Risk factors of non-sentinel lymph node metastasis in breast cancer with 1–2 sentinel lymph node micrometastases: a case control study

doi:10.21203/rs.3.rs-2091343/v1

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Risk factors of non-sentinel lymph node metastasis in breast cancer with 1–2 sentinel lymph node micrometastases: a case control study

https://doi.org/10.21203/rs.3.rs-2091343/v1

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published 06 Apr, 2023

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Backgrround

The randomized trials include ACOSOG Z0011 and IBCSG 23 − 01 had found that, the survival rates were not different in patients with cT1/2N0 and 1–2 sentinel lymph node (SLN) positive, macro/micro metastases who underwent breast-conserving therapy and micrometastases who underwent total mastectomy (TM), when axillary lymph node dissection (ALND) was omitted. However, for patients with cT1/2N0 and 1–2 SLN macrometastases who underwent TM, there was no published clinical research evidence whether ALND can be exempted. This study aimed to investigate the risk factors of non-sentinel lymph node (nSLN) metastasis in breast cancer patients with 1–2 SLN macrometastases undergoing TM.

Methods

The clinicopathological data of 1491 breast cancer patients underwent TM and SLNB from January 2017 to February 2022 were retrospectively analyzed. Univariate and multivariate analyses were performed to analyze the risk factors for nSLN metastasis.

Results

A total of 273 patients with 1–2 SLN macrometastases underwent TM were enrolled. Postoperative pathological data showed that 35.2% patients had nSLN metastasis. The results of multivariate analysis indicated that tumor size (TS) (P = 0.002; OR: 1.051; 95% CI: 1.019–1.084) and ratio of SLN macrometastases (P = 0.0001; OR: 12.597: 95% CI: 4.302–36.890) were the independent risk factors for nSLN metastasis in breast cancer with 1–2 SLN macrometastases underwent TM. The ROC curve analysis suggested that when TS ≤ 22mm and ratio of SLN macrometastases ≤ 0.33, the incidence of nSLN metastasis could be reduced to 17.1%.

Conclusions

The breast cancer patients with cT1/2N0 stage, undergoing TM and 1–2 SLN macrometastases, when the TS ≤ 22mm and macrometastatic SLN does not exceed 1/3 of the total number of detected SLN, the incidence of nSLN metastasis is significantly reduced, and whether ALND can be exempted deserves further exploration.

Breast cancer

Total mastectomy

Sentinel lymph node

Macrometastasis

non-Sentinel lymph node

Risk factor

In recent years, with the continuous rising of incidence, breast cancer has become one of the most common malignant tumors harmful to women's health. The axillary lymph node dissection (ALND) used to be the standard treatment of axillary surgery for early breast cancer. However, the complications such as upper limb motor dysfunction, lymphedema, and sensory loss that may be caused by ALND seriously affect nearly 39% of postoperative patients [1].

With the application of sentinel lymph node biopsy (SLNB) and the support of its safety studies, the surgical management of the axillary in breast cancer patients has undergone major changes [2]. For patients with cN + before surgery, ALND is still recommended. However, for patients with cN0, SLNB should be recommended as much as possible after being informed of its safety and possible risks to reduce the risk of postoperative complications. Among them, for patients with positive sentinel lymph node (SLN), according to the ACOSOG Z0011 study, it is safe and feasible to avoid ALND in patients with cT1/2N0 and 1–2 SLN positive (macro/micro metastases) who receive breast-conserving therapy (BCT) [3]. For patients with cT1/2N0 and 1–2 SLN micrometastases who underwent total mastectomy (TM), ALND exemption can also be considered based on the results of the IBCSG 23 − 01 study [4]. For patients with cT1/2N0 and 1–2 SLN macrometastases who underwent TM, the EORTC AMAROS study supports the safe and feasible replacement of ALND by axillary radiotherapy (ART) [5]. However, there is still insufficient evidence from clinical studies to support whether further axillary treatment including ALND or ART can be safely exempted.

In previous studies, a variety of clinicopathological factors have been considered to be associated with non-sentinel lymph node (nSLN) metastasis in SLN-positive breast cancer [6–9]. This study will further explore the risk factors related to nSLN metastasis in patients under specific conditions with cT1/2N0 stage, undergoing TM and 1–2 SLN macrometastases. It is helpful for clinical identification of low-risk patients with nSLN metastasis under such conditions, so as to guide the treatment decision whether ALND or ART can be exempted.

