Prognostic Importance of Axillary Lymph Node Response to Neoadjuvant Systemic Therapy on Axillary Surgery in Breast Cancer-A Single Center Experience.

Neoadjuvant systemic treatment (NST) is the standard treatment for HER2+, triple-negative (TN), and highly proliferative luminal HER2- early breast cancer. Pathologic complete response (pCR) after NST is associated with improved outcomes. We evaluated the predictive factors for axillary-pCR (AXpCR) and its impact on the extent of axillary node surgery. This retrospective study included 92 patients (median age of 50.4 years) with an initially node-positive disease. Patients were treated with molecular subtype-specific NST (4.3% were luminal A-like, 28.3% luminal HER2-, 26.1% luminal HER2+, 18.5% HER2+ non-luminal, and 22.8% TN). Axillary-, breast- and total-pCR were achieved in 52.2%, 48.9%, and 38% of patients, respectively. In a binary logistic regression model for the whole population, the only independent factor significantly associated with AXpCR was breast-pCR (OR 7.4; 95% CI 2.6-20.9; p < 0.001). In patients who achieved breast-pCR, aggressive subtypes (HER2+ and TN; OR 11.24) and clinical tumor stage (OR 0.10) had a significant impact on achieving AXpCR. Axillary lymph node dissection was avoided in 53.3% of patients. In conclusion, in node-positive patients with HER2+ and TN subtypes, who achieved breast-pCR after NST, de-escalation of axillary surgery could be considered in most cases.

[New treatment options in system therapy for breast carcinoma and associated new side effects].

INTRODUCTION: Breast cancer today has a significantly better prognosis than two to three decades ago. Treatment options have improved significantly. However, new systemic therapy has also resulted in side effects that clinicians must first become familiar with in order to be able to treat them optimally. This article gives an overview of the most important innovations in the last 10 years in the field of systemic therapy in breast cancer and also shows the most important side effects and their management.

The Lucerne Toolbox 2 to optimise axillary management for early breast cancer: a multidisciplinary expert consensus.

Clinical axillary lymph node management in early breast cancer has evolved from being merely an aspect of surgical management and now includes the entire multidisciplinary team. The second edition of the "Lucerne Toolbox", a multidisciplinary consortium of European cancer societies and patient representatives, addresses the challenges of clinical axillary lymph node management, from diagnosis to local therapy of the axilla. Five working packages were developed, following the patients' journey and addressing specific clinical scenarios. Panellists voted on 72 statements, reaching consensus (agreement of 75% or more) in 52.8%, majority (51%-74% agreement) in 43.1%, and no decision in 4.2%. Based on the votes, targeted imaging and standardized pathology of lymph nodes should be a prerequisite to planning local and systemic therapy, axillary lymph node dissection can be replaced by sentinel lymph node biopsy ( ± targeted approaches) in a majority of scenarios; and positive patient outcomes should be driven by both low recurrence risks and low rates of lymphoedema.

Localization Techniques for Non-Palpable Breast Lesions: Current Status, Knowledge Gaps, and Rationale for the MELODY Study (EUBREAST-4/iBRA-NET, NCT 05559411).

BACKGROUND: Surgical excision of a non-palpable breast lesion requires a localization step. Among available techniques, wire-guided localization (WGL) is most commonly used. Other techniques (radioactive, magnetic, radar or radiofrequency-based, and intraoperative ultrasound) have been developed in the last two decades with the aim of improving outcomes and logistics. METHODS: We performed a systematic review on localization techniques for non-palpable breast cancer. RESULTS: For most techniques, oncological outcomes such as lesion identification and clear margin rate seem either comparable with or better than for WGL, but evidence is limited to small cohort studies for some of the devices. Intraoperative ultrasound is associated with significantly higher negative margin rates in meta-analyses of randomized clinical trials (RCTs). Radioactive techniques were studied in several RCTs and are non-inferior to WGL. Smaller studies show higher patient preference towards wire-free localization, but little is known about surgeons' and radiologists' attitudes towards these techniques. CONCLUSIONS: Large studies with an additional focus on patient, surgeon, and radiologist preference are necessary. This review aims to present the rationale for the MELODY (NCT05559411) study and to enable standardization of outcome measures for future studies.

The forgotten node: Axillary surgery mandates expertise.

The therapeutic role of axillary dissection in breast cancer is gradually abandoned. However, in some cases axillary dissection is still indicated, and this mandates expertise in planning the operation according to imaging, understanding of current methods of axillary marking, and expertise in performing a more radical resection. In this comment we describe cases of gross nodal disease that was left behind at the time of axillary dissection and was later noted on a radiation planning CT.

