Axillary lymph node dissection in breast cancer patients after sentinel node biopsy^*

Introduction

Axillary lymph node status has for long been the most important prognostic factor in patients with primary breast cancer [1]. Axillary lymph node dissection (ALND) provides the most accurate staging of axillary lymph nodes and the primary objective of ALND is, besides staging, local disease control [2]. Furthermore, axillary lymph node status determines adjuvant treatment protocols based on the number of macro metastases in the axillary lymph nodes, and survival is improved and recurrence reduced when patients receive adjuvant treatment corresponding to their axillary status [2,3]. Advancements in adjuvant systemic therapy and radiotherapy have improved loco-regional control of breast cancer and the therapeutic value of axillary surgery has been diminished as well [4]. Besides this an increasing number of patients are treated with neoadjuvant therapy, which may result in complete pathologic response with remission of axillary metastases in about 30% of patients [5–8]. Thus, axillary dissection can be spared in these patients.

In Denmark, breast cancer patients are treated according to national guidelines from the DBCG. The preoperative examination includes ultrasonography (US) of the axillary lymph nodes and fine needle aspiration if suspicious lymph nodes are present. A systematic review and meta-analysis from 2014 found that 50% of women with axillary involvement can be identified preoperatively by axillary US-guided biopsy [9]. Staging of patients who are clinically node negative on US is done by sentinel lymph node biopsy (SLNB). SLNB is followed by ALND if metastases are found in the sentinel node (SN). In 2013, ALND was restricted to patient with macro metastases (>2 mm) [10].

ALND can cause significant morbidity such as impaired arm-/shoulder mobility, sensory disturbances, lymphedema and persistent pain. The prevalence of sequelae is influenced by the extent of the axillary surgery. ALND is associated with an increased prevalence and intensity of pain as well as an increased number and sensory disturbances compared with SLNB [11–13].

In a randomized trial (ACOSOG Z0011), the American College of Surgeons Oncology Group studied disease-free survival and mortality in selected patients with positive SNs treated with or without ALND [14]. The trial showed that ALND can be omitted in a patient group with one or two positive SNs, treated with breast conserving surgery (BCS) and adjuvant radiotherapy without compromising loco-regional control or survival. However this study did not reach planned inclusion of patients and more than hundred institutions contributed some of which only included few patients. Surgical treatment of the axilla is still the gold standard in patients with extensive nodal involvement. It is therefore important to identify patients with a high risk of extensive axillary involvement besides SN.

The aim of this study is to further characterize patients with extensive nodal involvement among women with early stage breast cancer, who are preoperatively clinically node negative, based on preoperative US with or without fine needle aspiration cytology, who were found with macro metastases in SN. The results may be used to select high-risk patients who might benefit from axillary surgery or maybe neoadjuvant treatment for down-staging the axilla. We chose to include patients treated after the implementation nation-wide mammography screening in 2010 in order to base the study on a data material where clinical practice is similar of today.

Material and methods

Patients

Data on patients diagnosed with primary unilateral breast cancer, in 2010 and through 2015, were retrieved from the DBCG database. In Denmark, clinical and histopathological data and information on treatment and follow-up status on patients with breast cancer are registered in the DBCG national database, which was established in 1977. Data are prospectively entered into the database from all Danish departments involved in the diagnosis and treatment of breast cancer. The database is considered to have a close to complete reporting of all cases [15]. Missing data were obtained from the Danish Pathology Data Bank.

In the analysis, we included patients who were preoperatively clinically node negative but were found to have macro metastases on SLNB. The exclusion criteria were age ≥80 years and, neoadjuvant treatment. Patients who did not receive SLNB were not included in the analysis, as well as patients who did not receive ALND after SLNB with macro metastases. We set a minimum of 10 lymph nodes as standard for a sufficient ALND and excluded women with <10 lymph nodes removed.

Statistical analysis

Univariate and multivariate logistic regression were used to estimate odds ratios (OR) with 95% confidence intervals (CI) for ten or more nodes with macrometastases, and a supplementary analysis considering 4 + macrometastases an event. The Wald test was used to test hypotheses on parameters. Included in the models were age, histological type and grade, tumor size, ER and HER2 status. Unknowns were included in largest categories. P < .05 was considered statistically significant. All statistical analyses were performed using SAS statistical software, version 5.1 (SAS Institute Inc, NC, USA).