Patients and data collection

The clinicopathological data of patients with invasive breast cancer who underwent TM and SLNB in the People's Hospital of Guangxi Zhuang Autonomous Region and the Fourth Affiliated Hospital of Guangxi Medical University from January 2017 to February 2022 were retrospectively analyzed. SLN-positive patients underwent further ALND. The clinicopathological data included: age, BMI, total number of SLN, number of negative SLN, ratio of SLN macrometastases, preoperative neutrophil lymphocyte ratio (NLR), tumor size (TS), lymphovascular invasion (LVI), histological grade, human epidermal growth factor receptor-2 (HER2) status, estrogen receptor (ER) status, progesterone receptor (PR) status, Ki-67 index, pathological type, multifocal lesions, family history of malignancy and menstrual status, etc.

Inclusion and exclusion criteria

Inclusion criteria:

(1) Diagnosed with invasive breast cancer and received TM and axillary SLNB;

(2) TS ≤ 5cm with cN0 (no palpable enlarged lymph nodes, no abnormal morphological and echoic lymph nodes were found on ultrasound) [10];

(3) With 1–2 macrometastatic SLN and underwent ALND;

Exclusion criteria:

(1) SLN was negative, only isolated tumor cell clusters or micrometastases, and ≥ 3 macrometastases were found during operation;

(2) Received neoadjuvant therapy;

(3) Incomplete clinicopathological data;

SLNB and ALND procedure

After anesthesia and disinfection, take 2 ml of 1% methylene blue were injected into the areola subcutaneously 5– 10 minutes before surgery. Blue-stained lymph nodes and their adjacent enlarged non-blue-stained lymph nodes were searched along the blue-stained lymphatic vessels as SLN and sent for intraoperative frozen pathological diagnosis. SLN-positive patients underwent further ALND. Axillary lymph nodes were routinely dissected at level I to II, and some patients were dissected to level III.

Judgment criteria

Histological grade [11]: Using the modified Scarff-Bloom-Richardson grading system: according to the proportion of glandular tube formation, cell atypia and mitotic count, each of the three indicators was independently assessed and given 1–3 points. The histological grade of invasive carcinoma was divided into grade Ⅰ (3–5 points), grade Ⅱ (6–7 points) and grade Ⅲ (8–9 points) according to the combined total score.

Tumor size: The pathological findings (gross and microscopic measurements) size of a primary tumor were the main results, combined with imaging modalities such as mammography, ultrasound, and MR imaging. For patients with intraductal carcinoma, the size of the invasion was the criterion.

Types of SLN metastasis: According to definitions of the American Joint Committee on Cancer (AJCC). ITCs is defined as small clusters of cells ≤ 0.2 mm, or single tumor cells, or fewer than 200 cells in a single histologic cross-section. Micrometastasis is defined as tumor deposits > 0.2 mm but ≤ 2.0 mm in largest dimension. Macrometastasis is defined as tumor deposits > 2.0 mm in largest dimension.

Ratio of SLN micrometastases: The ratio of the number of macrometastatic SLN to the total number of SLN.

Statistical analysis

The SPSS 23 Statistics software application was used to perform to determine risk factors. Chi-squared test was usually used for categorical data, while Students T test or Wilcoxon Rank Sum was used for continuous measurement data. Multivariate unconditional logistic regression analysis was used for multivariate correlation analysis. The diagnostic accuracy was assessed by receiver operating characteristic (ROC) analysis. The area under the ROC curve (AUC) was used to evaluate the critical value of relevant factors. P < 0.05 was considered to indicate a statistically significant difference.

Patients and treatments

A total of 1,491 patients with invasive breast cancer underwent TM and SLNB, all of whom were female. Among them, patients with SLN 1–2 macrometastases accounted for 18.3% (n = 273), with an average age of 51.5 years. Pathological data after ALND showed that a total of 35.2% (n = 96) patients developed nSLN metastasis (Figure 1).

Univariate and multivariate analyses

The comparison of clinicopathological factors showed that there were significant differences in total number of SLN, number of negative SLN, ratio of SLN macrometastases, TS, LVI, pathological type and tumor site between the nSLN-positive and nSLN-negative patients (P < 0.05), while There was no significant difference between the two groups in age, BMI, NLR, histological grade, molecular type, ER status, PR status, Ki-67 index, HER2 status, multifocal lesions, menstrual status and family history of malignancy (Table 1).

The clinicopathological factors of total number of SLN, number of negative SLN, ratio of SLN macrometastases, TS, LVI, pathological types and tumor sites were included in multivariate analysis. The results indicated that TS (P = 0.002; OR: 1.051; 95% CI: 1.019–1.084) and Ratio of SLN macrometastases (P = 0.0001; OR: 12.597; 95% CI: 4.302–36.890) were the independent risk factors for nSLN metastasis in breast cancer with 1–2 SLN macrometastases undergoing TM (Table 2).

