this study. MD was assessed as percentage MD (PMD) using a semiautomated method and two readers for every patient. Multiple logistic regression analyses with nodal status as outcome were used to investigate the predictive value of PMD in addition to age, tumor size, Ki-67, estrogen receptor (ER), progesterone receptor (PR), grading, histology, and multi-focality. Results: Multifocality, tumor size, Ki-67 and grading were relevant predictors for nodal status. Adding PMD to a prediction model which included these factors did not significantly improve the prediction of nodal status (p = 0.24, likelihood ratio test). Conclusion: Nodal status could be predicted quite well with the factors multifocality, tumor size, Ki-67 and grading. PMD does not seem to play a role in the lymphatic spread of tumor cells. It could be concluded that the amount of extracellular matrix and stromal cell content of the breast which is reflected by MD does not influence the probability of malignant breast cells spreading from the primary tumor to the lymph nodes.

For many breast cancer (BC) risk factors, there is growing evidence concerning molecular subtypes for which the risk factor is specific. With regard to mammographic density (MD), there are inconsistent data concerning its association with estrogen receptor (ER) and progesterone receptor (PR) expression. The aim of our study was to analyze the association between ER and PR expression and MD. In our case-only study, data on BC risk factors, hormone receptor expression and MD were available for 2,410 patients with incident BC. MD was assessed as percent MD (PMD) using a semiautomated method by two readers for every patient. The association of ER/PR and PMD was studied with multifactorial analyses of covariance with PMD as the target variable and including well-known factors that are also associated with MD, such as age, parity, use of hormone replacement therapy, and body mass index (BMI). In addition to the commonly known associations between PMD and age, parity, BMI and hormone replacement therapy, a significant inverse association was found between PMD and ER expression levels. Patients with ER-negative tumors had an average PMD of 38%, whereas patients with high ER expression had a PMD of 35%. A statistical trend toward a positive association between PMD and PR expression was also seen. PMD appears to be inversely associated with ER expression and may correlate positively with PR expression. These effects were independent of other risk factors such as age, BMI, parity, and hormone replacement therapy, possibly suggesting other pathways that mediate this effect., (Copyright © 2012 UICC.)

There is growing evidence that certain breast cancer (BC) risk factors specifically increase the risk for specific molecular tumor subtypes. Different molecular subtypes of BC can partly be described by analyzing proliferation in tumors. Very few data are available regarding the association of mammographic density (MD), as a BC risk factor, with proliferation. The aim of this study was to analyze the association between Ki-67 expression in BCs and MD. In this case-only study, data on BC risk factors, hormone receptor expression, and MD were available for 1,975 patients with incident BC. MD was assessed as percentage mammographic density (PMD) using a semiautomated method by two readers for every patient. The association of the Ki-67 proliferation index and PMD was studied using multifactorial analyses of covariance (ANCOVA), with PMD as the target variable and including well-known factors that are also associated with MD such as age, parity, use of hormone replacement therapy (HRT), and body mass index (BMI). There were no significant differences in PMD between women with BC who had low and high Ki-67 values (P = 0.31). However, there were relevant differences in women with low BMI (P = 0.07), and in women using postmenopausal HRT (P = 0.06) as well as in women with low PR values (P = 0.07). In these subgroups, the Ki-67 expression index increased with decreasing PMD. Likewise PMD is correlated with BMI, parity status, and menopausal status stronger in patients with low proliferating tumors, and with progesterone receptor expression in patients with high proliferating tumors. MD correlates inversely with Ki-67 proliferation in BC tumors only in some subgroups of BC patients, defined by commonly known BC risk factors that are usually associated with MD as well.

Purpose: Mammographic characteristics are known to be correlated to breast cancer risk. Percent mammographic density (PMD), as assessed by computer-assisted methods, is an established risk factor for breast cancer. Along with this assessment the absolute dense area (DA) of the breast is reported as well. Aim of this study was to assess the predictive value of DA concerning breast cancer risk in addition to other risk factors and in addition to PMD. Methods: We conducted a case control study with hospital-based patients with a diagnosis of invasive breast cancer and healthy women as controls. A total of 561 patients and 376 controls with available mammographic density were included into this study. We describe the differences concerning the common risk factors BMI, parital status, use of hormone replacement therapy (HRT) and menopause between cases and controls and estimate the odds ratios for PMD and DA, adjusted for the mentioned risk factors. Furthermore we compare the prediction models with each other to find out whether the addition of DA improves the model. Results: Mammographic density and DA were highly correlated with each other. Both variables were as well correlated to the commonly known risk factors with an expected direction and strength, however PMD (ρ = -0.56) was stronger correlated to BMI than DA (ρ = -0.11). The group of women within the highest quartil of PMD had an OR of 2.12 (95 % CI: 1.25-3.62). This could not be seen for the fourth quartile concerning DA. However the assessment of breast cancer risk could be improved by including DA in a prediction model in addition to common risk factors and PMD. Conclusions: The inclusion of the parameter DA into a prediction model for breast cancer in addition to established risk factors and PMD could improve the breast cancer risk assessment. As DA is measured together with PMD in the process of computer-assisted assessment of PMD it might be considered to include it as one additional breast cancer risk factor that is obtained from breast imaging.

