Axillary nodal metastatic burden in patients with breast cancer with clinically positive axillary nodes.

BACKGROUND: The aim of this study was to determine preoperative factors and tumour characteristics related to a high nodal tumour burden in patients with clinically node-positive breast cancer. These findings were used to construct a predictive tool to evaluate the patient-specific risk of having more than two axillary lymph node metastases. METHODS: Altogether, 507 consecutive patients with breast cancer and axillary lymph node metastasis diagnosed by preoperative ultrasound-guided needle biopsy were reviewed. These patients underwent breast surgery and axillary lymph node dissection at Helsinki University Hospital between 2010 and 2014. Patients were grouped into those with one or two, and those with more than two lymph node metastases. RESULTS: There were 153 patients (30·2 per cent) with one or two lymph node metastases and 354 (69·8 per cent) with more than two metastases. Five-year disease-free survival was poorer for the latter group (P = 0·032). Five-year overall survival estimates for patients with one or two and those with more than two lymph node metastases were 87·0 and 81·4 per cent respectively (P = 0·215). In multivariable analysis, factors significantly associated with more than two lymph node metastases were: age, tumour size, lymphovascular invasion in the primary tumour, extracapsular extension of metastasis in lymph nodes, and morphology of lymph nodes. These factors were included in a multivariable predictive model, which had an area under the curve of 0·828 (95 per cent c.i. 0·787 to 0·869). CONCLUSION: The present study provides a patient-specific prediction model for evaluating nodal tumour burden in patients with clinically node-positive breast cancer.

Patterns of axillary staging and management in clinically node positive breast cancer patients treated with neoadjuvant systemic therapy: Results of a survey amongst breast cancer specialists.

INTRODUCTION: Various options for axillary staging after neoadjuvant systemic therapy (NST) are available for breast cancer patients with a clinically positive axillary node (cN+). This survey assessed current practices amongst breast cancer specialists. MATERIALS AND METHODS: A survey was performed amongst members of the European Society of Surgical Oncology and two UK-based Associations: the Association of Breast Surgery and the British Association of Surgical Oncology. The survey included 3 parts: 1. general information, 2. diagnostic work-up and 3. axillary staging after NST. RESULTS: A total of 310 responses were collected: parts 1, 2 and 3 were fully completed by 282 (91%), 270 (87.1%) and 225 (72.6%) respondents respectively. After NST, 153/267 (57.3%) respondents currently perform ALND routinely and 114 (42.7%) respondents perform less invasive restaging of the axilla with possible omission of ALND. In the latter group, 85% does and 15% does not use nodal response seen on imaging to guide the axillary restaging procedure. Regarding respondents that do use imaging: 95% would perform a less invasive staging procedure in case of complete nodal response on imaging (63% sentinel lymph node biopsy (SLNB), excision of a previously marked positive node with SLNB (21%) and without SLNB (11%)). In case of no nodal response on imaging 77% would perform ALND. CONCLUSION: Current axillary staging and management practices in cN + patients after NST vary widely. To determine optimal axillary staging and management in terms of quality of life and oncologic safety, breast specialists are encouraged to include patients in clinical trials/prospective registries.

European Society of Surgical Oncology's strategy for clinical research: Paving the way for a culture of research in cancer surgery.

As part of its mission to promote the best surgical care for cancer patients, the European Society of Surgical Oncology (ESSO) has been developing multiple programmes for clinical research along with its educational portfolio. This position paper describes the different research activities of the Society over the past decade and an action plan for the upcoming five years to lead innovative and high quality surgical oncology research. ESSO proposes to consider pragmatic research methodologies as a complement to randomised clinical trials (RCT), advocates for increased funding and operational support in conducting research and aims to enable young surgeons to be active in research and establish partnerships for translational research activities.

EUSOMA position regarding breast implant associated anaplastic large cell lymphoma (BIA-ALCL) and the use of textured implants.

During the last two decades the number of breast implants used in aesthetic, oncologic and risk reducing surgery has increased substantially mainly due to the improvement and confirmed safety of these devices. Since identification of the first case of anaplastic large cell lymphoma associated with a breast implant (BIA-ALCL) 20 years ago, there has been an increase in the number of reports of this very rare disease, demonstrating a clear association with breast implants. Whilst the majority of cases are localised and cured by implant removal and full capsulectomy, a small percentage require chemotherapy and the mortality rate is very low. The evidence linking BIA-ALCL to implant surface texturing, as the majority of cases were diagnosed in patients with textured implants, has raised concerns about the long term safety of these devices resulting in patient and regulatory authority concerns globally. We hereby present the current published knowledge about the link between BIA-ALCL and implant surface texture and a review of current regulatory and professional body advice across Europe, which may enable a better understanding of this rare disease, how to manage and ultimately prevent it. We conclude by giving EUSOMA recommendation, towards the unnecessary change in attitudes towards implant based surgery, according to the most recent available published evidence as long as patients are properly informed about the risk of BIA-ALCL.

