Non-visualized sentinel nodes in breast cancer patients; prevalence, risk factors, and prognosis.

BACKGROUND: Evidence and consensus is lacking in international guidelines regarding axillary treatment recommendations for patients in whom a sentinel lymph node (SLN) cannot be visualized (non-vSLN) during the sentinel node procedure. In this study we aimed to determine the prevalence of non-vSLNs in a Dutch population of breast cancer patients and to examine predictors and survival rate for non-vSLN. METHODS: A nationwide, retrospective, population-based study was performed including 116,920 patients with invasive breast cancer who underwent a SLN procedure in the Netherlands between January 2005 and December 2013. RESULTS: Of the 76,472 clinically negative patients who underwent a SLN procedure, 1924 patients (2.5%) had a non-vSLN, of whom 1552 (80.7%) underwent an ALND. Multivariate analysis showed predictive factors for non-vSLN: older age (p < 0.001), diagnosis in the period 2005-2009 (p < 0.001), larger tumor size (p = 0.003), and extensive nodal involvement (p < 0.001). Multivariate survival analysis showed a significantly worse survival (HR 1.18, 95% CI 1.03-1.34, p = 0.015) for non-vSLNs patients. However, in the non-vSLN group, an ALND was not statistically significantly associated with a better survival (HR 0.96, 95% CI 0.53-1.75, p = 0.891). CONCLUSION: Patients with non-vSLNs had less favorable disease characteristics and a worse survival compared to patients with a visualized SLN. Performing an ALND was not associated with a significantly better survival in patients with non-vSLNs. However, further research on the necessity of axillary treatment in this specific patient group is required.

Potential impact of application of Z0011 derived criteria to omit axillary lymph node dissection in node positive breast cancer patients.

BACKGROUND: The ACOSOG Z0011 trial, a randomized controlled trial among patients with sentinel node positive breast cancer treated with breast conserving therapy, concluded that axillary lymph node dissection (ALND) can be omitted in these patients. However, questions were raised on the general applicability if the results of the Z0011 trial. Therefore, the aim of this study was to assess the practice changing effect of the Z0011 trial by quantifying the proportion of all node positive breast cancer patients who meet the inclusion criteria which are based on the Z0011 trial, thus in whom an ALND could be omitted. METHODS: A multicenter population based study including patients with clinical T1-2N0-1M0 invasive non-metastatic breast cancer, a positive sentinel node or ultrasound guided lymph node biopsy, treated with breast conserving therapy and adjuvant systemic therapy between January 2007 and December 2012. RESULTS: A total of 11,031 patients had invasive breast cancer including 3051 cases treated with breast conserving therapy and adjuvant systemic therapy. Subsequently, 916 cases with a positive nodal status underwent an ALND of whom 558 cases (60.9%), representing 5.1% of the total breast cancer population, would potentially have fulfilled the Z0011 criteria. CONCLUSION: Application of Z0011 based criteria is practice changing in nearly 61% of all node positive patients, which could result in omission of the ALND in a substantial number of patients in the future. Further research has to be performed on the applicability of these conclusions to other categories of breast cancer patients.

Predictors for extensive nodal involvement in breast cancer patients with axillary lymph node metastases.

PURPOSE: Various prediction models have been developed to predict the risk of having no additional axillary metastases in patients with a positive sentinel lymph node biopsy (SLNB), thereby disregarding patients with a positive ultrasound-guided lymph node biopsy (UGLNB). However, in the post-Z0011 trial era it is important to identify all patients with extensive nodal involvement for whom axillary treatment might still be beneficial. Therefore, the aim of this study is to identify factors predicting extensive nodal involvement (≥3 positive nodes) in the axilla, with the emphasis on the method of axillary staging: node positivity by UGLNB versus SLNB. METHODS: All patients diagnosed with invasive breast cancer between January 2006 and December 2011 at the Máxima Medical Center were included. Univariate and multivariate logistic regression analyses were performed. RESULTS: We included 302 cases, representing 301 node positive patients, of whom 177 cases had 1 or 2 positive lymph nodes and 125 cases had ≥3 positive lymph nodes. Multivariate analyses showed that a positive UGLNB (OR = 5.10; 95%CI = 2.78-9.36), lymphovascular invasion (OR = 3.60; 95%CI = 1.79-7.23) and a larger tumor size (OR = 1.03 per mm increase; 95%CI = 1.00-1.06) were significantly associated with extensive nodal involvement in patients with invasive breast cancer. CONCLUSION: This study shows that a positive axilla, determined by UGLNB, is the most important factor for predicting further extensive nodal involvement. Hence, the role of axillary staging by ultrasound should be redefined since it might play an important role in selecting patients who may still benefit from axillary treatment.

Extra-nodal extension of sentinel lymph node metastasis is a marker of poor prognosis in breast cancer patients: A systematic review and an exploratory meta-analysis.

