乳腺癌患者血清HER-2 胞外域水平与癌组织HER-2 表达的相关性及其临床意义

doi:10.3877/cma.j.issn.1674-0807.2016.01.004

目的

探讨乳腺癌患者血清HER-2 胞外域(ECD)水平与癌组织HER-2 表达的相关性及其与临床病理因素的关系。

方法

回顾性分析2013 年8 月至2014 年1 月重庆市肿瘤研究所收治的93 例乳腺癌患者的血清和新鲜癌组织标本,采用化学发光免疫分析法检测患者血清中HER-2 ECD 水平,同时采用免疫组织化学法(IHC)和荧光原位杂交法(FISH)检测癌组织中HER-2 的表达状态,将患者血清HER-2 ECD 水平与癌组织中HER-2 的表达进行对比研究,并采用χ² 检验或Fisher 确切概率检验分析其与临床病理因素的关系,用t 检验比较癌组织HER-2 阳性者与阴性者之间血清HER-2 ECD 的表达水平,用Kappa 检验分析血清学方法与组织学方法检测HER-2 的一致性,用Spearman 等级相关分析肿瘤TNM 分期与血清HER-2 ECD 水平的相关性。

结果

在93 例乳腺癌患者中,癌组织HER-2 阳性者30 例,HER-2 阴性者63 例,并且,癌组织HER-2 阳性者血清HER-2 ECD 水平为(22.18±22.38) ng/ml,明显高于癌组织HER-2 阴性者的(10.19±2.01) ng/ml(t=-4.209,P＜0.001)。 Kappa 一致性检验显示,血清学方法与组织学方法检测HER-2 的一致性较好(Kappa=0.519, P＜0.001)。乳腺癌患者血清HER-2 ECD 水平与远处转移情况(P=0.013)、肿瘤TNM 分期(r=0.213,P=0.042)、ER 及PR 状态(χ²=6.206、11.853,P=0.013、0.001)有关,而与年龄(χ²=0.607,P=0.436)、肿瘤大小(P=0.109)、区域淋巴结状态(P=0.106)、Ki67 及p53 表达(χ²=0.349、0.076,P=0.555、0.782)无关。 ER、PR 阴性者癌组织HER-2 阳性率均高于ER、PR 阳性者(χ²=15.368、24.733,P 均＜0.001)。

结论

乳腺癌患者血清HER-2 ECD 水平与癌组织HER-2 状态相关性较好,可作为组织学检测的一种补充,可为患者提供HER-2 连续动态监测,为乳腺癌的临床管理提供客观的参考信息。

关键词: 乳腺肿瘤, 受体, 表皮生长因子, 化学发光测定法, 免疫测定

Objective

To investigate the correlation between serum level of HER-2 extracellular domain (ECD) and HER-2 expression in tumor tissue of breast cancer patients and their relationship with clinicopathological parameters respectively.

Methods

Totally 93 breast cancer patients in Chongqing Cancer Institute from August 2013 to January 2014 were enrolled in this retrospective study. Those patients' serum and fresh tumor tissue samples were collected. Serum HER-2 ECD levels were measured by chemiluminescence immunoassay. HER-2 expression in tumor tissue was assessed by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH). The results of serum HER-2 ECD levels and HER-2 expression in tumor tissue were compared,and their correlation with clinicopathological parameters was analyzed using χ² test or Fisher's exact probability test. t test was used to compare serum HER-2 ECD levels between HER-2 positive group and HER-2 negative group. The consistency of HER-2 level detected by serological method and histological method was analyzed by Kappa test. The correlation between tumor TNM staging and serum HER-2 ECD level was analyzed by Spearman rank test.

Results

There were 30 patients with HER-2 positive expression and 63 with HER-2 negative in 93 breast cancer patients. The serum HER-2 ECD level in HER-2 positive group was (22.18±22.38) ng/ml, significantly higher than (10.19±2.01) ng/ml in HER-2 negative group (t=-4.209, P＜0.001). As for HER-2 detection, serological method showed a good consistency with histological method (Kappa=0.519, P＜0.001). The serum HER-2 ECD level in breast cancer patients was correlated with distal metastasis (P=0.013), tumor TNM staging (r=0.213,P=0.042), ER and PR status(χ²=6.206,11.853;P=0.013, 0.001), but not related to the patient's age (χ² =0.607,P=0.436),tumor size (P=0.109), regional lymph node status (P=0.106), Ki67 and p53 expression (χ² =0.349,0.076;P= 0.555, 0.782). The positive rate of HER-2 in tumor tissue in ER/PR negative patients was significantly higher than that in ER/PR positive patients (χ² = 15.368, 24.733; all P ＜0.001).

Conclusions

There is a significant correlation between serum HER-2 ECD level and HER-2 status in tumor tissue. The detection of serum HER-2 ECD level could be used as a supplement of histological detection to monitor continuous dynamic changes of HER-2 and provide objective references for clinical management of breast cancer.

