Internal mammary sentinel lymph node biopsy for breast cancer: a long-term follow-up research for assessment of prognosis and guiding individualized internal mammary lymph node irradiation

doi:10.19401/j.cnki.1007-3639.2023.02.007

Abstract

Abstract:

Background and purpose: Internal mammary lymph node irradiation (IMNI) improves survival in patients with internal mammary lymph node (IMLN) high-risk metastatic breast cancer. The purpose of this study was to study the advantages of internal mammary sentinel lymph node (IMLN) biopsy (IM-SLNB) for assessing prognosis and directing individualized IMNI. Methods: This study evaluated patients recruited in three prospective clinical trials (NCT01642511, NCT03541278, and NCT03024463) from November 2011 to December 2021, assessed for prognostic risk variables based on IMSLN metastatic status and prognosis between subgroups. In patients who received regional lymph node irradiation, the implementation status, survival benefit, and influence of IMNI on radiation-induced lung injury (RILI) were studied. The primary endpoint was disease-free survival (DFS), with overall survival (OS) and RILI as secondary endpoints. Results: The study enrolled 537 patients and had a 60-month median follow-up. Patients with IMSLN metastasis had a significantly worse 5-year DFS and OS (DFS: 95.1% vs 71.4%, OS: 99.1% vs 90.1%, both P<0.05), and IMSLN metastatic status was an independent risk factor for DFS and OS (both P<0.05). Adding IMNI did not improve DFS (P = 0.099) or OS (P = 0.486) in patients with negative IMSLN, while it did increase the risk of RILI (OR = 3.678, P<0.05). However, adding IMNI improved 5-year DFS (87.3% vs 52.5%, P = 0.040) for patients with positive IMSLN but had no effect on OS (P = 0.603). Conclusion: This study discovered that IMSLN metastatic status has significant prognostic importance. Patients with IMSLN metastasis who receive IMNI have significantly improved prognosis, and patients without IMSLN metastasis have a much lower risk of RILI by being exempt from IMNI without worse prognosis.

Key words: Breast cancer, Sentinel lymph node biopsy, Internal mammary lymph nodes, Irradiation, Prognosis

CLC Number:

R737.9

CHEN Yuguang, SUN Xiao, BI Zhao, QIU Pengfei, DUAN Baowei, FAN Qingda, WANG Yongsheng. Internal mammary sentinel lymph node biopsy for breast cancer: a long-term follow-up research for assessment of prognosis and guiding individualized internal mammary lymph node irradiation[J]. China Oncology, 2023, 33(2): 142-151.

