Axillary lymph node removal in de novo metastatic breast cancer

Introduction

Breast cancer (BC) remains a significant health concern worldwide, with a substantial impact on morbidity and mortality in women (1). The incidence of BC has increased by 0.5% per year annually and the incidence of de novo metastatic BC (dnMBC) is increasing despite widespread mammography screening (2,3). While advancements in BC screening and treatment modalities have improved outcomes for many patients, dnMBC presents a distinct challenge due to its advanced metastatic nature at initial diagnosis. dnMBC is characterized by the spread of BC beyond the breast and regional lymph nodes to distant sites, such as the bones, lungs, liver, or brain, at the time of diagnosis. It is a relatively rare condition, affecting approximately 5–10% of all BC patients. However, its prognosis is generally poor, with a median survival time of only 2–3 years (4-7).

Several retrospective studies have indicated that women diagnosed with dnMBC may experience enhanced survival rates following the surgical removal of the primary tumor. However, the interpretation and generalizability of these findings are limited due to potential selection bias. Four clinical trials have evaluated the impact of local surgical resection of the primary lesion in dnMBC (8-11). Three of these trials demonstrated improved locoregional control, yet they did not reveal any statistically significant difference in overall survival (OS). The fourth trial reported an improvement in 5-year OS, but this finding drew criticism due to concerns that patients in the surgery group may have been in a more favorable prognostic category before the intervention (11). However, there were still 26.8–57.2% of patients receiving local surgery in the real world and the results found that local surgical resection of the primary lesion was associated with better survival outcomes in this population (12-15).

Historically, the primary goal of axillary lymph node dissection (ALND) in non-metastatic BC has been to accurately stage the disease and guide adjuvant treatment decisions. Additionally, ALND is believed to provide local control by removing potentially cancerous lymph nodes in the axilla. However, its role in dnMBC patients has been a subject of debate and investigation. In light of this, the objective of our study was to examine the trends and impact of ALND in patients diagnosed with dnMBC using a population-based cohort. We present this article in accordance with the STROBE reporting checklist (available at https://gs.amegroups.com/article/view/10.21037/gs-24-130/rc).

Methods

Patients

This retrospective study utilized data from the Surveillance, Epidemiology, and End Results (SEER) program to include patients diagnosed with dnMBC between 2010 and 2020 (16). The SEER program, a resource by the National Cancer Institute, is a comprehensive source of cancer statistics providing data on cancer incidence, demographics, clinicopathological variables, treatment, and vital status from 18 cancer registries across the United States. The analysis included women who met the following criteria: (I) diagnosed with dnMBC aged 18 years or above; (II) underwent local surgery including breast-conserving surgery or mastectomy; (III) with or without additional ALND during local surgery. Patients were excluded from the analysis if they had missing data on tumor (T) stage, nodal (N) stage, estrogen receptor (ER) status, progesterone receptor (PR) status as well as human epidermal growth factor receptor 2 (HER2) status. In addition, those with unavailable sites of distant metastasis (DM) were also excluded from the analysis. As the SEER program only contains anonymized data, our study was exempt from the approval process by the ethics committee. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013).

Variables

The analysis incorporated the following variables: years of diagnosis, age, race, tumor grade, histology, T stage, N stage, ER status, PR status, HER2 status, receipt of chemotherapy, surgical procedure, and sites of DM. The definition of DM sites included bone, brain, liver, lung, or distant lymph nodes. The primary outcomes of this study were breast cancer-specific survival (BCSS) and OS. BCSS was calculated from the time of dnMBC diagnosis to the time of death specifically due to BC or the follow-up cutoff. OS was measured from the time of dnMBC diagnosis to the time of death from any cause or the follow-up cutoff.

Statistical analysis

The Chi-square test was utilized to compare the demographic and clinicopathological variables between the groups that underwent ALND and those that did not. Binomial logistic regression was carried out to identify the independent predictors associated with the receipt of ALND. To mitigate selection bias between the ALND and non-ALND cohorts, a 1:1 propensity score matching (PSM) was implemented. BCSS and OS curves were plotted by the Kaplan-Meier method and the log-rank test was employed to compare the differences between these curves. Multivariate Cox proportional analysis was applied to determine the independent prognostic factors significantly related to survival outcomes. Sensitivity analyses were conducted after stratifying the demographic and clinicopathological variables to verify the robustness of the results. All statistical analyses were carried out using the SPSS statistical software (version 25.0, IBM Corporation, Armonk, NY, USA). P values less than 0.05 were defined as statistical significance.

