Which Patients Do We Need to Test for BRCA1/2 Mutation? Feasibility of Adjuvant Olaparib Treatment in Early Breast Cancer-Real-World Data from Two Large German Breast Centers.

BACKGROUND: Approximately 6% of women with breast cancer carry pathogenic germline variants in predisposition genes such as BRCA1 and BRCA2. Depending on personal and family cancer history, it is therefore recommended to test for hereditary breast cancer. Moreover, as shown by the phase III OlympiA trial, olaparib significantly improves overall survival in patients with HER2 negative (HER2-) early breast cancer who (1) carry a BRCA1 or BRCA2 germline mutation (gBRCA1/2-positive), (2) have received (neo)adjuvant chemotherapy and (3) are at high clinical risk. The objective of the current analysis was to determine the number of patients with early HER2- breast cancer who are at high clinical risk, according to the inclusion criteria of OlympiA, and to estimate how many of these patients would meet the criteria for hereditary cancer testing in a real-world analysis. METHODS: All patients included in this retrospective analysis were treated for early breast cancer (eBC) at the Department of Gynecology and Obstetrics, Ulm University Hospital, Germany, and the Department of Women's Health at Tuebingen University Hospital, Germany, between January 2018 and December 2020. Patients were identified as high risk, in line with the clinicopathological determiners used in the OlympiA trial. The criteria of the German Consortium for Hereditary Breast and Ovarian Cancer were used to identify patients who qualify for hereditary cancer testing. RESULTS: Of 2384 eligible patients, 1738 patients (72.9%) showed a hormone receptor positive (HR+)/HER2- tumor biology, 345 patients (14.5%) displayed HER2+ breast cancer and 301 patients (12.6%) suffered from HR-/HER2- breast cancer (TNBC). Of 2039 HER2- breast cancer patients, 271 patients (13.3%) were at high clinical risk. This cohort encompassed 130 of the 1738 patients with HR+/HER2- breast cancer (7.5%) and 141 of 301 patients with TNBC (46.8%). A total of 121 of 271 patients (44.6%) with high clinical risk met the criteria for hereditary cancer testing (34 of 130 (26.2%) HR+/HER2- patients and 87 of 141 (61.7%) patients with TNBC). CONCLUSION: Approximately one in ten patients with HR+/HER2-, and half of the patients with TNBC, meet the high-risk criteria according to OlympiA. Half of these patients do not meet the criteria for hereditary cancer testing and should therefore be tested for the presence of gBRCA1/2 mutations, irrespective of their own or family cancer history. The overall number of patients with early breast cancer benefiting from olaparib needs to be investigated in future studies.

Best Practice Guideline - DEGUM Recommendations on Breast Ultrasound. / Best Practice Guideline ­ Empfehlungen der DEGUM zur Durchführung und Beurteilung der Mammasonografie.

Alongside mammography, breast ultrasound is an important and well-established method in assessment of breast lesions. With the "Best Practice Guideline", the DEGUM Breast Ultrasound (in German, "Mammasonografie") working group, intends to describe the additional and optional application modalities for the diagnostic confirmation of breast findings and to express DEGUM recommendations in this Part II, in addition to the current dignity criteria and assessment categories published in Part I, in order to facilitate the differential diagnosis of ambiguous lesions.The present "Best Practice Guideline" has set itself the goal of meeting the requirements for quality assurance and ensuring quality-controlled performance of breast ultrasound. The most important aspects of quality assurance are explained in this Part II of the Best Practice Guideline.

Potential of Lesion-to-Fat Elasticity Ratio Measured by Shear Wave Elastography to Reduce Benign Biopsies in BI-RADS 4 Breast Lesions.

