HER2低表达乳腺癌新辅助化疗效果及其预后特征：一项单中心回顾性研究

doi:10.19401/j.cnki.1007-3639.2023.07.006

摘要/Abstract

摘要：

背景与目的：人表皮生长因子受体2（human epidermal growth factor receptor 2，HER2）是影响乳腺癌患者预后的主要标志物之一，也是乳腺癌病理学分型最主要的参考因素。本研究旨在探讨HER2低表达（HER2-low）乳腺癌患者的临床病理学特征，以及其在新辅助化疗中与疗效及预后的相关性。方法：回顾性纳入2009—2018年于复旦大学附属肿瘤医院接受新辅助化疗的HER2阴性乳腺癌患者的临床病理学相关信息，并将患者区分为HER2-low及无表达（HER2-0）组，分析其特征差异，采用单因素和多因素分析评估新辅助化疗后达病理学完全缓解（pathological complete response，pCR）的独立影响因素，采用Kaplan-Meier曲线评估不同HER2表达组的预后差异。结果：入组的772例患者中激素受体（hormonal receptor，HR）阳性患者的HER2-low比例显著高于HR阴性患者。Logistic回归模型多因素分析结果显示，肿瘤大小（P<0.001）、HR（P = 0.026）及HER2表达（P = 0.018）是pCR的独立预测因素。亚组分析提示，在三阴性乳腺癌（triple-negative breast cancer，TNBC）中，HER2-0与HER2-low的pCR率差异无统计学意义（P = 0.598）；而在Luminal型乳腺癌中，HER2-low患者pCR率为9.4%，显著低于HER2-0的19.3%（P = 0.003）。在非pCR（non-pCR）患者的生存分析中，HER2-low患者的预后显著优于HER2-0患者（P<0.001），其5年生存率达72.2%，而HER2-0仅为56.0%。结论：HER2蛋白表达不同的HER2阴性患者具有不同的临床病理学特征，并与患者的化疗敏感性及预后有关。

关键词: 人表皮生长因子受体2, 乳腺癌, 新辅助治疗, 病理学完全缓解, 预后

Abstract:

Background and purpose: Human epidermal growth factor receptor 2 (HER2) is one of the main markers affecting the prognosis of breast cancer patients and the most important reference factor for the pathological classification of breast cancer. This study aimed to investigate the clinicopathological features of breast cancer with low expression of HER2 and its correlation with therapeutic effect and prognosis in neoadjuvant chemotherapy. Methods: The patients with HER2-negative breast cancer who received neoadjuvant chemotherapy in Fudan University Shanghai Cancer Center from 2009 to 2018 were retrospectively included. Clinicopathological information was collected, and the patients were divided into groups with low expression of HER2 (HER2-low) and no expression of HER2 (HER2-0), and their characteristic differences were analyzed. The independent influencing factors of pathological complete response (pCR) after neoadjuvant chemotherapy were evaluated by univariate and multifactorial methods, and the prognostic differences among different HER2 expression groups were evaluated by Kaplan-Meier curve. Results: In the 772 patients enrolled in this study, the proportion of HER2-low was significantly higher in hormonal receptor (HR) positive patients than in HR negative patients. Multivariate analysis of logistic regression model showed that tumor size (P<0.001), HR (P = 0.026) and HER2 expression (P = 0.018) were independent predictors of pCR. Subgroup analysis indicated that there was no significant difference in pCR rates between HER2-0 and HER2-low triple-negative breast cancer (TNBC) (P = 0.598). In Luminal breast cancer, the pCR rate of HER2-low patients was 9.4%, which was significantly lower compared with HER2-0 patients (19.3%, P = 0.003). In the survival analysis of non-pCR patients, the prognosis of HER2-low patients was significantly better compared with HER2-0 patients (P<0.001), and the 5-year survival rate was 72.2%, while the 5-year survival rate of HER2-0 patients was only 56.0%. Conclusion: HER2-negative patients with different expressions of HER2 protein have different clinicopathological characteristics, which are related to the chemotherapy sensitivity and prognosis of patients.

Key words: Human epidermal growth factor receptor 2, Breast cancer, Neoadjuvant chemotherapy, Pathological complete response, Prognosis

中图分类号:

R737.9

王若曦, 吉芃, 龚悦, 陈盛. HER2低表达乳腺癌新辅助化疗效果及其预后特征：一项单中心回顾性研究[J]. 中国癌症杂志, 2023, 33(7): 686-692.

WANG Ruoxi, JI Peng, GONG Yue, CHEN Sheng. Response rate and clinical outcome of HER2-low breast cancer after neoadjuvant therapy: a single-center retrospective study[J]. China Oncology, 2023, 33(7): 686-692.