Results

Patient baseline characteristic

A total of 6,838 patients were included in the study (Figure 1), of which 5,562 (81.3%) were in the ALND group and 1,276 (18.7%) in the non-ALND group. The baseline characteristics of patients are listed in Table 1. The median age of diagnosis was 58 years. There were 4,372 (63.9%) who were of White race, 3,428 (50.1%) had an undifferentiated disease, 5,217 (76.3%) had invasive ductal carcinoma, and 5,440 (79.6%) had nodal-positive disease. Regarding BC subtype (BCS), 3,880 (56.7%), 1,157 (16.9%), 699 (9.8%), and 1,132 (16.6%) patients had hormone receptor (HoR)⁺/HER2⁻, HoR⁺/HER2⁺, HoR⁻/HER2⁺, and HoR⁻/HER2⁻, respectively. Bone (n=4,082, 59.7%) was the most common site of DM, followed by distant lymph nodes (n=1,805, 26.4%), lung (n=1,645, 24.1%), liver (n=1,329, 19.4%), and brain (n=241, 3.5%). There were 5,144 (75.2%), 1,232 (18.0%), 364 (5.3%), 88 (1.3%), and 10 (0.1%) patients who had one, two, three, four, and five sites of DM, respectively. There were significant differences in age, race, tumor grade, histology, T stage, N stage, surgical procedure, chemotherapy receipt, and the sites of DM between those with and without ALND (all P<0.05) (Table 1). However, a similar distribution in BCS (P=0.696) was found between those with and without ALND. A total of 396 pairs of patients were completely matched using PSM (Table 1).

Figure 1 The flow chart of the cohort selection. BC, breast cancer; T, tumor; N, nodal; X, unknown; ER, estrogen receptor; PR, progesterone receptor; HER2, human epidermal growth factor receptor 2; BCS, breast cancer subtype; M, metastasis; ALND, axillary lymph node dissection.

Trends of ALND during the study period

The trends of ALND in dnMBC patients between 2010 and 2020 are shown in Figure 2. There were 79.1% of patients received ALND in 2010 and 83.4% of patients received ALND in 2020. The probability of ALND increased slightly between 2010 and 2020, but there was no statistically significant difference (P=0.153).

Figure 2 The trends of ALND during the study period. ALND, axillary lymph node dissection.

Binomial logistic regression was performed to determine the independent predictors of ALND receipt (Table 2). The results showed that patients with Hispanic race [vs. White, odds ratio (OR) 1.336, 95% confidence interval (CI): 1.082–1.650, P=0.007], diagnosed in later years (OR 1.026, 95% CI: 1.004–1.048, P=0.02), received mastectomy (vs. breast-conserving surgery, OR 3.915, 95% CI: 3.389–4.523, P<0.001), received chemotherapy (vs. no chemotherapy, OR 1.606, 95% CI: 1.394–1.850, P<0.001) were the independent predictive factors associated with the receipt of ALND. However, those with advanced T stage (T4 vs. T1, OR 0.470, 95% CI: 0.381–0.581, P<0.001), lung metastasis only (vs. bone metastasis only, OR 0.709, 95% CI: 0.569–0.882, P=0.002), and multiple metastases (vs. bone metastasis only, OR 0.568, 95% CI: 0.483–0.667, P<0.001) were associated with non-receipt of ALND.

Survival

The median follow-up was 33 months. A total of 3,679 patients died, including 3,162 patients died with BC (85.9%). Those treated with ALND had better BCSS and OS compared to those without ALND. Before PSM, the 5-year BCSS was 51.1% and 38.2% in those with and without ALND, respectively (P<0.001) (Figure 3A). The 5-year OS was 45.9% and 32.3% in those with and without ALND, respectively (P<0.001) (Figure 3B). Similar results were found after PSM (Figure 3C,3D).

Figure 3 Comparison of BCSS and OS between those with and without ALND. (A) BCSS before propensity score matching. (B) OS before propensity score matching. (C) BCSS after propensity score matching. (D) OS after propensity score matching. ALND, axillary lymph node dissection; BCSS, breast cancer-specific survival; OS, overall survival.

Prognostic analyses

The results of multivariate Cox proportional analysis revealed that patients who underwent ALND exhibited significantly improved BCSS [hazard ratio (HR) 0.657, 95% CI: 0.598–0.722, P<0.001] and OS (HR 0.685, 95% CI: 0.628–0.746, P<0.001) compared to those who did not before PSM (Table 3). Furthermore, age, race, grade, histology, T stage, N stage, BCS, surgical procedure, chemotherapy, and the sites of DM were also identified as independent prognostic factors associated with BCSS and OS. In the cohort balanced by PSM, the addition of ALND was still significantly associated with improved BCSS (HR 0.631, 95% CI: 0.517–0.771, P<0.001) and OS (HR 0.694, 95% CI: 0.577–0.835, P<0.001) compared to those who did not (Table 4).