OBJECTIVES: We evaluated whether lesion-to-fat ratio measured by shear wave elastography in patients with Breast Imaging Reporting and Data System (BI-RADS) 3 or 4 lesions has the potential to further refine the assessment of B-mode ultrasound alone in breast cancer diagnostics. METHODS: This was a secondary analysis of an international diagnostic multicenter trial (NCT02638935). Data from 1288 women with breast lesions categorized as BI-RADS 3 and 4a-c by conventional B-mode ultrasound were analyzed, whereby the focus was placed on differentiating lesions categorized as BI-RADS 3 and BI-RADS 4a. All women underwent shear wave elastography and histopathologic evaluation functioning as reference standard. Reduction of benign biopsies as well as the number of missed malignancies after reclassification using lesion-to-fat ratio measured by shear wave elastography were evaluated. RESULTS: Breast cancer was diagnosed in 368 (28.6%) of 1288 lesions. The assessment with conventional B-mode ultrasound resulted in 53.8% (495 of 1288) pathologically benign lesions categorized as BI-RADS 4 and therefore false positives as well as in 1.39% (6 of 431) undetected malignancies categorized as BI-RADS 3. Additional lesion-to-fat ratio in BI-RADS 4a lesions with a cutoff value of 1.85 resulted in 30.11% biopsies of benign lesions which correspond to a reduction of 44.04% of false positives. CONCLUSIONS: Adding lesion-to-fat ratio measured by shear wave elastography to conventional B-mode ultrasound in BI-RADS 4a breast lesions could help reduce the number of benign biopsies by 44.04%. At the same time, however, 1.98% of malignancies were missed, which would still be in line with American College of Radiology BI-RADS 3 definition of <2% of undetected malignancies.

The Potential of Shear Wave Elastography to Reduce Unnecessary Biopsies in Breast Cancer Diagnosis: An International, Diagnostic, Multicenter Trial.

PURPOSE: In this prospective, multicenter trial we evaluated whether additional shear wave elastography (SWE) for patients with BI-RADS 3 or 4 lesions on breast ultrasound could further refine the assessment with B-mode breast ultrasound for breast cancer diagnosis. MATERIALS AND METHODS: We analyzed prospective, multicenter, international data from 1288 women with breast lesions rated by conventional 2 D B-mode ultrasound as BI-RADS 3 to 4c and undergoing 2D-SWE. After reclassification with SWE the proportion of undetected malignancies should be < 2 %. All patients underwent histopathologic evaluation (reference standard). RESULTS: Histopathologic evaluation showed malignancy in 368 of 1288 lesions (28.6 %). The assessment with B-mode breast ultrasound resulted in 1.39 % (6 of 431) undetected malignancies (malignant lesions in BI-RADS 3) and 53.80 % (495 of 920) unnecessary biopsies (biopsies in benign lesions). Re-classifying BI-RADS 4a patients with a SWE cutoff of 2.55 m/s resulted in 1.98 % (11 of 556) undetected malignancies and a reduction of 24.24 % (375 vs. 495) of unnecessary biopsies. CONCLUSION: A SWE value below 2.55 m/s for BI-RADS 4a lesions could be used to downstage these lesions to follow-up, and therefore reduce the number of unnecessary biopsies by 24.24 %. However, this would come at the expense of some additionally missed cancers compared to B-mode breast ultrasound (rate of undetected malignancies 1.98 %, 11 of 556, versus 1.39 %, 6 of 431) which would, however, still be in line with the ACR BI-RADS 3 definition (< 2 % of undetected malignancies).

Intelligent multi-modal shear wave elastography to reduce unnecessary biopsies in breast cancer diagnosis (INSPiRED 002): a retrospective, international, multicentre analysis.

BACKGROUND: Breast ultrasound identifies additional carcinomas not detected in mammography but has a higher rate of false-positive findings. We evaluated whether use of intelligent multi-modal shear wave elastography (SWE) can reduce the number of unnecessary biopsies without impairing the breast cancer detection rate. METHODS: We trained, tested, and validated machine learning algorithms using SWE, clinical, and patient information to classify breast masses. We used data from 857 women who underwent B-mode breast ultrasound, SWE, and subsequent histopathologic evaluation at 12 study sites in seven countries from 2016 to 2019. Algorithms were trained and tested on data from 11 of the 12 sites and externally validated using the additional site's data. We compared findings to the histopathologic evaluation and compared the diagnostic performance between B-mode breast ultrasound, traditional SWE, and intelligent multi-modal SWE. RESULTS: In the external validation set (n = 285), intelligent multi-modal SWE showed a sensitivity of 100% (95% CI, 97.1-100%, 126 of 126), a specificity of 50.3% (95% CI, 42.3-58.3%, 80 of 159), and an area under the curve of 0.93 (95% CI, 0.90-0.96). Diagnostic performance was significantly higher compared to traditional SWE and B-mode breast ultrasound (P < 0.001). Unlike traditional SWE, positive-predictive values of intelligent multi-modal SWE were significantly higher compared to B-mode breast ultrasound. Unnecessary biopsies were reduced by 50.3% (79 versus 159, P < 0.001) without missing cancer compared to B-mode ultrasound. CONCLUSION: The majority of unnecessary breast biopsies might be safely avoided by using intelligent multi-modal SWE. These results may be helpful to reduce diagnostic burden for patients, providers, and healthcare systems.

