Predictors of sentinel lymph node metastasis in Chinese women with clinical T1-T2 N0 breast cancer and a normal axillary ultrasound

Abstract

Background

The clinicopathological predictors of sentinel lymph node (SLN) metastasis in clinical T1-T2 N0 (cT1-T2 N0) patients with a normal axillary ultrasound (AUS) are unclear.

Purpose

To assess the association between clinicopathological characteristics of a primary tumor and SLN metastasis in cT1-T2 N0 patients with a normal AUS.

Material and Methods

Patients who were diagnosed with cT1-T2 N0 invasive breast cancer and who obtained normal AUS results between October 2016 and September 2018 in a single hospital were included. Clinicopathological data were collected to explore the predictors of SLN metastasis using a multivariate logistic regression model.

Results

SLN metastasis occurred in 26 patients (18.4%) among 141 AUS-normal patients, of which 24 cases (17.0%) had one or two nodal involvements. In the univariate analysis, tumor location, estrogen receptor (ER) status, progesterone receptor (PR) status, and lymphovascular invasion (LVI) were significantly associated with SLN metastasis (P < 0.05). The multivariate analysis showed that tumor location in the upper outer quadrant (odds ratio [OR] = 4.49, 95% confidence interval [CI] = 1.63–12.37; P = 0.004), positive PR status (OR = 13.35, 95% CI = 1.60–111.39; P = 0.017), and positive LVI (OR = 8.66, 95% CI = 2.20–34.18; P = 0.002) were independent high-risk factors for SLN metastasis. The area under the receiver operating characteristic curve of the regression model was 0.787 (95% CI = 0.694–0.881; P < 0.001).

Conclusion

Tumor location in the upper outer quadrant, positive PR, and LVI status were found to be significantly high-risk factors for SLN metastasis among cT1-T2 N0 breast cancer patients with a normal AUS result.

Keywords

Breast cancer sentinel lymph node metastasis predictors axillary ultrasonography

Introduction

Axillary lymph node (ALN) metastasis is an important predictor of recurrence and overall survival in patients with breast cancer. Sentinel lymph node biopsy (SLNB) is currently considered the standard of care for axillary staging in cN0 breast cancer without neoadjuvant therapy (1). In the past two decades, several randomized trials demonstrated no difference in regional control, disease-free survival, or overall survival between cN0 patients who had undergone SLNB and axillary lymph node dissection (ALND) (2 –4). SLNB also reduced the rate of complications of axillary surgery and improved quality of life (3,5). However, only 20%–30% of patients have axillary nodal metastasis based on SLNB (4). Axillary management has been further influenced by the ACOSOG Z0011 trial, which indicated that SLNB without ALND is safe in patients with one or two sentinel lymph node metastases who are candidates for breast-conserving surgery and whole-breast radiation therapy (6). Moreover, SLNB is still associated with side effects as a traumatic procedure. Previous trials have reported that 25% of patients suffer complications such as seroma (6.0%–7.1%), paresthesia (8.6%–12.0%), and lymphedema (6.0%–8.0%) after SLNB (7,8).

Ultrasonography has been confirmed as a favorable non-invasive method to evaluate the status of ALN (9). Previous studies have shown that axillary ultrasound (AUS) has good performance for the identification of ALN metastases (sensitivity of 50%–84% and specificity of 80%–92%), with a higher sensitivity achieved in combination with ultrasound-guided needle biopsy (10 –12). Previous studies have focused on the recognition ability of AUS for ALN metastasis, but few of these studies have specifically evaluated the characteristics and risk factors for SLN metastasis in cN0 patients with a normal AUS. Prospective studies, such as the SOUND trial (13) and the BOOG 2013–08 trial (14), are in progress to explore whether SLNB can be avoided in cN0 patients receiving breast-conserving therapy. The aim of the present study was to retrospectively assess the risk factors for SLN metastasis in patients with cT1-T2 N0 breast cancer with normal AUS results.