The metastatic spread of breast cancer accelerates during sleep.

The metastatic spread of cancer is achieved by the haematogenous dissemination of circulating tumour cells (CTCs). Generally, however, the temporal dynamics that dictate the generation of metastasis-competent CTCs are largely uncharacterized, and it is often assumed that CTCs are constantly shed from growing tumours or are shed as a consequence of mechanical insults1. Here we observe a striking and unexpected pattern of CTC generation dynamics in both patients with breast cancer and mouse models, highlighting that most spontaneous CTC intravasation events occur during sleep. Further, we demonstrate that rest-phase CTCs are highly prone to metastasize, whereas CTCs generated during the active phase are devoid of metastatic ability. Mechanistically, single-cell RNA sequencing analysis of CTCs reveals a marked upregulation of mitotic genes exclusively during the rest phase in both patients and mouse models, enabling metastasis proficiency. Systemically, we find that key circadian rhythm hormones such as melatonin, testosterone and glucocorticoids dictate CTC generation dynamics, and as a consequence, that insulin directly promotes tumour cell proliferation in vivo, yet in a time-dependent manner. Thus, the spontaneous generation of CTCs with a high proclivity to metastasize does not occur continuously, but it is concentrated within the rest phase of the affected individual, providing a new rationale for time-controlled interrogation and treatment of metastasis-prone cancers.

Oncoplastic breast consortium recommendations for mastectomy and whole breast reconstruction in the setting of post-mastectomy radiation therapy.

AIM: Demand for nipple- and skin- sparing mastectomy (NSM/SSM) with immediate breast reconstruction (BR) has increased at the same time as indications for post-mastectomy radiation therapy (PMRT) have broadened. The aim of the Oncoplastic Breast Consortium initiative was to address relevant questions arising with this clinically challenging scenario. METHODS: A large global panel of oncologic, oncoplastic and reconstructive breast surgeons, patient advocates and radiation oncologists developed recommendations for clinical practice in an iterative process based on the principles of Delphi methodology. RESULTS: The panel agreed that surgical technique for NSM/SSM should not be formally modified when PMRT is planned with preference for autologous over implant-based BR due to lower risk of long-term complications and support for immediate and delayed-immediate reconstructive approaches. Nevertheless, it was strongly believed that PMRT is not an absolute contraindication for implant-based or other types of BR, but no specific recommendations regarding implant positioning, use of mesh or timing were made due to absence of high-quality evidence. The panel endorsed use of patient-reported outcomes in clinical practice. It was acknowledged that the shape and size of reconstructed breasts can hinder radiotherapy planning and attention to details of PMRT techniques is important in determining aesthetic outcomes after immediate BR. CONCLUSIONS: The panel endorsed the need for prospective, ideally randomised phase III studies and for surgical and radiation oncology teams to work together for determination of optimal sequencing and techniques for PMRT for each patient in the context of BR.

The double S technique to achieve aesthetic flat closure after conventional mastectomy.

BACKGROUND: Lateral excess tissue after mastectomy is a frequent problem, which should be included into preoperative planning. Women with lateral tissue abundance are frequently impaired cosmetically and functionally. We suggest a novel oncoplastic mastectomy technique to eliminate the above mentioned. METHODS: Surgical technique Two small horizontal lines are drawn, one line above and one line below the Nipple Areola Complex. These lines should represent the possible skin excision and allow tight skin closure. Consecutively, two ending points of the incision are planned, one close to the xyphoid area and the other one in the anterior axillary line. These points are then interconnected in an s-shaped manner to form a double s-shaped skin excision. RESULTS: The double S-shaped technique is an easy reproducible technique which not only allows good access to the lateral side of the mastectomy, but also and mainly the reduction of lateral fat and skin. CONCLUSION: The double S mastectomy allows for simultaneous removal of access in the axillary region, eliminating skin, and fat as needed and preventing the lateral dog ear.

Retrospective, Multicenter Analysis Comparing Conventional with Oncoplastic Breast Conserving Surgery: Oncological and Surgical Outcomes in Women with High-Risk Breast Cancer from the OPBC-01/iTOP2 Study.

