HER2阳性浸润性乳腺癌新辅助治疗反应的预测因子及治疗前后HER2状态变化的评估

doi:10.19401/j.cnki.1007-3639.2022.05.007

中国癌症杂志 ›› 2022, Vol. 32 ›› Issue (5): 417-426.doi: 10.19401/j.cnki.1007-3639.2022.05.007

HER2阳性浸润性乳腺癌新辅助治疗反应的预测因子及治疗前后HER2状态变化的评估

刘建兰¹()(), 陈黛诗², 胡泓³, 周冬仙³, 胡锦涛¹()()

1.深圳市人民医院（暨南大学第二临床医学院,南方科技大学第一附属医院）病理科,广东深圳 518020
2.深圳市人民医院（暨南大学第二临床医学院,南方科技大学第一附属医院）耳鼻咽喉科,广东深圳 518020
3.深圳市人民医院（暨南大学第二临床医学院,南方科技大学第一附属医院）甲乳外科,广东深圳 518020

收稿日期:2021-11-01 修回日期:2022-02-20 出版日期:2022-05-30 发布日期:2022-06-09
通信作者: 胡锦涛 E-mail:liujianlan2013@163.com;huqiuhan@126.com
作者简介:刘建兰（ORCID: 0000-0001-6910-5829）,硕士,主治医师 E-mail: liujianlan2013@163.com
基金资助:
深圳市自然科学基金(JCYJ20190807145415068);国家自然科学基金(31801160)

Predictors of response to neoadjuvant treatment and changes to HER2 status in HER2-positive invasive breast cancer

LIU Jianlan¹()(), CHEN Daishi², HU Hong³, ZHOU Dongxian³, HU Jintao¹()()

1. Department of Pathology, Shenzhen People’s Hospital (The Second Clinical Medical College, Jinan University, The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen 518020, Guangdong Province, China
2. Department of Otorhinolaryngology, Shenzhen People’s Hospital (The Second Clinical Medical College, Jinan University, The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen 518020, Guangdong Province, China
3. Department of Thyroid and Breast Surgery, Shenzhen People’s Hospital (The Second Clinical Medical College, Jinan University, The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen 518020, Guangdong Province, China

Received:2021-11-01 Revised:2022-02-20 Published:2022-05-30 Online:2022-06-09
Contact: HU Jintao E-mail:liujianlan2013@163.com;huqiuhan@126.com

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）阳性浸润性乳腺癌对抗于HER2新辅助治疗的反应显著,然而不同患者的反应并不一致,部分反应较差。本研究旨在探讨HER2阳性乳腺癌新辅助治疗反应的预测因子,并进一步评估新辅助治疗前后HER2状态的不一致性。方法： 收集深圳市人民医院2019—2021年经术前粗针穿刺活检确诊的110例HER2阳性乳腺癌患者,经新辅助治疗后行手术切除。采用免疫组织化学（immunohistochemistry,IHC）及荧光原位杂交（fluorescence in situ hybridization,FISH）检测术前穿刺标本中的HER2表达状态,并评估新辅助治疗后手术切除标本的病理学完全缓解（pathological complete response,pCR）状态及残余肿瘤负荷（residual cancer burden,RCB）分级,评价不同HER2状态对新辅助治疗效果的影响,并进一步比较新辅助治疗前后HER2、雌激素受体（estrogen receptor,ER）及孕激素受体（progesterone receptor,PR）状态的一致性。结果：110例乳腺癌患者根据HER2 IHC表达状态分为弥漫3+组（81例）、异质性3+组（20例）和2+且FISH基因扩增（2+FISH+）组（9例）。HER2弥漫3+组pCR率为54.3%,明显高于异质性3+组（5.0%）和2+FISH+组（11.1%）,差异有统计学意义（P<0.05）,而异质性3+组和2+FISH+组的RCB分级更高。多因素分析显示,HER2弥漫3+是pCR的独立预测因子。7例（11.9%）HER2阳性乳腺癌患者在新辅助治疗后HER2转为阴性,大多数（85.7%）为异质性3+组和2+FISH+组病例。结论： HER2异质性会影响HER2阳性乳腺癌的新辅助治疗反应,评价穿刺活检标本中HER2 IHC异质性,并对新辅助治疗后残留癌灶HER2、ER和PR状态重新评估,有利于指导下一步治疗。新型抗体药物偶联物（antibody-drug conjugate,ADC）的出现有望为HER2异质性阳性乳腺癌患者带来生存获益。

关键词: 人表皮生长因子受体2异质性, 乳腺癌, 新辅助治疗

Abstract:

