Our study showed an acceptable FNR of 9.9% for single tracer (blue-dye) guided SLNB in patients with initial biopsy-proven node-positive disease treated with NAC. Compared to the NSABP-B32 trial, the residual axillary disease for node-positive patients in neoadjuvant settings was resistant to chemotherapy, which will increase the regional recurrence rate. Therefore, to further decrease the FNR in this setting, we tentatively designed a flowchart by marking a metastatic lymph node with a metal clip before NAC, assessing the axillary lymph node status using AUS after NAC, and retrieving as many SLNs as possible, including the clipped node, during the surgery. For patients who were AUS- (cN-) after NAC, without retrieving the clipped SLN or restricting the SLN number, the FNR with blue-dye guided SLNB was 2.5%. Additionally, for patients who were AUS+ (cN+), the FNR decreased from 17.1% to 4.8% when removing ≥4 SLNs, including the clipped node. With this flowchart, the overall FNR decreased from 9.9% to 3.3%.
In previous studies, using AUS alone to predict the axillary status in initial node positive patients after NAC showed a high FNR of 12.6-61.3%.[29-31] Recent literature has focused on post-NAC AUS assessment as a complementary tool in patient selection for SLNB. A study associated with an SN-FNAC trial showed that patients with no residual nodal disease identified by node morphology in AUS after NAC had a lower FNR than those with residual disease (2.7% vs. 10.8%). However, there was no consistent criteria mandated among radiologists to classify nodes as being positive or negative. In our study, AUS was also used to assess axillary load after NAC. Patients were classified as AUS-/AUS+ according to node morphology whether the asymmetric cortical thickening ≥3 mm or the metamorphosis in the fatty hilum. The AUS- group had a lower FNR of 2.5% compared to 17.1% in the AUS+ group. However, 25.5% of the patients in our study and 19.6% in SN-FNAC trial with AUS+ who achieved ypN0 finally underwent unnecessary ALND. Therefore, another effective strategy is needed to decrease the FNR in patient with AUS+.
According to well-designed prospective trials, marking the pathologic metastatic node before NAC and retrieving the marked node during SLNB has been considered an effective method to precisely evaluate the status of the marked node for residual disease after NAC and to improve the FNR.[10,12,14] However, the FNR-improving effect of this method was not obvious in our study. Most patients recruited in our study had cN2-3 disease (55.3%). Patients with cN1 disease accounted for 44.7% in our study compared to 94.6% in the Z1071 trial. It can be suggested that since this method can only mark one metastasis lymph node, when it is applied to patients with a heavy disease burden in the axilla at diagnosis, its ability to reflect the overall axillary status would be limited. As a result, the FNR-improving effect would be masked. Besides, it is reported that in the real world, the FNR of marking and removing a previously positive axillary lymph node for breast cancer after NAC ranges from 0% to 28.6%.[22-41] So this clipped-marked method may not decrease FNR in all populations. However, we found differences in the SLN FNR between those cases when the clip was identified in the SLN versus those cases with the clip identified in the ALND specimen, and this difference may be clinically relevant. And among 117 patients with the clipped node retrieved in a SLN, up to 90.6% (106/117) had metastatic disease or a chemotherapy response in the clipped node, which allows evaluation for the response to neoadjuvant chemotherapy in that specific node. So, the importance and necessity of marking the metastatic node before NAC cannot be ignored. Marking the positive node at the time of diagnosis of breast cancer is still a potentially useful tool for those patients receiving NAC.
Previous studies showed that the use of a dual-tracer may improve the low IR and high FNR associated with fibrosis of the lymphatic channels and altering patterns of lymphatic drainage after NAC, with the IR ranging from 92.3% to 97.5% and FNR ranging from 7.7% to 16.0%.[2,10,23-25,42] However, due to the lack of radioisotope availability, the single blue-dye method has been in widespread use, especially in developing countries, because it is safe, cheap and does not need the nuclear medicine department and gamma probes.[25,43-46] Using a single-tracer, some studies showed a similar IR (94.9% to 95.8%) but a higher FNR (22% to 36.4%) than that of dual lymphatic mapping in this setting.[21,22] Although, the IR is a crucial determining factor reflecting the ability to identify the SLNs for SLNB, a recent meta-analysis showed that there is no significant difference in IR when the SLN was tagged using the different mapping methods (p = 0.55). A prior study at the Memorial Sloan Kettering Cancer Center supported that it was mostly the nodal status pre-NAC, not the SLNB technique, which affect the retrieval number of SLNs. Moreover, the result of the ACOSOG Z1071 trial, which supported increasing the number of SLNs to improve the FNR, incentivizes surgeons to remove as many SLNs as possible to reduce FNR in real clinical practice.[10,47,49,50] Although our study has achieved an acceptable FNR (9.9%) for blue-dye guided SLNB, it is a single-center study with a small number of cases and lack of external verification. Hence, we tentatively designed a flowchart to optimize patient selection and improve FNR in patients with this condition with the assist of post-NAC axillary ultrasound. According to our study results, for AUS- patients after NAC, we suggest that retrieving ≥2 SLNs including the marked node during SLNB is adequate. For AUS+ patients, retrieving ≥4 SLNs, including the marked node, may effectively and accurately evaluate the nodal status.
This study has a few limitations. Firstly, in our study, we did not have comparison groups using radioactive isotope or combined method (radioactive isotope and blue-dye) for SLNB, so we were unable to firmly determine whether single-tracer only (radioactive isotope or blue-dye) is feasible and accurate enough compared to dual-tracer. Secondly, compared to several other large sample studies, our research sample size is medium, with 142 patients enrolled. However, our study is exploratory and prospective, trying to determine the reliability of SLNB using a single tracer for initial node-positive breast cancer treated with NAC, and we are hoping to expand this practice to other institutions to determine if these results are reproducible in a community setting.