Circulating Micro-RNAs as Potential Blood-Based Markers for Early Stage Breast Cancer Detection

INTRODUCTION: MicroRNAs (miRNAs, miRs) are a class of small, non-coding RNA molecules with relevance as regulators of gene expression thereby affecting crucial processes in cancer development. MiRNAs offer great potential as biomarkers for cancer detection due to their remarkable stability in blood and their characteristic expression in many different diseases. We investigated whether microarray-based miRNA profiling on whole blood could discriminate between early stage breast cancer patients and healthy controls. METHODS: We performed microarray-based miRNA profiling on whole blood of 48 early stage breast cancer patients at diagnosis along with 57 healthy individuals as controls. This was followed by a real-time semi-quantitative Polymerase Chain Reaction (RT-qPCR) validation in a separate cohort of 24 early stage breast cancer patients from a breast cancer screening unit and 24 age matched controls using two differentially expressed miRNAs (miR-202, miR-718). RESULTS: Using the significance level of p<0.05, we found that 59 miRNAs were differentially expressed in whole blood of early stage breast cancer patients compared to healthy controls. 13 significantly up-regulated miRNAs and 46 significantly down-regulated miRNAs in our microarray panel of 1100 miRNAs and miRNA star sequences could be detected. A set of 240 miRNAs that was evaluated by radial basis function kernel support vector machines and 10-fold cross validation yielded a specificity of 78.8%, and a sensitivity of 92.5%, as well as an accuracy of 85.6%. Two miRNAs were validated by RT-qPCR in an independent cohort. The relative fold changes of the RT-qPCR validation were in line with the microarray data for both miRNAs, and statistically significant differences in miRNA-expression were found for miR-202. CONCLUSIONS: MiRNA profiling in whole blood has potential as a novel method for early stage breast cancer detection, but there are still challenges that need to be addressed to establish these new biomarkers in clinical use

TILGen: A Program to Investigate Immune Targets in Breast Cancer Patients - First Results on the Influence of Tumor-Infiltrating Lymphocytes

Background: Despite advancements in the treatment of primary and metastatic breast cancer, many patients lack a durable response to these treatments. Patients with triple-negative breast cancer (TNBC) and human epidermal growth factor receptor 2(HER2)-positive breast cancer who do not have a pathological complete response (pCR) after neoadjuvant chemotherapy (NACT) have a very poor prognosis. Tumor-infiltrating lymphocytes (TILs) have been identified as a predictive marker for pCR after NACT in TNBC and HER2-positive breast cancer. These patient populations could also be suitable for novel treatment strategies including neoepitope-based therapies. This work analyses the effect of TILs on the pCR in neoadjuvantly treated patients in the TILGen study and presents the procedures aimed at establishing neoepitope-based therapies in this study. Methods: Neoadjuvantly treated HER2-positive and TNBC patients were eligible for the presented analysis concerning the association between TILs and pCR. A total of 146 patients could be identified within the TILGen study. TILs were evaluated as percentage of stromal tumor tissue in core biopsies at primary diagnosis. The phenotype ‘lymphocyte-predominant breast cancer' (LPBC) was associated with pCR by logistic regression adjusted for estrogen receptor status, progesterone receptor status, HER2 status, age at diagnosis, and grading. Results: LPBC was seen in 24 (16.4%) patients. In this patient group, 66.7% achieved a pCR, while the pCR rate was 32.8% in patients with a low TIL count. The adjusted odds ratio was 6.60 (95% confidence interval 2.02-21.56; p < 0.01). Conclusion: TILs are a strong predictor of pCR in TNBC and HER2-positive breast cancer patients. Implications for the use of this information including the effect on prognosis might help to identify patients most likely to benefit from a neoepitope-based therapy approach

Breast Imaging and Interventional Procedures – the Basis for Oncoplastic Breast Surgery

Preoperative staging of breast cancer based on breast imaging is mandatory. Breast imaging is a general term that encompasses mammography, breast sonography, and magnetic resonance tomography (MRT) of the breast (magnetic resonance mammography, MRM). It is known that earlier diagnosis of breast cancer is more likely to result in a favorable oncological outcome. In this context, use and limitations of MRM in diagnosis and staging of breast cancer as well as its influence on surgical procedures have to be discussed. Different interventional procedures have been developed. The histological results of interventional procedures guided by ultrasound, stereotactic mammography or MRT have to be integrated in planning surgical resection margins in oncoplastic breast-conserving surgery. Image-guided wire markings are an important tool for planning these surgical resection margins. This paper gives an overview on the importance of breast imaging, interventional procedures, and wire markings for breast-conserving surgical therapy.Die komplementäre Mammadiagnostik bildet die Grundlage für das präoperative Staging beim Mammakarzinom. Zur komplementären Mammadiagnostik gehören im Speziellen die Mammografie, die Mammasonografie und die Magnetresonanztomografie (MRT) der Mamma (Magnetresonanz-Mammografie, MRM). Je früher die Diagnose eines Mammakarzinoms erfolgt, desto besser ist die Prognose. In diesem Zusammenhang müssen besonders Stellenwert, Einsatz und Limitationen der MRM bei Diagnose und Staging des Mammakarzinoms sowie ihre Auswirkungen auf das operative Vorgehen diskutiert werden. Die histologischen Ergebnisse nach sonografisch, stereotaktisch oder MRT-gesteuerter interventioneller Diagnostik sollten in die Planung der Resektionsgrenzen im Rahmen der brusterhaltenden, onkoplastischen Mammachirurgie integriert werden. Für die Planung der Resektionsgrenzen stellen die unterschiedlichsten bildgebend gesteuerten Markierungstechniken wichtige Instrumente dar. Diese Arbeit gibt einen aktuellen Überblick über die Bedeutung der bildgebenden Mammadiagnostik, der interventionellen Diagnostik und der Markierungstechniken für die Planung und Durchführung der brusterhaltenden, operativen Therapie des Mammakarzinoms