Intraoperative Ultrasound-Guided Excision of Non-Palpable and Palpable Breast Cancer: Systematic Review and Meta-Analysis.

Wire-guided localization (WGL) is the most frequently used localization technique in non-palpable breast cancer (BC). However, low negative margin rates, patient discomfort, and the possibility of wire dislocation have been discussed as potential disadvantages, and re-operation due to positive margins may increase relapse risk. Intraoperative ultrasound (IOUS)-guided excision allows direct visualization of the lesion and the resection volume and reduces positive margins in palpable and non-palpable tumors. We performed a systematic review on IOUS in breast cancer and 2 meta-analyses of randomized clinical trials (RCTs). In non-palpable BC, 3 RCTs have shown higher negative margin rates in the IOUS arm compared to WGL. Meta-analysis confirmed a significant difference between IOUS and WGL in terms of positive margins favoring IOUS (risk ratio 4.34, p < 0.0001, I2 = 0%). 41 cohort studies including 3291 patients were identified, of which most reported higher negative margin and lower re-operation rates if IOUS was used. In palpable BC, IOUS was compared to palpation-guided excision in 3 RCTs. Meta-analysis showed significantly higher rates of positive margins in the palpation arm (risk ratio 2.84, p = 0.0047, I2 = 0%). In 13 cohort studies including 942 patients with palpable BC, negative margin rates were higher if IOUS was used, and tissue volumes were higher in palpation-guided cohorts in most studies. IOUS is a safe noninvasive technique for the localization of sonographically visible tumors that significantly improves margin rates in palpable and non-palpable BC. Surgeons should be encouraged to acquire ultrasound skills and participate in breast ultrasound training.

The importance of multi-modal imaging and clinical information for humans and AI-based algorithms to classify breast masses (INSPiRED 003): an international, multicenter analysis.

OBJECTIVES: AI-based algorithms for medical image analysis showed comparable performance to human image readers. However, in practice, diagnoses are made using multiple imaging modalities alongside other data sources. We determined the importance of this multi-modal information and compared the diagnostic performance of routine breast cancer diagnosis to breast ultrasound interpretations by humans or AI-based algorithms. METHODS: Patients were recruited as part of a multicenter trial (NCT02638935). The trial enrolled 1288 women undergoing routine breast cancer diagnosis (multi-modal imaging, demographic, and clinical information). Three physicians specialized in ultrasound diagnosis performed a second read of all ultrasound images. We used data from 11 of 12 study sites to develop two machine learning (ML) algorithms using unimodal information (ultrasound features generated by the ultrasound experts) to classify breast masses which were validated on the remaining study site. The same ML algorithms were subsequently developed and validated on multi-modal information (clinical and demographic information plus ultrasound features). We assessed performance using area under the curve (AUC). RESULTS: Of 1288 breast masses, 368 (28.6%) were histopathologically malignant. In the external validation set (n = 373), the performance of the two unimodal ultrasound ML algorithms (AUC 0.83 and 0.82) was commensurate with performance of the human ultrasound experts (AUC 0.82 to 0.84; p for all comparisons > 0.05). The multi-modal ultrasound ML algorithms performed significantly better (AUC 0.90 and 0.89) but were statistically inferior to routine breast cancer diagnosis (AUC 0.95, p for all comparisons ≤ 0.05). CONCLUSIONS: The performance of humans and AI-based algorithms improves with multi-modal information. KEY POINTS: • The performance of humans and AI-based algorithms improves with multi-modal information. • Multimodal AI-based algorithms do not necessarily outperform expert humans. • Unimodal AI-based algorithms do not represent optimal performance to classify breast masses.

The potential of combined shear wave and strain elastography to reduce unnecessary biopsies in breast cancer diagnostics - An international, multicentre trial.