Sensitivity analyses

We used stratified analysis to characterize the patients who might be expected to benefit from the ALND in the PSM cohort (Figure 4). The results of the multivariate Cox proportional analysis showed that in most subgroups, BCSS and OS were significantly higher in the ALND group than in the non-ALND group. However, patients with early T stage, N0 disease, HoR⁻/HER2⁻ disease, receipt of breast-conserving surgery, no chemotherapy, live metastasis only, lung metastasis only, and distant lymph node metastasis only did not benefit from the ALND.

Figure 4 Adjusted hazard ratios for breast cancer-specific survival (A) and overall survival (B) between those with and without ALND after stratifying by the demographic and clinicopathological variables. T, tumor; N, nodal; BCS, breast cancer subtype; HoR, hormone receptor; HER2, human epidermal growth factor receptor 2; HR, hazard ratio; CI, confidence interval; ALND, axillary lymph node dissection.

The effect of the number of removed lymph nodes on survival outcomes

In those with ALND (n=5,562), the median number of removed lymph nodes (RLNs) was 9 (25th percentile 4, 75th percentile 16; range, 1 to 60). In the four categories of the RLNs (1–4, 5–9, 10–16, and >16), the number of RLNs was not significantly associated with BCSS and OS. The 5-year BCSS was 53.8%, 51.6%, 49.6%, and 49.5% in those with RLNs 1–4, 5–9, 10–16, and >16, respectively (P=0.266) (Figure 5A). The 5-year OS was 48.5%, 46.3%, 44.3%, and 44.7% in those with RLNs 1–4, 5–9, 10–16, and >16, respectively (P=0.288) (Figure 5B).

Figure 5 Comparison of breast cancer-specific survival (A) and overall survival (B) among the four categories of the number of RLNs. RLNs, removed lymph nodes.

Discussion

The role of ALND in dnMBC patients remains a subject of debate and investigation. This study aimed to investigate the effect of ALND in patients with dnMBC and our study found that 81.3% of patients with dnMBC had ALND during their surgery at the local site. Moreover, the receipt of ALND was associated with better survival outcomes in this population.

Several prospective studies have found that local surgical resection did not improve the survival of patients with dnMBC (8-11). In addition, two recent meta-analyses included randomized control trials to investigate the effect of locoregional therapy on survival and quality of life in dnMBC, the results showed that breast surgery may benefit locoregional control but does not improve OS and quality of life in dnMBC patients (17,18). However, there were still 26.8–57.2% of patients undergoing local surgical treatment in the real world, and studies have found that local surgery could further improve the survival of patients (12-15,19). As an important part of BC surgery, ALND or sentinel lymph node biopsy (SLNB) plays a crucial role in the staging and treatment decisions for non-metastatic BC. However, the value of ALND for dnMBC patients following local surgery remains unclear. In this study, we found a higher proportion of undergoing ALND following local surgery (81.3%), which is higher than our previous study involving patients diagnosed from 1990 to 2010 (63.2%) (20). In the prospective studies, ALND or SLNB was performed in dnMBC patients who received local surgery (8,9,11). In a retrospective study, there were also 55–79% of patients receiving ALND (21,22). A higher proportion of the receipt of ALND in this population may reflect a belief among some clinicians that ALND can provide more accurate staging information and guide adjuvant therapy decisions, even in the context of metastatic disease. In addition, the lack of clear guidelines or consensus on the management of the axilla in dnMBC may also lead to variability in practice (23,24). Moreover, it may also be driven by patient preference, as some patients may opt for more aggressive surgical approaches with the hope of achieving better disease control. The results of the multivariable analysis showed that those diagnosed in later years were having a higher proportion of patients undergoing ALND. This trend is noteworthy given the ongoing debate about the role of ALND in this patient population and reflects the complexity of decision-making in managing the axilla in dnMBC.

