Nationwide registry study on trends in localization techniques and reoperation rates in non-palpable ductal carcinoma in situ and invasive breast cancer.

BACKGROUND: There is a transition from wire-guided localization (WGL) of non-palpable breast cancer to other localization techniques. Multiple prospective studies have sought to establish superior clinical outcomes for radioactive-seed localization (RSL), but consistent and congruent evidence is missing. METHODS: In this study, female patients with breast cancer operated with breast-conserving surgery after tumour localization of a non-palpable breast cancer or ductal carcinoma in situ (DCIS) were included. The cohort was identified from the nationwide Netherlands Breast Cancer Audit conducted between 2013 and 2018. Trends in localization techniques were analysed. Univariable and multivariable analyses were performed to assess the association between the localization technique and the probability of a reoperation. RESULTS: A total of 28 370 patients were included in the study cohort. The use of RSL increased from 15.7 to 61.1 per cent during the study years, while WGL decreased from 75.4 to 31.6 per cent. The localization technique used (RSL versus WGL) was not significantly associated with the odds of a reoperation, regardless of whether the lesion was DCIS (odds ratio 0.96 (95 per cent c.i. 0.89 to 1.03; P = 0.281)) or invasive breast cancer (OR 1.02 (95 per cent c.i. 0.96 to 1.10; P = 0.518)). CONCLUSION: RSL is rapidly replacing WGL as the preoperative localization technique in breast surgery. This large nationwide registry study found no association between the type of localization technique and the odds of having a reoperation, thus confirming the results of previous prospective cohort studies.

Diagnostic performance of axillary ultrasound and standard breast MRI for differentiation between limited and advanced axillary nodal disease in clinically node-positive breast cancer patients.

Preoperative differentiation between limited (pN1; 1-3 axillary metastases) and advanced (pN2-3; ≥4 axillary metastases) nodal disease can provide relevant information regarding surgical planning and guiding adjuvant radiation therapy. The aim was to evaluate the diagnostic performance of preoperative axillary ultrasound (US) and breast MRI for differentiation between pN1 and pN2-3 in clinically node-positive breast cancer. A total of 49 patients were included with axillary metastasis confirmed by US-guided tissue sampling. All had undergone breast MRI between 2008-2014 and subsequent axillary lymph node dissection. Unenhanced T2-weighted MRI exams were reviewed by two radiologists independently. Each lymph node on the MRI exams was scored using a confidence scale (0-4) and compared with histopathology. Diagnostic performance parameters were calculated for differentiation between pN1 and pN2-3. Interobserver agreement was determined using Cohen's kappa coefficient. At final histopathology, 67.3% (33/49) and 32.7% (16/49) of patients were pN1 and pN2-3, respectively. Breast MRI was comparable to US in terms of accuracy (MRI reader 1 vs US, 71.4% vs 69.4%, p = 0.99; MRI reader 2 vs US, 73.5% vs 69.4%, p = 0.77). In the case of 1-3 suspicious lymph nodes, pN2-3 was observed in 30.4% on US (positive predictive value (PPV) 69.6%) and in 22.2-24.3% on MRI (PPV 75.7-77.8%). In the case of ≥4 suspicious lymph nodes, pN1 was observed in 33.3% on US (negative predictive value (NPV) 66.7%) and in 38.5-41.7% on MRI (NPV 58.3-61.5%). Interobserver agreement was considered good (k = 0.73). In clinically node-positive patients, the diagnostic performance of axillary US and breast MRI is comparable and limited for accurate differentiation between pN1 and pN2-3. Therefore, there seems no added clinical value of preoperative breast MRI regarding nodal staging in patients with positive axillary US.

Prognostic impact of repeat sentinel lymph node biopsy in patients with ipsilateral breast tumour recurrence.

