Comparison of survival outcomes between axillary conservation and axillary lymph node dissections in N1 early breast cancer: a propensity-matched SEER analysis

Background Sentinel lymph node dissection (SLND) is an alternative to axillary lymph node dissection (ALND) for breast cancer surgery. But the criteria of SLND only for patients with limited disease in the sentinel node is disputed. Methods From the Surveillance, Epidemiology, and End Results (SEER) database, 2000–2015, we identified 97,296 early breast cancer females with 1–3 axillary lymph nodes macro-metastasis. Of them, 1–5 (axillary conservation group), 6–9, and ≥ 10 (ALND group) axillary lymph nodes were dissected in 28,639, 16,838, and 51,819 patients, respectively. According to the criteria of the ACOSOG Z0011 trial, two historical cohort studies of patients who underwent lumpectomy or mastectomy were conducted and the survival outcomes between ALND and axillary conservation were compared. Results Overall, dissection of 6–9 regional lymph nodes resulted in the worst prognosis. After propensity-matched analysis, it was found that patients in the axillary conservation group had worse survival than the ALND group in overall survival. No significant difference in prognosis between the group undergoing lumpectomy was found both in OS and BCSS. Subgroup analysis revealed that Grade 3, T2, two lymph nodes positive, or Her2 positive were the main causes of worse survival in the axillary conservation group. Conclusion Not all patients with N1 early breast cancer suit axillary conservation. Axillary conservation was sufficient in patients who were treated with lumpectomy. ALND cannot be omitted in patients who were ineligible for the Z0011 and undergoing mastectomy with the following characteristics: T2, Grade 3, two positive lymph nodes, and Her2 positive, which may be better complemented to the Z0011 trial. Hence, under different surgical methods, the clinical precision treatment of ALND or axillary preservation is essential. Supplementary Information The online version contains supplementary material available at 10.1007/s12094-022-03017-0.


Introduction
Axillary lymph node dissection (ALND) has been the standard approach to treat breast cancer for more than 100 years because of its reliability in identifying nodal metastases and achieving regional control. However, ALND is associated with a significant risk of complications such as lymphedema, numbness, axillary web syndrome, and decreased range of motion of the upper extremity [1]. Sentinel lymph node biopsy (SLNB) was, therefore, developed to accurately stage the tumor-draining axillary nodes with lower morbidity than that with ALND [2]. SLND alone is the accepted management for patients in whom sentinel lymph nodes (SLN) are histologically free of tumor. Axillary lymph node dissection (ALND), long used to identify women with axillary nodal metastases, was replaced as a staging procedure by the less morbid sentinel lymph node dissection (SLND) in the era of ZOO11 [3].
Currently, for patients with limited disease in the sentinel node, SLN biopsy (SLNB) alone, SLNB and nodal radiotherapy, and neoadjuvant chemotherapy are alternatives with supportive evidence in the setting of node-positive disease, (ACOSOG Z0011 trial, IBCSG 23-01 trial, and AMAROS trial) [4][5][6]. In addition, in patients with clinically nodepositive breast cancer, neoadjuvant chemotherapy (NAC) can eradicate the disease in axillary lymph nodes, with nodal pathologic complete response rates exceeding 40%, reducing the need for axillary lymph node dissection (ALND) [7]. The ACOSOG Z0011 trial found that, among patients with T1-2 breast cancer, no palpable axillary lymph node, 1-2 sentinel lymph nodes containing metastases, and underwent lumpectomy and irradiation, overall survival of patients treated with sentinel lymph node dissection alone was noninferior to overall survival for those treated with axillary lymph node dissection [6]. The EORTC 10,981-22,023 AMAROS trial showed that for patients with T1-2 primary breast cancer, no palpable lymphadenopathy, and a positive sentinel node, axillary lymph node dissection, and axillary radiotherapy provide comparable axillary control [5].
According to the above researches, patients meeting the Z0011 criteria may be eligible to avoid ALND; however, a recommendation may sometimes be ambiguous for patients with positive SLNs who do not fulfill the Z0011 criteria [8].
Additionally, although studies have demonstrated that ALND can be replaced in certain conditions, subgroup analyses demonstrate that ALND produced a trend of better prognosis in some cases [5]. Even in the era of Z0011, a number of surgeons choose to perform ALND in patients who meet the criteria for axillary conservation. Therefore, even if multiple guidelines explicitly recommend axillary conservation, some patients undergo overtreatment. Evidence suggests that patients with potentially avoidable ALND represent 21% of the expected patients with lymphedema [9]. A recent survey revealed that 49.0% of surgeons (most of them were lower volume breast surgeons) recommended ALND for a single axillary lymph node with macro-metastasis [10]. In brief, since the Z0011 trial started the era of axillary conservation, to date, the debate over expanding or narrowing their indications has been continuing. This is primarily due to insufficient population-based real-world data.
To examine the practical effects of axillary conservation since the Z0011 trial, we reviewed the Surveillance, Epidemiology, and End Results (SEER) database of the US National Cancer Institute to compare the survival outcomes between ALND and axillary conservation in N1 early breast cancer to further explore the criteria of ALND alternatives.