Variability in breast cancer surgery training across Europe: An ESSO-EUSOMA international survey.

BACKGROUND: At present there is a lack of standardization of training in breast cancer surgery across Europe. The aim of this survey was to assess current practice in Europe regarding training in breast cancer (BC) surgery. MATERIAL AND METHODS: General surgeons, surgical oncologists, gynecologist, and plastic surgeons in Europe were invited to participate in this bespoke survey including 19 questions. RESULTS: The survey was sent to 3.000 surgical oncologists across Europe. A total of 671 physicians (387 general surgeons, 152 gynecologists, 126 surgical oncologist, 31 plastic surgeons) answered the survey (23% response rate). Four hundred and sixty-eight physicians devoted between 50% -100% of their job to treating breast cancer. 45% worked in a community/University hospital within a dedicated Breast Unit. Specific additional breast surgery training was not universal: 20% had undertaken an accredited breast fellowship, 30% in a Breast Unit as a trainee, 21% had done additional courses, masters or diploma and 8% had not done any additional training. The majority (61%) of respondents worked in Units treating >150 BC cases per year, while 26% of the responders treat >120 new primary cases per year, and 23% less than 50 new cases a year. Multivariate analysis showed that breast surgeons working in a Breast Unit and treating more than 50 cases/year significantly performed oncoplastic procedures. CONCLUSION: There is a great variability in breast cancer surgery training in Europe. It is imperative to develop quality standards for breast cancer surgery training to ensure that patients get standardized and certified surgical management regardless of the country in which they are treated.

Aesthetic and functional outcome after breast conserving surgery - Comparison between conventional and oncoplastic resection.

BACKGROUND: Recent studies implicate that oncoplastic breast cancer surgery provides better aesthetic outcome than conventional resection. Several factors have been associated with poor aesthetic outcome. This study aims to compare patient-reported aesthetic and functional outcome after conventional and oncoplastic resection and to evaluate prognostic factors for poor aesthetic outcome in a population-based setting. METHODS: 637 patients having breast conserving treatment (BCT) due to unilateral primary breast cancer at a single hospital district during 2010 were included. Aesthetic and functional outcome were evaluated using two questionnaires three years after surgery. RESULTS: Questionnaires were returned by 379 (59%) patients; 293 (77%) of these had conventional and 86 (23%) oncoplastic resection. Patients in oncoplastic resection group had larger tumour diameter (p < 0.001), larger resection specimens (p < 0.001), and more often multifocal tumours (p = 0.032), node positive cancer (p = 0.029) and lower quadrant tumour localization (p = 0.007). Aesthetic outcome according to BCTOS questionnaire was good in 284 (75%) patients; 52 (61%) patients in the oncoplastic group and 230 patients (81%) in the conventional resection group, p < 0.001. Larger tumour diameter (p = 0.033), multifocality (p = 0.022), weight of resection specimen (<0.001) and oncoplastic surgery (p < 0.001) were predicting poor aesthetic outcome, when all patients were included. Tumour multifocality (p = 0.013) remained predictor of poor aesthetic outcome in conventional resection group but not in oncoplastic resection group. CONCLUSIONS: Patient satisfaction to aesthetic outcome after BCT is high. Conventional resection provides good aesthetic outcome in appropriately selected patients. Oncoplastic resection enables BCT in patients with larger and multifocal tumours with favourable aesthetic outcome.

Deregulated hepsin protease activity confers oncogenicity by concomitantly augmenting HGF/MET signalling and disrupting epithelial cohesion.

