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Importance: The role of axillary lymph node dissection (ALND) to determine nodal burden to inform systemic therapy recommendations in patients with clinically node (cN)-positive breast cancer (BC) is currently unknown., Objective: To address the association of ALND with systemic therapy in cN-positive BC in the upfront surgery setting and after neoadjuvant chemotherapy (NACT)., Design, Setting, and Participants: This was a prospective, observational, cohort study conducted from August 2018 to June 2022. This was a preplanned study within the phase 3 randomized clinical OPBC-03/TAXIS trial. Included were patients with confirmed cN-positive BC from 44 private, public, and academic breast centers in 6 European countries. After NACT, residual nodal disease was mandatory, and a minimum follow-up of 2 months was required., Exposures: All patients underwent tailored axillary surgery (TAS) followed by ALND or axillary radiotherapy (ART) according to TAXIS randomization. TAS removed suspicious palpable and sentinel nodes, whereas imaging-guidance was optional. Systemic therapy recommendations were at the discretion of the local investigators., Results: A total of 500 patients (median [IQR] age, 57 [48-69] years; 487 female [97.4%]) were included in the study. In the upfront surgery setting, 296 of 335 patients (88.4%) had hormone receptor (HR)-positive and Erb-B2 receptor tyrosine kinase 2 (ERBB2; formerly HER2 or HER2/neu)-negative disease: 145 (49.0%) underwent ART, and 151 (51.0%) underwent ALND. The median (IQR) number of removed positive lymph nodes without ALND was 3 (1-4) nodes compared with 4 (2-9) nodes with ALND. There was no association of ALND with the proportion of patients undergoing adjuvant chemotherapy (81 of 145 [55.9%] vs 91 of 151 [60.3%]; adjusted odds ratio [aOR], 0.72; 95% CI, 0.19-2.67) and type of systemic therapy. Of 151 patients with NACT, 74 (51.0%) underwent ART, and 77 (49.0%) underwent ALND. The ratio of removed to positive nodes was a median (IQR) of 4 (3-7) nodes to 2 (1-3) nodes and 15 (12-19) nodes to 2 (1-5) nodes in the ART and ALND groups, respectively. There was no observed association of ALND with the proportion of patients undergoing postneoadjuvant systemic therapy (57 of 74 [77.0%] vs 55 of 77 [71.4%]; aOR, 0.86; 95% CI, 0.43-1.70), type of postneoadjuvant chemotherapy (eg, capecitabine: 10 of 74 [13.5%] vs 10 of 77 [13.0%]; trastuzumab emtansine-DM1: 9 of 74 [12.2%] vs 11 of 77 [14.3%]), or endocrine therapy (eg, aromatase inhibitors: 41 of 74 [55.4%] vs 36 of 77 [46.8%]; tamoxifen: 8 of 74 [10.8%] vs 6 of 77 [7.8%])., Conclusion: Results of this cohort study suggest that patients without ALND were significantly understaged. However, ALND did not inform systemic therapy recommendations.

Purpose: The aim of this study was to evaluate clinical practice heterogeneity in use of neoadjuvant systemic therapy (NST) for patients with clinically node-positive breast cancer in Europe., Methods: The study was preplanned in the international multicenter phase-III OPBC-03/TAXIS trial (ClinicalTrials.gov Identifier: NCT03513614) to include the first 500 randomized patients with confirmed nodal disease at the time of surgery. The TAXIS study's pragmatic design allowed both the neoadjuvant and adjuvant setting according to the preferences of the local investigators who were encouraged to register eligible patients consecutively., Results: A total of 500 patients were included at 44 breast centers in six European countries from August 2018 to June 2022, 165 (33%) of whom underwent NST. Median age was 57 years (interquartile range [IQR], 48-69). Most patients were postmenopausal (68.4%) with grade 2 and 3 hormonal receptor-positive and human epidermal growth factor receptor 2-negative breast cancer with a median tumor size of 28 mm (IQR 20-40). The use of NST varied significantly across the countries (p < 0.001). Austria (55.2%) and Switzerland (35.8%) had the highest percentage of patients undergoing NST and Hungary (18.2%) the lowest. The administration of NST increased significantly over the years (OR 1.42; p < 0.001) and more than doubled from 20 to 46.7% between 2018 and 2022., Conclusion: Substantial heterogeneity in the use of NST with HR+/HER2-breast cancer exists in Europe. While stringent guidelines are available for its use in triple-negative and HER2+ breast cancer, there is a need for the development of and adherence to well-defined recommendations for HR+/HER2-breast cancer., (© 2023. The Author(s).)