Der Gynäkologe / Zukünftige Entwicklungen in der Brustbildgebung

Bildgebung spielt eine zentrale Rolle in der Sekundär- und Tertiärprävention von Brustkrebs. Bildgebende Verfahren werden eingesetzt im Screening, zur Abklärung klinischer Auffälligkeiten oder im Screening detektierter Befunde und zur Therapieplanung anhand invasiver, bildgestützter Biopsien sowie zur Abschätzung der Ausdehnung oder des Ansprechens auf neoadjuvante Therapien und für präoperative Clip- und Drahtmarkierungen. Auch in der Verlaufsbeobachtung nach abgeschlossener Brustkrebstherapie spielt die Bildgebung eine wesentliche Rolle. Die wichtigsten bildgebenden Verfahren sind nach wie vor Mammographie und Ultraschall. Während Letzterer an einer starken Untersucherabhängigkeit leidet, ist die Sensitivität der Mammographie im Fall der röntgenologisch dichten Brust eingeschränkt. Sowohl Mammographie als auch Ultraschall in ihrer Basisform bieten keine krankheitsspezifischen Informationen und erfordern so eine invasive Abklärung eines Großteils der auffälligen Befunde mit letztendlich benigner Diagnose. Aus diesem Grund besteht großes Interesse an der Weiterentwicklung bestehender Verfahren und an der Entwicklung neuer bildgebender Verfahren zur Reduktion falsch-positiver Befunde bei gleichzeitig möglichst verbesserter Tumordetektion. Der vorliegende Übersichtsartikel adressiert die relevantesten, bereits zur Verfügung stehenden Techniken und ihren potenziellen Nutzen in der Praxis.Imaging plays a central role in secondary and tertiary breast cancer prevention. Imaging procedures are used for screening, to clarify clinical abnormalities or findings detected in screening and to guide treatment by confirming the diagnosis by image-guided biopsy, by assessing disease extent, response to neoadjuvant treatment and preoperative clip and wire localization. Finally, imaging is used for follow-up examinations after breast cancer treatment. The most broadly applied imaging tests are mammography and ultrasound. While the latter suffers from interobserver variability, the sensitivity of mammography is reduced in women with radiologically dense breasts. In their basic forms mammography and ultrasound do not provide disease-specific information and therefore necessitate invasive clarification of the majority of conspicuous findings that ultimately yield benign diagnoses. Therefore, improvements of old and new imaging tests are developed and tested to reduce the number of false positive findings while also trying to improve breast cancer detection rates. The current review article addresses the most relevant and currently used techniques and their potential benefits in clinical practice.(VLID)358038

Differentiation of ductal carcinoma in situ versus fibrocystic changes by magnetic resonance imaging: are there pathognomonic imaging features?

Background In breast magnetic resonance imaging (MRI), the diagnosis of ductal carcinoma in situ (DCIS) remains controversial; the most challenging cause of false-positive DCIS diagnosis is fibrocystic changes (FC). Purpose To search for typical and pathognomonic patterns of DCIS and FC using a standard clinical MRI protocol. Material and Methods Consecutive patients scheduled for breast MRI (standardized protocols @ 1.5T: dynamic-T1-GRE before/after Gd-DTPA [0.1 mmol/kg body weight (BW)]; T1-TSE), with subsequent pathological sampling, were investigated. Sixteen MRI descriptors were prospectively assessed by two experienced radiologists in consensus (blinded to pathology) and explored in patients with DCIS (n = 77) or FC (n = 219). Univariate and multivariate statistics were performed to identify the accuracy of descriptors (alone, combined). Furthermore, pathognomonic descriptor-combinations with an accuracy of 100% were explored (χ2 statistics; decision trees). Results Six breast MRI descriptors significantly differentiated DCIS from FC (Pcorrected < 0.05; odds ratio < 7.9). Pathognomonic imaging features were present in 33.8% (n = 100) of all cases allowing the identification of 42.9% of FC (n = 94). Conclusion Pathognomonic patterns of DCIS and FC were frequently observed in a standard clinical MRI protocol. Such imaging patterns could decrease the false-positive rate of breast MRI and hence might help to decrease the number of unnecessary biopsies in this clinically challenging subgroup