Material and Methods

Patient population

A total of 178 consecutive patients with cT1-T2 N0 invasive breast cancer underwent AUS between October 2016 and September 2018 at Peking University International Hospital. Of the 178 patients, 141 (79.2%) had normal AUS results and were subjected to SLNB (Table 1). All the included patients were women; the primary tumor was diagnosed as invasive breast cancer; patients did not have multifocal or multicentric tumors; patients did not receive neoadjuvant therapy before lymph node biopsy; and patients did not have contraindications for ultrasound-guided needle biopsy and SLNB based on the ASCO clinical practice guideline (1). The clinicopathological data, including age, menstrual status, tumor size on ultrasound, tumor histology, tumor grade, estrogen receptor (ER) status, progesterone receptor (PR) status, HER2 status, and lymphovascular invasion (LVI), were collected for analysis (Table 2). ER status and PR status were considered positive if >1% of tumor nuclei were positive by immunohistochemistry (15). HER2 status was considered positive if the immunohistochemistry score was 3 + or 2 + with confirmation of HER2 gene amplification by fluorescence in situ hybridization or in situ hybridization (16). This study was approved by the Ethics Committee of Peking University International Hospital.

Table 1.

Patient demographics.

Characteristic	Total
Age (years)
Median (range)	55 (25–80)
≤45	42 (29.8)
>45	99 (70.2)
Menstrual status
Premenopausal	57 (40.4)
Postmenopausal	84 (59.6)
Tumor size* (cm)
≤2	92 (65.2)
>2	49 (34.8)
Tumor location^†
Upper inner quadrant	51 (36.2)
Upper outer quadrant	58 (41.1)
Lower inner quadrant	12 (8.5)
Lower outer quadrant	20 (14.2)
Tumor histology
Ductal	122 (86.5)
Lobular	5 (3.5)
Others	14 (9.9)
Tumor grade
I–II	101 (71.6)
III	20 (14.2)
Others	20 (14.2)
Estrogen receptor
Negative	30 (21.3)
Positive	111 (78.7)
Progesterone receptor
Negative	38 (27.0)
Positive	103 (73.0)
Her2
Negative	112 (79.4)
Positive	29 (20.6)
Lymphovascular invasion
No	128 (90.8)
Yes	13 (9.2)

Values are given as n (%).

*Tumor size was defined as the maximum diameter of the primary tumor measured by ultrasonography.

^†Central tumors were included in the quadrant where the main tumor was located.

Table 2.

Univariate analysis of clinicopathological characteristics of SLN metastasis.

Variables	SLN (−)	SLN ( + )	P value
Total	115	26
Age (years)			0.057
≤ 45	30 (85.9)	12 (14.1)
> 45	85 (71.4)	14 (28.6)
Menstrual status			0.123
Premenopausal	43 (85.7)	14 (14.3)
Postmenopausal	72 (75.4)	12 (24.6)
Tumor size (cm)			0.660
≤ 2	76 (82.6)	16 (17.4)
> 2	39 (79.6)	10 (20.4)
Tumor location			0.005
Upper outer quadrant	41 (70.7)	17 (29.3)
Outside upper outer quadrant	74 (89.2)	9 (10.8)
Tumor histology			0.237
Ductal	99 (81.1)	23 (18.9)
Lobular	3 (60.0)	2 (40.0)
Others	13 (92.9)	1 (7.1)
Tumor grade			0.227
I-II	79 (78.2)	22 (21.8)
III	18 (90.0)	2 (10.0)
Others	18	2
Estrogen receptor			0.016
Negative	29 (96.7)	1 (3.3)
Positive	86 (77.5)	25 (22.5)
Progesterone receptor			0.003
Negative	37 (97.4)	1 (2.6)
Positive	78 (75.7)	25 (24.3)
Her-2			0.072
Negative	88 (78.6)	24 (21.4)
Positive	27 (93.1)	2 (6.9)
Lymphovascular invasion			0.003
No	109 (85.2)	19 (14.8)
Yes	6 (46.2)	7 (53.8)

Values are given as n (%).

SLN, sentinel lymph node.

Axillary ultrasonography

Axillary ultrasonography was evaluated by two sonographers with >5 years of experience. AUS results were defined as normal if the AUS did not detect any lymph nodes or the structure of the cortex and medulla were clear and the cortex thickness was <3 mm and if the fatty hilum was visible (17). AUS results were defined as abnormal as follows: regular target annular lymph node with a cortical thickness ≥3 mm; eccentric target annular lymph node with a local cortical thickness ≥3 mm; and hypoechoic lymph nodes with effacement of the fatty hilum (17).

