G Helms

Sentinel-lymph-node biopsy in patients with breast cancer before and after neoadjuvant chemotherapy (SENTINA): a prospective, multicentre cohort study.

BACKGROUND The optimum timing of sentinel-lymph-node biopsy for breast cancer patients treated with neoadjuvant chemotherapy is uncertain. The SENTINA (SENTinel NeoAdjuvant) study was designed to evaluate a specific algorithm for timing of a standardised sentinel-lymph-node biopsy procedure in patients who undergo neoadjuvant chemotherapy. METHODS SENTINA is a four-arm, prospective, multicentre cohort study undertaken at 103 institutions in Germany and Austria. Women with breast cancer who were scheduled for neoadjuvant chemotherapy were enrolled into the study. Patients with clinically node-negative disease (cN0) underwent sentinel-lymph-node biopsy before neoadjuvant chemotherapy (arm A). If the sentinel node was positive (pN1), a second sentinel-lymph-node biopsy procedure was done after neoadjuvant chemotherapy (arm B). Women with clinically node-positive disease (cN+) received neoadjuvant chemotherapy. Those who converted to clinically node-negative disease after chemotherapy (ycN0; arm C) were treated with sentinel-lymph-node biopsy and axillary dissection. Only patients whose clinical nodal status remained positive (ycN1) underwent axillary dissection without sentinel-lymph-node biopsy (arm D). The primary endpoint was accuracy (false-negative rate) of sentinel-lymph-node biopsy after neoadjuvant chemotherapy for patients who converted from cN1 to ycN0 disease during neoadjuvant chemotherapy (arm C). Secondary endpoints included comparison of the detection rate of sentinel-lymph-node biopsy before and after neoadjuvant chemotherapy, and also the false-negative rate and detection rate of sentinel-lymph-node biopsy after removal of the sentinel lymph node. Analyses were done according to treatment received (per protocol). FINDINGS Of 1737 patients who received treatment, 1022 women underwent sentinel-lymph-node biopsy before neoadjuvant chemotherapy (arms A and B), with a detection rate of 99.1% (95% CI 98.3-99.6; 1013 of 1022). In patients who converted after neoadjuvant chemotherapy from cN+ to ycN0 (arm C), the detection rate was 80.1% (95% CI 76.6-83.2; 474 of 592) and false-negative rate was 14.2% (95% CI 9.9-19.4; 32 of 226). The false-negative rate was 24.3% (17 of 70) for women who had one node removed and 18.5% (10 of 54) for those who had two sentinel nodes removed (arm C). In patients who had a second sentinel-lymph-node biopsy procedure after neoadjuvant chemotherapy (arm B), the detection rate was 60.8% (95% CI 55.6-65.9; 219 of 360) and the false-negative rate was 51.6% (95% CI 38.7-64.2; 33 of 64). INTERPRETATION Sentinel-lymph-node biopsy is a reliable diagnostic method before neoadjuvant chemotherapy. After systemic treatment or early sentinel-lymph-node biopsy, the procedure has a lower detection rate and a higher false-negative rate compared with sentinel-lymph-node biopsy done before neoadjuvant chemotherapy. These limitations should be considered if biopsy is planned after neoadjuvant chemotherapy. FUNDING Brustkrebs Deutschland, German Society for Senology, German Breast Group.

Abstract S2-2: Sentinel Lymph Node Biopsy Before or After Neoadjuvant Chemotherapy - Final Results from the Prospective German, multiinstitutional SENTINA-Trial -