ROC analysis of TS and ratio of SLN macrometastases

The cut-off points of TS and ratio of SLN macrometastases determined by receiver operating characteristic (ROC) analysis were 22mm (AUC 0.625, sensitivity 60.4%, specificity 64.4%, P < 0.001, Figure 2) and 0.33 (AUC 0.680, sensitivity 64.6%, specificity 65.5%), P < 0.001, Figure 3), respectively. When TS > 22mm and ratio of SLN macrometastases > 0.33, the incidence of nSLN metastasis was 73.6%, and when TS ≤ 22mm and Ratio of SLN macrometastases ≤ 0.33, the incidence of nSLN metastasis decreased to 17.1% (Table 3).

In the comprehensive treatment of breast cancer, surgery still has an irreplaceable clinical status. With the gradual change of the treatment concept, the principle of surgical treatment has shifted from maximum tolerable treatment to minimum effective treatment. The SLNB technique has become a routine axillary treatment for patients with clinically node-negative breast cancer. For SLN-positive breast cancer patients, ALND is still the primary treatment [12]. However, 34.3–77.3% of patients with SLN-positive were found to have no nSLN metastasis after ALND [6, 8, 10]. With the announcement of the 10-year follow-up results of the ACOSOG Z0011 trial [3] and the IBCSG 23 − 01 trial [4], TM with 1–2 SLN micrometastases and BCT with 1–2 SLN micro/macro metastases of breast cancer patients, it is safe to avoid ALND. However, whether patients with TM and 1–2 SLN macrometastases can be exempted from ALND is still insufficient evidence from clinical studies. Among this study, the patients with TM and 1–2 SLN macrometastases, 64.8% of the patients did not develop nSLN metastasis. Means that it did not benefit from having undergone ALND surgery. To explore the risk factors related to nSLN metastasis in patients undergoing TM and 1–2 SLN macrometastases, and screen the patients who can avoid ALND, which is of great significance to reduce the trauma caused by surgery.

There have been many previous studies on the risk factors related to SLN-positive and nSLN metastasis in breast cancer, but few studies have focused on the conditions of TM with SLN macrometastases. Previous studies have found that the size of SLN metastases, extracapsular invasion of SLN, the number of positive and negative SLN, the ratio of positive SLN, TS, LVI, histological grade, NLR and other clinicopathological factors were all related to the occurrence of nSLN metastasis [6–9]. In the analysis of our group, under the conditions of cT1/2N0 and TM with 1–2 SLN macrometastases, we found that the total number of SLN, number of negative SLN, ratio of SLN macrometastases, TS, LVI, pathological type and tumor site were correlated with the occurrence of nSLN metastasis. Multivariate analysis further found that TS and ratio of SLN macrometastases were independent predictors of nSLN metastasis. When TS > 22mm and ratio of SLN macrometastases > 0.33, the incidence of nSLN metastasis was 73.6%, and when TS ≤ 22mm and ratio of SLN macrometastases ≤ 0.33, the incidence of nSLN metastasis decreased to 17.1%. It is suggested that selecting a small tumor burden before surgery and increasing the number of SLN detected during surgery can improve the accuracy of negative prediction of nSLN. It has important reference value for evaluating whether to exempt ALND.

Although ALND is currently recommended for patients with SLN-positive breast cancer undergoing TM, the real-world data on SLN-positive disease without ALND are equally noteworthy. Among the entire study cohort of 4093 patients had T1/2N0M0 breast cancer with 1–2 SLN metastases and underwent TM. ALND rates decreased from 89.9% in 2010 to 55.5% in 2015. Rates decreased from 82–8% in patients with SLN micrometastases and from 93–63% in those with macrometastases. In multivariable analysis, factors associated with omission of ALND were pT1 status, older age, more SLN removed, fewer positive SLN, and SLN micrometastasis [13]. In addition, in another study of 329 patients with 1–2 SLN metastases who underwent TM, 201 patients received ALND. Compared with patients who received SLNB alone, patients who received ALND were characterized by higher tumor grade and higher proportion of hormone receptor-negative. After a median follow-up of 51 months, there were no significant differences in OS and local recurrence rates between the two groups [14]. Kim and his colleagues observed 3632 breast cancer patients who underwent TM with 1–2 SLN metastases, of which 883 patients did not receive ALND. No difference in OS between the two groups at a median follow-up of 54 months [15]. All the above data suggest that it appears to be safe to avoid ALND in breast cancer patients with TM and 1–2 SLN metastases when selecting appropriate low-risk cases.