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References 21

[1]	WHELAN T J, OLIVOTTO I A, PARULEKAR W R, et al. Regional nodal irradiation in early-stage breast cancer[J]. N Engl J Med, 2015, 373(4): 307-316. doi: 10.1056/NEJMoa1415340
[2]	POORTMANS P M, WELTENS C, FORTPIED C, et al. Internal mammary and medial supraclavicular lymph node chain irradiation in stage Ⅰ-Ⅲ breast cancer (EORTC 22922/10925): 15-year results of a randomised, phase 3 trial[J]. Lancet Oncol, 2020, 21(12): 1602-1610. doi: 10.1016/S1470-2045(20)30472-1
[3]	POORTMANS P M, COLLETTE S, KIRKOVE C, et al. Internal mammary and medial supraclavicular irradiation in breast cancer[J]. N Engl J Med, 2015, 373(4): 317-327. doi: 10.1056/NEJMoa1415369
[4]	THORSEN L B J, OVERGAARD J, MATTHIESSEN L W, et al. Internal mammary node irradiation in patients with node-positive early breast cancer: fifteen-year results from the Danish breast cancer group internal mammary node study[J]. J Clin Oncol, 2022, 40(36): 4198-4206. doi: 10.1200/JCO.22.00044
[5]	HENNEQUIN C, BOSSARD N, SERVAGI-VERNAT S, et al. Ten-year survival results of a randomized trial of irradiation of internal mammary nodes after mastectomy[J]. Int J Radiat Oncol Biol Phys, 2013, 86(5): 860-866. doi: 10.1016/j.ijrobp.2013.03.021
[6]	BUDACH W, KAMMERS K, BOELKE E, et al. Adjuvant radiotherapy of regional lymph nodes in breast cancer - a meta-analysis of randomized trials[J]. Radiat Oncol, 2013, 8: 267. doi: 10.1186/1748-717X-8-267 pmid: 24225206
[7]	CONG B B, CAO X S, CAO L, et al. Internal mammary lymph nodes radiotherapy of breast cancer in the era of individualized medicine[J]. Oncotarget, 2017, 8(46): 81583-81590. doi: 10.18632/oncotarget.v8i46
[8]	QIU P F, WANG X E, WANG Y S. Indications for individual internal mammary node irradiation[J]. Lancet Oncol, 2021, 22(2): e40. doi: 10.1016/S1470-2045(20)30739-7
[9]	邱鹏飞, 王永胜. 前哨淋巴结时代乳腺癌的精准区域处理: 演进与展望[J]. 中国癌症杂志, 2022, 32(8): 680-687. doi: 10.19401/j.cnki.1007-3639.2022.08.002
	QIU P F, WANG Y S. Precise regional management of breast cancer in the sentinel lymph node era: evolution and prospect[J]. China Oncol, 2022, 32(8): 680-687.
[10]	QIU P F, LIU J J, LIU Y B, et al. A modified technology could significantly improve the visualization rate of the internal mammary sentinel lymph nodes in breast cancer patients[J]. Breast Cancer Res Treat, 2012, 136(1): 319-321. doi: 10.1007/s10549-012-2203-5
[11]	QIU P F, WANG Y S. ASO author reflections: internal mammary sentinel lymph node biopsy-time for the back of internal mammary staging?[J]. Ann Surg Oncol, 2020, 27(2): 384-385. doi: 10.1245/s10434-019-07838-2
[12]	VERONESI U, CASCINELLI N, BUFALINO R, et al. Risk of internal mammary lymph node metastases and its relevance on prognosis of breast cancer patients[J]. Ann Surg, 1983, 198(6): 681-684. doi: 10.1097/00000658-198312000-00002 pmid: 6639172
[13]	KIM Y B, BYUN H K, KIM D Y, et al. Effect of elective internal mammary node irradiation on disease-free survival in women with node-positive breast cancer: a randomized phase 3 clinical trial[J]. JAMA Oncol, 2022, 8(1): 96-105. doi: 10.1001/jamaoncol.2021.6036
[14]	MATZINGER O, HEIMSOTH I, POORTMANS P, et al. Toxicity at three years with and without irradiation of the internal mammary and medial supraclavicular lymph node chain in stage Ⅰ to Ⅲ breast cancer (EORTC trial 22922/10925)[J]. Acta Oncol, 2010, 49(1): 24-34. doi: 10.3109/02841860903352959
[15]	POORTMANS P M, STRUIKMANS H, DE BROUWER P, et al. Side effects 15 years after lymph node irradiation in breast cancer: randomized EORTC trial 22922/10925[J]. J Natl Cancer Inst, 2021, 113(10): 1360-1368. doi: 10.1093/jnci/djab113
[16]	THORSEN L B, THOMSEN M S, BERG M, et al. CT-planned internal mammary node radiotherapy in the DBCG-IMN study: benefit versus potentially harmful effects[J]. Acta Oncol, 2014, 53(8): 1027-1034. doi: 10.3109/0284186X.2014.925579 pmid: 24957557
[17]	CAO X S, YANG G R, CONG B B, et al. The lymphatic drainage pattern of internal mammary sentinel lymph node identified by small particle radiotracer (^99mTc-dextran 40) in breast[J]. Cancer Res Treat, 2019, 51(2): 483-492. doi: 10.4143/crt.2018.062
[18]	CONG B B, QIU P F, LIU Y B, et al. Validation study for the hypothesis of internal mammary sentinel lymph node lymphatic drainage in breast cancer[J]. Oncotarget, 2016, 7(27): 41996-42006. doi: 10.18632/oncotarget.v7i27
[19]	邱鹏飞. 新型示踪技术引导乳腺癌内乳前哨淋巴结活检术的显像率与适应证研究[D]. 济南: 山东大学, 2020.
[20]	孙晓. 乳腺癌内乳区前哨淋巴结活检术的前瞻性临床验证研究[D]. 济南: 山东大学, 2020.
[21]	WANG Y S, LV Q, ZHU S G, et al. Prospective, multicenter, clinical validation study of the repeatability and accuracy of internal mammary sentinel lymph node biopsy with modified injection technique (CBCSG026/CBCSG027)[C]. 2022 San Antonio Breast Cancer Symposium; San Antonio, TX, Dec 6-10, 2022 (abstr P2-14-06).