Hepsin belongs to a family of cell-surface serine proteases, which have sparked interest as therapeutic targets because of the accessibility of extracellular protease domain for inhibitors. Hepsin is frequently amplified and/or overexpressed in epithelial cancers, but it is not clear how enhanced hepsin expression confers a potential for oncogenicity. We show that hepsin is consistently overexpressed in more than 40% of examined breast cancers, including all major biological subtypes. The effects of doxycycline-induced hepsin overexpression were examined in mammary epithelial organoids, and we found that induced hepsin acutely downmodulates its cognate inhibitor, hepatocyte growth factor (HGF) activator inhibitor type 1 (HAI-1). Hepsin-induced depletion of cellular HAI-1 led to a sharp increase in pericellular serine protease activity. The derepressed hepsin proteolytically activated downstream serine proteases, augmented HGF/MET signalling and caused deterioration of desmosomes and hemidesmosomes; structures important for cell cohesion and cell-basement membrane interaction. Moreover, chronic induction of hepsin considerably shortened the latency of Myc-dependent tumourigenesis in the mouse mammary gland. The serine protease and uPA system inhibitor WX-UK1, identified as a micromolar range hepsin inhibitor, prevented hepsin from augmenting HGF/MET signalling and disrupting desmosomes and hemidesmosomes. The findings suggest that the oncogenic activity of hepsin arises not only from elevated expression level but also from depletion of HAI-1, events which together trigger gain-of-function activity impacting HGF/MET signalling and epithelial cohesion. Thus, hepsin overexpression is a major oncogenic conferrer to a serine protease activity involved in breast cancer dissemination.

Breast cancer prognosis and isolated tumor cell findings in axillary lymph nodes after core needle biopsy and fine needle aspiration cytology: Biopsy method and breast cancer outcome.

BACKGROUND: It is unknown whether performing a core needle biopsy (CNB) to diagnose breast cancer increases the incidence of isolated tumor cells (ITC) in the axillary sentinel lymph nodes. METHODS: Patients diagnosed with unilateral invasive pT1 breast cancer (≤2 cm in diameter, n = 1525) at a single center between February 2001 and August 2005 were included in this prospective observational cohort study. The patients were categorized into two groups according to the type of the preoperative breast needle biopsy performed, the CNB and the fine needle aspiration cytology (FNAC) groups, and followed up for a median of 9.5 years after breast surgery. RESULTS: 868 (56.9%) patients had FNAC and 657 (43.2%) CNB. In the subset of patients with no axillary metastases (pN0, n = 1005) 70 patients had ITC, 37 (4.3%) out of the 546 patients in FNAC group and 33 (5.0%) out of the 459 patients in the CNB group (p = 0.798). The type of tumor biopsy did not influence breast cancer-specific survival (p = 0.461) or local recurrence-free survival (p = 0.814) in univariable survival analyses. Overall, survival favored the CNB group in a univariable analysis, but no difference in survival emerged in a multivariable analysis (p = 0.718). CONCLUSIONS: CNB was not associated with a greater incidence of ITC in axillary lymph nodes as compared with FNAC, and did not have an adverse effect on survival outcomes in a patient population treated with modern adjuvant therapies.

Feasibility of Day Surgery in Patients With Breast Conservation and Sentinel Node Biopsy: A Randomized Controlled Trial.

BACKGROUND AND AIMS: The aim of this study was to analyze feasibility of day surgery in breast cancer patients with breast conserving surgery and sentinel node biopsy. MATERIAL AND METHODS: The study was a randomized controlled trial comparing day surgery with one night hospital stay in breast cancer patients with breast conserving surgery and sentinel node biopsy. A total of 40 patients with ⩽3-cm tumor and clinically N0 were randomized to one night stay group and 38 patients to day surgery group. Within discharge, patients and their relatives were given questionnaires in order to evaluate their experience regarding the duration of hospital stay. RESULTS: Randomized groups were similar regarding patient age and tumor stage. A total of 18 (47%) day surgery group patients were discharged the same day. The most common reason for overnight hospital stay was axillary clearance, 9 (24%). None of the patients in the day surgery group, but 2 patients in the overnight hospital stay group had re-operation due to complications. Perception and preference results were analyzed both according to randomization and actual treatment groups. Patients in both groups had rather similar experiences on the first postoperative day. Also, spouse's or relative's perception after discharge was similar in both groups. CONCLUSION: Day surgery was well received by the patients and their relatives. Day surgery appears as feasible in patients with breast conservation and sentinel node biopsy.

A predictive tool to estimate the risk of axillary metastases in breast cancer patients with negative axillary ultrasound.

BACKGROUND: Sentinel node biopsy (SNB) is the "gold standard" in axillary staging in clinically node-negative breast cancer patients. However, axillary treatment is undergoing a paradigm shift and studies are being conducted on whether SNB may be omitted in low-risk patients. The purpose of this study was to evaluate the risk factors for axillary metastases in breast cancer patients with negative preoperative axillary ultrasound. METHODS: A total of 1,395 consecutive patients with invasive breast cancer and SNB formed the original patient series. A univariate analysis was conducted to assess risk factors for axillary metastases. Binary logistic regression analysis was conducted to form a predictive model based on the risk factors. The predictive model was first validated internally in a patient series of 566 further patients and then externally in a patient series of 2,463 patients from four other centers. All statistical tests were two-sided. RESULTS: A total of 426 of the 1,395 (30.5 %) patients in the original patient series had axillary lymph node metastases. Histological size (P < 0.001), multifocality (P < 0.001), lymphovascular invasion (P < 0.001), and palpability of the primary tumor (P < 0.001) were included in the predictive model. Internal validation of the model produced an area under the receiver operating characteristics curve (AUC) of 0.731 and external validation an AUC of 0.79. CONCLUSIONS: We present a predictive model to assess the patient-specific probability of axillary lymph node metastases in patients with clinically node-negative breast cancer. The model performs well in internal and external validation. The model needs to be validated in each center before application to clinical use.