BACKGROUND: Shear wave elastography (SWE) and strain elastography (SE) have shown promising potential in breast cancer diagnostics by evaluating the stiffness of a lesion. Combining these two techniques could further improve the diagnostic performance. We aimed to exploratorily define the cut-offs at which adding combined SWE and SE to B-mode breast ultrasound could help reclassify Breast Imaging Reporting and Data System (BI-RADS) 3-4 lesions to reduce the number of unnecessary breast biopsies. METHODS: We report the secondary results of a prospective, multicentre, international trial (NCT02638935). The trial enrolled 1288 women with BI-RADS 3 to 4c breast masses on conventional B-mode breast ultrasound. All patients underwent SWE and SE (index test) and histopathologic evaluation (reference standard). Reduction of unnecessary biopsies (biopsies in benign lesions) and missed malignancies after recategorising with SWE and SE were the outcome measures. RESULTS: On performing histopathologic evaluation, 368 of 1288 breast masses were malignant. Following the routine B-mode breast ultrasound assessment, 53.80% (495 of 920 patients) underwent an unnecessary biopsy. After recategorising BI-RADS 4a lesions (SWE cut-off ≥3.70 m/s, SE cut-off ≥1.0), 34.78% (320 of 920 patients) underwent an unnecessary biopsy corresponding to a 35.35% (320 versus 495) reduction of unnecessary biopsies. Malignancies in the new BI-RADS 3 cohort were missed in 1.96% (12 of 612 patients). CONCLUSION: Adding combined SWE and SE to routine B-mode breast ultrasound to recategorise BI-RADS 4a patients could help reduce the number of unnecessary biopsies in breast diagnostics by about 35% while keeping the rate of undetected malignancies below the 2% ACR BI-RADS 3 definition.

Best Practice Guideline - DEGUM Recommendations on Breast Ultrasound. / Best Practice Guideline ­ Empfehlungen der DEGUM zur Durchführung und Beurteilung der Mammasonografie ­ TEIL I ­ Untersuchungstechnik, Ultraschall-DEGUM-Kriterien und deren Dokumentation.

For many years, breast ultrasound has been used in addition to mammography as an important method for clarifying breast findings. However, differences in the interpretation of findings continue to be problematic 1 2. These differences decrease the diagnostic accuracy of ultrasound after detection of a finding and complicate interdisciplinary communication and the comparison of scientific studies 3. In 1999, the American College of Radiology (ACR) created a working group (International Expert Working Group) that developed a classification system for ultrasound examinations based on the established BI-RADS classification of mammographic findings under consideration of literature data 4. Due to differences in content, the German Society for Ultrasound in Medicine (DEGUM) published its own BI-RADS-analogue criteria catalog in 2006 3. In addition to the persistence of differences in content, there is also an issue with formal licensing with the current 5th edition of the ACR BI-RADS catalog, even though the content is recognized by the DEGUM as another system for describing and documenting findings. The goal of the Best Practice Guideline of the Breast Ultrasound Working Group of the DEGUM is to provide colleagues specialized in senology with a current catalog of ultrasound criteria and assessment categories as well as best practice recommendations for the various ultrasound modalities.

Evaluation of sonographic detectability of different markers within an in vitro simulation model of the axilla.

PURPOSE: Clip-marking of axillary lymph nodes with initial biopsy-confirmed metastasis is required for targeted axillary dissection (TAD), which includes sentinel lymph node dissection (SLND) and selective localization and removal of the clipped targeted lymph node. There have been several studies which examined the feasibility of TAD in routine clinical use. In this context, the optimal clip visualisation was noted as one of the crucial limiting factors. We, therefore, evaluated the sonographic detectability of 10 different commercially available markers within an in vitro model simulating the anatomical composition of the axilla. METHODS: In this standardised model consisting of porcine fat with 30 mm thickness, the visibility of a total of ten markers was analysed in all 3 planes (parallel, diagonal, orthograde) with wire guidance and then classified into either "visibility good", "visibility moderate" or "visibility poor" with regard to the alignment of the transducer. Additionally, "real-life conditions" were simulated, in which the markers were searched without any wires guidance. RESULTS: It was observed that, while not all markers are detectable in fatty tissue, markers with spherical shape (non-embedded Inconel or Nitinol) or rectangular-shaped Titanium markers with embedded material have a clear advantage. 3D-shaped markers can always be detected in all three axes, which is of particular importance in the axilla with its pyramid shape and fatty tissue. CONCLUSION: The shape and the embedding of the material play a crucial role for visibility and efficacy of the marker, as reliable marking of suspicious and pathological axillary lymph nodes is essential for TAD.

