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High mammographic density (MD) is associated with an increased risk of breast cancer, however the underlying mechanisms are largely unknown. This research aimed to identify microRNAs (miRNAs) that play a role in the development of extremely dense breast tissue. In the discovery phase, 754 human mature miRNAs were profiled in 21 extremely high MD- and 20 very low MD-derived nipple aspirate fluid (NAF) samples from healthy women. In the validation phase, candidate miRNAs were assessed in a cohort of 89 extremely high MD and 81 very low MD NAF samples from healthy women. Independent predictors of either extremely high MD or miRNA expression were identified by logistic regression and linear regression analysis, respectively. mRNA targets and pathways were identified through miRTarBase, TargetScan, and PANTHER pathway analysis. Statistical analysis identified four differentially expressed miRNAs during the discovery phase. During the validation, linear regression ( p = 0.029; fold change = 2.10) and logistic regression ( p = 0.048; odds ratio = 1.38) showed that hsa-miR-29c-5p was upregulated in extremely high MD-derived NAF. Identified candidate mRNA targets of hsa-miR-29c-5p are CFLAR, DNMT3A, and PTEN. Further validation and exploration of targets and downstream pathways of has-miR-29c-5p will provide better insight into the processes involved in the development of high MD and in the associated increased risk of breast cancer.

Background: Nipple fluid aspiration (NFA) is a technique to acquire nipple aspirate fluid (NAF), which is considered a rich source of breast-specific biomarkers. Originating directly from the mammary ducts, this liquid biopsy can offer insight into the process of carcinogenesis at its earliest stage and therefore could be of added value to the current imaging-based breast cancer screening tools. With that in mind, it is necessary to know how well NFA is tolerated., Aim: To evaluate the participants' tolerability of NFA compared to breast imaging screening methods and blood draws., Materials and Methods: Three cohorts of women underwent NFA: healthy women (n = 190), women diagnosed with breast cancer (n = 137) and women at high risk of developing breast cancer (n = 48). A 0-10 discomfort score of NFA, mammography, breast MRI and blood draws, was filled in at the study visits, which took place once or annually., Results: The median discomfort rate of NFA was 1, which was significantly lower than the median discomfort of mammography and breast MRI (5 and 3, respectively, p < 0.001), but significantly higher than median discomfort for blood draws (0, p < 0.001). The great majority of women would undergo the procedure again (98%) and recommend it to others (97%)., Conclusion: This study shows that NFA was well tolerated by healthy women, women diagnosed with breast cancer and high-risk women. This makes NFA a feasible method to pursue as a potential future breast cancer early detection tool, based on resident biomarkers., Trial Registration: NL41845.041.12 , NL57343.041.16 and NL11690.041.06 in trialregister.nl., (© 2022. The Author(s).)

Nipple aspirate fluid (NAF) is an intraductal mammary fluid that, because of its close proximity to and origin from the tissue from which breast cancer originates, is a promising source of biomarkers for early breast cancer detection. NAF can be non-invasively acquired via the nipple by aspiration using a suction device; using oxytocin nasal spray helps increase yield and tolerability. The aspiration procedure is generally experienced as more tolerable than the currently used breast imaging techniques mammography and breast magnetic resonance imaging. Future applications of NAF-derived biomarkers include their use as a tool in the detection of breast carcinogenesis at its earliest stage (before a tumor mass can be seen by imaging), or as a supporting diagnostic tool for imaging, such as when imaging is less reliable (to rule out false positives from imaging) or when imaging is not advisable (such as during pregnancy and breastfeeding). Ongoing clinical studies using NAF samples will likely shed light on NAF's content and clinical potential. Here, we present a narrative review and perspectives of NAF research at a glance.