In our study, patients with smaller tumor sizes were more likely to receive ALND. Therefore, it is hypothesized that healthier patients or those with less extensive disease are more likely to undergo ALND. However, our results showed that patients with multiple sites of DM was the independent predictive factor associated with no receipt of ALND in this population. This trend may reflect evolving attitudes in clinicians and patients towards the role of ALND in dnMBC management. As axillary surgery may further decrease the potential tumor burden in dnMBC, it may reduce its potential for dissemination to new metastatic localizations (25). However, it is critical to balance these potential benefits with the potential risks and complications of ALND, including lymphedema, shoulder dysfunction, and postoperative pain.

In patients with early-stage BC, SLNB is sufficient for axillary staging assessment and guiding treatment decisions (26). In our study, 79.6% of patients had nodal-positive disease, which is similar to the results of several prospective and retrospective studies (77–94.2%) (9,15,27,28). Moreover, we also found that more extensive ALND did not increase the survival of patients. Therefore, SLNB may also be sufficient for patients with dnMBC without lymphadenopathy in preoperative assessment. For patients with non-metastatic BC who need ALND, a minimum of 10 lymph nodes removed for a complete ALND is recommended by numerous trials (29,30). However, several studies also found that the removal of more than 10 lymph nodes did not result in a significant survival benefit even in high-risk nodal-positive BC patients (31,32). It is crucial to remember that the decision to perform ALND should be made individually, considering the patient’s overall health, the extent and characteristics of the disease, and the potential benefits and risks of the procedure. This decision should be made as part of a multidisciplinary discussion that includes the patient’s preferences and values.

Several studies have explored the efficacy of ALND in dnMBC. A previous study from ours included patients diagnosed between 1990 and 2010, and the results showed that patients who underwent ALND had better BCSS and OS (20). The findings from De Wit et al. also showed survival benefits with the addition of ALND in dnMBC (21). However, a meta-analysis included 16 studies and found that ALND could not improve the OS of patients (22). We should note that the above studies have been grouped for a long time, and cannot reflect the current clinical treatment practice of dnMBC. The treatment of advanced BC has made substantial progress in the past decade (33-35). In this study, we included patients diagnosed between 2010 and 2020, which reflected contemporary clinical practice. Our study showed that patients who underwent ALND had better BCSS and OS, and this was observed across various clinicopathological subgroups.

The observed survival benefit associated with ALND in our study may be attributed to various factors that reflect the complex interplay of tumor biology, patient characteristics, and treatment modalities. First, ALND provides valuable information about the extent of axillary nodal involvement, which can help guide adjuvant systemic therapy decisions. Accurate staging may allow for more personalized treatment strategies, potentially leading to improved outcomes. Second, ALND may have a direct therapeutic effect by reducing the total tumor burden. The removal of axillary lymph nodes could decrease the likelihood of disease recurrences, which might contribute to better survival outcomes. Third, patients selected for ALND are likely to be in better overall health or have fewer comorbidities, which could contribute to improved survival outcomes. Moreover, patients who undergo ALND might be more compliant with adjuvant therapies and follow-up visits due to their engagement with the healthcare system, which could indirectly contribute to better survival outcomes. Finally, there is growing interest in the potential immunomodulatory effects of surgical interventions such as ALND. By removing immunosuppressive tumor-draining lymph nodes, ALND could potentially enhance the body’s immune response to cancer, and the immunity was restored after tumor surgery (36).

While our study adds valuable insights to the role of ALND in managing dnMBC, it is not without limitations. First, the retrospective nature of our study and the reliance on PSM to control for confounding factors highlight the need for caution in interpreting the results. Second, the information regarding chemotherapy regimens, endocrine therapy, target therapy as well as immunotherapy was not included in the SEER database. Third, comorbidities, treatment compliance, and quality of life between the two groups were not recorded in the SEER program. Finally, the presence of metastasectomy and the precise timing of surgery following a diagnosis of dnMBC were not recorded in the SEER database.

Conclusions

In conclusion, our study suggests that ALND is associated with improved survival outcomes in dnMBC patients. These findings advocate for a re-evaluation of the role of surgical interventions in dnMBC, emphasizing the need for personalized treatment strategies that consider the potential benefits of ALND. Further research is essential to validate these findings and to explore the mechanisms of ALND conferring a survival advantage in this population.

Acknowledgments

The authors acknowledge the efforts of the Surveillance, Epidemiology, and End Results (SEER) Program tumor registries in the creation of the SEER database.

Funding: None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://gs.amegroups.com/article/view/10.21037/gs-24-130/rc

Peer Review File: Available at https://gs.amegroups.com/article/view/10.21037/gs-24-130/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://gs.amegroups.com/article/view/10.21037/gs-24-130/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. This study did not require approval from the institutional review board due to the de-identified information in the SEER program. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013).

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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