Axillary ultrasound for prediction of response to neoadjuvant therapy in the context of surgical strategies to axillary dissection in primary breast cancer: a systematic review of the current literature.

PURPOSE: Data on the optimal treatment strategy for patients undergoing neoadjuvant therapy (NAT) who initially presented with metastatic nodes and convert to node-negative disease (cN+ → ycN0) are limited. Since NAT leads to axillary downstaging in 20-60% of patients, the question arises whether these patients might be offered less-invasive procedures than axillary dissection, such as sentinel node biopsy or targeted removal of lymph nodes marked before therapy. METHODS: We performed a systematic review of clinical studies on the use of axillary ultrasound for prediction of response to NAT and ultrasound-guided marking of metastatic nodes for targeted axillary dissection. RESULTS: The sensitivity of ultrasound for prediction of residual node metastasis was higher than that of clinical examination and MRI/PET in most studies; specificity ranged in large trials from 37 to 92%. The diagnostic performance of ultrasound after NAT seems to be associated with tumor subtype: the positive predictive value was highest in luminal, the negative in triple-negative tumors. Several trials evaluated the usefulness of ultrasound for targeted axillary dissection. Before NAT, nodes were most commonly marked using ultrasound-guided clip placement, followed by ultrasound-guided placement of a radioactive seed. After chemotherapy, the clip was detected on ultrasound in 72-83% of patients; a comparison of sonographic visibility of different clips is lacking. Detection rate after radioactive seed placement was ca. 97%. CONCLUSION: In conclusion, ultrasound improves prediction of axillary response to treatment in comparison to physical examination and serves as a reliable guiding tool for marking of target lymph nodes before the start of treatment. High quality and standardization of the examination is crucial for selection of patients for less-invasive surgery.

Percutaneous Ultrasound-Guided Core Needle Biopsy: Comparison of 16-Gauge versus 14-Gauge Needle and the Effect of Coaxial Guidance in 1065 Breast Biopsies - A Prospective Randomized Clinical Noninferiority Trial.

PURPOSE: Ultrasound-guided core needle biopsy (CNB) is considered the standard assessment to diagnose sonographically visible suspicious breast mass lesions. Based on nonrandomized trials, the current German guidelines recommend at least three cylinders with ≤ 14-gauge needle biopsy. However, no recommendation is made as to how many specimens are needed with a smaller needle size, such as 16-gauge, or if biopsy with coaxial guidance improves diagnostic accuracy and quality. Therefore, in a prospective monocentric unblinded randomized controlled clinical noninferiority trial, the diagnostic accuracy of 16-gauge versus 14-gauge core needle biopsy, with and without coaxial guidance, was evaluated. MATERIALS AND METHODS: 1065 breast biopsies were included in order to analyze the number of core samples necessary to obtain an appropriate rate of diagnostic quality adequate for histological evaluation, and to achieve high diagnostic accuracy and diagnostic yield. Histological results were verified by surgery or long-term follow-up of at least two years up to five years. RESULTS: In order to obtain an additive diagnostic accuracy of > 99 %, a minimum of two cylinders with 14-gauge biopsy were required. The diagnostic accuracy and the diagnostic quality of 14-gauge biopsy were not affected by the coaxial technique. When performing a 16-gauge biopsy, five cylinders were required to achieve an additive diagnostic accuracy of > 99 %. Without coaxial guidance, 16-gauge CNB required at least three samples, whereas five needle passes with coaxial-guided 16-gauge biopsy were needed. CONCLUSION: The diagnostic accuracy and quality of ultrasound-guided 16-gauge core needle biopsy were inferior to the 14-gauge needle size, regardless of the use of a coaxial technique.

Background parenchymal enhancement in pregnancy-associated breast cancer: a hindrance to diagnosis?