Item	Case (n=537)	Percentage/%	Item	Case (n=537)	Percentage/%
Age	48.9±9.0 (27.0-78.0)		Grade
BMI	23.9±3.1 (16.4-39.7)		Ⅰ	9	1.7
Menopausal status			Ⅱ	326	60.7
No	331	61.6	Ⅲ	163	30.3
Yes	206	38.4	N/A	39	7.3
Laterality			No. of ALN positive
Left	305	56.8	0	263	49.0
Right	232	43.2	1-3	173	32.2
Tumor location			4-9	57	10.6
Lateral	282	52.5	≥10	44	8.2
Central/medial	248	46.2	IMSLN
Unknown	7	1.3	Negatvie	440	81.9
Pathological size/cm			Positive	97	18.1
≤2	271	50.4	ER
2-5	243	45.3	Negatvie	133	24.8
>5	23	4.3	Positive	404	75.2
Histological type			PR
Ductal	483	89.9	Negatvie	168	31.3
Lobular	15	2.8	Positive	369	68.7
Mucinous	8	1.5	HER2
Microinfiltration	23	4.3	Negatvie	380	70.8
Other special types	8	1.5	Positive	132	24.6
Lymphatic invasion			N/A	25	4.6
No	465	86.6	Tumor subtype
Yes	72	13.4	HR positive/HER2 negatvie	316	58.8
No. of IMSLN	1.8±0.9 (1-6)		HER2 positive	132	24.6
Surgery type			TNBC	64	11.9
Mastectomy	502	93.5	N/A	25	4.7
Lumpectomy	35	6.5

