Although traditional axillary surgery remains one of the standard management options, optimal treatment of the axilla has been an evolving area aimed at reducing its related morbidity. According to the most recent NCCN guidelines for invasive breast cancer, standard ALND or SLNB is recommended in selected cases when the nodes are clinically negative following NAC and fine-needle aspiration (FNA), or core biopsy is positive before preoperative chemotherapy . ALND, as a means for achieving local disease control, carries an indisputable and often unacceptable risk of complications, such as seroma, infection, and lymphedema . However, previous studies that analyzed patients with primary breast cancer or who underwent NAC found that 40–60% of those who underwent ALND had no residual axillary disease [5, 6, 8]. In our study population, 56% of the patients had no residual nodal metastasis following axillary dissection, which was performed owing to a positive sentinel nodal biopsy result at the time of surgery. Thus, a substantial portion of patients may have been subjected to the significant morbidity of extensive axillary surgery without receiving any clinical benefit. Therefore, our study aimed to determine a tool that allows a surgeon to be more discerning in choosing a subgroup of patients who may be spared from the possible morbidity of ALND based on available clinical information before and during a scheduled surgery. Our nomogram was composed of the following four variables: number of metastatic SLN(s), number of frozen nodes, PR positivity, and preoperative clinical N stage. These parameters were available before proceeding towards a complete ALND. The prognostic role of PR positivity has been well known, and it was also reflected as one of the statistically significant factors for the nomogram [9, 10].
Relatively few models have been proposed for predicting NSLNM for patients who underwent NAC. Thus, we reviewed several nomograms for patients who were treated with or without NAC and compared them with this study’s results [5, 11–15]. One of the most widely used nomograms was developed by Van Zee et al., which included eight statistically significant variables of pathological size, LVI, method of detection, number of positive SLNs, multifocality, and number of negative SLNs . ER status and nuclear grade were included in the model but failed to demonstrate a significant association with the likelihood of NSLNM. The overall discriminative ability of this nomogram, as measured by the ROC curve, was 0.76 for the retrospective population. The AUC value for the corresponding prospective population was 0.77. However, this model is only applicable to patients without NAC. Patients who were treated with NAC may require another version of the nomogram to accurately predict NSLNM. Moreover, the variables, such as pathological tumor size and LVI, may not always be available in a routine frozen section pathology during surgery.
Jeruss et al. proposed a model for predicting the likelihood of NSLNM(s) in patients with a positive SLN following preoperative chemotherapy . They included the following five clinicopathologic factors: method of detection of SLN metastasis, multicentricity, initial lymph node status, pathologic tumor size, and LVI. The AUC of this model was 0.85, and the bootstrap-corrected AUC was 0.76. Since their study population included only patients with one metastatic sentinel node who underwent NAC, the applicability of this nomogram to patients with more than one nodal disease burden may be limited. The variables of this nomogram also included pathologic tumor size and LVI, which overlapped with the previous prediction model proposed by Van Zee et al. In many institutions, both parameters may be available only in a permanent pathology report.
Ryu et al. proposed another prediction model of NSLNM for patients who received preoperative chemotherapy . They created a nomogram composed of the following four variables: pathologic T stage, LVI, SLN metastasis size, and number of positive SLN metastases. Their nomogram exhibited an AUC value of 0.791 and 0.705 for the internal and external validation cohorts, respectively. The number of patients included in the developing cohort was 197, while the number of patients included in the external validation cohort was 30. To develop the nomogram, we analyzed 384 patients’ data and tested the formula with the data of 174 patients from different time windows. Besides the difference in the number of patients included the data involved 57 patients who were SLN negative but underwent ALND, whereas our study included only patients with one to three positive SLN(s) for analysis.
Despite the similarities and differences, the aforementioned studies and our study share the goal of accurately predicting NSLNM in patients who have undergone either upfront surgery or NAC followed by surgery. The results may help a surgeon be more discerning in determining the candidates for ALND. Each surgeon indeed has his/her own threshold to decide whether to proceed towards complete ALND or de-escalate axillary management, which could be influenced by setting an individual cut-off value using this nomogram. Parameters presented in Table 5 could be utilized as a reference. However, various clinicopathologic factors, including initial nodal status and response to chemotherapy, need to be comprehensively considered for optimal decision-making.
However, de-escalation of axillary surgery in eligible patients might raise concerns about possible residual metastatic nodal disease and the associated risk of tumor recurrence in the future. Nguyen et al. discovered a significant shift in the axillary surgery trend for patients with clinical N1 treated with NAC, with SLN surgery becoming more common while ALND becoming less common . Although de-escalation of axillary surgery following NAC has been an increasing trend, significant prospective data regarding disease recurrence and related survival are lacking .
A retrospective study compared the survival result between SLNB alone and complete extent ALND in patients with one to three positive sentinel nodes on intraoperative frozen biopsy following preoperative chemotherapy . After a median follow-up of 59.4 months for 483 patients (SLNB alone, 188; ALND, 295), no significant difference was observed in the survival between the two groups of patients. The analysis suggested that limited axillary surgery may be one of the possible surgical options for selected eligible patients.
On the other hand, Almahariq et al. reported that SLNB alone was associated with significantly lower survival than the ALND group (Hazards ratio [HR] 1.7, 95% CI 1.3–2.2, p < 0.001), with an estimated 5-year overall survival of 71% in the SLNB-only group compared with 77% of the ALND group (p = 0.01), upon comparing the survival of a total of 1617 eligible patients with ypN1 in the National Cancer Database . However, they found that SLNB may have comparable results with ALND in the selected patients with luminal A or B tumors with a single metastatic lymph node disease (HR 1.03, 95% CI 0.59–1.8, p = 0.91). They were cautious about reducing the extent of axillary surgery; however, they also demonstrated that limiting axillary surgery may be feasible in some selected patients with favorable tumor biology. Until further conclusive clinical data is published, we believe that a more cautious approach to patients with ypN1 breast cancer is still appropriate; however, being more discerning in choosing eligible patients is worthwhile for reducing the range of axillary management.
There are several limitations to this study. Considering the single institutional, retrospective nature of this study, we acknowledge the potential existence of selection bias among eligible patients. Heterogeneity was observed in baseline patient characteristics between the test and validation groups. The baseline group had a higher proportion of patients with clinical N0, whereas the validation cohort had a higher proportion of patients with clinical N2. Despite its different period of the treatment time window, the resulting nomogram was validated only in a patient cohort from a single institution. External validation with a sufficient number of patients and patients with different background demographic data should be conducted to further validate the correlation of this proposed nomogram.