Aim: We developed tailored axillary surgery (TAS) to reduce the axillary tumor volume in patients with clinically node-positive breast cancer to the point where radiotherapy can control it. The aim of this study was to quantify the extent of tumor load reduction achieved by TAS., Methods: International multicenter prospective study embedded in a randomized trial. TAS is a novel pragmatic concept for axillary surgery de-escalation that combines palpation-guided removal of suspicious nodes with the sentinel procedure and, optionally, imaging-guided localization. Pre-specified study endpoints quantified surgical extent and reduction of tumor load., Results: A total of 296 patients were included at 28 sites in four European countries, 125 (42.2%) of whom underwent neoadjuvant chemotherapy (NACT) and 71 (24.0%) achieved nodal pathologic complete response. Axillary metastases were detectable only by imaging in 145 (49.0%) patients. They were palpable in 151 (51.0%) patients, of whom 63 underwent NACT and 21 had residual palpable disease after NACT. TAS removed the biopsied and clipped node in 279 (94.3%) patients. In 225 patients with nodal disease at the time of surgery, TAS removed a median of five (IQR 3-7) nodes, two (IQR 1-4) of which were positive. Of these 225 patients, 100 underwent ALND after TAS, which removed a median of 14 (IQR 10-17) additional nodes and revealed additional positive nodes in 70/100 (70%) of patients. False-negative rate of TAS in patients who underwent subsequent ALND was 2.6%., Conclusions: TAS selectively reduced the tumor load in the axilla and remained much less radical than ALND., Competing Interests: Declaration of interest statement Outside the submitted work, W.P. Weber received research support from Takeda Pharmaceuticals International paid to the Swiss Group for Clinical Cancer Research (SAKK) and personal honoraria from Genomic Health, Inc., USA. Support for meetings was paid to his institution from Sandoz, Genomic Health, Medtronic, Novartis Oncology, Pfizer and Eli Lilly. Hisham Fansa has no financial interest, and receives royalty payments from Springer-Nature publishers for two textbooks on breast surgery. Florian Fitzal was editor of Oncoplastic Surgery part I and II (SPRINGER), received travel support and scientific support from COMESA (Mentor), NOVARTIS, ROCHE, ASTRA ZENECA, PFIZER, MYRIAD, NANOSTRING, BONDIMED (Polytech, Integra), Lilly, had an advisory role for PFIZER, ASTRA ZENECA, LILLY, ROCHE, and was founder of BREAST ANALYZING TOOL (BAT; breastanalyzing.com). All other authors declare no competing interests relevant to this manuscript., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Several studies and a meta-analysis showed that fibrin sealant patches reduced lymphatic drainage after various lymphadenectomy procedures. Our goal was to investigate the impact of these patches on drainage after axillary dissection for breast cancer., Methods: In a phase III superiority trial, we randomized patients undergoing breast-conserving surgery at 14 Swiss sites to receive versus not receive three large TachoSil ® patches in the dissected axilla. Axillary drains were inserted in all patients. Patients and investigators assessing outcomes were blinded to group assignment. The primary endpoint was total volume of drainage., Results: Between March 2015 and December 2016, 142 patients were randomized (72 with TachoSil ® and 70 without). Mean total volume of drainage in the control group was 703 ml [95% confidence interval (CI) 512-895 ml]. Application of TachoSil ® did not significantly reduce the total volume of axillary drainage [mean difference (MD) -110 ml, 95% CI -316 to 94, p = 0.30]. A total of eight secondary endpoints related to drainage, morbidity, and quality of life were not improved by use of TachoSil ® . The mean total cost per patient did not differ significantly between the groups [34,253 Swiss Francs (95% CI 32,625-35,880) with TachoSil ® and 33,365 Swiss Francs (95% CI 31,771-34,961) without, p = 0.584]. In the TachoSil ® group, length of stay was longer (MD 1 day, 95% CI 0.3-1.7, p = 0.009), and improvement of pain was faster, although the latter difference was not significant [2 days (95% CI 1-4) vs. 5.5 days (95% CI 2-11); p = 0.2]., Conclusions: TachoSil ® reduced drainage after axillary dissection for breast cancer neither significantly nor relevantly.