PURPOSE: The purpose of this study is to investigate the detectability of pregnancy-associated breast cancer (PABC) in lactating glandular tissue on magnetic resonance imaging (MRI) by using pre- and post-contrast acquisitions and their derived postprocessed images and compare these results to ultrasound (US) and mammography (MG). MATERIALS AND METHODS: We reviewed the electronic database for women with PABC and existing breast MRI. MR images (T2-weighted short inversion-recovery sequence [STIR], dynamic contrast-enhanced T1-weighted gradient echo sequence and postprocessed subtraction images [early post-contrast minus pre-contrast]) were retrospectively evaluated (image quality, parenchymal/tumour enhancement kintetics, tumour size and additional lesions). Supplemental subtraction images (latest post-contrast minus early post-contrast) to reduce plateau enhancement were additionally calculated and tumour conspicuity and size were measured. Findings were compared to US and MG reports. RESULTS: Nineteen patients (range 27-42 years) were included. Background parenchymal enhancement (BPE) was minimal (n=1), mild (n=3), moderate (n=7) and marked (n=8) with kinetics measured plateau (n=8), continuous (n=10) and not quantifiable (n=1). Tumour kinetics presented wash-out (n=17) and plateau (n=2). Eighteen of nineteen tumours were identified on the supplemental subtraction images. All tumours were visible on US; 12/19 were visible on MG (63.2%). MRI detected additional malignant lesions in two patients. CONCLUSION: Despite high BPE of the lactating breast, MRI securely detects carcinomas and identifies satellite lesions. By using supplemental subtraction images, background enhancement can be eliminated to facilitate diagnosis. US remains a reliable diagnostic tool, but additional MRI is recommended to rule out satellite/contralateral lesions. MG interpretations can be difficult due to high parenchymal density. KEY POINTS: • Despite high background enhancement, MRI of the breast confidently detects carcinomas and identifies further lesions in the lactating breast. • By using supplemental subtraction images, background enhancement in the lactating breast can be eliminated to facilitate diagnosis. • US remains a reliable diagnostic tool. Mammography can be limited due to extremely dense breast tissue related to lactation.

Prediction of Non-sentinel Lymph Node Metastases After Positive Sentinel Lymph Nodes Using Nomograms.

BACKGROUND/AIM: Only 30-50% of patients with sentinel lymph node (SLN) metastases present with further axillary lymph node metastases. Therefore, up to 70% of patients with positive SLN are overtreated by axillary dissection (AD) and may suffer from complications such as sensory disturbances or lymphedema. According to the current S3 guidelines, AD can be avoided in patients with a T1/T2 tumor if breast-conserving surgery with subsequent tangential irradiation is performed and no more than two SLNs are affected. Additionally, use of nomograms, that predict the probability of non-sentinel lymph node (NSLN) metastases, is recommended. Therefore, models for the prediction of NSLN metastases in our defined population were constructed and compared with the published nomograms. PATIENTS AND METHODS: In a retrospective study, 2,146 primary breast cancer patients, who underwent SLN biopsy at the University Women's Hospital in Tuebingen, were evaluated by dividing the patient group in a training and validation collective (TC or VC). Using the SLN-positive TC patients, three models for the prediction of the likelihood of NSLN metastases were adapted and were then validated using the SLN-positive VC patients. In addition, the predictive power of nomograms from Memorial Sloan Kettering Cancer Center (MSKCC), Stanford, and the Cambridge model were compared with regard to our patient collective. RESULTS: A total of 2,146 patients were included in the study. Of these, 470 patients had positive SLN, 295 consisted the training collective and 175 consisted the validation collective. In a regression model, three variants - with 11, 6 and 2 variables - were developed for the prediction of NSLN metastases in our defined population and compared to the most frequently used nomograms. Our variants with 11 and with 6 variables were proven to be a particularly suitable model and showed similarly good results as the published MSKCC nomogram. CONCLUSION: Our developed nomograms may be used as a prediction tool for NSLN metastases after positive SLN.

Relationship Between Hematogenous Tumor Cell Dissemination and Cellular Immunity in DCIS Patients.