BACKGROUND: Ipsilateral breast tumour recurrence (IBTR) has an unfavourable prognosis, with a significant subsequent risk of distant recurrence. Repeat sentinel lymph node biopsy (rSLNB) has recently been demonstrated to be technically feasible and useful in tailoring adjuvant treatment plans in patients with IBTR. The prognostic impact of rSLNB in patients with IBTR remains unclear. This study analysed the risk of distant recurrence after IBTR, and evaluated the prognostic impact of rSLNB and other patient and tumour characteristics on distant recurrence-free survival. METHODS: Data were obtained from the SNARB (Sentinel Node and Recurrent Breast Cancer) study. Cox proportional hazards analyses were performed to assess the prognostic effect of tumour, patient and treatment factors on distant recurrence-free survival. RESULTS: Of the 515 included patients, 230 (44·7 per cent) had a tumour-negative rSLNB and 46 (8·9 per cent) a tumour-positive rSLNB. In 239 patients (46·4 per cent) the rSLNB procedure was unsuccessful. After a median follow-up of 5·1 years, 115 patients (22·3 per cent) had developed a recurrence. The overall 5-year distant recurrence-free survival rate was 84·2 (95 per cent c.i. 80·7 to 87·7) per cent. An interval of less than 2 years between primary breast cancer treatment and ipsilateral recurrence (P = 0·018), triple-negative IBTR (P = 0·045) and absence of adjuvant chemotherapy after IBTR (P = 0·010) were independently associated with poor distant recurrence-free survival. The association between the outcome of rSLNB and distant recurrence-free survival was not statistically significant (P = 0·682). CONCLUSION: The outcome of rSLNB is not an important prognostic factor for distant recurrence, and its value as a staging tool in patients with IBTR seems disputable.

Does the subtype of breast cancer affect the diagnostic performance of axillary ultrasound for nodal staging in breast cancer patients?

INTRODUCTION: Imaging findings can be affected by histopathological characteristics, such as breast cancer subtypes. The aim was to determine whether the diagnostic performance, in particular negative predictive value (NPV), of axillary US differs per subtype of breast cancer. METHODS: All patients diagnosed between 2008 and 2016 in our hospital with primary invasive breast cancer and an axillary US prior to axillary surgery were included. Histopathology of axillary surgery specimens served as gold standard. The NPV, sensitivity, specificity, positive predictive value (PPV) and accuracy of the axillary US were determined for the overall population and for each subtype (ER+/PR+HER2-,HER2+, triple negative tumors). The Chi-square test was used to determine the difference in diagnostic performance parameters between the subtypes. RESULTS: A total of 1094 breast cancer patients were included. Of these, 35 were diagnosed with bilateral breast cancer, resulting in 1129 cancer cases. Most common subtype was ER+/PR+HER2- in 858 cases (76.0%), followed by 150 cases of HER2+ tumors (13.3%) and 121 cases of triple negative tumors (10.7%). Sensitivity, specificity and accuracy of axillary US did not significantly differ between the subtypes. There was a significant difference for NPV between triple negative tumors and HER2+ tumors (90.3% vs. 80.2%, p = 0.05) and between HER2+ and ER/PR+HER2- tumors (80.2% vs. 87.2%, p = 0.04). CONCLUSION: There was no significant difference in the diagnostic performance of axillary US between the subtypes, except for NPV. This was highest in triple negative subtype and lowest in HER2+ tumors. This can be explained by the difference in prevalence of axillary lymph node metastases in our cohort.

Diagnostic performance of gadofosveset-enhanced axillary MRI for nodal (re)staging in breast cancer patients: results of a validation study.

AIM: To evaluate diagnostic performance of gadofosveset (GDF)-enhanced magnetic resonance imaging (MRI) in addition to T2-weighted (T2W) MRI for nodal (re)staging in newly diagnosed breast cancer patients. MATERIALS AND METHODS: Ninety patients underwent axillary T2W- and GDF-MRI. Two radiologists independently scored each lymph node; first on T2W-MRI, subsequently adjusting their score on GDF-MRI. Diagnostic performance parameters were calculated on node-by-node and patient-by-patient validation with histopathology as the reference standard. Furthermore, learning curve analysis for reading GDF-MRI was performed. RESULTS: In patient-by-patient validation, overall reader performances for T2W- and GDF-MRI were similar with area under the receiver operating characteristic curves (AUC) of 0.75 and 0.77 (p=0.731) for reader 1 and 0.79 and 0.72 (p=0.156) for reader 2. For node-by-node validation, AUC values of T2W- and GDF-MRI were 0.76 and 0.82 (p=0.018) and 0.77 and 0.77 (p=0.998) for reader 1 and 2. The AUC for reader 1 was 0.71 for first one-third of nodes evaluated, improving to 0.80 and 0.95 for the next and last one-third, respectively. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) improved from 38%, 89%, 56%, and 79% to 60%, 93%, 64%, and 92%. The AUC of reader 2 improved from 0.69 to 0.79. CONCLUSION: The present study confirmed that GDF-MRI, in addition to T2W-MRI, has potential as a non-invasive method for nodal (re)staging in breast cancer.