Purpose: Evaluation of feasibility and clinical performance of a tomosynthesis-guided vacuum-assisted breast biopsy (TVAB) system compared to Stereotaxy (SVAB)., Materials and Methods: All biopsies were performed on consecutive patients: 148 TVAB biopsies and 86 biopsies on different patients using SVAB. Evaluation criteria for each biopsy were technical feasibility, histopathology, procedure time, and complications., Results: All 148 TVAB biopsies were technically successful, and gained the targeted groups of microcalcifications (100 %). In 1 of 86 SVAB procedures, it was not possible to gain the targeted microcalcifications (1 %), in 3 of 86 the needle had to be adjusted (4 %). All TVAB biopsies were performed without clinically relevant complications. Distortions were biopsied exclusively by TVAB, mean size 0.9 cm, p < 0.0001. Of the 24 distortions, 13 were cancer, 11 Radial Scars/ CSL. The mean procedure time for TVAB was 15.4 minutes (range 7-28 min), for SVAB 23 minutes (range 11-46 min), p < 0.0001., Conclusions: TVAB is able to biopsy small architectural distortions with high accuracy. TVAB is easily feasible and appears to have the same degree of clinical performance for diagnosing microcalcifications. The increased number of biopsied distortions by TVAB is presumably due to increased use of tomosynthesis and its diagnostic potential., Key Points: • TVAB is easily feasible. • TVAB is able to target architectural distortions with high accuracy. • TVAB diagnoses microcalcifications with the same clinical performance as SVAB.

Sentinel lymph node biopsy (SLNB) is the standard surgical procedure for the axilla in early node-negative breast cancer. To date, the "gold standard" to localize the sentinel lymph node (SLN) is the radiotracer (99m)Tc with or without blue dye. The aim of this study was to evaluate potential equivalency of the new SentiMag(®) technique in comparison to the "gold standard". Within this prospective, multicentric and multinational non-inferiority study including 150 patients (99m)Tc was compared with the magnetic technique, using superparamagnetic iron oxide particles (SPIOs, Sienna+(®)) for localization of SLNs. The results showed a detection rate per patient of 97.3% (146/150) for (99m)Tc vs. 98.0% (147/150) for Sienna+(®) with a similar average number of removed SLNs per patient and a higher per patient malignancy detection rate for the SPIO tracer. We obtained convincing results that magnetic SLNB can be performed easily, safely and equivalently well in comparison to the radiotracer method., (Copyright © 2014 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: The presence of lymph node metastases is the most important prognostic factor in early stage breast cancer. Whether bone marrow micrometastases (BMM) impact the prognosis in sentinel lymph node (SLN)-negative breast cancer patients remains a matter of debate. Therefore, the objective of this study was to assess the impact of BMM on 5-year disease-free and overall survival among those patients., Methods: We analyzed 410 patients with early stage breast cancer (pT1 and pT2 ≤ 3 cm, cN0) who were prospectively enrolled into the Swiss Multicenter Sentinel Lymph Node Study in Breast Cancer between January 2000 and December 2003. All patients underwent bone marrow aspiration followed by SLN biopsy. All SLN were stained with hematoxylin and eosin and immunohistochemistry (Lu-5, CK-22). Cancer cells in the bone marrow were identified after staining with monoclonal antibodies A45-B/B3 against CK-8, -18, and -19., Results: Negative SLN were found in 67.6% (277 of 410) of the enrolled patients. Of those, BMM status was negative in 75.8% (210 of 277) and positive in 24.2% (67 of 277) patients. Median follow-up was 61 (range 11-96) months. Five-year disease-free survival was 93.6% (95% confidence interval [CI] 89.1-96.0) in BMM-negative and 92.2% (95% CI 82.5-96.2) in BMM-positive patients (p = 0.50). Five-year overall survival was 92.7% (95% CI 87.9-95.8) for the BMM-negative and 92.5% (95% CI 83.4-96.2) for the BMM-positive group (p = 0.85)., Conclusions: This is one of the first prospective studies to examine 5-year disease-free and overall survivals in SLN-negative patients in correlation to their BMM status. Although BMM are identified in one of four SLN-negative patients, they do not impact disease-free and overall survival.