Invasive breast cancer is the most common malignancy in women. Its most common site of metastasis is represented by the lymph nodes of axilla, and the sentinel lymph node (SLN) is the first station of nodal metastasis. Axillary SLN biopsy accurately predicts axillary lymph node status and has been accepted as standard of care for nodal staging in breast cancer. To date, the morphologic aspects of SLN metastasis have not been considered by the oncologic staging system. Extranodal extension (ENE) of nodal metastasis, defined as extension of neoplastic cells through the nodal capsule into the peri-nodal adipose tissue, has recently emerged as an important prognostic factor in several types of malignancies. It has also been considered as a possible predictor of non-sentinel node tumor burden in SLN-positive breast cancer patients. We sought out to clarify the prognostic role of ENE in SLN-positive breast cancer patients in terms of overall and disease-free survival by conducting a systematic review and meta-analysis. Among 172 screened articles, 5 were eligible for the meta-analysis; they globally include 624 patients (163 ENE+ and 461 ENE-) with a median follow-up of 58 months. ENE was associated with a higher risk of both mortality (RR = 2.51; 95% CI: 1.66-3.79, p < 0.0001, I(2) = 0%) and recurrence of disease (RR = 2.07, 95% CI: 1.38-3.10, p < 0.0001, I(2) = 0%). These findings recommend the consideration of ENE from the gross sampling to the histopathological evaluation, in perspectives to be validated and included in the oncologic staging.

Two decades of axillary management in breast cancer.

BACKGROUND: Axillary lymph node dissection (ALND) in patients with breast cancer provides prognostic information. For many years, positive nodes were the most important indication for adjuvant systemic therapy. It was also believed that regional control could not be achieved without axillary clearance in a positive axilla. However, during the past 20 years the treatment and staging of the axilla has undergone many changes. This large population-based study was conducted in the south-east of the Netherlands to evaluate the changing patterns of care regarding the axilla, including the introduction of sentinel lymph node biopsy (SLNB) in the late 1990s, implementation of the results of the American College of Surgeons Oncology Group Z0011 study, and the initial effects of the European Organization for Research and Treatment of Cancer AMAROS study. METHODS: Data from the population-based Eindhoven Cancer Registry of all women diagnosed with invasive breast cancer in the south of the Netherlands between January 1993 and July 2014 were used. RESULTS: The proportion of 34,037 women staged by SLNB without completion ALND increased from 0 per cent in 1993-1994 to 69·0 per cent in 2013-2014. In the same period the proportion undergoing ALND decreased from 88·8 to 18·7 per cent. Among women with one to three positive lymph nodes, the proportion undergoing SLNB alone increased from 10·6 per cent in 2011-2012 to 37·6 per cent in 2013-2014. CONCLUSION: This population-based study demonstrated the radical transformation in management of the axilla since the introduction of SLNB and following the recent publication of trials on management of the axilla with a low metastatic burden.

The role of ultrasound-guided lymph node biopsy in axillary staging of invasive breast cancer in the post-ACOSOG Z0011 trial era.

BACKGROUND: Axillary status in invasive breast cancer, established by sentinel lymph node biopsy (SLNB) or ultrasound-guided lymph node biopsy, is an important prognostic indicator. The ACOSOG Z0011 trial showed that axillary dissection may be redundant in selected sentinel node-positive patients, raising questions on the applicability of these conclusions on ultrasound positive patients. The purpose of this study was to evaluate potential differences in patient and tumor characteristics and survival between axillary node positive patients after ultrasound (US group) or sentinel lymph node procedure (SN group). METHODS: Patients diagnosed with invasive breast cancer at the Máxima Medical Center between January 2006 and December 2011 were studied. RESULTS: In total, 302 node-positive cases were included: 139 and 163 cases in the US and SN groups, respectively. Patients in the US group were older at diagnosis (p < 0.001), more often had palpable nodes (p < 0.001), mastectomy (p < 0.001), larger tumors (p < 0.001), higher tumor grade (p = 0.001), lymphovascular invasion (p = 0.035), a positive Her2Neu (p = 0.006), and a negative hormonal receptor status (p = 0.003). Also, they were more likely to have more lymph nodes with macrometastases (p < 0.001), extranodal extension (p < 0.001), and involvement of level-III-lymph node (p < 0.001). Finally, they showed a worse disease-free survival [hazard ratio (HR) = 2.71; 95 % confidence interval (CI) = 1.49-4.92] and overall survival (HR = 2.67; 95 % CI = 1.48-4.84) than the SN group. CONCLUSIONS: These results suggest that ultrasound-positive patients have less favorable disease characteristics and a worse prognosis than SN-positive patients. Therefore, we conclude that omitting an ALND is as yet only applicable, as concluded in the Z0011, in patients with a positive SLNB.