Routine use of standard breast MRI compared to axillary ultrasound for differentiating between no, limited and advanced axillary nodal disease in newly diagnosed breast cancer patients.

OBJECTIVES: To compare standard breast MRI to dedicated axillary ultrasound (with or without tissue sampling) for differentiating between no, limited and advanced axillary nodal disease in breast cancer patients. METHODS: All patients who underwent breast MRI and dedicated axillary ultrasound between 2009 and 2014 were eligible. Exclusion criteria were recurrent disease, neoadjuvant systemic therapy and not receiving completion axillary lymph node dissection after positive sentinel lymph node biopsy (SLNB). Two radiologists independently reassessed all MRI exams. Axillary ultrasound findings were retrospectively collected. Probability of advanced axillary nodal disease (pN2-3) given clinically node negative (cN0) or limited (cN1) findings was calculated, with corresponding negative predictive value (NPV) to exclude pN2-3 and positive predictive value (PPV) to identify axillary nodal disease. Histopathology served as gold standard. RESULTS: A total of 377 cases resulted in 81.4% no, 14.4% limited and 4.2% advanced axillary nodal disease at final histopathology. Probability of pN2-3 given cN0 for breast MRI and axillary ultrasound was 0.7-0.9% versus 1.5% and probability of pN2-3 given cN1 was 11.6-15.4% versus 29.0%. When cN1 on breast MRI was observed, PPV to identify positive axillary nodal disease was 50.7% and 59.0%. CONCLUSIONS: Evaluation of axillary nodal status on standard breast MRI is comparable to dedicated axillary ultrasound in breast cancer patients. In patients who underwent preoperative standard breast MRI, axillary ultrasound is only required in case of suspicious nodal findings on MRI.

The diagnostic performance of sentinel lymph node biopsy in pathologically confirmed node positive breast cancer patients after neoadjuvant systemic therapy: A systematic review and meta-analysis.

PURPOSE: To provide a systematic review and meta-analysis of studies investigating sentinel lymph node biopsy after neoadjuvant systemic therapy in pathologically confirmed node positive breast cancer patients. METHODS: Pubmed and Embase databases were searched until June 19th, 2015. All abstracts were read and data extraction was performed by two independent readers. A random-effects model was used to pool the proportion for identification rate, false-negative rate (FNR) and axillary pCR with 95% confidence intervals. Subgroup analyses affirmed potential confounders for identification rate and FNR. RESULTS: A total of 997 abstracts were identified and eventually eight studies were included. Pooled estimates were 92.3% (90.8-93.7%) for identification rate, 15.1% (12.7-17.6%) for FNR and 36.8% (34.2-39.5%) for axillary pCR. After subgroup analysis, FNR is significantly worse if one sentinel node was removed compared to two or more sentinel nodes (23.9% versus 10.4%, p = 0.026) and if studies contained clinically nodal stage 1-3, compared to studies with clinically nodal stage 1-2 patients (21.4 versus 13.1%, p = 0.049). Other factors, including single tracer mapping and the definition of axillary pCR, were not significantly different. CONCLUSION: Based on current evidence it seems not justified to omit further axillary treatment in every clinically node positive breast cancer patients with a negative sentinel lymph node biopsy after neoadjuvant systemic therapy.

The role of MRI in axillary lymph node imaging in breast cancer patients: a systematic review.