Data source
The SEER program includes the cancer incidence and mortality data of 18 population-based registries that represent approximately 30% of the American population. We obtained the data from the SEER database using SEER*Stat software v8.3.6 based on November 2018 submission (1975-2016 varying

Patient selection
From 2001 to 2015, we identified 146,374 females with T1-2N1M0 breast cancer based on Breast-Adjusted AJCC 6th Stage. The following were the other selection criteria: axillary lymph nodes examined ≥ 1 and with 1-3 axillary lymph nodes macro-metastasis. The exclusion criteria were as follows: (1) age at diagnosis < 18 years or > 85 years; (2) diagnosis not confirmed; (3) patients with incomplete survival data and follow-up information; (4) patients who did not undergo surgery; and (5) more than one malignancy. Finally, 97,296 patients were included in the study.
In the SEER database, the information regarding SLND and ALND is imperfect. Therefore, the number of regional nodes examined was used to determine the axillary lymph node surgical process [11]: 1-5 nodes examined represented axillary conservation surgery; ≥ 10 nodes examined represented ALND; 6-9 nodes examined represented uncertain procedures. Accordingly, all patients were categorized into the following three groups: Group 1 included patients in whom 1-5 regional nodes were examined; Group 2 included those in whom 6-9 regional nodes were examined; Group 3 included those in whom ≥ 10 regional nodes were examined.

Statistical analysis
For demographic and clinicopathological data, continuous variables were compared using Student's t test or analysis of variance (ANOVA), and categorical variables were compared using Pearson's Chi-square test or rank-sum test. Survival curves were plotted according to the Kaplan-Meier method and compared using the log-rank test. Univariate and multivariate Cox's proportional hazards regression models were constructed to analyze the factors associated with survival.
Subsequently, we performed propensity score matching (PSM) to further evaluate the effects of the number of regional nodes examined (1-5 or ≥ 10) on survival by adjusting for sex, year of diagnosis, histologic type, T stage, hormone receptor status, HER2 status, type of surgery, number of positive regional nodes, and radiation and chemotherapy (exact match and match tolerance = 0).
Lastly, according to the criteria of the ACOSOG Z0011 trial (women with clinical T1-T2 invasive breast cancer between 2001 and 2015 with 1-2 lymph nodes containing metastases), we also conducted two historical cohort studies of patients who underwent lumpectomy or mastectomy to evaluate the effects of the number of regional nodes examined on the survival.
The median duration of follow-up was 56, 81, and 88 months for Groups 1, 2, and 3, respectively (p < 0.001). Kaplan-Meier curves that compare the survival between the three groups are shown in Fig. 1. Particularly, patients in Group 2 had the worst survival (p < 0.001). Between Group 1 and Group 3, there was no significant difference in the OS (p = 0.3001); however, patients in Group 1 had a better prognosis according to BCSS (p < 0.001). Multivariate Cox proportional hazards regression analyses revealed that the number of lymph nodes examined was an independent risk factor in terms of both OS and BCSS (Appendix , Supplementary Tables 1 and 2).
After PSM, 21,022 patients were included in each group and all the critical variables were balanced between them in Table 2. Kaplan-Meier curves comparing the survival between the two groups are shown in Fig. 2. Patients in Group 1 had worse survival in OS (p = 0.0168), while there was no significant difference between the two groups according to BCSS (p = 0.5579).
Separately, for patients treated with lumpectomy, Kaplan-Meier curves demonstrated no significant difference between the two groups both in OS (p = 0.1141) and BCSS (p = 0.8608). For patients treated with mastectomy, OS was different (p = 0.0384) but BCSS was not (p = 0.2559) (Appendix, Supplementary Fig. 1).