SLNB

All SLNBs were treated with the ^99mTc-rituximab radionuclide tracing method as described previously (18). Patients were injected with a radionuclide at a dose of 18.5 MBq in the morning before the operation. SLNB was performed under local anesthesia. All nodes with a radioactive counting rate ≥10% of the hottest node were extracted. Pathological types of nodal disease were defined as macrometastasis (>2.0 mm) or micrometastasis (0.2–2.0 mm), and isolated tumor cells (≤0.2 mm).

Statistical methods

Clinicopathological data were summarized using descriptive statistics. In the univariate analysis, Pearson's chi-square test (Fisher's exact test was used where counts <5) was used to compare the differences in categorical data between groups to determine their associations with SLN metastasis. A logistic regression model was constructed to evaluate the risk factors that were significantly associated with SLN metastasis in the univariate analysis. A receiver operating characteristic (ROC) curve was used to evaluate the predictive ability of the regression model for SLN metastasis. A P value <0.05 was defined as statistically significant. SPSS v25.0 (IBM Corp., Chicago, IL, USA) was used for statistical processing.

Results

The demographic and clinicopathological characteristics of the 141 patients with clinical T1-2 N0 breast cancer and a normal AUS are listed in Table 1. Among these individuals, there were 2.9 ± 1.6 SLNs obtained per patient (Suppl. Table 1). According to the pathological type of nodal disease, 12 cases were macrometastasis (8.5%), 14 were micrometastasis (9.9%), and 4 (2.8%) were isolated tumor cells (ITC). Since ITCs do not affect clinical management based on current guidelines, the four cases with ITCs were excluded from SLN metastases, resulting in 26 patients (18.4%) with SLN metastasis in the cohort of 141 patients (Suppl. Table 1). Of these 26 patients with SLN metastases, 24 (92.3%) had 1–2 SLN metastases, and 2 (7.7%) had ≥3 SLN metastases; of the 26 patients, eight also underwent ALND and two cases had ≥3 lymph node metastases at final surgery.

In the univariate analysis, variables that were significantly associated with SLN metastasis were tumor location, ER status, PR status, and LVI (Table 2). Of the tumors located in the upper outer quadrant, 29.3% had SLN metastasis, whereas 10.8% of tumors located in other quadrants had SLN metastasis (P = 0.005). ER-positive and PR-positive tumors were more likely to have SLN metastasis than hormone receptor-negative tumors (22.5% vs. 3.3%, P = 0.016; 24.3% vs. 2.6%, P = 0.003, respectively). Patients with LVI were more likely to have SLN metastasis than patients without LVI (P = 0.003). On the other hand, there were no significant associations of age (P = 0.057), menstrual status (P = 0.123), tumor size (P = 0.660), tumor grade (P = 0.227), or HER-2 status (P = 0.072) with SLN metastasis.

The multivariate regression analysis showed that tumor location in the upper outer quadrant (odds ratio [OR] = 4.49, 95% confidence interval [CI] = 1.63–12.37; P = 0.004), PR status (OR = 13.35, 95% CI = 1.60–111.39; P = 0.017), and LVI (OR = 8.66, 95% CI = 2.20–34.18; P = 0.002) were independent risk factors for SLN metastasis (Table 3). These independent risk factors for SLN metastasis—tumor location in the upper outer quadrant, PR status, and LVI—were included in a prediction model, yielding an area under the ROC curve of 0.787 (95% CI = 0.694–0.881; P < 0.001) (Fig. 1).

Fig. 1.

ROC curves for the prediction of SLN metastasis by logistic models. ROC, receiver operating characteristic; SLN, sentinel lymph node.

Table 3.

Multivariate analysis of the clinicopathological characteristics of sentinel lymph node metastasis.

Variable	OR	95% CI	P value
Tumor location			0.004
Outside upper outer quadrant	1.00
Upper outer quadrant	4.49	1.63–12.37
Progesterone receptor			0.017
Negative	1.00
Positive	13.35	1.60–111.39
Lymphovascular invasion			0.002
No	1.00
Yes	8.66	2.20–34.18

CI, confidence interval; OR, odds ratio.