Objective: The purpose of this study is to compare the diagnostic value of one-view digital breast tomosynthesis versus two-view full-field digital mammography (FFDM) alone, and versus a combined reading of both modalities., Materials and Methods: The datasets of one-view digital breast tomosynthesis and two-view FFDM of abnormal mammograms in 144 consecutive women admitted for diagnostic workup with clinical signs and symptoms (n = 78) or recalled from screening (n = 66) were read alone and in a combined setting. The malignant or benign nature of the lesions was established by histologic analysis of biopsied lesions or by 12-16-month follow-up., Results: Eighty-six of the 144 patients were found to have breast cancer. The BI-RADS categories for one-view digital breast tomosynthesis were significantly better than those for two-view FFDM (p < 0.001) and were equal to those of the combined reading in both women admitted for diagnostic workup and women recalled from screening. The sensitivity and negative predictive values of digital breast tomosynthesis were superior to those of FFDM in fatty and dense breasts overall and in women admitted for diagnostic workup and in women recalled from screening. Only 11% of digital breast tomosynthesis examinations required additional imaging, compared with 23% of FFDMs., Conclusion: In patients with abnormal mammograms, one-view digital breast tomosynthesis had better sensitivity and negative predictive value than did FFDM in patients with fatty and dense breasts. They also suggest that digital breast tomosynthesis would likely increase the predictive values if incorporated in routine screening.

Objective: To assess the accuracy of sentinel lymph node (SLN) frozen section in a prospective multicenter study of early-stage breast cancer patients., Summary Background Data: The decision to perform an immediate completion axillary node dissection (ALND) is based on results of SLN frozen section. However, SLN frozen sections are not routinely performed in all centers. Moreover, the accuracy of SLN frozen section remains a matter of great debate., Methods: Prospective multicenter trial analyzing 659 early stage breast cancer patients (pT1 and pT2

Breast conserving surgery followed by radiation therapy is the treatment of choice for early breast cancer. For patients who choice or need a mastectomy, breast reconstruction provides an acceptable alternative. Breast cancer surgery has been evolving through minimally invasive approaches. Sentinel node biopsy has already remplaced axillary lymph node dissection in the evaluation of the axilla. Local ablation of the tumor may be a valuable alternative to surgery in the future.

Background: The sentinel lymph node (SLN) status has proven to accurately reflect the remaining axillary lymph nodes and represents the most important prognostic factor. It is unknown whether an association exists between the SLN status and the presence of bone marrow (BM) micrometastases. The objective of the present investigation was to evaluate whether or not such an association exists., Methods: In the present investigation 410 patients with early stage breast cancer (pT1 and pT2

Objective: To assess the morbidity after sentinel lymph node (SLN) biopsy compared with SLN and completion level I and II axillary lymph node dissection (ALND) in a prospective multicenter study., Summary Background Data: ALND after breast cancer surgery is associated with considerable morbidity. We hypothesized: 1) that the morbidity in patients undergoing SLN biopsy only is significantly lower compared with those after SLN and completion ALND level I and II; and 2) that SLN biopsy can be performed with similar intermediate term morbidity in academic and nonacademic centers., Methods: Patients with early stage breast cancer (pT1 and pT2