OBJECTIVES: To assess whether MRI can exclude axillary lymph node metastasis, potentially replacing sentinel lymph node biopsy (SLNB), and consequently eliminating the risk of SLNB-associated morbidity. METHODS: PubMed, Cochrane, Medline and Embase databases were searched for relevant publications up to July 2014. Studies were selected based on predefined inclusion and exclusion criteria and independently assessed by two reviewers using a standardised extraction form. RESULTS: Sixteen eligible studies were selected from 1,372 publications identified by the search. A dedicated axillary protocol [sensitivity 84.7 %, negative predictive value (NPV) 95.0 %] was superior to a standard protocol covering both the breast and axilla simultaneously (sensitivity 82.0 %, NPV 82.6 %). Dynamic, contrast-enhanced MRI had a lower median sensitivity (60.0 %) and NPV (80.0 %) compared to non-enhanced T1w/T2w sequences (88.4, 94.7 %), diffusion-weighted imaging (84.2, 90.6 %) and ultrasmall superparamagnetic iron oxide (USPIO)- enhanced T2*w sequences (83.0, 95.9 %). The most promising results seem to be achievable when using non-enhanced T1w/T2w and USPIO-enhanced T2*w sequences in combination with a dedicated axillary protocol (sensitivity 84.7 % and NPV 95.0 %). CONCLUSIONS: The diagnostic performance of some MRI protocols for excluding axillary lymph node metastases approaches the NPV needed to replace SLNB. However, current observations are based on studies with heterogeneous study designs and limited populations. MAIN MESSAGES: • Some axillary MRI protocols approach the NPV of an SLNB procedure. • Dedicated axillary MRI is more accurate than protocols also covering the breast. • T1w/T2w protocols combined with USPIO-enhanced sequences are the most promising sequences.

Noninvasive nodal restaging in clinically node positive breast cancer patients after neoadjuvant systemic therapy: a systematic review.

OBJECTIVE: To provide a systematic review of studies comparing the diagnostic performance of noninvasive techniques and axillary lymph node dissection in the identification of initially node positive patients with pathological complete response of axillary lymph nodes to neoadjuvant systemic therapy. METHODS: PubMed and Embase databases were searched until May 21st, 2014. First, duplicate studies were eliminated. Next, study abstracts were read by two readers to assess eligibility. Studies were selected based on predefined inclusion criteria. Of these, data extraction was performed by two readers independently. RESULTS: Of the 987 abstracts that were considered for inclusion, four were eligible for final analysis, which included a total of 572 patients. The diagnostic performance of clinical examination, axillary ultrasound, breast MRI, whole body (18)F-FDG PET-CT, and a prediction model to identify patients with pathological complete response were investigated. Studies were often limited by small sample size. Furthermore, systemic therapy regimens and definitions of clinical and pathological complete response were variable, refraining further pooling of data. The reported positive predictive value of different techniques to identify patients with axillary pathological complete response after neoadjuvant systemic therapy varied between 40% and 100%. CONCLUSION: At present, there is no accurate noninvasive restaging technique able to identify patients with complete axillary response after neoadjuvant systemic therapy.

Inconsistent selection and definition of local and regional endpoints in breast cancer research.

BACKGROUND: Results in breast cancer research are reported using study endpoints. Most are composite endpoints (such as locoregional recurrence), consisting of several components (for example local recurrence) that are in turn composed of specific events (such as skin recurrence). Inconsistent endpoint selection and definition might lead to unjustified conclusions when comparing study outcomes. This study aimed to determine which locoregional endpoints are used in breast cancer studies, and how these endpoints and their components are defined. METHODS: PubMed was searched for breast cancer studies published in nine leading journals in 2011. Articles using endpoints with a local or regional component were included and definitions were compared. RESULTS: Twenty-three different endpoints with a local or regional component were extracted from 44 articles. Most frequently used were disease-free survival (25 articles), recurrence-free survival (7), local control (4), locoregional recurrence-free survival (3) and event-free survival (3). Different endpoints were used for similar outcomes. Of 23 endpoints, five were not defined and 18 were defined only partially. Of these, 16 contained a local and 13 a regional component. Included events were not specified in 33 of 57 (local) and 27 of 50 (regional) cases. Definitions of local components inconsistently included carcinoma in situ and skin and chest wall recurrences. Regional components inconsistently included specific nodal sites and skin and chest wall recurrences. CONCLUSION: Breast cancer studies use many different endpoints with a locoregional component. Definitions of endpoints and events are either not provided or vary between trials. To improve transparency, facilitate trial comparison and avoid unjustified conclusions, authors should report detailed definitions of all endpoints.

The impact of the pathological lymph node status on adjuvant systemic treatment recommendations in clinically node negative breast cancer patients.