Cross-validation of three predictive tools for non-sentinel node metastases in breast cancer patients with micrometastases or isolated tumor cells in the sentinel node.

BACKGROUND: We cross-validated three existing models for the prediction of non-sentinel node metastases in patients with micrometastases or isolated tumor cells (ITC) in the sentinel node, developed in Danish and Finnish cohorts of breast cancer patients, to find the best model to identify patients who might benefit from further axillary treatment. MATERIAL AND METHOD: Based on 484 Finnish breast cancer patients with micrometastases or ITC in sentinel node a model has been developed for the prediction of non-sentinel node metastases. Likewise, two separate models have been developed in 1577 Danish patients with micrometastases and 304 Danish patients with ITC, respectively. The models were cross-validated in the opposite cohort. RESULTS: The Danish model for micrometatases was accurate when tested in the Finnish cohort, with a slight change in AUC from 0.64 to 0.63. The AUC of the Finnish model decreased from 0.68 to 0.58 when tested in the Danish cohort, and the AUC of the Danish model for ITC decreased from 0.73 to 0.52, when tested in the Finnish cohort. The Danish micrometastatic model identified 14-22% of the patients as high-risk patients with over 30% risk of non-sentinel node metastases while less than 1% was identified by the Finish model. In contrast, the Finish model predicted a much larger proportion of patients being in the low-risk group with less than 10% risk of non-sentinel node metastases. CONCLUSION: The Danish model for micrometastases worked well in predicting high risk of non-sentinel node metastases and was accurate under external validation.

International multicenter tool to predict the risk of four or more tumor-positive axillary lymph nodes in breast cancer patients with sentinel node macrometastases.

Recently, many centers have omitted routine axillary lymph node dissection (ALND) after metastatic sentinel node biopsy in breast cancer due to a growing body of literature. However, existing guidelines of adjuvant treatment planning are strongly based on axillary nodal stage. In this study, we aim to develop a novel international multicenter predictive tool to estimate a patient-specific risk of having four or more tumor-positive axillary lymph nodes (ALN) in patients with macrometastatic sentinel node(s) (SN). A series of 675 patients with macrometastatic SN and completion ALND from five European centers were analyzed by logistic regression analysis. A multivariate predictive model was created and validated internally by 367 additional patients and then externally by 760 additional patients from eight different centers. All statistical tests were two-sided. Prevalence of four or more tumor-positive ALN in each center's series (P = 0.010), number of metastatic SNs (P < 0.0001), number of negative SNs (P = 0.003), histological size of the primary tumor (P = 0.020), and extra-capsular extension of SN metastasis (P < 0.0001) were included in the predictive model. The model's area under the receiver operating characteristics curve was 0.766 in the internal validation and 0.774 in external validation. Our novel international multicenter-based predictive tool reliably estimates the risk of four or more axillary metastases after identifying macrometastatic SN(s) in breast cancer. Our tool performs well in internal and external validation, but needs to be further validated in each center before application to clinical use.

Outcome of patients with ductal carcinoma in situ and sentinel node biopsy.

BACKGROUND: In sentinel node biopsy (SNB), tumor-positive findings, mainly micrometastases and isolated tumor cells (ITC) have been found in up to 8%-16% of patients with pure ductal carcinoma in situ (DCIS) or microinvasive DCIS (DCISM). The prognostic significance of such findings is largely unknown. The aim of this study is to examine the outcome of DCIS and DCISM patients with SNB. METHODS: A total of 280 breast cancer patients with pure or microinvasive DCIS underwent SNB between April 2001 and December 2010 at the Breast Surgery Unit of Helsinki University Central Hospital. Patient, tumor, SNB procedure, and follow-up data were gathered. The median follow-up was 50 months (range 7-123 months). RESULTS: Altogether, 21 patients had tumor-positive sentinel node findings. Of these, 14 were in pure DCIS patients (1 macrometastasis, 1 micrometastasis, 12 ITC) and 7 in DCISM patients (1 macrometastasis, 2 micrometastases, 4 ITC). Also, 16 patients, 10 with pure DCIS and 6 with DCISM, underwent completion axillary lymph node dissection (ALND). Only 1 of them, a patient with DCISM, had additional tumor positive finding in the ALND. During a median follow-up of 50 months (range 7-123 months) there were 5 local recurrences. One patient with pure DCIS and tumor-negative SNB developed overt axillary metastases and later also distant metastases. CONCLUSIONS: DCIS and DCISM patients do have tumor positive findings, but a majority of these are ITC or micrometastases. In light of this study, these findings do not affect the outcome of DCIS or DCISM patients.