Discussion

Axillary staging is important in the treatment strategy for breast cancer. With the development of ultrasound equipment and refined diagnostic standards, AUS for ALN staging in breast cancer has been widely used among clinicians. Previous studies have shown that AUS has good performance characteristics for the identification of ALN metastases (10 –12). However, the feasibility of AUS for the exclusion of SLN metastasis remains unclear.

In our study, there was a 18.4% SLN metastasis rate in cT1-T2 N0 patients with a normal AUS. Our results are consistent with a metastasis rate of 16.5%–25.6% previously reported (19 –21). However, the rate of 18.4% SLN metastases in our study was included both macrometastatic (8.5%) and micrometastatic (9.9%) SLN, but excluded isolating tumor cells. The prognostic roles of micrometastatic lymph nodes are still under debate. Hansen et al. (22) reported that patients with pN1(mi) tumors had a similar survival to those with pN0 tumors, while the NSABP B-32 study (23) revealed that micrometastatic disease was an independent prognostic factor leading to a small but statistically significant decrease in survival, given that the majority of patients in these studies receive breast-conserving therapy when the patients had a pN1(mi) tumor. On the other hand, the proportion of breast-conserving therapy is around 30% in China; therefore, in the current study, we included the micrometastatic lymph nodes.

Indeed, of 26 patients with positive SLN in this study, 24 (92.3%) patients had only 1–2 SLN metastases, and 2 (7.7%) had ≥3 SLN metastases. Of the 26 patients, eight underwent further ALND after SLN biopsy, only two patients had ≥3 lymph node metastases at final surgery, and no further additional lymph node involvement was found in the remaining six cases. Our findings suggested that only a very small fraction of patients with small tumors and normal AUS have >2 positive lymph nodes. Therefore, our findings are agreement with the ongoing SOUND trial that small tumors with normal AUS may have an opportunity to avoid SLNB.

To identify individuals who are at a high risk of SLN metastasis and therefore may not be safely exempted from SLNB, we further investigated the clinicopathological factors for SLN metastasis. In this study, our multivariate analysis revealed that tumor location in the upper outer quadrant, PR status, and LVI were independent risk factors for SLN metastasis. Previous studies suggested that age at diagnosis, tumor size, tumor location, LVI, and histological grade were most commonly described as independent predictors for SLN metastasis (24 –26). Our data showed that tumor location in the upper outer quadrant was significantly associated with SLN metastasis (OR = 4.49), which was in agreement with the lymphatic drainage patterns of the breast. Other studies also showed that the upper outer quadrant was associated with a high incidence of ALN metastasis, and some nomograms have incorporated tumor location as a risk factor to predict the likelihood of SLN metastasis (27 –29). The association between hormone receptor (ER and/or PR) status and ALN metastasis is controversial (30). Some studies showed that hormone receptor status was an independent significant predictor (20,25,31,32), while others did not (26,33,34). In our study, PR status rather than ER status was an independent significant predictor for SLN metastasis (OR = 13.35). LVI has also been shown to be associated with lymph node metastasis and an adverse prognosis (35–37). Our results consistently revealed that the SLN metastasis risk of LVI-positive patients was approximately nine times higher than that of LVI-negative patients.

The present study has some limitations. First, certain differences in the working experiences of sonographers may have affected our results. Second, this study was a retrospective study with a limited sample size, resulting in potential selection bias; therefore, caution is required when interpretation of our results. Third, the evaluation of LVI in the primary tumor with preoperative core needle biopsy may be challenging for precisely determining LVI status due to limited volume of tissue; however, vacuum-assisted biopsy has been utilized in small tumor diagnosis and can provide a larger volume of tissue for evaluation of LVI.

In conclusion, our study suggested that approximately 18.4% of patients with breast cancer with cT1-T2 N0 tumor and normal AUS results have a positive SLN. Patients with a tumor located in the upper outer quadrant, a positive PR status, and LVI are at a significantly higher risk of SLN metastasis. There are ongoing studies, such as the SOUND trial (13), to explore the possibility of minimizing the axillary surgery including SLNB among cN0 patients. The present study also suggested that the majority of patient with small tumors and a normal AUS are more like to have a negative SLN or may have only 1–2 SLNs involved; these patients are the potential candidates for omitting SLNB as only a very small subset of patients may have >2 lymph nodes involved. Therefore, we may need predictive markers to sort out the high-risk patients and spare the majority of low-risk patients in patients with cT1-T2 tumor and a normal AUS.