Several independent randomized controlled trials are initiated to investigate whether sentinel lymph node biopsy can be safely omitted in clinically node negative breast cancer patients with negative axillary ultrasound findings, who are treated with breast conserving therapy. A consequence of omitting sentinel lymph node biopsy is absence of pathological lymph node status information. We aimed to investigate the impact of omitting sentinel lymph node biopsy on adjuvant systemic treatment recommendations. Data from all consecutive patients with invasive breast cancer and negative axillary ultrasound findings treated with breast conserving therapy and sentinel lymph node biopsy between 2008 and 2012 were collected from a prospective database. Two methods, Adjuvant! Online and the Dutch breast cancer guideline 2012, were used to determine the adjuvant systemic treatment recommendations of every patient. At first, each patient was considered to be lymph node negative, and secondly the patients' true pathological lymph node status was used. A total of 303 patients were consecutively included. Pathological lymph node status was pN0 in 72.3 %, pN0(i+) in 12.9 %, pN1mi+ in 5.6 %, pN1 in 7.3 %, and pN2 in 2.0 % of the patients. The decision to recommend adjuvant systemic treatment changed due to the pathological lymph node status in 1.0 % of the patients (3/303) when using Adjuvant! Online and in 3.6 % (11/303) when using the 2012 Dutch breast cancer guideline. The impact of the pathological lymph node status on adjuvant systemic treatment recommendations in clinically node negative breast cancer patients with negative axillary ultrasound findings treated with breast conserving therapy is limited. The safety of omitting the sentinel lymph node biopsy should be confirmed by the initiated randomized controlled trials.

Axillary ultrasound for preoperative nodal staging in breast cancer patients: is it of added value?

BACKGROUND: New insights show that an axillary lymph node dissection (ALND) may not always be indicated for metastases detected by ultrasound (pathologically proven). This study investigated whether axillary ultrasound accurately predicts pN0, pN1 and pN2-pN3 status. METHODS: Data were retrospectively collected from all consecutive patients with invasive breast cancer who underwent (primary) surgery between 2008 and 2012. False negative percentages and negative predictive values (NPVs) for sonographic nodal staging were calculated for all patients and again for cT1-2 patients treated by breast conserving therapy (BCT). RESULTS: A total of 577 axillary ultrasounds were included. After negative ultrasound findings (cN0), pathology showed pN2-pN3 disease in 4.4% of these cases, with an NPV of 95.5% (93.4-97.1%). When cN1 (1-3 suspicious nodes) was predicted, pathology showed pN2-pN3 disease in 41.2%, with an NPV of 58.5% (44.2-71.5%). In the subgroup of patients with cT1-2 breast cancer that were treated by BCT, pathology showed pN2-pN3 disease in 2.3% after negative ultrasound findings (cN0), with an NPV of 97.7% (94.9-99.0%). When cN1 was predicted (n = 12), pathology showed pN2-pN3 disease in 50.0%, with an NPV of 50.0% (22.3-77.9%). A direct ALND was performed in these 12 cN1 cases; pathology showed six patients with pN1 (three patients with one and three with two macrometastases) and six with pN2-pN3 disease (4, 5, 11, 13, 16 or 22 macrometastases, respectively). CONCLUSION: In conclusion, a negative axillary ultrasound generally excludes the presence of pN2-pN3 disease. An axillary ultrasound cannot accurately differentiate between pN1 and pN2-pN3. It could be argued that the standard performance of an axillary ultrasound in breast cancer patients is questionable; multidisciplinary discussion could guide decisions on the use of axillary ultrasound for the individual patient.

No increase of local recurrence rate in breast cancer patients treated with skin-sparing mastectomy followed by immediate breast reconstruction.

BACKGROUND: The aim of this study was to evaluate the incidence of local recurrence after SSM with IBR and to determine whether complications lead to postponement of adjuvant therapy. METHOD: Patients that underwent IBR after SSM between 2004 and 2011 were included. RESULTS: A total of 157 reconstruction procedures were performed in 147 patients for invasive breast cancer (n = 117) and ductal carcinoma in situ (n = 40). The median follow-up was 39 months [range 6-97]. Estimated 5-year local recurrence rate was 2.9% (95% CI 0.1-5.7). The median time to start adjuvant therapy was 27.5 days [range 19-92] in 18 patients with complications, and 23.5 days [range 8-54] in 46 patients without complications (p = 0.025). CONCLUSION: In our single-institution cohort, IBR after SSM carried an acceptable local recurrence rate. Complications caused a delay of adjuvant treatment but this was within guidelines and therefore not clinically relevant.