Background and purpose: The response of human epidermal growth factor receptor 2 (HER2)-positive invasive breast cancer to HER2 targeted neoadjuvant therapy is significant. However, the response is not uniform, and a proportion of patients respond poorly. This study aimed to identify predictors of response in the neoadjuvant treatment and to assess the discordance rate of HER2 status between pre- and post-treatment specimens in HER2-positive breast cancer. Methods: The study group included 110 HER2-positive breast cancer patients treated with neoadjuvant therapy and surgery who were diagnosed from 2019 to 2021 in Shenzhen People’s Hospital. Immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) were used to detect the expression of HER2 in core needle biopsy specimens. Pathological complete response (pCR) and residual cancer burden (RCB) of surgically resected specimens after neoadjuvant therapy were used to assess the therapy response of patients. HER2, estrogen receptor (ER) and progesterone receptor (PR) status were further assessed in the residual invasive carcinoma present after neoadjuvant therapy. Results: One hundred and ten breast cancer patients were divided into IHC diffuse 3+ group (n=81), heterogeneous 3+ group (n=20), IHC 2+ and FISH amplified (2+FISH+) group (n=9). The pCR rate of HER2 diffuse 3+ group was 54.3%, which was significantly higher compared with heterogeneous 3+ group (5.0%) and 2+FISH+ group (11.1%), and the difference was statistically significant (P<0.05). RCB categories were higher in heterogeneous 3+ and 2+FISH+ groups. Multivariate analysis showed that HER2 diffuse 3+ was an independent predictor of pCR. Seven cases (11.9%) became HER2-negative, the majority (85.7%) from heterogeneous 3+ and 2+FISH+ groups. Conclusion: HER2 heterogeneity predicts the neoadjuvant therapy response of HER2-positive breast cancer. Evaluation of the heterogeneity of HER2 IHC in biopsy specimens and repeating HER2, ER and PR testing after neoadjuvant treatment should therefore be considered, which will facilitate further management decisions. The patients with HER2 heterogeneity may potentially benefit from the novel antibody-drug conjugate (ADC).

Key words: Human epidermal growth factor receptor 2 heterogeneity, Breast cancer, Neoadjuvant therapy

中图分类号:

R737.9

刘建兰, 陈黛诗, 胡泓, 周冬仙, 胡锦涛. HER2阳性浸润性乳腺癌新辅助治疗反应的预测因子及治疗前后HER2状态变化的评估[J]. 中国癌症杂志, 2022, 32(5): 417-426.

LIU Jianlan, CHEN Daishi, HU Hong, ZHOU Dongxian, HU Jintao. Predictors of response to neoadjuvant treatment and changes to HER2 status in HER2-positive invasive breast cancer[J]. China Oncology, 2022, 32(5): 417-426.

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参考文献 23

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Characteristic	HER2			χ²	P value
Characteristic	Diffuse 3+	Heterogeneous 3+	2+FISH+	χ²	P value
Age/year				0.226	0.893
≤50	53 (65.4)	12 (60.0)	6 (66.7)
>50	28 (34.6)	8 (40.0)	3 (33.3)
ER				4.628	0.099
Positive	45 (55.6)	14 (70.0)	8 (88.9)
Negative	36 (44.4)	6 (30.0)	1 (11.1)
PR				0.868	0.648
Positive	54 (66.7)	15 (75.0)	7 (77.8)
Negative	27 (33.3)	5 (25.0)	2 (22.2)
Ki-67 proliferation index				4.319	0.115
≥30%	54 (66.7)	18 (90.0)	6 (66.7)
<30%	27 (33.3)	2 (10.0)	3 (33.3)
Tumor size D/cm				3.717	0.446
>5	12 (14.8)	6 (30.0)	1 (11.1)
2-5	59 (72.8)	11 (55.0)	6 (66.7)
≤2	10 (12.3)	3 (15.0)	2 (22.2)
Lymph node metastasis				2.703	0.259
+	41 (50.6)	12 (60.0)	7 (77.8)
-	40 (49.4)	8 (40.0)	2 (22.2)
Histology type				0.361	0.835
NST	80 (98.8)	20 (100.0)	9 (100.0)
ILC	1 (1.2)	0 (0.0)	0 (0.0)
Neoadjuvant treatments				0.192	0.908
Chemotherapy+dual anti-HER2	59 (72.8)	14 (70.0)	6 (66.7)
Chemotherapy+single anti-HER2	22 (27.2)	6 (30.0)	3 (22.2)