Supplemental Material

sj-doc-1-acr-10.1177_02841851211054191 - Supplemental material for Predictors of sentinel lymph node metastasis in Chinese women with clinical T1-T2 N0 breast cancer and a normal axillary ultrasound

Supplemental material, sj-doc-1-acr-10.1177_02841851211054191 for Predictors of sentinel lymph node metastasis in Chinese women with clinical T1-T2 N0 breast cancer and a normal axillary ultrasound by Fenfen Fu, Yonghui Zhang, Jie Sun, Chun Zhang, Dongjie Zhang, Lingduo Xie, Futao Chu, Xue Yu and Yuntao Xie in Acta Radiologica

Footnotes

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by the National Natural Science Foundation of China (grant number 81802635, 81974422).

ORCID iD

Yuntao Xie

Supplemental material

Supplemental material for this article is available online.

References

Lyman

Somerfield

Bosserman

, et al. Sentinel lymph node biopsy for patients with early-stage breast cancer: American society of clinical oncology clinical practice guideline update. J Clin Oncol 2017;35:561–564.

Veronesi

Paganelli

Viale

, et al. A randomized comparison of sentinel-node biopsy with routine axillary dissection in breast cancer. N Engl J Med 2003;349:546–553.

Mansel

Fallowfield

Kissin

, et al. Randomized multicenter trial of sentinel node biopsy versus standard axillary treatment in operable breast cancer: the ALMANAC trial. J Natl Cancer Inst 2006;98:599–609.

Krag

Anderson

Julian

, et al. Technical outcomes of sentinel-lymph-node resection and conventional axillary-lymph-node dissection in patients with clinically node-negative breast cancer: results from the NSABP B-32 randomised phase III trial. Lancet Oncol 2007;8:881–888.

Ashikaga

Krag

Land

, et al. Morbidity results from the NSABP B-32 trial comparing sentinel lymph node dissection versus axillary dissection. J Surg Oncol 2010;102:111–118.

Giuliano

Hunt

Ballman

, et al. Axillary dissection vs no axillary dissection in women with invasive breast cancer and sentinel node metastasis: a randomized clinical trial. JAMA 2011;305:569–575.

Lucci

McCall

Beitsch

, et al. Surgical complications associated with sentinel lymph node dissection (SLND) plus axillary lymph node dissection compared with SLND alone in the American College of Surgeons Oncology Group Trial Z0011. J Clin Oncol 2007;25:3657–3663.

Wilke

McCall

Posther

, et al. Surgical complications associated with sentinel lymph node biopsy: results from a prospective international cooperative group trial. Ann Surg Oncol 2006;13:491–500.

Choi

Park

Seo

, et al. Preoperative axillary lymph node evaluation in breast cancer. Ultrasound Q 2017;33:6–14.

10.

Vaidya

Vyas

Thakur

, et al. Role of ultrasonography to detect axillary node involvement in operable breast cancer. Eur J Surg Oncol 1996;22:140–143.

11.

Yang

Ahuja

Tang

, et al. High resolution sonographic detection of axillary lymph node metastases in breast cancer. J Ultrasound Med 1996;15:241–246.

12.

Motomura

Inaji

Komoike

, et al. Gamma probe and ultrasonographically-guided fine-needle aspiration biopsy of sentinel lymph nodes in breast cancer patients. Eur J Surg Oncol 2001;27:141–145.

13.

Gentilini

Veronesi

. Abandoning sentinel lymph node biopsy in early breast cancer? A new trial in progress at the European institute of oncology of Milan (SOUND: sentinel node vs observation after axillary UltraSouND). Breast 2012;21:678–681.

14.

van Roozendaal

Vane

MLG

van Dalen

, et al. Clinically node negative breast cancer patients undergoing breast conserving therapy, sentinel lymph node procedure versus follow-up: a Dutch randomized controlled multicentre trial (BOOG 2013–08). BMC Cancer 2017; 17:459.

15.

Hammond

Hayes

Dowsett

, et al. American Society of Clinical Oncology/College of American Pathologists guideline recommendations for immunohistochemical testing of estrogen and progesterone receptors in breast cancer. J Clin Oncol 2010;28:2784–2795.

16.