Results

A total of 20498 patients were included in the study. Based on the listed criteria 1530 patients were excluded due to neoadjuvant treatment, misclassification and diagnosis with only DCIS/LCIS after reexamination of the pathology reports or because they met other exclusion criteria (Supplementary material). Of the remaining patients 1,703 did not have SLNB performed as they immediately underwent ALND because of axillary metastases found by US with or without US-guided fine needle aspiration. The remaining 17265 patients were clinically node negative and underwent SLNB. A total of 3554 patients had macro metastases in one or more SN and 3,541 subsequently had ALND. In 13,469 patients, no macro metastases were found in SN but 194 patients had macro metastases in non SNs removed during the SLNB procedure. No matter of the macro metastases were identified as a radioactive lymph node, a blue dye–stained lymph node or another lymph node resected during the SLNB procedure they were considered SN positive. A total of 181 of them went on to have an ALND. In 242 cases SN could not be identified and these patients were treated with ALND. Among these, 92 patients had macro metastases.

Altogether 3814 clinically node negative patients had macrometastases in the axilla and an ALND. 126 were excluded because less than 10 lymph nodes had been removed during SLNB and ALND. The final cohort consisted of 3,688 patients of which only 6% (215 patients) had ≥10 lymph nodes with macrometastases (Table 1). The majority (3473 patients) had ≤9 lymph nodes with macrometastases and among these, 2946 (80%) had only 1–3 macrometastasis. (Table 2).

Table 1. Characteristics of 3688 Danish women where macrometastases were found in SLNB and subsequent ALND subdivided according to the number of macrometastases.

	Total (3688)	1–3 Macro (2946)	4–9 Macro (527)	≥10 Macro (215)
	No (%)	No (%)	No (%)	No (%)
Age, y
<50	963 (26.1)	785 (26.6)	139 (26.4)	39 (18.1)
50–59	1095 (29.7)	869 (29.5)	163 (30.9)	63 (29.3)
60–69	1242 (33.7)	994 (33.7)	162 (30.7)	86 (40.0)
70–79	388 (10.5)	298 (10.1)	63 (12.0)	27 (12.6)
Diagnosis
Ductal	3016 (81.8)	2473 (83.9)	407 (77.2)	136 (63.3)
Lobular	526 (14.3)	355 (12.1)	97 (18.4)	74 (34.4)
Other	146 (4,0)	118 (4.0)	23 (4.4)	5 (2.3)
Tumor size, mm
≤10	390 (10.6)	355 (12.1)	24 (4.6)	11 (5.1)
11–20	1686 (45.7)	1417 (48.1)	207 (39.3)	62 (28.8)
21–50	1462 (39.6)	1093 (37.1)	261 (49.5)	108 (50.2)
>50	145 (3.9)	76 (2.6)	35 (6.6)	34 (15.8)
Unknown	5 (0.1)	5 (0.2)	0 (0.0)	0 (0.0)
Grade
I	857 (23.2)	738 (25.1)	96 (18.2)	23 (10.7)
II	1784 (48.4)	1384 (47.0)	275 (52.2)	125 (58.1)
III	872 (23.6)	682 (23.2)	130 (24.7)	60 (27.9)
Unknown	175 (4.7)	142 (4.8)	26 (4.9)	7 (3.3)
ER status
Positive	3324 (90.1)	2658 (90.2)	471 (89.4)	195 (90.7)
Negative	350 (9.5)	275 (9.3)	55 (10.4)	20 (9.3)
Unknown	14 (0.4)	13 (0.4)	1 (0.2)	0 (0.0)
HER2 status
Normal	3113 (84.4)	2523 (85.6)	420 (79.7)	170 (79.1)
Positive	499 (13.5)	367 (12.5)	95 (18.0)	37 (17.2)
Unknown	76 (2.1)	56 (1.9)	12 (2.3)	8 (3.7)

Table 2. Univariate and multivariable analysis of risk for ≥10 macrometastases compared to 1–9 macrometastases in the 3688 Danish patients with macrometastases SLNB and subsequent ALND.

