Omission of Completion Axillary Lymph Node Dissection for Patients with Breast Cancer Treated by Upfront Mastectomy and Sentinel Node Isolated Tumor Cells or Micrometastases

Simple Summary Omission of completion axillary lymph node dissection (cALND) in patients undergoing mastectomy with sentinel node (SN) isolated tumor cells (ITC) or micrometastases is discussed. We evaluated the impact of cALND omission on survival in breast cancer (BC) patients treated by mastectomy with SN ITC or micrometastases. Among 554 BC, the non-SN involvement rate was 13.2%. With a median follow-up of 66.46 months, multivariate analysis showed that cALND omission was significantly associated with overall survival (OS, HR: 2.583, p = 0.043), disease-free survival (DFS, HR: 2.538, p = 0.008), and metastasis-free survival (MFS, HR: 2.756, p = 0.014). For Her2-positive or triple-negative patients, DFS was significantly impacted by cALND omission (HR: 38.451, p = 0.030). In ER-positive Her2-negative patients, DFS, OS, RFS, and MFS were also significantly affected (HR: 2.358, 3.317, 2.538, 2.756). For 161 patients ≤ 50 years with ER-positive/Her2-negative BC, OS and BCSS were notably associated with cALND omission (HR: 103.47 and 50.874). These findings suggest a negative prognostic impact of cALND omission in patients with SN micrometastases or ITC. Abstract Omission of completion axillary lymph node dissection (cALND) in patients undergoing mastectomy with sentinel node (SN) isolated tumor cells (ITC) or micrometastases is debated due to potential under-treatment, with non-sentinel node (NSN) involvement detected in 7% to 18% of patients. This study evaluated the survival impact of cALND omission in a cohort of breast cancer (BC) patients treated by mastectomy with SN ITC or micrometastases. Among 554 early BC patients (391 pN1mi, 163 ITC), the NSN involvement rate was 13.2% (49/371). With a median follow-up of 66.46 months, multivariate analysis revealed significant associations between cALND omission and overall survival (OS, HR: 2.583, p = 0.043), disease-free survival (DFS, HR: 2.538, p = 0.008), and metastasis-free survival (MFS, HR: 2.756, p = 0.014). For Her2-positive or triple-negative patients, DFS was significantly affected by cALND omission (HR: 38.451, p = 0.030). In ER-positive Her2-negative BC, DFS, OS, recurrence-free survival (RFS), and MFS were significantly associated with cALND omission (DFS HR: 2.358, p = 0.043; OS HR: 3.317; RFS HR: 2.538; MFS HR: 2.756). For 161 patients aged ≤50 years with ER-positive/Her2-negative cancer, OS and breast cancer-specific survival (BCSS) were notably impacted by cALND omission (OS HR: 103.47, p = 0.004; BCSS HR: 50.874, p = 0.035). These findings suggest a potential negative prognostic impact of cALND omission in patients with SN micrometastases or ITC. Further randomized trials are needed.

Next, validation was achieved for cALND omission in BC with one or two involved SN by micro-or macrometastases without extensive capsular rupture and breast conservative treatment with adjuvant chemotherapy and/or endocrine therapy and radiotherapy [4], and for cALND omission in BC with involved SN by micrometastases with BCS or mastectomy [9].In these two trials, the indication for SLNB was limited to tumors <50 mm.Axillary surgical de-escalation continues with recent preliminary results from two randomized trials [10,11] and pending results from other randomized trials [12][13][14].
For patients treated with upfront mastectomy and SN isolated tumor cells (ITC: pN0(i+) sn) or micrometastases (pN1mi sn), evidence for cALND omission remains limited due to underrepresentation in the IBCSG 23-01 trial [9].In the SENOMIC trial, patients with SN micrometastases underwent BCS or mastectomy without cALND, yet the risk of involved non-sentinel nodes (NSN) remains significant, exposing patients to undertreatment.Adjuvant chemotherapy (AC) and postmastectomy radiotherapy (PMRT) with regional nodal irradiation (RNI) are often not indicated for these patients, unlike those with NSN involvement where these treatments are typically recommended.
This study aimed to evaluate the survival impact of cALND omission in a large cohort of BC patients treated with upfront mastectomy and SN ITC or micrometastases, considering tumor subtypes and age subgroups.