Characteristic	RCB			χ²	P value
Characteristic	0	Ⅰ	Ⅱ+Ⅲ	χ²	P value
Age/year				0.753	0.686
≤50	31 (67.4)	15 (68.2)	25 (59.5)
>50	15 (32.6)	7 (31.8)	17 (40.5)
ER				7.74	0.021
Positive	21 (45.7)	16 (72.7)	30 (71.4)
Negative	25 (54.3)	6 (27.3)	12 (28.6)
PR				6.063	0.048
Positive	26 (56.5)	18 (81.8)	32 (76.2)
Negative	20 (43.5)	4 (18.2)	10 (23.8)
Ki-67 proliferation index				1.233	0.540
≥30%	35 (76.1)	14 (63.6)	29 (69.0)
<30%	11 (23.9)	8 (36.4)	13 (31.0)
tumor size D/cm				6.296	0.178
>5	4 (8.7)	4 (18.2)	11 (26.2)
2-5	34 (73.9)	14 (63.6)	28 (66.7)
≤2	8 (17.4)	4 (18.2)	3 (7.1)
Lymph node metastasis				1.484	0.476
+	23 (50.0)	11 (50.0)	26 (61.9)
-	23 (50.0)	11 (50.0)	16 (38.1)
Histology type				1.404	0.496
NST	45 (97.8)	22 (100.0)	42 (100.0)
ILC	1 (2.2)	0 (0.0)	0 (0.0)
Neoadjuvant treatments				0.483	0.786
Chemotherapy+dual anti-HER2	33 (71.7)	17 (77.3)	29 (69.0)
Chemotherapy+single anti-HER2	13 (28.3)	5 (22.7)	13 (28.6)

Parameter	Risk/reference	pCR/non-pCR n/n (%)			Univariant analysis			Multivariant analysis
Parameter	Risk/reference	pCR/non-pCR n/n (%)			OR	95% CI	P value	OR	95% CI	P value
HER2	Diffuse 3+/heterogeneous 3+/2+FISH+	44/37 (54.3)	1/19 (5)	1/8 (11.1)	7.501	2.268-24.802	0.001	6.912	2.048-23.329	0.002
Age/year	>50/≤50	15/24 (38.5)	31/40 (43.7)		0.806	0.363-1.790	0.597	-	-	-
ER	-/+	25/18 (58.1)	21/46 (31.3)		3.042	1.373-6.743	0.006	1.711	0.574-5.100	0.335
PR	-/+	20/14 (58.8)	26/50 (34.2)		2.747	1.196-6.308	0.017	1.784	0.555-5.734	0.331
Ki-67 proliferation index	≥30%/<30%	35/43 (44.9)	11/21 (34.4)		1.554	0.661-3.654	0.312	-	-	-
Tumor size D/mm	>5/≤5	4/15 (21.1)	42/49 (46.2)		0.311	0.096-1.010	0.052	0.371	0.104-1.323	0.126
Lymph node metastasis	-/+	23/27 (46)	23/37 (38.3)		1.370	0.640-2.935	0.417	-	-	-

Parameter	Risk/reference	pCR/non-pCR n/n (%)		Univariant analysis			Multivariant analysis
Parameter	Risk/reference	pCR/non-pCR n/n (%)		OR	95% CI	P value	OR	95% CI	P value
Age/year	>50/≤50	13/15 (46.4)	31/22 (58.5)	0.615	0.245-1.546	0.302	-	-	-
ER	-/+	23/13 (63.9)	21/24 (46.7)	2.022	0.824-4.961	0.124	1.474	0.449-4.840	0.523
PR	-/+	18/9 (66.7)	26/28 (48.1)	2.154	0.823-5.636	0.118	1.457	0.408-5.196	0.562
Ki-67 proliferation index	≥30%/<30%	34/20 (63.0)	10/17 (37.0)	2.890	1.110-7.523	0.03	2.479	0.920-6.676	0.073
Tumor size D/mm	>5/≤5	4/8 (33.3)	40/29 (58.0)	0.363	0.100-1.319	0.124	0.506	0.130-1.963	0.324
Lymph node metastasis	-/+	21/19 (52.5)	23/18 (56.1)	0.865	0.361-2.075	0.865	-	-	-

Pre-treatment	Total	Post-treatment		P value
Pre-treatment	Total	Positive	Negative	P value
HER2				<0.001
Diffuse 3+	34 (57.6)	33 (97.1)	1 (2.9)
Heterogeneous 3+	18 (30.5)	15 (83.3)	3 (16.7)
2+FISH+	7 (11.9)	4 (57.1)	3 (42.9)
ER				>0.05
Positive	43 (71.7)	41 (95.3)	2 (4.7)
Negative	17 (28.3)	2 (11.8)	15 (88.2)
PR				0.267
Positive	46 (78.0)	37 (80.4)	9 (19.6)
Negative	13 (22.0)	4 (30.8)	9 (69.2)

HER2阳性浸润性乳腺癌新辅助治疗反应的预测因子及治疗前后HER2状态变化的评估

Predictors of response to neoadjuvant treatment and changes to HER2 status in HER2-positive invasive breast cancer

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