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参考文献 21

[1]	CHOONG G M, CULLEN G D, O'SULLIVAN C C. Evolving standards of care and new challenges in the management of HER2-positive breast cancer[J]. CA Cancer J Clin, 2020, 70(5): 355-374. doi: 10.3322/caac.v70.5
[2]	WOLFF A C, HAMMOND M E H, ALLISON K H, 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]. J Clin Oncol, 2018, 36(20): 2105-2122. doi: 10.1200/JCO.2018.77.8738 pmid: 29846122
[3]	KROP I E, LORUSSO P, MILLER K D, et al. A phase Ⅱ study of trastuzumab emtansine in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer who were previously treated with trastuzumab, lapatinib, an anthracycline, a taxane, and capecitabine[J]. J Clin Oncol, 2012, 30(26): 3234-3241. doi: 10.1200/JCO.2011.40.5902
[4]	BASELGA J, LEWIS PHILLIPS G D, VERMA S, et al. Relationship between tumor biomarkers and efficacy in EMILIA, a phase Ⅲ study of trastuzumab emtansine in HER2-positive metastatic breast cancer[J]. Clin Cancer Res, 2016, 22(15): 3755-3763. doi: 10.1158/1078-0432.CCR-15-2499
[5]	KIM S B, WILDIERS H, KROP I E, et al. Relationship between tumor biomarkers and efficacy in TH3RESA, a phase Ⅲ study of trastuzumab emtansine (T-DM1) vs treatment of physician’s choice in previously treated HER2-positive advanced breast cancer[J]. Int J Cancer, 2016, 139(10): 2336-2342. doi: 10.1002/ijc.v139.10
[6]	LEE C K, DAVIES L, GEBSKI V J, et al. Serum human epidermal growth factor 2 extracellular domain as a predictive biomarker for lapatinib treatment efficacy in patients with advanced breast cancer[J]. J Clin Oncol, 2016, 34(9): 936-944. doi: 10.1200/JCO.2015.62.4767 pmid: 26811533
[7]	MODI S N, JACOT W, YAMASHITA T, et al. Trastuzumab deruxtecan in previously treated HER2-low advanced breast cancer[J]. N Engl J Med, 2022, 387(1): 9-20. doi: 10.1056/NEJMoa2203690
[8]	HORTOBAGYI G N. Comprehensive management of locally advanced breast cancer[J]. Cancer, 1990, 66(6 Suppl): 1387-1391. doi: 10.1002/1097-0142(19900915)66:14+<1387::aid-cncr2820661414>3.0.co;2-i pmid: 2205369
[9]	SCHWARTZ G F, HORTOBAGYI G N. Proceedings of the consensus conference on neoadjuvant chemotherapy in carcinoma of the breast, April 26-28, 2003, Philadelphia, Pennsylvania[J]. Cancer, 2004, 100(12): 2512-2532. doi: 10.1002/cncr.20298 pmid: 15197792
[10]	Expert group of expert consensus on neoadjuvant treatment of breast cancer in China edition. Expert consensus on neoadjuvant treatment of breast cancer in China (2021 edition)[J]. China Oncol, 2022, 32(1): 80-89.
[11]	《中国乳腺癌新辅助治疗专家共识2022年版》专家组. 中国乳腺癌新辅助治疗专家共识(2022年版)[J]. 中国癌症杂志, 2022, 32(1): 80-89. doi: 10.19401/j.cnki.1007-3639.2022.01.011
	Expert group of expert consensus on neoadjuvant treatment of breast cancer in China (2022 edition). Expert consensus on neoadjuvant treatment of breast cancer in China (2022 edition)[J]. China Oncol, 2022, 32(1): 80-89.
[12]	MODI S N, SAURA C, YAMASHITA T, et al. Trastuzumab deruxtecan in previously treated HER2-positive breast cancer[J]. N Engl J Med, 2020, 382(7): 610-621. doi: 10.1056/NEJMoa1914510
[13]	TAKEGAWA N, TSURUTANI J, KAWAKAMI H, et al. Fam-] trastuzumab deruxtecan, antitumor activity is dependent on HER2 expression level rather than on HER2 amplification[J]. Int J Cancer, 2019, 145(12): 3414-3424. doi: 10.1002/ijc.v145.12
[14]	PRAT A, BARDIA A, CURIGLIANO G, et al. An overview of clinical development of agents for metastatic or advanced breast cancer without ERBB2 amplification (HER2-low)[J]. JAMA Oncol, 2022. [Online ahead of print].
[15]	DENKERT C, SEITHER F, SCHNEEWEISS A, et al. Clinical and molecular characteristics of HER2-low-positive breast cancer: pooled analysis of individual patient data from four prospective, neoadjuvant clinical trials[J]. Lancet Oncol, 2021, 22(8): 1151-1161. doi: 10.1016/S1470-2045(21)00301-6 pmid: 34252375
[16]	易巧, 左怀全. HER2低表达乳腺癌的临床病理学特征及其新辅助化疗疗效的相关影响因素分析[J]. 中国普外基础与临床杂志, 2022, 29(9): 1213-1219.
	YI Q, ZUO H Q. Clinicopathological features of breast cancer with low HER2 expression and analysis of factors related to the efficacy of neoadjuvant chemotherapy[J]. Chin J Bases Clin Gen Surg, 2022, 29(9): 1213-1219.
[17]	SCHETTINI F, CHIC N, BRASÓ-MARISTANY F, et al. Clinical, pathological, and PAM50 gene expression features of HER2-low breast cancer[J]. NPJ Breast Cancer, 2021, 7(1): 1. doi: 10.1038/s41523-020-00208-2 pmid: 33397968
[18]	HU X E, YANG P, CHEN S H, et al. Clinical and biological heterogeneities in triple-negative breast cancer reveals a non-negligible role of HER2-low[J]. Breast Cancer Res, 2023, 25(1): 34. doi: 10.1186/s13058-023-01639-y pmid: 36998014
[19]	MODI S, PARK H, MURTHY R K, et al. Antitumor activity and safety of trastuzumab deruxtecan in patients with HER2-low-expressing advanced breast cancer: results from a phase Ⅰb study[J]. J Clin Oncol, 2020, 38(17): 1887-1896. doi: 10.1200/JCO.19.02318
[20]	FERNANDEZ A I, LIU M, BELLIZZI A, et al. Examination of low ERBB2 protein expression in breast cancer tissue[J]. JAMA Oncol, 2022, 8(4): 1-4. doi: 10.1001/jamaoncol.2021.7239 pmid: 35113160
[21]	TARANTINO P, HAMILTON E, TOLANEY S M, et al. HER2-low breast cancer: pathological and clinical landscape[J]. J Clin Oncol, 2020, 38(17): 1951-1962. doi: 10.1200/JCO.19.02488 pmid: 32330069