Material and Methods
From a large multicenter cohort, early BC patients who underwent upfront mastectomy in 13 French cancer centers between 1990 and 2023 were retrospectively reviewed and we selected those with pN0(i+) or pN1mi LN metastases.
Endocrine receptors (ER) were positive if either or both estrogen and progesterone receptors were positive, with a 10% positive tumor nuclei threshold and Her2 status was considered positive if positive by fluorescence in situ hybridization or immunohistochemistry scored at 3+.
Multivariate regression analyses were used to determine significant factors associated with cALND and radiotherapy.
Overall survival (OS) was determined by months elapsed between mastectomy and death of any cause, disease-free survival (DFS) by months elapsed between mastectomy and death of any cause or recurrence, relapse-free survival (RFS) by months elapsed between mastectomy and recurrence, metastasis-free survival (MFS) by months elapsed between mastectomy and metastases, breast-cancer specific survival (BCSS) by months elapsed between mastectomy and death associated with recurrence.
Survival analysis was performed for ER-positive Her2-negative BC patients ≤ 50 years and >50 years.Menopausal status was not recorded.For patients ≤ 50 years old, AC is usually administered when NSN at cALND is involved by macrometastases.For patients > 50 years, AC is administered according to clinical, histological, and genomic risk factors.

Statistics
Standard descriptive statistics were used to describe patient and tumor characteristics.All statistical tests were two sided.The level of statistical significance was set at a p-value ≤ 0.05.Statistical analyses were performed using the SPSS 16.0 (SPSS Inc., Chicago, IL, USA).

Survival Results and Axillary Recurrence Rates
Results of ACOSOG Z0011 trial demonstrate equivalent survival results between SLNB alone (436 patients) and SLNB with cALND (420 patients) for early BC with 1 or 2 SN micrometastases (301 patients) or macrometastases treated by BCS, adjuvant chemotherapy and or endocrine therapy, and whole breast radiotherapy [4].However, a substantial axillary irradiation with high tangential irradiation fields, which can control the residual tumor burden (27.3% in cALND arm) was delivered in 18.9% of patients [15].Only one nodal axillary recurrence was observed in a patient in the SLNB alone arm and none in the cALND arm.
Preliminary results of the SENOMAC trial [10] show no statistical RFS difference (median follow-up: 46.8 months) between cALND and ALND omission for early BC patients with macrometastases treated by BCS (n = 1620) or mastectomy (n = 920).The primary end-point was OS.The non-sentinel lymph node involvement rate was 34.5%.Radiotherapy was performed in 89.9% and 88.4% of patients in the SLNB alone arm and in the cALND arm, respectively.
The AATRM trial [16] included 233 patients with SN micrometastases randomized between SLNB alone (121 patients) and SLNB with cALND (112 patients): 225 treated by BCS and whole breast irradiation and 18 treated by mastectomy.At 5 years, the DFS rate was 98.2 percent for all patients without a statistically significant difference between the two groups.The axillary recurrence rate was 1.6% (2/121) in the SLNB alone arm: 1 patient treated by BCS without cALND (1/113: 0.9%) and 1 patient treated by mastectomy without cALND (1/8: 12.5%).
The SENOMIC trial [17] included patients with SN micrometastases treated by SLNB alone and BCS (349 patients) or mastectomy (217 patients: 38.3%).Patients who had mastectomy had significantly larger and higher-grade tumors than those operated with BCS and were more often in the youngest and oldest age groups.PMRT was performed in 30.9% of patients (67/217) and adjuvant chemotherapy in 55.8% (121/217).Patients who underwent mastectomy had a lower crude 3-year event-free survival rate than those treated by BCS (93.8 versus 97.8 percent, p = 0.011).On univariate analysis, patients who had mastectomy without adjuvant radiotherapy had a significantly higher risk of recurrence than those treated by BCS (HR: 2.91, CI 95% 1.25-6.75).Four isolated axillary recurrences were diagnosed in 217 patients after mastectomy (1.8%) of whom one had loco-regional irradiation and in 1 of 349 after BCS (0.3 per cent) (p = 0.054).
In a SEER database population [23], early BC patients with SN micrometastases treated by BCS, were compared according to the axillary surgery (SLNB alone and SLNB with cALND).Using a propensity score matched analysis, there was no difference in survival between patients who underwent axillary dissection and those who had SLNB alone.
No comparative survival results between SLNB alone and SLNB with cALND are available in the literature specifically for patients pN1mi treated by mastectomy without axillary radiotherapy.However, it was reported that, on Berg level 1, PMRT gives a dose at least equivalent to the one given by post-breast-conserving surgery radiotherapy [24].
Limitations: The main limitation is the retrospective design of this study.Despite multivariate analysis adjusted on numerous criteria, several biases can persist in the comparison between SLNB alone and SLNB with cALND.These results underline a possible negative prognostic effect of cALND omission in patients with SN micrometastases or isolated tumor cells.Consequently, results of randomized trials are required to demonstrate non-inferior results of cALND omission in comparison with cALND.In SENOMIC trial [17], there was no randomization, and all patients were treated without cALND by BCS or mastectomy.Previous randomized trials included very few patients with SN micrometastases treated by mastectomy [9,16].
In the non-inferiority POSNOC trial [12], with randomization between cALND or not, the main objective was 5-year axillary recurrence in patients with 1 or 2 macrometastases.The Dutch BOOG 2013-07 trial [25] will investigate whether completion axillary treatment can be safely omitted in SLN-positive breast cancer patient's cT1-2 N0 treated with mastectomy with 1 to 3 SLN macrometastases.
In the non-inferiority SERC trial [13], with randomization between cALND or not, a stratification between SN micrometastases or isolated tumor cells and SN macrometastases was realized.The main objective was DFS.External validation of patients with SN micrometastases included in SERC trial was reported [22].It is the only trial that can answer this situation.We hope to report the first survival results in the next months.