Key words: Breast neoplasms, Receptor, epidermal growth factor, Chemiluminescent measurements, Immunoassay

表1 乳腺癌患者血清HER-2 ECD 水平与癌组织HER-2表达的关系 [例(%)]

血清HER-2 ECD	癌组织HER-2		合计
血清HER-2 ECD	阳性	阴性	合计
阳性	14(93.3)	1(6.7)	15(100.0)
阴性	16(20.5)	62(79.5)	78(100.0)
合计	30(32.3)	63(67.7)	93(100.0)

表1 乳腺癌患者血清HER-2 ECD 水平与癌组织HER-2表达的关系 [例(%)]

血清HER-2 ECD	癌组织HER-2		合计
血清HER-2 ECD	阳性	阴性	合计
阳性	14(93.3)	1(6.7)	15(100.0)
阴性	16(20.5)	62(79.5)	78(100.0)
合计	30(32.3)	63(67.7)	93(100.0)

表2 乳腺癌患者临床病理因素与血清HER-2 ECD 水平及癌组织HER-2 表达的关系

临床病理因素	例数	血清HER-2 ECD(例)		χ²值	P值	癌组织HER-2(例)		χ²值	P值
临床病理因素	例数	阳性	阴性	χ²值	P值	阳性	阴性	χ²值	P值
年龄
＜50岁	60	11	49	0.607	0.436^a	22	38	1.504	0.220^a
≥50岁	33	4	29	0.607	0.436^a	8	25	1.504	0.220^a
肿瘤大小
T₁	12	0	12		0.109^b	2	10		0.294^b
T₂	52	7	45			15	37
T₃	19	6	13			9	10
T₄	10	2	8			4	6
区域淋巴结
N₀	39	4	35		0.106^b	12	27		0.733^b
N₁	23	2	21			6	17
N₂	26	8	18			10	16
N₃	5	1	4			2	3
远处转移
无	89	12	77		0.013^b	27	62		0.097^b
有	4^c	3	1		0.013^b	3	1		0.097^b
TNM分期
Ⅰ	10	0	10		0.003^b	2	8		0.242^b
Ⅱ	42	3	39			12	30
Ⅲ	37	9	28			13	24
Ⅳ	4	3	1			3	1
ER
阳性	52	4	48	6.206	0.013^a	8	44	15.368	＜0.001^a
阴性	41	11	30	6.206	0.013^a	22	19	15.368	＜0.001^a
PR
阳性	44	1	43	11.853	0.001^a	3	41	24.733	＜0.001^a
阴性	49	14	35	11.853	0.001^a	27	22	24.733	＜0.001^a
Ki67^d
阳性	69	13	56	0.349	0.555^f	26	43	3.631	0.057^a
阴性	20	2	18	0.349	0.555^f	3	17	3.631	0.057^a
p53^e
阳性	34	5	29	0.076	0.782^a	9	25	0.206	0.650^a
阴性	35	6	29	0.076	0.782^a	11	24	0.206	0.650^a

表2 乳腺癌患者临床病理因素与血清HER-2 ECD 水平及癌组织HER-2 表达的关系

临床病理因素	例数	血清HER-2 ECD(例)		χ²值	P值	癌组织HER-2(例)		χ²值	P值
临床病理因素	例数	阳性	阴性	χ²值	P值	阳性	阴性	χ²值	P值
年龄
＜50岁	60	11	49	0.607	0.436^a	22	38	1.504	0.220^a
≥50岁	33	4	29	0.607	0.436^a	8	25	1.504	0.220^a
肿瘤大小
T₁	12	0	12		0.109^b	2	10		0.294^b
T₂	52	7	45			15	37
T₃	19	6	13			9	10
T₄	10	2	8			4	6
区域淋巴结
N₀	39	4	35		0.106^b	12	27		0.733^b
N₁	23	2	21			6	17
N₂	26	8	18			10	16
N₃	5	1	4			2	3
远处转移
无	89	12	77		0.013^b	27	62		0.097^b
有	4^c	3	1		0.013^b	3	1		0.097^b
TNM分期
Ⅰ	10	0	10		0.003^b	2	8		0.242^b
Ⅱ	42	3	39			12	30
Ⅲ	37	9	28			13	24
Ⅳ	4	3	1			3	1
ER
阳性	52	4	48	6.206	0.013^a	8	44	15.368	＜0.001^a
阴性	41	11	30	6.206	0.013^a	22	19	15.368	＜0.001^a
PR
阳性	44	1	43	11.853	0.001^a	3	41	24.733	＜0.001^a
阴性	49	14	35	11.853	0.001^a	27	22	24.733	＜0.001^a
Ki67^d
阳性	69	13	56	0.349	0.555^f	26	43	3.631	0.057^a
阴性	20	2	18	0.349	0.555^f	3	17	3.631	0.057^a
p53^e
阳性	34	5	29	0.076	0.782^a	9	25	0.206	0.650^a
阴性	35	6	29	0.076	0.782^a	11	24	0.206	0.650^a

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Correlation of serum level of HER-2 extracellular domain with HER-2 expression in tumor tissue of breast cancer patients and clinical significance

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Correlation of serum level of HER-2 extracellular domain with HER-2 expression in tumor tissue of breast cancer patients and clinical significance