A simple nomogram to evaluate the risk of nonsentinel node metastases in breast cancer patients with minimal sentinel node involvement.

BACKGROUND: Tumor-positive sentinel node biopsy (SNB) suggests a risk of nonsentinel node metastases in breast cancer. This risk is lower after micrometastasis or isolated tumor cells (ITC) in the sentinel node (SN), and recent studies suggest that completion axillary lymph node dissection (ALND) might not improve outcome in these patients. We aim to validate existing predictive models and to develop a new model for micrometastatic and ITC patients. METHODS: A series of 484 patients with micrometastases or ITC in SN followed by ALND was used to evaluate factors affecting nonsentinel node involvement. Logistic regression analysis was performed to construct a predictive model, which was validated by a separate series of 51 patients. RESULTS: Only 7.2% of patients had additional metastases on completion ALND. Tumor diameter and multifocality associated with nonsentinel status on multivariate analysis. A predictive model was constructed showing good [area under the curve (AUC) 0.791] discrimination in the validation series. Previously published models performed poorly in our patient population. CONCLUSIONS: Nonsentinel node metastases are rare with micrometastasis or ITC in SN. Most published predictive models for nonsentinel node involvement perform poorly in the present patient population. We developed a new predictive model which seems to perform well in discriminating patients with more than 10% risk of additional metastases. However, the presented nomogram needs to be validated with an independent patient series to evaluate its accuracy, especially for high-risk patients.

Multicentre validation of different predictive tools of non-sentinel lymph node involvement in breast cancer.

Sentinel lymph node (SN) biopsy offers the possibility of selective axillary treatment for breast cancer patients, but there are only limited means for the selective treatment of SN-positive patients. Eight predictive models assessing the risk of non-SN involvement in patients with SN metastasis were tested in a multi-institutional setting. Data of 200 consecutive patients with metastatic SNs and axillary lymph node dissection from each of the 5 participating centres were entered into the selected non-SN metastasis predictive tools. There were significant differences between centres in the distribution of most parameters used in the predictive models, including tumour size, type, grade, oestrogen receptor positivity, rate of lymphovascular invasion, proportion of micrometastatic cases and the presence of extracapsular extension of SN metastasis. There were also significant differences in the proportion of cases classified as having low risk of non-SN metastasis. Despite these differences, there were practically no such differences in the sensitivities, specificities and false reassurance rates of the predictive tools. Each predictive tool used in clinical practice for patient and physician decision on further axillary treatment of SN-positive patients may require individual institutional validation; such validation may reveal different predictive tools to be the best in different institutions.

Breast cancer in very young women.

AIMS: The purpose was to analyse the characteristics, treatment, recurrences and survival of very young women with breast cancer. METHODS: 212 female breast cancer patients ≤35 years old were treated during 1997-2007. The median follow-up time was 78 months. RESULTS: 117 patients had lymph node metastases and 14 distant metastases at diagnosis. 81 (38%) tumours were hormone receptor negative and 130 (65%) grade 3. HER2 positivity was seen in 47 (34%) and triple negativity in 35 (26%) of the 137 tumours with known HER2 status. 140 women were treated with mastectomy and 68 with breast conserving surgery. 163 patients received postoperative radiotherapy, 175 adjuvant chemotherapy, 95 endocrine therapy and 18 trastuzumab. 63 patients experienced a recurrence, of which 20 had only a locoregional recurrence. 10 (15%) of the women with breast conserving surgery experienced ipsilateral breast tumour recurrence while ipsilateral thoracic wall recurrence was seen in 8 patients (6%) after mastectomy. Seven of these eight patients did not receive postmastectomy radiotherapy. DFI was shorter in patients with hormone receptor positive tumours. At the end of follow-up 44 women had died. The 5-year OS was 80%. CONCLUSIONS: The 5-year OS for young women has become better but is still lower than for all breast cancer patients. DFI was shorter in patients with hormone receptor positive disease. Locoregional recurrences were seen more often after breast conserving surgery.