BACKGROUND/AIM: By definition, tumor cells do not pass the epithelial basement membrane in pre-invasive lesions. However, recently, it was shown that hematogenous tumor cell dissemination already takes place in patients with ductal carcinoma in situ (DCIS), giving disseminated tumor cells (DTCs) in the bone marrow the opportunity to interact with the peripheral immune system. We, therefore, investigated the relationship between DTCs and the peripheral innate and adaptive immune system of DCIS patients, as immunosurveillance might also be impaired in pre-invasive lesions. MATERIALS AND METHODS: We analyzed the peripheral immune status of 115 DCIS patients by flow cytometry. Results were correlated with presence of DTCs, that were detected in the bone marrow by immunocytochemistry (pan-cytokeratin antibody A45-B/B3) using the automated cellular imaging system (ACIS) according to the international society of hematotherapy and graft engineering (ISHAGE) evaluation criteria. Apoptotic DTCs were characterized by positive M30 staining and cytomorphological criteria. RESULTS: In contrast to breast cancer, we found no significant correlation between appearance of DTCs and quantitative distribution of T-cell sub-populations, B and NK-cells neither in the bone marrow nor in the peripheral blood. Moreover, DTCs did not affect the expression of important immunomodulatory antigens for functional integrity of specific immune response such as, TCR-ζ, CD28 or CD95. Interestingly, 39% of DTCs were positive for M30 expression and showed cytomorphological signs of apoptosis. CONCLUSION: In contrast to breast cancer, DTCs of DCIS seem to be less immunogenic, which might result in a diverging way to evade immunosurveillance.

Ultrasound-guided cryoablation of breast fibroadenoma: a pilot trial.

PURPOSE: The aim of the study was to evaluate cryoablation (CA) under ultrasound guidance in the office setting with liquid nitrogen system for patients with fibroadenoma (FA). METHODS: For this prospective multicenter trial, an office-based cryosurgical system was used to treat histological confirmed benign FA with a maximum dimension of 3 cm. Sixty CA procedures were performed under ultrasound guidance. A freeze-thaw-freeze treatment cycle was performed according to the size of the FA. During the CA procedure continuous ultrasound monitoring was performed, verifying engulfment of the FA. Patients attended four follow-up visits at 1 week, 3, 6 months and 1 year and underwent ultrasound, physical examination and photography. RESULTS: Data were collected and analyzed in 60 cases. 59 of 60 FA (98 %) were fully engulfed by the ice ball. No serious adverse events occurred related to the IceSense3 system. At the 1-year follow-up, the FAs were gone in 93% of the cases. Prior to CA procedure, 76% of the FAs were palpable. Afterwards in some cases (22%), a scar/cryo lesion was palpable. 28% of the patients reported pain, described as mild or moderate, compared to 2% after 1 year. Cosmetic results at 12 months follow-up were reported as good or excellent in 100% by physician and in 97% by patients. CONCLUSIONS: The cryodestruction of the FA using liquid nitrogen system proved functional and safe, while showing meaningful reduction in volume, palpability, pain and cosmetic satisfying outcomes.

Detection and clinical relevance of hematogenous tumor cell dissemination in patients with ductal carcinoma in situ.

Hematogenous tumor cell dissemination is a crucial step in systemic disease progression and predicts reduced clinical outcome in breast cancer patients. Only invasive cancers are assumed to shed tumor cells into the bloodstream and infiltrate lymph nodes. However, recent studies revealed that disseminated tumor cells (DTCs) may be detected in bone marrow (BM) of patients with preinvasive lesions, i.e., ductal carcinoma in situ (DCIS). The purpose of this analysis was to examine the incidence and clinical value of DTC detection in a large series of patients with pure DCIS. 404 patients treated for DCIS at the University Hospital Tuebingen, Germany were included into this analysis. BM was analyzed by immunocytochemistry (pancytokeratin antibody A45-B/B3) using ACIS system (Chromavision) according to the ISHAGE evaluation criteria. Sentinel nodes were analyzed in 316 patients by step sectioning and hematoxylin-eosin staining. DTCs were detected in 63 of 404 patients (16 %). No correlation was observed between BM status and tumor size, grading, histology or Van Nuys prognostic index. In two cases, metastatic spread into lymph nodes was observed; isolated tumor cells were found in one patient. After a median follow-up of 45 months (range 3-131 months), 3 % of BM positive patients died compared to 1 % of BM negative patients (p = 0.254). Relapse of any kind was observed in 7 % of patients with DTCs vs. 5 % of patients without DTCs (p = 0.644). The differences in overall (p = 0.088) and disease-free survival (p = 0.982) calculated by log-rank test were not statistically significant. Tumor cell dissemination may be detected in patients diagnosed with DCIS. Whether these cells disseminate from real preinvasive mammary lesions or represent the earliest step of microinvasion, remains unclear. A longer follow-up may be necessary to accurately assess clinical value of these cells in DCIS patients.

Disseminated tumor cells as a monitoring tool for adjuvant therapy in patients with primary breast cancer.