Purpose: Investigation of nipple aspirate fluid (NAF)-based microRNAs (miRNAs) as a potential screening tool for women at increased risk of developing breast cancer is the scope of our research. While aiming to identify discriminating NAF-miRNAs between women with different mammographic densities, we were confronted with an unexpected confounder: NAF sample appearance. Here we report and alert for the impact of NAF color and cloudiness on miRNA assessment., Methods: Seven classes of NAF colors coupled with cloudiness appearance were established. Using 173 NAF samples from 154 healthy women (19 samples were bilaterally collected), the expression of 14 target and 2 candidate endogenous control (EC) miRNAs was investigated using Taqman Advanced miRNA assays to identify significant differential expression patterns between color-cloudiness classes. Inter- and intra-individual variation of miRNA expression was analyzed using the coefficient of variation (CV)., Results: We found that between the seven NAF classes, fold change miRNA expression differences ranged between 2.4 and 19.6 depending on the interrogated miRNA. Clear NAF samples exhibited higher miRNA expression levels compared to cloudy NAF samples with fold change differences ranging between 1.1 and 6.2. Inter-individual and intra-individual miRNA expression was fairly stable (CV < 15 %), but nevertheless impacted by NAF sample appearance. Within NAF classes, inter-individual variation was largest for green samples (CV 6-15 %) and smallest for bloody samples (CV 2-6 %)., Conclusions: Our data indicate that NAF color and cloudiness influence miRNA expression and should, therefore, be systematically registered using an objective color classification system. Given that sample appearance is an inherent feature of NAF, these variables should be statistically controlled for in multivariate data analyses. This cautionary note and recommendations could be of value beyond the field of NAF-miRNAs, given that variability in sample color and cloudiness is likewise observed in liquid biopsies such as urine, cerebrospinal fluid and sputum, and could thereby influence the levels of miRNAs and other biomarkers., (© 2021. The Author(s).)

Introduction: Pathological nipple discharge (PND) is a common breast-related complaint for referral to a surgical breast clinic because of its association with breast cancer. The aim of this meta-analysis was to compare the diagnostic efficacy of magnetic resonance imaging (MRI) and ductoscopy in patients with PND. Additionally, we determined the most cost-efficient strategy for the treatment of PND and the detection of breast cancer in PND patient without radiological suspicion for malignancy., Materials and Methods: PubMed and EMBASE were searched to collect the relevant literature from the inception of both diagnostic methods until January 27th 2020. The search yielded 815 original citations, of which 10 studies with 894 patients were finally included for analysis. Costs of ductoscopy, MRI and duct excision surgery were obtained from the UMC Utrecht as established in the year 2019. These costs included: medical personnel, overhead costs, material costs and sterilisation costs., Results: The meta-analysis showed no significant difference in sensitivity between ductoscopy (44%) and MRI (76%) for the detection of malignancy in patients with PND. However, ductoscopy (98%) had a statistically significantly higher specificity than MRI (84%). Individual costs were €1401.33, €822.13 and €6494.27 for ductoscopy, MRI and duct excision surgery, respectively. Full diagnostic strategy involving ductoscopy was on average €1670.97, while with MRI it was €2070.27., Conclusion: Patients undergoing MRI are more often (false) positive which more often leads to duct excision surgery referrals compared to ductoscopy. This makes ductoscopy significantly more cost-effective compared MRI in patients with PND without radiological suspicion for malignancy.

Introduction: Since current studies on locally advanced pancreatic cancer (LAPC) mainly report from single, high-volume centers, it is unclear if outcomes can be translated to daily clinical practice. This study provides treatment strategies and clinical outcomes within a multicenter cohort of unselected patients with LAPC., Materials and Methods: Consecutive patients with LAPC according to Dutch Pancreatic Cancer Group criteria, were prospectively included in 14 centers from April 2015 until December 2017. A centralized expert panel reviewed response according to RECIST v1.1 and potential surgical resectability. Primary outcome was median overall survival (mOS), stratified for primary treatment strategy., Results: Overall, 422 patients were included, of whom 77% (n = 326) received chemotherapy. The majority started with FOLFIRINOX (77%, 252/326) with a median of six cycles (IQR 4-10). Gemcitabine monotherapy was given to 13% (41/326) of patients and nab-paclitaxel/gemcitabine to 10% (33/326), with a median of two (IQR 3-5) and three (IQR 3-5) cycles respectively. The mOS of the entire cohort was 10 months (95%CI 9-11). In patients treated with FOLFIRINOX, gemcitabine monotherapy, or nab-paclitaxel/gemcitabine, mOS was 14 (95%CI 13-15), 9 (95%CI 8-10), and 9 months (95%CI 8-10), respectively. A resection was performed in 13% (32/252) of patients after FOLFIRINOX, resulting in a mOS of 23 months (95%CI 12-34)., Conclusion: This multicenter unselected cohort of patients with LAPC resulted in a 14 month mOS and a 13% resection rate after FOLFIRINOX. These data put previous results in perspective, enable us to inform patients with more accurate survival numbers and will support decision-making in clinical practice., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Women identified with an increased risk of breast cancer due to mutations in cancer susceptibility genes or a familial history of breast cancer undergo tailored screening with the goal of detecting tumors earlier, when potential curative interventions are still possible. Ideally, screening would identify signs of carcinogenesis even before a tumor is detectable by imaging. This could be achieved by timely signaling of altered biomarker levels for precancerous processes in liquid biopsies. Currently, the Nipple Aspirate Fluid (NAF) and the Trial Early Serum Test BREAST cancer (TESTBREAST), both ongoing, prospective, multicenter studies, are investigating biomarkers in liquid biopsies to improve breast cancer screening in high-risk women. The NAF study focuses on changes over time in miRNA expression levels both in blood and NAF samples, whereas the TESTBREAST study analyzes changes in protein levels in blood samples at sequential interval timepoints. These within-subject changes are studied in relation to later occurrence of breast cancer using a nested case-control design. These longitudinal studies face their own challenges in execution, such as hindrances in logistics and in sample processing that were difficult to anticipate. This article offers insight into those challenges and concurrently aims to provide useful strategies for the set-up of similar studies. See related commentary by Sauter, p. 429 ., (©2020 American Association for Cancer Research.)