Wolff

Hammond

MEH

Allison

, et al. Human epidermal growth factor receptor 2 testing in breast cancer: American Society of Clinical Oncology/College of American Pathologists clinical practice guideline focused update. J Clin Oncol 2018;36:2105–2122.

17.

Huo

Yan

Zhang

, et al. Morphology-based criteria for ultrasonic assessment of axillary lymph node status in primary breast cancer. Zhonghua Yi Xue Za Zhi 2012;92:672–674.

18.

Wang

Fan

, et al. (99 m)Tc-rituximab as a tracer for sentinel lymph node biopsy in breast cancer patients: a single-center analysis. Breast Cancer Res Treat 2018;168:365–370.

19.

Tucker

Cyr

Ademuyiwa

, et al. Axillary ultrasound accurately excludes clinically significant lymph node disease in patients with early stage breast cancer. Ann Surg 2016;264:1098–1102.

20.

Chen

Wang

, et al. Feasibility of using negative ultrasonography results of axillary lymph nodes to predict sentinel lymph node metastasis in breast cancer patients. Cancer Med. 2018;7:3066-3072.

21.

Jackson

Mylander

Rosman

, et al. Normal axillary ultrasound excludes heavy nodal disease burden in patients with breast cancer. Ann Surg Oncol 2015;22:3289–3295.

22.

Hansen

Grube

, et al. Impact of micrometastases in the sentinel node of patients with invasive breast cancer. J Clin Oncol 2009;27:4679–4684.

23.

Weaver

Ashikaga

Krag

, et al. Effect of occult metastases on survival in node-negative breast cancer. N Engl J Med 2011;364:412–421.

24.

Caywood

Gray

Hentz

, et al. Older age independently predicts a lower risk of sentinel lymph node metastasis in breast cancer. Ann Surg Oncol 2005;12:1061–1065.

25.

Viale

Zurrida

Maiorano

, et al. Predicting the status of axillary sentinel lymph nodes in 4351 patients with invasive breast carcinoma treated in a single institution. Cancer 2005;103:492–500.

26.

Minami

Sakimura

Irie

, et al. Predictive factors among clinicopathological characteristics for sentinel lymph node metastasis in T1-T2 breast cancer. Cancer Manag Res 2021;13:215–223.

27.

Bevilacqua

Kattan

Fey

, et al. Doctor, what are my chances of having a positive sentinel node? A validated nomogram for risk estimation. J Clin Oncol 2007;25:3670–3679.

28.

Chen

Liu

, et al. Development of nomograms to predict axillary lymph node status in breast cancer patients. BMC Cancer 2017;17:561.

29.

Desai

Hoskin

Day

, et al. Effect of primary breast tumor location on axillary nodal positivity. Ann Surg Oncol 2018;25:3011–3018.

30.

Patani

Dwek

Douek

. Predictors of axillary lymph node metastasis in breast cancer: a systematic review. Eur J Surg Oncol 2007;33:409–419.

31.

Tan

Heng

, et al. Predictors of axillary lymph node metastases in women with early breast cancer in Singapore. Singapore Med J 2005;46:693–697.

32.

Sandoughdaran

Malekzadeh

Mohammad Esmaeil

. Frequency and predictors of axillary lymph node metastases in Iranian women with early breast cancer. Asian Pac J Cancer Prev 2018;19:1617–1620.

33.

Yoshihara

Smeets

Laenen

, et al. Predictors of axillary lymph node metastases in early breast cancer and their applicability in clinical practice. Breast 2013;22:357–361.

34.

Malter

Hellmich

Badian

, et al. Factors predictive of sentinel lymph node involvement in primary breast cancer. Anticancer Res 2018;38:3657–3662.

35.

Braun

Flucke

Debald

, et al. Detection of lymphovascular invasion in early breast cancer by D2–40 (podoplanin): a clinically useful predictor for axillary lymph node metastases. Breast Cancer Res Treat 2008;112:503–511.

36.

Cornwell

McMasters

Chagpar

. The impact of lymphovascular invasion on lymph node status in patients with breast cancer. Am Surg 2011;77:874–877.

37.

Fujii

Yajima

Tatsuki

, et al. Significance of lymphatic invasion combined with size of primary tumor for predicting sentinel lymph node metastasis in patients with breast cancer. Anticancer Res 2015;35:3581–3584.

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