Our study showed that patients with ypN0 and ypNmi had comparable RFS and OS outcomes, while those with ypN + had a negative impact on oncologic outcomes. Notably, axillary LN status could not be accurately ascertained solely by the micrometastases of SLN. Instances of SLNmi often coincided with additional LN metastases and correlated with worse RFS compared to patients who were SLN-negative. Consequently, our findings suggest that axillary staging via ALND in patients with SLNmi should be considered following NST.
The association between residual axillary disease and prognosis is well-documented [19–21]. We hypothesized the existence of a subgroup of patients who might exhibit a more favorable prognosis, even in the presence of residual axillary tumor burden, such as micrometastases. Our findings substantiate this, demonstrating that patients with ypNmi have a more favorable prognosis compared to those with ypN+, and their oncologic outcomes are on par with those of ypN0. Prior to our investigation, only two retrospective studies, to the best of our knowledge, examined residual nodal burden. Nijinatten et al. studied prognosis as a function of metastatic LN size in a single institution [22], in which all patients were cN + and 3.8% of patients were classified as ypNitc/mi. They reported a similar prognosis for ypNitc/mi and ypN0 patients, superior to that of ypN + patients. Our results align with these findings within a similar patient population, despite a higher ypNmi percentage (9.1%) in our study. Conversely, Wong et al. contended that post-NST patients with isolated tumor cells or micrometastases had a worse prognosis than those with ypN0 in both a single institution cohort and the National Cancer Database (NCDB) [23]. They reported ypNmi rates of 9.1% and 4.7% in their respective cohorts. However, their study included patients who underwent SLNB without ALND in survival analysis. In contrast, our study exclusively enrolled patients who had 10 or more axillary LNs dissected to optimally evaluate axillary nodal status.
SLNB is a valuable intraoperative tool for predicting axillary LN metastases, though it is observed to yield higher rates of false negatives in NST patients compared to those in a primary surgical setting [24, 25]. The SENTINA trial demonstrated a FNR of 18.5% when two SLNs were removed, despite clinical conversion to node negativity post-NST [11]. In our cohort, the mean number of removed SLNs was 2.62, resulting in an elevated FNR of 23.8%. Furthermore, we noted that 17.9% of SLN-negative patients had verifiable axillary LN metastases.
Our findings indicate a substantially higher incidence of additional metastases in patients with SLNmi relative to those with SLN-negative results. Prior to our investigation, Moo et al. documented that 64% of SLNmi patients exhibited non-SLN metastases, a significantly higher figure than the 17% observed in SLN-negative patients [26]. Our study corroborated these findings, revealing additional metastases in 51.1% of SLNmi patients, 58.3% of which were macrometastases. However, in the adjuvant setting, specifically within the American College of Surgeons Oncology Group Z0011 trial, the incidence of additional metastases among SLNmi was considerably lower, at roughly ten percent [27]. This discrepancy suggests a heightened likelihood of additional metastases in NST patients with SLNmi compared to those in the adjuvant setting. In a novel discovery, we also found that SLNmi patients exhibited lower RFS rates than SLN-negative patients. Collectively, these findings suggest the necessity of ALND in patients with SLNmi following NST.
In the analysis of risk factors linked to additional metastases in SLNmi patients, a correlation was observed with pathological tumor size exceeding ypT2, ER-positive/HER2-negative subtype, and low Ki-67 LI (≤ 14%). These findings can be contextualized within the sphere of NST responsiveness. It is well established that ER-positive/HER2-negative tumors present a lower overall response rate [28, 29]. Additionally, low levels of Ki-67 LI associated with reduced pCR rates [30, 31]. Consequently, it can be inferred that SLNB accuracy is interrelated with NST response, and SLNmi is more likely to exhibit additional metastases in patients demonstrating a suboptimal response to chemotherapy.
One limitation of this study includes the potential selection bias stemming from its retrospective design. However, we were able to source relatively uniform and reliable clinicopathological data from two institutions and endeavored to accurately evaluate the axillary nodal status. Nonetheless, we were unable to consider the clinical nodal status as determined by imaging modalities. Future studies combining SLNB results with chemotherapy response evaluations via imaging examination in SLNmi cases may be necessary, as some studies suggest that the accuracy of axillary nodal status prediction can be enhanced when imaging examination results are integrated with SLNB outcomes [32].
In conclusion, ypNmi does not significantly impact patient prognosis when compared with ypN0, although ypN + is correlated with a notably worse survival outcome. However, SLNmi is an adverse prognostic indicator and a critical predictor of additional metastases, particularly in patients with a poor NST response. As such, additional ALND should be considered for verifying axillary nodal status in patients presenting with SLNmi.