	Unadjusted OR (95%CI)	p value	Adjusted OR (95%CI)	p value
Age, y		.029		.0031
<50	1.00 (ref)		1.00 (ref)
50–59	1.45 (0.96–2.18)		1.86 (1.222.86)
60–69	1.76 (1.20–2.60)		2.14 (1.42–3.21)
≥70	1.77 (1.07–2.94)		2.06 (1.22–3.47)
Diagnosis		<.0001		<.0001
Ductal	1.00 (ref)		1.00 (ref)
Lobular	3.47 (2.57–4.68)		3.09 (2.20–4.34)
Other	0.75 (0.30–1.86)		1.46 (0.53–3.57)
Tumor size, mm		<.0001		<.0001
≤10	0.76 (0.40–1.46)		0.84 (0.44–1.63)
11–20	1.00 (ref)		1.00 (ref)
21–50	2.10 (1.52–2.89)		1.78 (1.29–2.50)
>50	8.05 (5.08–12.8)		6.47(3.97–10.5)
Grade^a		<.0001		.0005
I	1.00 (ref)		1.00 (ref)
II	2.73 (1.74–4.29)		2.24 (1.41–3.57)
III	2.68 (1.64–4.37)		2.85 (1.66–4.89)
ER status		0.91		0.81
Positive	1.00 (ref)		1.00 (ref)
Negative	0.97 (0.61–1.56)		0.94 (0.56–1.58)
HER2 status		.083		0.06
Normal	1.00 (ref)		1.00 (ref)
Positive	1.39 (0.96–2.01)		1.47 (0.98–2.21)

^a If diagnosis is not ductal or lobular the reference is ductal grade I.

CI: Confidence interval; OR: odds ratio.

Age more than 50 years, lobular subtype, increasing tumor size and histologic grade II + III, were significantly associated with more than 10 positive nodes, when adjusting for age, histological type, tumor size, grade, ER and HER2 status (Table 2). The most profound risk factors was lobular subtype compared to ductal subtype (OR: 3.09; 95% CI: 2.20–4.34) and tumor size >50 mm. compared to size 11–20 mm. (OR: 6.47; 3.97–10.5).

We subsequently performed an exploratory analysis with a cutpoint of four or more positive nodes revealing similar results as mentioned above (data not shown).

Discussion

This large population-based study based on close to 4000 women with macrometastases in SN showed that only 15% harbor in all more than three macrometastases in the rest of the axilla. Currently, it is standard treatment to perform completion ALND removing on average more than 15 lymph nodes in patients with macrometastases in the SN, which means that many lymph nodes are unnecessarily removed, with increasing risk of arm morbidity but without therapeutic gain [16,17]. It is obvious that adherence to this guideline often leads to overtreatment.

Of the 17,265 clinically node negative patients, 3688 had macrometastases at SLNB and/or ALND, which equals 21.4%. Of these patients 215 (1.3%) had ≥10 lymph nodes with macrometastases.

The role of ALND in the treatment of SN-positive patients is currently being questioned and the ACOZOG Z0011 study by Guiliano et. al. argues that in a group of women ALND can be omitted when only 1 or 2 SN are with macrometastases [14]. Currently, the SENOMAC trial is including patients with macrometastases in 1-2 SN for randomization to either ALND or no ALND [18]. However, as the trend of de-escalation of axillary surgery becomes more widely implemented, it may be important to identify women who have a high risk of having many axillary metastases since this group could be at increased risk of axillary relapse if not treated with ALND. Furthermore, these women may befit from neoadjuvant therapy with chance of complete pathologic response in the axilla and hence omission of ALND.

Several other studies have previously tried to identify clinical and pathological characteristics of the primary tumor and SN significant for metastatic spread to other axillary lymph nodes, but these studies have not focused on the extent of metastatic spread [17,19]. Studies on prediction of extensive nodal involvement in the axilla exist but most of these studies include patients diagnosed as node positive on axillary US [20,21]. One previous European multicenter study has tried to identify risk factors for four or more positive axillary lymph nodes [22]. Like us, this study identified size of the primary tumor as a risk factor, as well as extracapsular extension and number of positive SN. To our knowledge, no previous study has focused on the risk of more than 10 positive axillary lymph nodes. In our study, only 6% of the SN-positive patients had metastases in >10 axillary nodes. These patients are rather candidates for neoadjuvant treatment than primary surgery.

The omission of ALND in SN-positive patients represents a shift in approach for surgical practice as this leaves a group of patients with residual disease in the axilla to be targeted by adjuvant therapy. This changing approach to patients with a positive SN will benefit women with limited axillary involvement as morbidity following axillary surgery will be reduced. It has been showed that ALND is associated with a higher prevalence of persistent pain, lymphedema and sensory disturbances than SLNB. It is out most important to continue to limit the number of women undergoing ALND without therapeutic benefit, but on the other hand not withhold ALND among women with high risk of axillary recurrence.

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

This work was funded by Krãftens Bekãmpelse.