Background and Purpose: Extracapsular spread (ECS) is frequent, but the specific sites of relapse are seldom given in the literature. In this study it was evaluated, if ECS might be an indicator for axillary irradiation., Patients and Methods: After a retrospective review of pathology reports, the information about ECS was available in 254 lymph node-positive patients: ECS was absent in 34% (ECS-negative; n = 87) and present in 66% (ECS-positive; n = 167). All patients were irradiated locally, 78 patients got periclavicular and 74 axillary irradiation (median total dose: 50.4 Gy). 240/254 patients (94.5%) received systemic treatment/s. Mean follow-up was 46 months., Results: The regional relapse rate was 4.6% without ECS versus 9.6% with ECS. The 5-year axillary relapse-free survival was 100% in ECS-negative and 90% in ECS-positive patients (p = 0.01), whereas corresponding values for periclavicular relapse-free survival (with ECS: 91% +/- 4%; without ECS: 94% +/- 3%; p = 0.77) and local relapse-free survival (with ECS: 86% +/- 4%; without ECS: 91% +/- 3%; p = 0.69) were not significantly different. chi(2)-tests revealed a high correlation of ECS with T-stage, number of positive lymph nodes and progesterone receptor status, comparisons with estrogen receptor, grade, or age were not significant. In multivariate analysis number of positive lymph nodes was solely significant for regional failure. Dividing the patients into those with one to three and those with four or more positive lymph nodes, ECS lost its significance for axillary failure., Conclusion: ECS was accompanied by an enhanced axillary failure rate in univariate analysis, which was no longer true after adjusting for the number of positive lymph nodes.

It is still an open debate whether tumor emboli in dermal lymphatics without inflammatory signs represent a similar bad prognosis like inflammatory breast cancer. We evaluated the prognostic role of dermal lymphatic invasion (DLI) in breast cancer with (DLI + ID) or without (DLI w/o ID) inflammatory disease (ID). From August 1988 to January 2000, 42 patients with DLI were irradiated. Twenty-five were classified as pT4, 13 out of them as pT4d (inflammatory disease); the 17 remaining patients had 1 T1c, 12 T2 and 4 T3 cancers with DLI. Axillary dissection revealed node-positive disease in 39/41 patients (median, 9 positive nodes). Thirty-eight out of 42 patients received adjuvant systemic treatment(s). After a mean follow-up of 33 months, 22/42 patients (52%) are disease-free. The actuarial 3-year disease-free survival is 50% (DLI w/o ID, 61%; DLI + ID, 31%; p < 0.03); the corresponding overall survival was 69% (DLI w/o ID, 87%; DLI + ID, 37%; p = 0.005). The presence or absence of ID was the only significant parameter for all endpoints in multivariate analyses. Dissemination occurred in 19 (45%), local relapse in 7 (n = 17%) and regional failure in 4 (10%). Nine patients (21%) had contralateral breast cancer/relapse. Despite the same histopathologic presentation, DLI w/o ID offered a significantly better disease-free survival and overall survival than ID. The finding of dermal lymphatic tumor invasion predicts a high probability for node-positive disease., (Copyright 2003 Wiley-Liss, Inc.)