Historical cohort study of patients undergoing lumpectomy according to ACOSOG Z0011 trial
According to the inclusion criteria of ACOSOG Z0011 trial (women with clinical T1-T2 invasive breast cancer between 2000 and 2016 with 1-2 lymph nodes containing metastases who underwent lumpectomy and irradiation), a historical cohort study was performed between patients in whom 1-5 or ≥ 10 regional lymph nodes were dissected using PSM for critical clinicopathological characteristics (Appendix, Supplementary Table 3). Overall, 7,765 patients were included in each group and the survival results suggested that there was no significant difference both in OS (p = 0.4168) and in BCSS (95% CI p = 0.2320) (Fig. 3). In the subgroup analyses, no significant differences were observed in BCSS (Appendix, Supplementary  Fig. 2).

Historical cohort study of patients undergoing mastectomy similar to ACOSOG Z0011 trial
To explore the effects of the number of dissected regional nodes on the survival in patients who underwent mastectomy, we conducted another historical cohort study of patients in whom 1-5 or ≥ 10 regional lymph nodes were dissected using PSM to identify the critical clinicopathological characteristics, referring to the inclusion criteria of the ACOSOG Z0011 trial (women with clinical T1-T2 invasive breast cancer between 2000 and 2016 with 1-2 lymph nodes containing metastases who underwent mastectomy); subsequently, 8,569 patients were included in each group (Appendix, Supplementary Table 4). Kaplan-Meier curves comparing survival in the three groups are shown in Fig. 4. Patients in whom 1-5 regional lymph nodes were dissected had a worse prognosis in both OS (p = 0.0098) and BCSS (p = 0.0387).
The subsequent subgroup analyses suggested that, under a few special conditions (histologic grade = 3; T stage = 2; regional nodes positive = 2; or Her2 status = positive), patients underwent mastectomy in whom 1-5 regional lymph nodes were dissected (axillary conservation) and had worse prognosis in BCSS (Fig. 5). Surprisingly, when we excluded these high-risk factors, axillary conservation resulted in a better prognosis (p = 0.0113, Fig. 6). In addition, for patients treated with mastectomy, radiotherapy could not reduce the gap of prognosis between axillary conservation and ALND (Appendix, Supplementary Fig. 3).