The presence of disseminated tumor cells (DTC) in the bone marrow (BM) of early breast cancer patients at initial surgery as well as during follow-up predicts an unfavorable outcome. This study aimed to assess whether adjuvant systemic therapy has the ability to eradicate DTC and to determine the clinical impact of DTC-persistence. Between 12 and 24 months after an initial BM aspiration during primary surgery (BMA1) a second and third bone marrow aspiration (BMA2 and BMA3, respectively) was performed. DTC were identified by immunocytochemistry (pancytokeratin antibody A45-B/B3) and cytomorphology. A total of 190 patients who were DTC-positive at BMA1 were eligible for this retrospective analysis. DTC persisted in 35 of 190 (19 %) patients at BMA2 and in 11 of 71 (16 %) patients at BMA3. DTC-persistence at BMA3 was significantly lower in patients that received adjuvant endocrine therapy (p = 0.017). At BMA2, DTC-positive patients were at an increased risk of disease recurrence (HR: 4.17, 95 % CI: 1.51-11.50, p = 0.003) and death (HR: 5.02, 95 % CI: 1.156-21.83, p = 0.031). At BMA3, the presence of DTC was associated with shorter disease free survival (HR: 3.20, 95 % CI: 1.05-9.78, p = 0.010). In conclusion, a majority of initially DTC-positive primary breast cancer patients turned negative during adjuvant treatment. As DTC-persistence predicted an adverse outcome, serial DTC-determination can identify patients that will probably benefit from additional or a switch of adjuvant therapy.

Measurement of tumour size with mammography, sonography and magnetic resonance imaging as compared to histological tumour size in primary breast cancer.

BACKGROUND: Tumour size in breast cancer influences therapeutic decisions. The purpose of this study was to evaluate sizing of primary breast cancer using mammography, sonography and magnetic resonance imaging (MRI) and thereby establish which imaging method most accurately corresponds with the size of the histological result. METHODS: Data from 121 patients with primary breast cancer were analysed in a retrospective study. The results were divided into the groups "ductal carcinoma in situ (DCIS)", invasive ductal carcinoma (IDC) + ductal carcinoma in situ (DCIS)", "invasive ductal carcinoma (IDC)", "invasive lobular carcinoma (ILC)" and "other tumours" (tubular, medullary, mucinous and papillary breast cancer). The largest tumour diameter was chosen as the sizing reference in each case. Bland-Altman analysis was used to determine to what extent the imaging tumour size correlated with the histopathological tumour sizes. RESULTS: Tumour size was found to be significantly underestimated with sonography, especially for the tumour groups IDC + DCIS, IDC and ILC. The greatest difference between sonographic sizing and actual histological tumour size was found with invasive lobular breast cancer. There was no significant difference between mammographic and histological sizing. MRI overestimated non-significantly the tumour size and is superior to the other imaging techniques in sizing of IDC + DCIS and ILC. CONCLUSIONS: The histological subtype should be included in imaging interpretation for planning surgery in order to estimate the histological tumour size as accurately as possible.

Relationship between circulating tumor cells and peripheral T-cells in patients with primary breast cancer.

BACKGROUND: Detection of circulating tumor cells (CTCs) in the peripheral blood of patients with primary breast cancer is associated with poor clinical outcome. Recent studies have found evidence for immunological influence on tumor cell dormancy. We therefore investigated the relationship between peripheral T-cells and CTCs, as immunological factors may contribute to the fate of CTCs. MATERIALS AND METHODS: The peripheral blood immune status of 116 patients with primary breast cancer was analyzed by flow cytometry. Results were correlated with the presence of CTCs and clinicopathological parameters of these patients. RESULTS: Appearance of CTCs was significantly associated with grade III tumors (p<0.05). Interestingly, CTC-positive patients presented with a significant increase of peripheral CD95(FAS)-positive T-helper cells. As immune response is regulated by CD95(APO-1/FAS)-CD95ligand interaction and tumor cells induce apoptosis via the CD95/CD95L (ligand) pathway, this might lead to tumor cell escape by apoptotic T-helper cells. CONCLUSION: Absence of T-cell help at the time of priming may result in a loss of long-term antigen-activation of CD8 lymphocytes and could lead to an ineffective anti-tumor cell response. This might contribute to systemic immunosuppression and open the door for tumor cell dormancy.