Background: The optimal timing for sentinel lymph node biopsy (SLNB) in the neoadjuvant setting is still unclear. Evidence for both, feasibility (detection rate, DR) and accuracy (false negative rate, FNR) of SLNB before and after primary systemic treatment (PST) is restricted to monocentric and/or retrospective trials. The success rates for SLNB are particularly unclear for patients who are downstaged from a cN1 to a ycN0 status. Material and Methods: The German SENTINA (SENTInel NeoAdjuvant) trial is a 4-arm prospective multicenter cohort study designed to evaluate a specific algorithm for the timing of a standardized SLNB procedure in patients, who undergo PST and to provide reliable data for the DR and FNR in different settings. Patients were categorized into four treatment arms according to the clinical axillary staging before and after chemotherapy. Patients with a cN0 status underwent SLNB prior to PST and were categorized as arm A and B: If the SLN was histologically negative no further axillary surgery was performed after PST (arm A), whereas in case of histologically positive SLN status, a second SLNB and axillary dissection (AD) was performed after PST (arm B). Patients with a cN1 status prior to PST underwent no axillary surgery prior to PST and were stratified as arm C and D: If patients converted to cN0 after PST, SLNB and AD were performed (arm C); patients presenting with cN1 status after PST underwent classical AD (arm D). Results: 1737 eligible patients from 103 institutions entered the trial. From these 662 patients were classified as arm A, 360 pts as arm B, 592 pts as arm C and 123 pts as arm D. The DR for SLNB was 1013/1022 (99.1%) before PST (arms A and B), 474/592 (80.1%) in Arm C (after PST), and 219/360 (60.8%) in arm B (after prior SLNB and PST) (p Conclusion: In patients, who convert from a positive to a negative cN stage during PST the DR for the SLNB is significantly lower compared to patients, who undergo SLNB prior to any other treatment. The FNR is less favorable compared to primary SLNB. Prior systemic and/or surgical treatment significantly impairs the success rates of SLNB. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr S2-2.

SENTinel Node Biopsy before or after NeoAdjuvant Systemic Treatment – The German SENTINA Trial.

Background: For patients with breast cancer undergoing neoadjuvant systemic treatment (NST) the optimal timing of sentinel node biopsy (SLNB) is unclear. While adequate axillary staging prior to NST could allow for a-priori tailoring of systemic treatment, SLNB after NST could spare those patients from complete axillary dissection (AD), who are free of metastases in the axilla or convert from a positive (Npos) to a negative (Nneg) axillary status following NST. For these patients, however, the reliability of SLNB to predict the axillary status remains yet to be prospectively confirmed.Material and Methods: The German SENTINA protocol, as a substudy of the German Geparquinto neoadjuvant trial of the AGO and the German Breast Group (GBG), is a 4-arm prospective multicenter case control study designed to examine the role of SLN in patients undergoing NST.Study design:Arm A before NST: clinically Nneg + negative SLN --> no add. Axillary surgery Arm B before NST: clinically Nneg + positive SLN --> sentinel-node-guided AD after NST Arm C before NST: clinically Npos, after NST: clinically Nneg --> sentinel-node-guided AD after NST Arm D before NST: clinically Npos, after NST: clinically Npos --> ADStudy objectives:1. to compare the detection rate of SLNB before and after NST2. to evaluate the number of patients with involved nodes despite being clinically Nneg before NST3. to determine the number of patients who convert from clinically Npos to histologically Nneg after NST4. to evaluate the false-negative rate of SNB for patients who convert from clinically Npos to histologically SNneg after NST5. to determine lymphatic pathway configuration, detection rate and false-negative rate of SLNB after prior SLNB6. to determine the false negative rate of intraoperative frozen section before and after NSTResults: Until now 366 patients from 30 institutions have been enrolled in this trial. 230 patients have completed primary systemic and surgical treatment. A total of 1508 patients were calculated as adequate to have the one-sided confidence interval of 95 % for the false negative rate of SLNB in the arms B and C not exceeding 10% (196 pts each). 82 pts entered arm A. Fifty-eight, 76 and 24 pts were recruited for the arms B, C and D respectively.Conclusion: To our knowledge the SENTINA trial is the first prospective multicenter study to evaluate the role of SLNB in the neoadjuvant setting. The SENTINA protocol will allow for a direct comparison of the feasibility and reproducibility of a standardized SLNB-procedure before and after NST. The study will provide reliable data on the predictive value of SLNB before and after NST in patients converting from a clinically positive to a negative axillary status and offer insights into the biology of axillary response to NST. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 1008.