Discussion
In this study, we focused on the effects of axillary conservation or ALND on the prognosis of early-stage breast cancer. By reviewing the SEER database, we found that the rate of axillary conservation increased sharply since 2000. Generally, patients in axillary conservation group had worse survival than the ALND group in OS, while there was no  significant difference in BCSS. Ji Hyeon Joo's study also reported there was no difference in BCSS between ALND and no ALND in patients undergoing lumpectomy [3]. We further revealed that in patients undergoing breast-conserving surgery and radiotherapy who met the criteria of the Z0011 trial, axillary conservation, and ALND resulted in comparable survival outcomes. Moreover, our findings indicated that in patients who met the criteria of the Z0011 trial but were treated with mastectomy, the prognosis of those who underwent axillary conservation was significantly worse than the prognosis of those who underwent ALND, especially in the subgroups of those with Grade 3, T2, two lymph nodes positive, or Her2 positive. The results of AMAROS trial confirmed that the type of axillary management (axillary lymph node dissection) in patients with a positive sentinel node does not affect survival [5]. Even, the AMAROS trial suggests that for such patients, axillary radiotherapy is a valid treatment option with less morbidity than axillary lymph node dissection. The above examples further support our conclusion.
In the SEER database, the classification of the axillary surgery for breast cancer is inaccurate; therefore, we redefined axillary conservation as "dissection of 1-5 regional lymph nodes" and ALND as "dissection of ≥ 10 regional lymph nodes" [11]. Patients with 6-9 regional lymph nodes dissected could not be classified precisely. Our results demonstrate that their prognoses were worse than those in the other two groups. This finding confirms the validity of our classification of ALND and further suggests that reduction in the number of regional lymph nodes dissected is not a good approach for ALND alternatives [12]. However, we have to admit that the number of lymph nodes examined as an independent risk factor. First, the staging system for breast cancer follows the TNM system with the most recent system approved by the American Joint Committee. Second, biological factors may affect the predilection of some malignant cells to selectively invade lymph nodes first in breast cancer [13]. Third, clinically, the number of lymph nodes decided the surgical approach and clinical prognosis [14].
This study was a real-world retrospective analysis based on population data; therefore, the clinicopathological characteristics between the groups were not balanced. Preliminary survival analysis demonstrated that patients in whom 1-5 regional lymph nodes were dissected had the best BCSS outcome, which may have much to do with the surgeon's tendency to select low-risk patients for axillary conservation. To reduce the selection bias, we performed a series of PSMs to adjust for critical clinicopathological characteristics. We chose 0 as match tolerance in each process, which assures identical critical clinicopathological characteristics between the two groups. After propensitymatched analysis, it was found that patients in the axillary conservation group had worse survival than the ALND group in OS, while there was no significant difference in BCSS.
Due to a significant risk of complications such as lymphedema, numbness, axillary web syndrome, and decreased range of motion of the upper extremity, finding an alternative treatment for ALND has always been one of the goals of breast cancer researchers [1]. Results from the ACOSOG Z0011 trial demonstrated that patients with limited disease in the sentinel node or nodes who are treated with breast-conserving surgery, whole-breast irradiation, and adjuvant systemic treatment can be spared from ALND without compromising the locoregional control or survival [6]. The Z0011 trial is of major importance in the management of patients with axillary lymph node-positive breast cancer [9]. Accordingly, an increasing number of patients who met the criteria of the Z0011 trial was averted from ALND [15]. Our results demonstrate that the rate of patients with N1 early breast cancer who underwent ALND decreased from 60.69 in 2001-2010 to 39.69% in 2011-2015, while the rate of axillary conservation increased from 21.15 to 44.56%. In contrast, in patients who were ineligible for the Z0011 trial, there were many attempts to avoid ALND [3,16]. The Z0011 trial began an era of ALND alternatives for patients with limited disease in the sentinel node; however, some eligible patients still underwent axillary dissection [10]. In this study, a lot of patients who met the criteria of the Z0011 trial underwent ALND between 2011 and 2015.