Pathologic nipple discharge (PND) is one of the most common breast-related complaints for referral because of its supposed association with breast cancer. The aim of this network meta-analysis (NMA) was to compare the diagnostic efficacy of ultrasound, mammogram, cytology, magnetic resonance imaging (MRI), and ductoscopy in patients with PND, as well as to determine the best diagnostic strategy to assess the risk of malignancy as cause for PND. Cochrane Library, PubMed, and Embase were searched to collect relevant literature from the inception of each of the diagnostic methods until January 27, 2020. The search yielded 1472 original citations, of which 36 studies with 3764 patients were finally included for analysis. Direct and indirect comparisons were performed using an NMA approach to evaluate the combined odd ratios and to determine the surface under the cumulative ranking curves (SUCRA) of the diagnostic value of different imaging methods for the detection of breast cancer in patients with PND. Additionally, a subgroup meta-analysis comparing ductoscopy to MRI when conventional imaging was negative was also performed. According to this NMA, sensitivity for detection of malignancy in patients with PND was highest for MRI (83%), followed by ductoscopy (58%), ultrasound (50%), cytology (38%), and mammogram (22%). Specificity was highest for mammogram (93%) followed by ductoscopy (92%), cytology (90%), MRI (76%), and ultrasound (69%). Diagnostic accuracy was the highest for ductoscopy (88%), followed by cytology (82%), MRI (77%), mammogram (76%), and ultrasound (65%). Subgroup meta-analysis (comparing ductoscopy to MRI when ultrasound and mammogram were negative) showed no significant difference in sensitivity, but ductoscopy was statistically significantly better with regard to specificity and diagnostic accuracy. The results from this NMA indicate that although ultrasound and mammogram may remain low-cost useful first choices for the detection of malignancy in patients with PND, ductoscopy outperforms most imaging techniques (especially MRI) and cytology., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: MicroRNAs (miRNAs) target 60% of human messenger RNAs and can be detected in tissues and biofluids without loss of stability during sample processing, making them highly appraised upcoming biomarkers for evaluation of disease. However, reporting of the abundantly expressed miRNAs in healthy samples is often surpassed. Here, we characterized for the first time the physiological miRNA landscape in a biofluid of the healthy breast: nipple aspirate fluid (NAF), and compared NAF miRNA expression patterns with publically available miRNA expression profiles of healthy breast tissue, breast milk, plasma and serum., Methods: MiRNA RT-qPCR profiling of NAF ( n = 41) and serum ( n = 23) samples from two healthy female cohorts was performed using the TaqMan OpenArray Human Advanced MicroRNA 754-Panel. MiRNA quantification data based on non-targeted or multi-targeted profiling techniques for breast tissue, breast milk, plasma and serum were retrieved from the literature by means of a systematic search. MiRNAs from each individual study were orderly ranked between 1 and 50, combined into an overall ranking per sample type and compared., Results: NAF expressed 11 unique miRNAs and shared 21/50 miRNAs with breast tissue. Seven miRNAs were shared between the five sample types. Overlap between sample types varied between 42% and 62%. Highly ranked NAF miRNAs have established roles in breast carcinogenesis., Conclusion: This is the first study to characterize and compare the unique physiological NAF-derived miRNA landscape with the physiological expression pattern in breast tissue, breast milk, plasma and serum. Breast-specific sources did not mutually overlap more than with systemic sources. Given their established role in carcinogenesis, NAF miRNA assessment could be a valuable tool in breast tumor diagnostics.

The authors of the recently published review, "Why the Gold Standard Approach by Mammography Demands Extension by Multiomics [...].