There have been several prospective controlled studies on whether axillary treatment can be exempted for patients with 1–2 SLN macrometastases undergoing TM. Among them, the SINODAR ONE study was a prospective noninferiority multicenter randomized study aimed at assessing the role of ALND in patients undergoing either BCT or TM for T1–2 breast cancer and presenting 1–2 SLN macrometastases. It was no significant differences in OS or RFS between ALND recipients and non-ALND recipients at a mean follow-up of 32 months in the 879 cases [16]. However, the low proportion of patients who underwent TM (24.8%) and the short follow-up time in this study still cannot alone answer the question of whether breast cancer patients who underwent TM with 1–2 SLN macrometastases can be exempted from ALND. In addition, SENOMAC and POSNOC studies are still in progress. The SENOMAC study, a non-inferiority study largely follows the inclusion criteria of the ACOSOG Z0011 study, but allows the inclusion of T1–3 patients who undergoing TM. A total of 3500 patients are randomized 1:1 to either undergo ALND or not, and the primary endpoint is breast cancer-specific survival at 5 years [17]. The POSNOC study is a randomised, multi-centre, non-inferiority trial, aimed to evaluate whether breast cancer patients with T1-2, 1–2 SLN macrometastases who undergoing TM or BCT without axillary treatment are non-inferior to ALND or ART. The sample size is 1900 and participants will be followed up for 5 years. The primary endpoint is axillary recurrence at 5 years. By June 2021, POSNOC study had completed 1866 cases [18]. The results of the ACOSOG Z0011 and IBCSG 23 − 01 studies have changed the previous breast cancer treatment strategy. We expect the new research results will lead to new treatment decisions. In the just-published SENOMAC study of health-related quality of life and arm morbidity after axillary surgery, 976 patients (501 in SLNB and 475 in ALND) were enrolled, found that arm morbidity was significantly worse affected by ALND than by SLNB one year after surgery. The results underline the importance of ongoing attempts to safely de-escalate axillary surgery [19].

This study is a retrospective study. The subject of the study is the breast cancer patients with T1/2, cN0 and TM with 1–2 SLN macrometastases that had not yet been supported by the results of randomized controlled studies. The study comprehensively evaluated the influence of different clinicopathological factors on nSLN metastasis and further analyzed the role of related influencing factors. It has certain reference significance for choosing whether to exempt ALND in clinical practice. However, there are some uncontrolled research biases in this study, which may have a certain impact on the results. We look forward to more randomized controlled studies to evaluate the safety of ALND exclusion in breast cancer patients with T1/2, cN0 and TM with 1–2 SLN macrometastases.

the breast cancer patients with cT1/2N0 stage, undergoing TM and 1–2 SLN macrometastases, the occurrence of nSLN metastasis is closely related to TS and the ratio of SLN macrometastases. when the TS ≤ 22mm and macrometastatic SLN does not exceed 1/3 of the total number of detected SLN, the incidence of nSLN metastasis is significantly reduced, and whether ALND can be exempted deserves further exploration.

TM, Total mastectomy

BTC, Breast-conserving therapy

SLN, Sentinel lymph node

nSLN, non-Sentinel lymph node

SLNB, Sentinel lymph node biopsy

ALND, Axillary lymph node dissection

ART, Axillary radiotherapy

NLR, Neutrophil lymphocyte ratio

TS, Tumor size

LVI, Lymphovascular invasion

ER, Estrogen receptor

PR, Progesterone receptor

HER2, Human epidermal growth factor receptor-2

ROC, Receiver operating characteristic

AUC, The area under the ROC curve

Ethics approval and consent to participate

The study was approved by the Institutional Ethics Review Board of the People's Hospital of Guangxi Zhuang Autonomous Region and the Fourth Affiliated Hospital of Guangxi Medical University.

Consent for publication

Not applicable

Availability of data and materials

The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.

Competing interests

The authors declare that they have no competing interests

Funding

This study received funding from Guangxi Zhuang Autonomous Region Health Commission Self-funded scientific research project (Z20200134)

Authors' contributions

JRY: study conception and design, interpretation of results; ZH: study conception and design, data collection and analysis, draft manuscript preparation; ZW and YJX：data collection and analysis, draft manuscript preparation; LHL, YPH, FMW, DH, and YHP: data collection. All authors approved the final version of the manuscript.