INTRODUCTION: Recent data suggest that margins ≥2 mm after breast-conserving surgery may improve local control in invasive breast cancer (BC). By allowing large resection volumes, oncoplastic breast-conserving surgery (OBCII; Clough level II/Tübingen 5-6) may achieve better local control than conventional breast conserving surgery (BCS; Tübingen 1-2) or oncoplastic breast conservation with low resection volumes (OBCI; Clough level I/Tübingen 3-4). METHODS: Data from consecutive high-risk BC patients treated in 15 centers from the Oncoplastic Breast Consortium (OPBC) network, between January 2010 and December 2013, were retrospectively reviewed. RESULTS: A total of 3,177 women were included, 30% of whom were treated with OBC (OBCI n = 663; OBCII n = 297). The BCS/OBCI group had significantly smaller tumors and smaller resection margins compared with OBCII (pT1: 50% vs. 37%, p = 0.002; proportion with margin <1 mm: 17% vs. 6%, p < 0.001). There were significantly more re-excisions due to R1 ("ink on tumor") in the BCS/OBCI compared with the OBCII group (11% vs. 7%, p = 0.049). Univariate and multivariable regression analysis adjusted for tumor biology, tumor size, radiotherapy, and systemic treatment demonstrated no differences in local, regional, or distant recurrence-free or overall survival between the two groups. CONCLUSIONS: Large resection volumes in oncoplastic surgery increases the distance from cancer cells to the margin of the specimen and reduces reexcision rates significantly. With OBCII larger tumors are resected with similar local, regional and distant recurrence-free as well as overall survival rates as BCS/OBCI.

The Role of HbA1c as a Positive Perioperative Predictor of Surgical Site and Other Postoperative Infections: An Explorative Analysis in Patients Undergoing Minor to Major Surgery.

BACKGROUND: Patients with diabetes mellitus type 2 (DM2) inhere impaired peripheral insulin action leading to higher perioperative morbidity and mortality rates, with hospital-acquired infections being one important complication. This post hoc, observational study aimed to analyze the impact of surgical and metabolic stress as defined by the surrogate marker hemoglobin A1c (HbA1c), in relation to self-reported DM2, on perioperative infection rates in a subcohort of the Surgical Site Infection (SSI) Trial population. METHODS: All patients of the SSI study were screened for HbA1c levels measured perioperatively for elective or emergency surgery and classified according to the American Diabetes Association HbA1c cutoff values. SSI and nosocomial infections, self-reported state of DM2 and type of surgery (minor, major) were assessed. RESULTS: HbA1c levels were measured in 139 of 5175 patients (2.7%) of the complete SSI study group. Seventy patients (50.4%) self-reported DM2, while 69 (49.6%) self-reported to be non-diabetic. HbA1c levels indicating pre-diabetes were found in 48 patients (34.5%) and diabetic state in 64 patients (46%). Forty-five patients of the group self-reporting no diabetes (65.2%) were previously unaware of their metabolic derangement (35 pre-diabetic and 10 diabetic). Eighteen infections were detected. Most infections (17 of 18 events) were found in patients with HbA1c levels indicating pre-/diabetic state. The odds for an infection was 3.9-fold (95% CI 1.4 to 11.3) higher for patients undergoing major compared to minor interventions. The highest percentage of infections (38.5%) was found in the group of patients with an undiagnosed pre-/diabetic state undergoing major surgery. CONCLUSIONS: These results encourage investment in further studies evaluating a more generous and specific use of HbA1c screening in patients without self-reported diabetes undergoing major surgery. Trial registration Clinicaltrials.gov identifier: NCT01790529.

Impact of Oncoplastic Breast Surgery on Rate of Complications, Time to Adjuvant Treatment, and Risk of Recurrence.

BACKGROUND: The aim of this study was to compare the risk of complications and recurrence between oncoplastic and conventional breast surgery. METHODS: This is a retrospective analysis of a consecutive series of 436 patients with stage I-III breast cancer who underwent surgery at the University Hospital of Basel between 2011 and 2018. RESULTS: The nipple/skin-sparing mastectomy (NSM/SSM) group showed significantly more delayed wound healing (32.7 vs. 5.8%, p < 0.001) and skin necrosis (13.9 vs. 1.9%, p = 0.020) compared to conventional mastectomy (CM), which corresponded to significantly higher odds of short-term complications (OR 2.34, 95% CI 1.02-5.35, p = 0.044). The incidence rate of long-term morbidity in oncoplastic breast-conserving surgery (OBCS) was significantly higher compared to conventional breast-conserving surgery (CBCS; 25.5 vs. 11.3 per 100 patient years [PY], p < 0.001), in particular concerning chronic pain (13.3 vs. 6.6, p = 0.011) and lymphedema (4.1 vs. 0.4, p = 0.003). Seroma as a long-term morbidity occurred more often in the CM group compared to the NSM/SSM group (5.8 vs. 0.5 per 100 PY, p = 0.004). Patients received adjuvant treatment earlier after CM compared to NSM/SSM (HR 1.83, 95% CI 1.05-3.19, p = 0.034). There were no significant differences in the incidence of positive margins nor in the odds of recurrence after OBCS versus CBCS and after NSM/SSM versus CM. CONCLUSIONS: Even though the present study confirmed expected differences in complications and morbidity, it suggested that oncoplastic surgery is oncologically safe. Patients undergoing NSM/SSM should be followed closely to allow early detection and treatment of frequently associated complications and ensure timely start of adjuvant therapy.

