Omission of axillary dissection in patients with microscopic residual nodal disease after neoadjuvant chemotherapy

Axillary lymph node dissection (ALND) is associated postoperatively with arm lymphedema, reduced shoulder mobility and local sensory dysfunction. Currently, tailored axillary surgery (TAS) and axillary reverse mapping have been developed to avoid arm lymphedema without increasing the risk of axillary recurrence (1-4). TAS involves removal of the clipped node(s), sentinel node(s) and any palpably abnormal nodes. TAS aims to convert a clinically node-positive axilla (cN⁺) into a clinically node-negative one (cN0), mainly through palpation-guided selective removal of grossly involved nodes (4). When a cN⁺ becomes cN0 after TAS, nodal irradiation is effective in reducing the axillary recurrence rate (1,2). A prospective randomized trial (TAXIS trial) comparing TAS in combination with axillary radiotherapy versus conventional ALND is being conducted in both the neoadjuvant systemic therapy (NAST) and upfront surgery settings (1). An analysis of the primary endpoint will be published in 2030 (2). The MicroNAC study may support the rationale of the ongoing TAXIS trial using TAS (1,2), though the surgical procedures are somewhat different between them.

A multicenter retrospective cohort study (MicroNAC study) was conducted to assess oncologic outcomes in breast cancer patients with residual micrometastatic nodal disease (ypN1mi) treated with or without conventional ALND after NAST (5). This study required down-staging to cN0 after NAST for cN⁺ patients. Residual micrometastases after NAST were histologically determined on frozen or paraffin sections obtained through either targeted axillary dissection (TAD), sentinel lymph node (SLN) biopsy or the MARI (Marking Axillary lymph nodes with Radioactive Iodine seeds) procedure. Results of the study can be summarized as follows: A total of 1,585 patients with ypN1mi disease were analyzed, of whom 804 patients (50.7%) underwent conventional ALND and 781 patients (49.3%) did not. Of the 804 patients who underwent ALND, additional positive nodes were found in 245 patients (30.5%) after NAST, including 123 patients with micrometastases and 102 patients with macrometastases. After surgery, regional radiotherapy was administered to 81.1% of patients who underwent ALND and to 78.7% of patients who did not. Additionally, adjuvant hormonal therapy was administered to 95.8% of patients with hormone receptor (HR)-positive tumors who underwent ALND and to 95.9% of patients with HR-positive tumors who did not undergo ALND.

With the median follow-up of 3.1 years, the overall rate of any axillary recurrence was only 2.0% in this study. Although current breast cancer guidelines have recommended completion ALND for all patients with residual micrometastases or macrometastases after NAST (6,7), the rate of axillary recurrence was not significantly different between patients treated with ALND and those without ALND in this study (1.7% vs. 2.3%; P=0.92). As shown in the landmark National Surgical Adjuvant Breast and Bowel Project (NSABP) B-04 trial, postoperative radiotherapy is effective in preventing axillary recurrence in cN0 patients (8). When examined by tumor subtypes, on the other hand, patients with triple-negative tumors who did not undergo ALND had significantly higher rates of axillary recurrence than those treated with ALND (8.7% vs. 2.4%, P=0.018). On multivariable analysis, omission of postoperative radiotherapy and triple-negative tumors, but not omission of ALND, were independently associated with an increased risk of axillary recurrence (5).

In contrast to triple-negative tumors, completion ALND was not detrimental for patients with HR-positive tumors or HER2-positive tumors who received appropriate adjuvant systemic therapies after surgery. NAST is highly effective in patients with HER2-positive tumors or in those with triple-negative tumors, achieving nodal pathologic complete response (pCR) in 44–78% of cases (9,10). In contrast, nodal pCR after NAST occurs in only approximately 20% of patients with HR-positive tumors (11,12). Nevertheless, Montagna et al. (5) reported that regional recurrence was rare in patients with HR-positive tumors treated with either SLN biopsy alone or ALND; however, most axillary recurrences occur within the first 5 years after surgery (13,14). In the ACOSOG Z0011 trial also, 7 of 11 patients (64%) experienced regional recurrences within 5 years, despite more than 80% of patients having HR-positive tumors (13). Only one case of regional recurrence was observed beyond 76 months of follow-up. However, it is well established that HR-positive tumors recur over a longer period of time. In the AMAROS trial, axillary recurrences occurred in 7 of 744 patients (0.9%) treated with ALND and 11 of 681 patients (1.6%) treated with axillary radiotherapy, with three and five isolated axillary recurrences, respectively. In total, eight events were found between 5 and 11 years of follow-up (15).

Even after 5 years of adjuvant hormonal therapy, patients with HR-positive tumors remain at risk of recurrence for at least 20 years after surgery (16). HR-positive tumors are characterized by a prolonged natural history (17). In the International Breast Cancer Study Group trial with 24 years of follow-up, patients with HR-positive tumors had a lower hazard of recurrence than those with HR-negative tumors during the first 5 years. Beyond 5 years, however, the hazard of recurrence was higher in patients with HR-positive tumors than in those with HR-negative tumors (17). Accordingly, long-term follow-up is recommended to confirm the findings of this study.

Of the 804 patients who underwent ALND in this study, additional involved nodes were found in 245 patients (30.5%) after NAST. This proportion is comparable to rates reported in the ACOSOG Z0011 and the AMAROS trials: the rate of additional positive nodes after SLN biopsy was 27.4% in the Z0011 trial (13) and 33% in the AMAROS trial (15). However, most patients who underwent the SLN biopsy did not develop axillary recurrence in either trial (18). These findings may suggest that omission of ALND is possible under multimodal treatment including nodal radiotherapy and hormonal therapy. Recently, the NSABP B51 randomized clinical trial with a median follow-up of 5 years has demonstrated that adjuvant regional nodal irradiation did not decrease the risk of breast cancer recurrence in patients who had negative axillary nodes after NAST (19). Nevertheless, these trials are not comparable, because these comparisons involve fundamentally different patient populations (NAST vs. upfront surgery; ypN1mi vs. ypN0). As the authors noted, moreover, this was a retrospective observational study, and the surgeons decided to omit ALND based on a lower baseline risk and patient preference (5). Nevertheless, omission of ALND in favor of regional radiotherapy is being investigated in a randomized setting (TAXIS trial) (1,2). Results from the TAXIS trial, with a long-term follow-up, are awaited to confirm the safety of this approach. In the era of multimodality therapy, completion ALND removing all axillary disease may not be required in either cN0 or cN⁺ patients.

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