Systematic analysis of parameters predicting pathological axillary status (ypN0 vs. ypN+) in patients with breast cancer converting from cN+ to ycN0 through primary systemic therapy (PST)

Optimization of axillary staging among patients converting from clinically node-positive disease to clinically node-negative disease through primary systemic therapy is needed. We aimed at developing a nomogram predicting the probability of positive axillary status after chemotherapy based on clinical/pathological parameters. Patients from study arm C of the SENTINA trial were included. Univariable/multivariable analyses were performed for 13 clinical/pathological parameters to predict a positive pathological axillary status after chemotherapy using logistic regression models. Odds ratios and 95%-confidence-intervals were reported. Model performance was assessed by leave-one-out cross-validation. Calculations were performed using the SAS Software (Version 9.4, SAS Institute Inc., Cary, NC, USA). 369 of 553 patients in Arm C were included in multivariable analysis. Stepwise backward variable selection based on a multivariable analysis resulted in a model including estrogen receptor (ER) status (odds ratio (OR) 3.916, 95% confidence interval (CI) 2.318–6.615, p < 0.001), multifocality (OR 2.106, 95% CI 1.203–3.689, p = 0.0092), lymphovascular invasion (OR 9.196, 95% CI 4.734–17.864, p < 0.001), and sonographic tumor diameter after PST (OR 1.034, 95% CI 1.010–1.059, p = 0.0051). When validated, our model demonstrated an accuracy of 70.2% using 0.5 as cut-point. An area under the curve of 0.81 was calculated. The use of individual parameters as predictors of lymph node status after chemotherapy resulted in an inferior accuracy. Our model was able to predict the probability of a positive axillary nodal status with a high accuracy. The use of individual parameters showed reduced predictive performance. Overall, tumor biology was the strongest parameter in our models.

Prediction of Non-sentinel Lymph Node Metastases After Positive Sentinel Lymph Nodes Using Nomograms

Background/Aim: Only 30-50% of patients with sentinel lymph node (SLN) metastases present with further axillary lymph node metastases. Therefore, up to 70% of patients with positive SLN are overtreated by axillary dissection (AD) and may suffer from complications such as sensory disturbances or lymphedema. According to the current S3 guidelines, AD can be avoided in patients with a T1/T2 tumor if breast-conserving surgery with subsequent tangential irradiation is performed and no more than two SLNs are affected. Additionally, use of nomograms, that predict the probability of non-sentinel lymph node (NSLN) metastases, is recommended. Therefore, models for the prediction of NSLN metastases in our defined population were constructed and compared with the published nomograms. Patients and Methods: In a retrospective study, 2,146 primary breast cancer patients, who underwent SLN biopsy at the University Womens Hospital in Tuebingen, were evaluated by dividing the patient group in a training and validation collective (TC or VC). Using the SLN-positive TC patients, three models for the prediction of the likelihood of NSLN metastases were adapted and were then validated using the SLN-positive VC patients. In addition, the predictive power of nomograms from Memorial Sloan Kettering Cancer Center (MSKCC), Stanford, and the Cambridge model were compared with regard to our patient collective. Results: A total of 2,146 patients were included in the study. Of these, 470 patients had positive SLN, 295 consisted the training collective and 175 consisted the validation collective. In a regression model, three variants – with 11, 6 and 2 variables – were developed for the prediction of NSLN metastases in our defined population and compared to the most frequently used nomograms. Our variants with 11 and with 6 variables were proven to be a particularly suitable model and showed similarly good results as the published MSKCC nomogram. Conclusion: Our developed nomograms may be used as a prediction tool for NSLN metastases after positive SLN.