Hepatic stellate cells suppress NK cell-sustained breast cancer dormancy.

The persistence of undetectable disseminated tumour cells (DTCs) after primary tumour resection poses a major challenge to effective cancer treatment1-3. These enduring dormant DTCs are seeds of future metastases, and the mechanisms that switch them from dormancy to outgrowth require definition. Because cancer dormancy provides a unique therapeutic window for preventing metastatic disease, a comprehensive understanding of the distribution, composition and dynamics of reservoirs of dormant DTCs is imperative. Here we show that different tissue-specific microenvironments restrain or allow the progression of breast cancer in the liver-a frequent site of metastasis4 that is often associated with a poor prognosis5. Using mouse models, we show that there is a selective increase in natural killer (NK) cells in the dormant milieu. Adjuvant interleukin-15-based immunotherapy ensures an abundant pool of NK cells that sustains dormancy through interferon-γ signalling, thereby preventing hepatic metastases and prolonging survival. Exit from dormancy follows a marked contraction of the NK cell compartment and the concurrent accumulation of activated hepatic stellate cells (aHSCs). Our proteomics studies on liver co-cultures implicate the aHSC-secreted chemokine CXCL12 in the induction of NK cell quiescence through its cognate receptor CXCR4. CXCL12 expression and aHSC abundance are closely correlated in patients with liver metastases. Our data identify the interplay between NK cells and aHSCs as a master switch of cancer dormancy, and suggest that therapies aimed at normalizing the NK cell pool might succeed in preventing metastatic outgrowth.

Identification of breast cancer patients with pathologic complete response in the breast after neoadjuvant systemic treatment by an intelligent vacuum-assisted biopsy.

BACKGROUND: Neoadjuvant systemic treatment elicits a pathologic complete response (pCR) in about 35% of women with breast cancer. In such cases, breast surgery may be considered overtreatment. We evaluated multivariate algorithms using patient, tumor, and vacuum-assisted biopsy (VAB) variables to identify patients with breast pCR. METHODS: We developed and tested four multivariate algorithms: a logistic regression with elastic net penalty, an Extreme Gradient Boosting (XGBoost) tree, Support Vector Machines (SVM), and neural network. We used data from 457 women, randomly partitioned into training and test set (2:1), enrolled in three trials with stage 1-3 breast cancer, undergoing VAB before surgery. False-negative rate (FNR) and specificity were the main outcome measures. The best performing algorithm was validated in an independent fourth trial. RESULTS: In the test set (n = 152), the logistic regression with elastic net penalty, XGboost tree, SVM, and neural network revealed an FNR of 1.2% (1 of 85 patients with missed residual cancer). Specificity of the logistic regression with elastic net penalty was 52.2% (35 of 67 women with surgically confirmed breast pCR identified), of the XGBoost tree 55.2% (37 of 67), of SVM 62.7% (42 of 67), and of the neural network 67.2% (45 of 67). External validation (n = 50) of the neural network showed an FNR of 0% (0 of 27) and a specificity of 65.2% (15 of 23). Area under the ROC curve for the neural network was 0.97 (95% CI, 0.94-1.00). CONCLUSION: A multivariate algorithm can accurately select breast cancer patients without residual cancer after neoadjuvant treatment.

Hypoxia Triggers the Intravasation of Clustered Circulating Tumor Cells.