Variables	DFS				OS
	Univariate Cox analysis		Multivariate Cox analysis		Univariate Cox analysis		Multivariate Cox analysis
	HR (95% CI)	P value	HR (95% CI)	P value	HR (95% CI)	P value	HR (95% CI)	P value
IMSLN (positive vs negative)	5.908 (3.194-10.928)	<0.001	3.652 (1.832-7.281)	<0.001	6.927 (2.783-17.240)	<0.001	3.232 (1.153-9.058)	0.026
Age	0.994 (0.960-1.030)	0.749			1.034 (0.984-1.086)	0.190
Menopausal status (yes vs no)	1.338 (0.721-2.480)	0.356			1.712 (0.694-4.222)	0.243
Tumor location (lateral vs central/medial)	1.622 (0.871-3.020)	0.127			1.993 (0.785-5.063)	0.147
No. of positive ALN	1.121 (1.083-1.160)	<0.001	1.090 (1.045-1.137)	<0.001	1.138 (1.082-1.196)	<0.001	1.100 (1.032-1.173)	0.003
Pathological size (cm)		0.002		0.006		<0.001		0.013
2-5 (vs≤2)	1.484 (0.760-2.899)	0.248	0.769 (0.374-1.577)	0.473	4.430 (1.250-15.700)	0.021	2.597 (0.697-9.673)	0.155
>5 (vs≤2)	5.367 (2.080-13.848)	<0.001	3.571 (1.357-9.395)	0.010	17.214 (3.850-76.970)	<0.001	9.514 (2.023-44.749)	0.004
Histological grade (Ⅲ vs Ⅰ-Ⅱ)	2.270 (1.230-4.189)	0.009	2.367 (1.273-4.400)	0.006	1.129 (0.429-2.973)	0.806
Lymphatic invasion (yes vs no)	1.106 (0.433-2.827)	0.833			1.137 (0.261-4.945)	0.864
ER (ER⁺ vs ER^-)	0.550 (0.291-1.039)	0.065			0.449 (0.180-1.115)	0.085
PR (PR⁺ vs PR^-)	0.668 (0.357-1.252)	0.208			0.575 (0.231-1.429)	0.233
HER2 (HER2⁺ vs HER2^-)	1.171 (0.583-2.353)	0.657			1.072 (0.386-2.979)	0.893
Tumor subtype		0.219				0.209
HER2+ ( vs HR⁺/HER2^-)	1.372 (0.657-2.864)	0.400			1.382 (0.463-4.124)	0.562
TN (vs HR⁺/HER2^-)	2.049 (0.902-4.653)	0.087			2.683 (0.899-8.011)	0.077
Radiotherapy (yes vs no)	1.384 0.731-2.621)	0.319			1.856 (0.686-5.024)	0.223

Item	No IMNI (n=142)	IMNI (n=101)	5-year DFS (IMNI vs no IMNI)	P value	HR (95% CI)
T₁	47	39	91.9% vs 85.5%	0.974	1.026 (0.228-4.617)
T_2-3	95	62	84.7% vs 90.3%	0.225	1.875 (0.680-5.175)
N₁	109	41	100.0% vs 92.7%	0.356	0.029 (0.000-52.000)
N_2-3	29	60	77.4% vs 74.6%	0.672	1.257 (0.435-3.633)
Ⅰ-Ⅱ	100	26	100.0% vs 95.2%	0.539	0.036 (0.000-1 486.000)
Ⅲ	42	75	82.5% vs 74.6%	0.919	0.952 (0.369-2.458)
Lateral	84	43	87.9% vs 90.1%	0.872	1.145 (0.218-6.009)
Central/medial	54	57	83.4% vs 85.8%	0.503	1.423 (0.506-3.998)
IMSLN positive	19	67	87.3% vs 52.5%	0.040	0.286 (0.087-0.943)
IMSLN negative	123	34	84.5% vs 96.5%	0.099	3.269 (0.488-21.890)

RILI	IMSLN^- (n=157)				P value	OR (95% CI)
	No IMNI (n=123)		IMNI (n=34)
	Grade 1-2	Grade 3	Grade 1-2	Grade 3
Acute pneumonitis	7 (5.7%)	0 (0.0%)	3 (8.8%)	0 (0.0%)	0.883	1.465 (0.360-5.960)
Delayed pneumonitis or fibrosis	10 (8.1%)	0 (0.0%)	10 (29.4%)	0 (0.0%)	<0.050	4.708 (1.870-11.840)
Total	17 (13.8%)		13 (38.2%)		<0.050	3.678 (1.604-8.434)
RILI	IMSLN⁺ (n=86)				P value	OR (95% CI)
	No IMNI (n=19)		IMNI (n=67)
	Grade 1-2	Grade 3	Grade 1-2	Grade 3
Acute pneumonitis	0 (0.0%)	0 (0.0%)	8 (11.9%)	0 (0.0%)	0.252	-
Delayed pneumonitis or fibrosis	2 (10.5%)	0 (0.0%)	10 (14.9%)	0 (0.0%)	0.909	1.491 (0.300-7.410)
Total	2 (10.5%)		18(26.8%)		0.234	3.122 (0.700-13.990)