Acknowledgements

Not applicable

Authors' information

Jian-rong Yang: Department of Surgery, People's Hospital of Guangxi Zhuang Autonomous Region, No.6 Taoyuan Road, Nanning, 530021, China, E-mail: [email protected]

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Table 1. Relationship between nSLN and clinicopathological factors

Characteristic	nSLN-negative (n = 177)	nSLN-positive (n = 96)	t/z/x²	P Value
Age at diagnosis (year)	51.24 ± 10.44	51.89 ± 11.93	-0.466	0.642
BMI (kg/m²)	23.31 (21.24–25.89)	23.12 (21.40–26.43)	-0.707	0.480
TS (mm)	20 (15–25)	25 (20–30)	-3.429	0.001
Total number of SLN	4 (3–5)	3 (2–4)	-2.937	0.003
Number of negative SLN	2.00 (1.00–4.00)	1.50 (0.25–3.00)	-3.959	0.001
Ratio of SLN macrometastases	0.33 (0.25–0.50)	0.50 (0.33–0.92)	-4.987	0.001
NLR	1.99 (1.61–2.68)	2.00 (1.53–2.67)	-0.803	0.423
Histological grade			6.428	0.093
Ⅰ	20 (11.3)	3 (3.1)
Ⅱ	113 (63.8)	63 (65.6)
Ⅲ	34 (19.2)	21 (21.9)
Unknown	10 (5.6)	9 (9.4)
Pathological type			4.164	0.041
Invasive ductal carcinoma	172 (97.2)	88 (91.7)
Others	5 (2.8)	8 (8.3)
LVI			6.893	0.009
Negative	119 (67.2)	49 (51.0)
Positive	58 (32.8)	47 (49.0)
ER status			0.092	0.761
< 10%	34 (19.2)	17 (17.7)
≥ 10%	143 (80.8)	79 (82.3)
PR status			0.026	0.872
< 10%	57 (32.2)	30 (31.3)
≥ 10%	120 (67.8)	66 (68.8)
Ki-67 index			1.660	0.436
< 14%	52 (29.4)	24 (25.0)
≥ 14%, ≤ 30%	67 (37.9)	44 (45.8)
> 30%	58 (32.8)	28 (29.2)
Her2 status			0.180	0.672
Negative	135 (76.3)	71 (74.0)
Positive	42 (23.7)	25 (26.0)
Molecular type			3.426	0.489
Luminal A	65 (36.7)	27 (28.1)
Luminal B-Her (-)	58 (32.8)	36 (37.5)
Luminal B-Her2 (+)	22 (12.4)	17 (17.7)
ERBB2 (+)	15 (8.5)	6 (6.3)
Basal-like	17 (9.6)	10 (10.4)
Tumor site			11.353	0.023
Upper outer	80 (45.2)	61 (63.5)
Lower outer	22 (12.4)	13 (13.7)
Lower inner	15 (8.5)	3 (3.2)
Upper inner	45 (25.4)	13 (13.7)
Central portion	15 (8.5)	6 (6.3)
Multifocal lesions			2.513	0.113
No	169 (95.5)	87 (90.6)
Yes	8 (4.5)	9 (9.4)
Menstrual status			1.887	0.170
Premenopausal	102 (57.6)	47 (49.0)
Postmenopausal	75 (42.4)	49 (51.0)
Family history of malignancy			3.227	0.196
None	133 (75.1)	71 (74.0)
Breast or ovarian cancer	16 (9.0)	4 (4.2)
Other malignant tumors	28 (15.8)	21 (21.9)

Table 2. Multivariate analysis of clinicopathological factors for nSLN metastasis

Characteristic	OR	95% CI	P Value
TS (mm)	1.051	1.019–1.084	0.002
Ratio of SLN macrometastases	12.597	4.302–36.890	0.0001
Tumor sites			0.054
Upper outer	1		reference
Lower outer	0.777	0.344–1.754	0.544
Lower inner	0.255	0.066–0.980	0.047
Upper inner	0.405	0.193–0.853	0.017
Central portion	0.468	0.159–1.377	0.168

Table 3. Relationship between tumor size, ratio of SLN macrometastases and incidence of nSLN metastasis

Characteristic	Amount	Incidence of nSLN metastasis
TS > 22mm and ratio of SLN macrometastases > 0.33	53	73.6%
TS > 22mm and ratio of SLN macrometastases ≤ 0.33	68	27.9%
TS ≤ 22mm and ratio of SLN macrometastases > 0.33	70	32.9%
TS ≤ 22mm and ratio of SLN macrometastases ≤ 0.33	82	17.1%
In total	273	35.2%

No competing interests reported.

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Risk factors of non-sentinel lymph node metastasis in breast cancer with 1–2 sentinel lymph node micrometastases: a case control study

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