Circulating tumor cells (CTCs) are shed from solid cancers in the form of single or clustered cells, and the latter display an extraordinary ability to initiate metastasis. Yet, the biological phenomena that trigger the shedding of CTC clusters from a primary cancerous lesion are poorly understood. Here, when dynamically labeling breast cancer cells along cancer progression, we observe that the majority of CTC clusters are undergoing hypoxia, while single CTCs are largely normoxic. Strikingly, we find that vascular endothelial growth factor (VEGF) targeting leads to primary tumor shrinkage, but it increases intra-tumor hypoxia, resulting in a higher CTC cluster shedding rate and metastasis formation. Conversely, pro-angiogenic treatment increases primary tumor size, yet it dramatically suppresses the formation of CTC clusters and metastasis. Thus, intra-tumor hypoxia leads to the formation of clustered CTCs with high metastatic ability, and a pro-angiogenic therapy suppresses metastasis formation through prevention of CTC cluster generation.

Tall cell carcinoma of the breast with reversed polarity (TCCRP) with mutations in the IDH2 and PIK3CA genes: a case report.

Tall cell carcinoma with reversed polarity (TCCRP) is a rare breast carcinoma with low malignant potential, initially named "breast tumor resembling the tall cell variant of papillary thyroid carcinoma", which has recently been recognized as a separate entity in the 5th edition of the WHO (World Health Organization) classification of breast tumors. Since the first report of this entity in 2003, more than 40 cases have been reported in the literature. Here, we report another case of this rare tumor in a 60-year-old woman. We performed immunohistochemical analyses and next-generation-sequencing (NGS) using the Oncomine™ Comprehensive DNA Panel (Thermo Fisher Scientific). The tumor showed the typical morphological features of TCCRP and a "triple-negative" phenotype. Moreover, we identified pathogenic mutations in the IDH2 (p.R172G) and PIK3CA (p.H1047R) genes. We report a case of TCCRP of the breast showing the characteristic morphologic, immunohistochemical and molecular features of this entity. There is still a limited number of cases with comprehensive molecular analyses reported in the literature. Therefore, we herewith contribute to a better understanding of the morphological and molecular characteristics as well as the clinical behavior of this rare entity.

Nectin-4 Expression Is an Independent Prognostic Biomarker and Associated With Better Survival in Triple-Negative Breast Cancer.

Background: Triple-negative breast cancer (TNBC) represents about 10-20% of all invasive breast cancers and is associated with a poor prognosis. The nectin cell adhesion protein 4 (Nectin-4) is a junction protein involved in the formation and maintenance of cell junctions. Nectin-4 has previously shown to be expressed in about 60% of TNBC as well as in TNBC metastases, but to be absent in normal breast tissue, which makes it a potential specific target for TNBC therapy. Previous studies have shown an association of Nectin-4 protein expression with worse prognosis in TNBC in a small patient cohort. The aim of our study was to explore the role of Nectin-4 in TNBC and confirm its impact on survival in a larger TNBC patient cohort. Material and Methods: We performed immunohistochemical staining for Nectin-4 on a tissue microarray encompassing 148 TNBC cases with detailed clinical annotation and outcomes data. Results: A high expression of Nectin-4 was present in 86 (58%) of the 148 TNBC cases. In multivariate survival analysis, high expression of Nectin-4 was associated with a significantly better overall survival when compared with low expression of Nectin-4 (p < 0.001). Nectin-4-high expression was also significantly associated with a lower tumor stage (p = 0.025) and pN0 lymph node stage (p = 0.034). Conclusion: Our results confirm that expression of Nectin-4 serves as a potential prognostic marker in TNBC and is associated with a significantly better overall survival. In addition, Nectin-4 represents a potential target in TNBC, and its role in molecular defined breast cancer subtype should be investigated in larger patient cohorts.

A Single-Cell Atlas of the Tumor and Immune Ecosystem of Human Breast Cancer.

Breast cancer is a heterogeneous disease. Tumor cells and associated healthy cells form ecosystems that determine disease progression and response to therapy. To characterize features of breast cancer ecosystems and their associations with clinical data, we analyzed 144 human breast tumor and 50 non-tumor tissue samples using mass cytometry. The expression of 73 proteins in 26 million cells was evaluated using tumor and immune cell-centric antibody panels. Tumors displayed individuality in tumor cell composition, including phenotypic abnormalities and phenotype dominance. Relationship analyses between tumor and immune cells revealed characteristics of ecosystems related to immunosuppression and poor prognosis. High frequencies of PD-L1+ tumor-associated macrophages and exhausted T cells were found in high-grade ER+ and ER- tumors. This large-scale, single-cell atlas deepens our understanding of breast tumor ecosystems and suggests that ecosystem-based patient classification will facilitate identification of individuals for precision medicine approaches targeting the tumor and its immunoenvironment.