Clinicopathological feature	Case			P value
Clinicopathological feature	HER2-0 (N=430)	HER2-low (N=342)	Total	P value
Age/year				0.377
<40	74 (17.2)	68 (19.9)	142 (18.4)
40-59	296 (68.8)	236 (69.0)	532 (68.9)
≥60	60 (14.0)	38 (11.1)	98 (12.7)
Menstrual state				0.666
Premenopausal	260 (60.5)	212 (62.0)	472 (61.1)
Postmenopausal	170 (39.5)	130 (38.0)	300 (38.9)
T stage				<0.001
T₂	164 (38.1)	118 (34.5)	282 (36.5)
T₃	180 (41.9)	188 (55.0)	368 (47.7)
T₄	86 (20.0)	36 (10.5)	122 (15.8)
Lymph node status				0.934
-	102 (23.7)	82 (24.0)	184 (23.8)
+	328 (76.3)	260 (76.0)	588 (76.2)
HR				<0.001
-	130 (30.2)	150 (43.9)	280 (36.3)
+	300 (69.8)	192 (56.1)	492 (63.7)
Ki-67 proliferation index				0.016
<20%	128 (29.8)	130 (38.0)	258 (33.4)
≥20%	302 (70.2)	212 (62.0)	514 (66.6)

Clinicopathological feature	Case (N=772) n	pCR n (%)	Univariate P value	Multifactorial P value	OR (95% CI)
Age/year			0.891	0.832	-
<40	142	24 (16.9)
40-59	532	96 (18.0)
≥60	98	16 (16.3)
Menstrual state			0.184	0.375
Premenopausal	472	90 (19.1)
Postmenopausal	300	46 (15.3)
T stage			<0.001	<0.001
T₂	282	70 (24.8)			Reference
T₃	368	56 (15.2)			0.543 (0.363-0.812)
T₄	122	10 (8.2)			0.274 (0.135-0.558)
Lymph node status			0.592	0.791
-	132	30 (16.3)
+	640	106 (18.0)
HR			0.036	0.026
-	280	60 (21.4)			Reference
+	492	76 (15.4)			0.638 (0.429-0.949)
Ki-67 proliferation index			0.190	0.307
<20%	258	52 (20.2)			Reference
≥20%	514	84 (16.3)			2.618 (1.456-4.707)
HER2 expression			0.044	0.018
0	430	88 (20.5)			Reference
1+	206	32 (15.5)			0.640 (0.405-1.010)
2+	136	16 (11.8)			0.474 (0.262-0.859)