Background: Hypoxia-inducible factor 1 alpha (hif-1alpha) furnishes tumor cells with the means of adapting to stress parameters like tumor hypoxia and promotes critical steps in tumor progression and aggressiveness. We investigated the role of hif-1alpha expression in patients with node-positive breast cancer., Methods: Tumor samples from 77 patients were available for immunohistochemistry. The impact of hif-1alpha immunoreactivity on survival endpoints was determined by univariate and multivariate analyses, and correlations to clinicopathological characteristics were determined by cross-tabulations., Results: hif-1alpha was expressed in 56% (n = 43/77) of the patients. Its expression correlated with progesterone receptor negativity (P = 0.002). The Kaplan-Meier curves revealed significantly shorter distant metastasis-free survival (DMFS) (P = 0.04, log-rank) and disease-free survival (DFS) (P = 0.04, log-rank) in patients with increased hif-1alpha expression. The difference in overall survival (OS) did not attain statistical significance (5-year OS, 66% without hif-1alpha expression and 55% with hif-1alpha expression; P = 0.21). The multivariate analysis failed to reveal an independent prognostic value for hif-1alpha expression in the whole patient group. The only significant parameter for all endpoints was the T stage (T3/T4 versus T1/T2: DMFS, relative risk = 3.16, P = 0.01; DFS, relative risk = 2.57, P = 0.03; OS, relative risk = 3.03, P = 0.03). Restricting the univariate and multivariate analyses to T1/T2 tumors, hif-1alpha expression was a significant parameter for DFS and DMFS., Conclusions: hif-1alpha is expressed in the majority of patients with node-positive breast cancer. It can serve as a prognostic marker for an unfavorable outcome in those with T1/T2 tumors and positive axillary lymph nodes.

Purpose: To evaluate if locoregional radiotherapy (RT) versus local irradiation only can alter the pattern of failure in breast cancer patients with extranodal invasion., Patients and Methods: From 08/1988 to 06/1998, 81 patients with extranodal invasion were treated with adjuvant RT (median total dose: 50.4 Gy), 46/81 only locally, 35/81 loco regionally due to presumed adverse parameters. The mean number of resected (positive) lymph nodes was 17 (seven). 78 patients received adjuvant systemic treatment(s)., Results: Patients treated with locoregional RT had significantly more often lymphatic vessel invasion (LVI; 63% vs. 28%; p = 0.003), T3/T4 tumors (43% vs. 17%; p = 0.014), and four or more positive lymph nodes (91% vs. 46%; p < 0.001) than patients irradiated only locally. Disease progression occurred in 24/81 patients (locoregional RT: 26% vs. local RT: 33%). The above risk factors were highly significant of worse outcome. Despite their overrepresentation in the locoregional RT group, no difference was found between both groups in regard to disease-free survival (DFS; p = 0.83) and overall survival (OS; p = 0.56), suggesting that regional RT was able to counterbalance the increased risk. There was even a trend toward a better 3-year DFS, 61% in locoregional RT and 37% in local RT, in the subgroup of patients with four or more positive lymph nodes. In a Cox regression model, higher T-stage, four or more positive lymph nodes, and LVI remained significant. For DFS and distant metastasis-free survival (DMFS), the absence of estrogen receptors and the omission of regional RT were also significant., Conclusion: Our data suggest that the addition of regional RT might be beneficial in selected subgroups of patients with extranodal invasion and other poor prognostic factors.

Members of the Eph family of receptor tyrosine kinase have been implicated in cell-cell communication and tissue integrity during embryogenesis. We have previously demonstrated cell type specific and hormone dependent EphB4 expression in the mouse mammary parenchyma suggesting involvement in the homeostasis of this organ. Since disruption of tissue organization is crucial for metastatic dissemination, we have investigated the expression of EphB4 during carcinogenesis of the human breast. Immunohistochemical analysis of 24 normal human breast samples and 124 consecutive breast carcinomas was correlated with tumor characteristics (stage, histology, grade, lymph node involvement) and the expression of ER, PR, Ki-67, p53 and HER2. In normal breast tissue, the EphB4 protein was expressed exclusively in parenchymal cells. Strikingly, a drastic reduction in the number of EphB4 protein expressing cells was observed in almost all invasive carcinomas analyzed, irrespective of the tumor type (p<0.0001). Furthermore, we found a highly significant correlation between EphB4 positivity and low histological grading of the tumor cells (p=0.002) suggesting that in breast cancer, EphB4 expression is not compatible with tumor progression. This raises the possibility that EphB4 could represent a potent tool for therapeutic intervention.