Conclusions
In this retrospective study, we report a non-sentinel involvement rate of 13.2% for patients treated by mastectomy with cALND after identification of SN micrometastases or isolated tumor cells.For all patients, in multivariate analysis, only the omission of cALND was significantly associated with OS (HR: 2.583) and DFS (HR: 2.538).For Her2-positive or triple-negative BC patients, DFS in multivariate analysis was significantly associated with omission of cALND (HR: 38.451, p = 0.030).For ER-positive Her2-negative BC patients, in multivariate analysis, DFS, OS, RFS and MFS were significantly associated with omission of cALND.OS and BCSS were significantly associated with omission of cALND for patients ≤ 50 years with ER-positive Her2-negative BC.These results underline a possible negative prognostic impact of cALND omission in patients with SN micrometastases or isolated tumor cells.Consequently, results of randomized trials are required to demonstrate noninferior results of cALND omission in comparison with cALND.

Figure 1 .
Figure 1.Disease-free survival for all patients according to completion axillary lymph node dissection (cALND) or not, in multivariate analysis.

Figure 1 .
Figure 1.Disease-free survival for all patients according to completion axillary lymph node dissection (cALND) or not, in multivariate analysis.

Figure 2 .
Figure 2. Disease-free survival (DFS) for Her2-positive or triple-negative breast cancer according to completion axillary lymph node dissection (cALND) or not, in multivariate analysis.

Figure 2 .
Figure 2. Disease-free survival (DFS) for Her2-positive or triple-negative breast cancer according to completion axillary lymph node dissection (cALND) or not, in multivariate analysis.

Figure 4 .
Figure 4. Disease-free survival (DFS) for ER-positive Her2-negative breast cancer patients ≤ 50 years according to completion axillary lymph node dissection (cALND) or not, in multivariate analysis.

Table 3 .
Significant factors associated with cALND in regression analysis.

Table 4 .
Significant factors associated with radiotherapy.

Table 5 .
Results of OS, DFS, RFS and MFS in univariate analysis for all patients, and for SLNB alone and SLNB with cALND.

Table 6 .
Survival results for all patients in multivariate analysis.

Table 7 .
Survival results for Her2-positive or triple-negative breast cancer patients in multivariate analysis.

Table 7 .
Survival results for Her2-positive or triple-negative breast cancer patients in multivariate analysis.

Table 8 .
Survival results for ER-positive Her2-negative breast cancer patients in multivariate analysis.

Table 9 .
Survival results for ER-positive Her2-negative breast cancer patients in multivariate analysis, according to age ≤ 50 years or >50 years.