Since the Z0011 trial, there were two contrasting attitudes toward axillary management. First, conservative surgeons demonstrated distrust of the trial, which resulted in overtreatment of eligible patients [10]. In this study, the analysis of a retrospective cohort simulating the Z0011 trial revealed that there was no significant difference in the prognosis of eligible patients who underwent axillary conservation or ALND. Furthermore, subgroup analysis did not reveal any special clinicopathological characteristics that could alter the results, which further excludes the potential risks [17,18]. Second, radical surgeons wished to expand the indications for ALND alternatives so that more patients could be exempted from axillary dissection [14,19]. As presented in our results, after propensity matched, patients in the axillary conservation group had worse survival than the ALND group in OS, while there was no significant difference in BCSS. The follow-up for patients with the 1-5 nodes group is limited. And the reasons were as follows: First, older Fig. 4 Kaplan-Meier curves of patients undergoing mastectomy similar to ACOSOG Z0011 trial. A Overall survival. Patients in whom 1-5 regional lymph nodes were dissected had worse progno-sis (p = 0.0098). B Breast cancer-specific survival. Patients in whom 1-5 regional lymph nodes were dissected had worse prognosis (p = 0.0387) adults accounted for the majority both in our study and in the Z0011trial, who suffered from many complications because of their poor general health physiological [20]. The adverse effects of surgery outweigh the clinical benefits in this subgroup. Therefore, it is necessary for us to explore precise treatment in early breast cancer surgical resection and axillary dissection.
For patients who were treated with mastectomy, our historical cohort study of patients who underwent mastectomy similar to the Z0011 trial demonstrated that the prognosis of the ALND group was still significantly better than the axillary conservation group, which differed from the results of some previous studies [3]. Subgroup analysis indicated that Grade 3, T2, two positive lymph nodes, and Her2 positive were the main reasons for the worse prognosis in the Her2 status = positive), patients in whom 1-5 regional lymph nodes were dissected had worse prognosis 1 3 axillary conservation group. After eliminating these factors, axillary conservation even led to a better prognosis, which implied that in patients with N1 early breast cancer who undergo mastectomy, Grade 1/2, T1, one positive lymph node, and Her2 negative were indications for axillary conservation. The ongoing Senomac trial may provide more useful information for this aspect in the future. Previous studies showed that axillary radiotherapy is a very important alternative to ALND. Our results indicated that, for patients treated with mastectomy, radiotherapy could not reduce the gap of prognosis between axillary conservation and ALND. However, because there is no data on axillary radiotherapy in the SEER database, the significance of this finding is quite limited.
This study has several limitations. First, instead of SLND, we just compared the survival outcomes between axillary conservation and ALND in N1 early breast cancer, which may not fully reflect the real-world clinical practice. Second, "no palpable lymphadenopathy" is an essential criterion both in the ACOSOG Z0011 trial and the AMAROS trial. However, due to a lack of information in the SEER database, this study did not include this condition in the analysis. This study did not examine local-regional recurrence which was a major limitation because the SEER database does not contain data regarding recurrence. We suspect that these are the following reasons. First, the majority of women included in the SEER were older than 50 years or had hormone receptor positive disease, which caused subsequent follow-up information missed. Second, local-regional recurrence, defined as tumor recurrence in lymph nodes in the ipsilateral axilla, infraclavicular fossa, or interpectoral area, had to be confirmed with histological or fine needle examination [5]. Finally, there were no records of Her2 status and molecular subtype in the SEER database until 2010. An insufficient number of cases may lead to inaccuracy of the result.

Conclusion
The safety of omitting ALND should be considered at all times, especially in patients with early-stage breast cancer. Therefore, we compare the survival outcomes between ALND and axillary conservation in N1 breast cancer patients undergoing lumpectomy or mastectomy in four historical cohort studies. In conclusion, not all patients with N1 early breast cancer are suitable for axillary conservation. Blindly expanding the indications for ALND alternatives will result in a poor prognosis. Nevertheless, axillary conservation is sufficient in patients who were ineligible for the Z0011 trial. Besides, although further related randomized trials are needed, patients with T1 breast cancer, Grade 1/2, one positive lymph node, Her2 negative, and undergoing mastectomy should be provided with axillary conservation rather than ALND.

Declarations
Conflict of interest All authors declare that they have no conflict of interest. Ethical approval This study used previously collected de-identified data, and the need for informed consent had been waived due to the retrospective nature of the study, and was deemed exempt from review by the Ethics Committee of the Affiliated Hospital of North Sichuan Medical College. In addition, this study was conducted in accordance with the Declaration of Helsinki.

Informed consent Not applicable.
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