The aim of our study involved the assessment of B-mode imaging and elastography with regard to their ability to predict mammographic density (MD) without X-rays. Women, who underwent routine mammography, were prospectively examined with additional B-mode ultrasound and elastography. MD was assessed quantitatively with a computer-assisted method (Madena). The B-mode and elastography images were assessed by histograms with equally sized gray-level intervals. Regression models were built and cross validated to examine the ability to predict MD. The results of this study showed that B-mode imaging and elastography were able to predict MD. B-mode seemed to give a more accurate prediction. R for B-mode image and elastography were 0.67 and 0.44, respectively. Areas in the B-mode images that correlated with mammographic dense areas were either dark gray or of intermediate gray levels. Concerning elastography only the gray levels that represent extremely stiff tissue correlated positively with MD. In conclusion, ultrasound seems to be able to predict MD. Easy and cheap utilization of regular breast ultrasound machines encourages the use of ultrasound in larger case-control studies to validate this method as a breast cancer risk predictor. Furthermore, the application of ultrasound for breast tissue characterization could enable comprehensive research concerning breast cancer risk and breast density in young and pregnant women.

Background: Mammographic density adjusted for age and body mass index (BMI) is a heritable marker of breast cancer susceptibility. Little is known about the biologic mechanisms underlying the association between mammographic density and breast cancer risk. We examined whether common low-penetrance breast cancer susceptibility variants contribute to interindividual differences in mammographic density measures., Methods: We established an international consortium (DENSNP) of 19 studies from 10 countries, comprising 16,895 Caucasian women, to conduct a pooled cross-sectional analysis of common breast cancer susceptibility variants in 14 independent loci and mammographic density measures. Dense and nondense areas, and percent density, were measured using interactive-thresholding techniques. Mixed linear models were used to assess the association between genetic variants and the square roots of mammographic density measures adjusted for study, age, case status, BMI, and menopausal status., Results: Consistent with their breast cancer associations, the C-allele of rs3817198 in LSP1 was positively associated with both adjusted dense area (P = 0.00005) and adjusted percent density (P = 0.001), whereas the A-allele of rs10483813 in RAD51L1 was inversely associated with adjusted percent density (P = 0.003), but not with adjusted dense area (P = 0.07)., Conclusion: We identified two common breast cancer susceptibility variants associated with mammographic measures of radiodense tissue in the breast gland., Impact: We examined the association of 14 established breast cancer susceptibility loci with mammographic density phenotypes within a large genetic consortium and identified two breast cancer susceptibility variants, LSP1-rs3817198 and RAD51L1-rs10483813, associated with mammographic measures and in the same direction as the breast cancer association., (©2012 AACR)

Introduction: Although mammographic density is an established risk factor for breast cancer, its use is limited in clinical practice because of a lack of automated and standardized measurement methods. The aims of this study were to evaluate a variety of automated texture features in mammograms as risk factors for breast cancer and to compare them with the percentage mammographic density (PMD) by using a case-control study design., Methods: A case-control study including 864 cases and 418 controls was analyzed automatically. Four hundred seventy features were explored as possible risk factors for breast cancer. These included statistical features, moment-based features, spectral-energy features, and form-based features. An elaborate variable selection process using logistic regression analyses was performed to identify those features that were associated with case-control status. In addition, PMD was assessed and included in the regression model., Results: Of the 470 image-analysis features explored, 46 remained in the final logistic regression model. An area under the curve of 0.79, with an odds ratio per standard deviation change of 2.88 (95% CI, 2.28 to 3.65), was obtained with validation data. Adding the PMD did not improve the final model., Conclusions: Using texture features to predict the risk of breast cancer appears feasible. PMD did not show any additional value in this study. With regard to the features assessed, most of the analysis tools appeared to reflect mammographic density, although some features did not correlate with PMD. It remains to be investigated in larger case-control studies whether these features can contribute to increased prediction accuracy.