乳腺癌新辅助化疗后雌、孕激素受体表达变化的临床意义

doi:10.3877/cma.j.issn.1674-0807.2021.06.003

目的

探讨乳腺癌患者新辅助化疗(NAC)前后ER、PR表达变化与NAC疗效之间的关系。

方法

回顾性分析从2015年1月到2017年6月在解放军总医院第五医学中心行蒽环类联合紫杉类NAC后肿瘤未达到pCR的127例HER-2阴性浸润性乳腺癌患者的临床资料。通过免疫组织化学方法测定NAC前后肿瘤组织中ER、PR的表达。分别按照核染色比例≥1%、>10%和>20%来定义ER、PR阳性，判断NAC前后ER和PR的表达状态，两者完全一致为一致组，否则为差异组。用χ²检验或秩和检验比较一致组和差异组的临床病理特征，t检验或秩和检验比较2组的肿瘤缓解率。进一步分析差异组中ER、PR的变化状态，分为ER阴转阳、ER阳转阴、PR阴转阳和PR阳转阴4个亚组，采用方差分析对3种标准下4个亚组的肿瘤缓解率进行比较。

结果

以1%为界值，一致组与差异组患者的临床病理特征比较，差异无统计学意义(P均>0.050)。以10%为界值，2组在PR表达上差异有统计学意义(χ²＝4.757，P＝0.029)。以20%为界值，差异组中腋窝淋巴结转移、ER、PR阳性及三阴性乳腺癌的比例更高(χ²＝5.572、8.683、11.724、4.686，P＝0.018、0.003、0.001、0.030)。以1%为界值，一致组和差异组的肿瘤缓解率分别为(35.9±26.8)%、(46.8±23.8)%，差异有统计学意义(t＝2.190, P＝0.032)。以10%及20%为界值，一致组和差异组的肿瘤缓解率比较，差异无统计学意义[M(P₂₅，P₇₅)：37.3(21.4，53.6)%比38.5(26.8，54.7)%, Z＝0.446, P＝0.656; 39.1(22.7，55.1)%比39.5(27.3, 56.9)%, Z＝0.548, P＝0.584]。在核染色比例≥1%、>10%和>20% 3种标准下，4个亚组肿瘤缓解率比较，差异均无统计学意义(F＝1.380、1.890、1.970，P＝0.266、0.146、0.131)。

结论

当ER、PR以核染色比例≥1%为阳性标准时，NAC后ER或者PR状态变化的乳腺癌患者有望获得更高的肿瘤缓解率。NAC后ER、PR状态的不同变化并不会对NAC的疗效产生影响。

关键词: 乳腺肿瘤, 新辅助治疗, 雌激素受体, 孕激素受体

Objective

To explore the relationship between the expression changes of estrogen receptor (ER)/progesterone receptor (PR) before and after neoadjuvant chemotherapy (NAC) and the efficacy of NAC in breast cancer patients.

Methods

The clinical data of 127 patients with HER-2-negative invasive breast cancer who had not achieved pCR after NAC (anthracycline and docetaxel-based regimen) in the Department of Pathology, Fifth Medical Center, General Hospital of PLA from January 2015 to June 2017 were retrospectively analyzed. ER and PR expressions in tumor tissues before and after NAC were determined by immunohistochemistry. ER/PR was regarded as positive if nuclear staining percentage ≥1%, > 10% or > 20%, respectively. The patients with different ER/PR expression status before and after NAC were in Group A, and others were in Group B. The χ² test or rank sum test was used to compare the clinicopathological characteristics between two groups. The t test or rank sum test was used to compare the tumor remission rates between two groups. According to the different change of ER and PR after NAC, Group A was divided into 4 subgroups: ER negative to positive subgroup, ER positive to negative subgroup, PR negative to positive subgroup and PR positive to negative subgroup. Analysis of variance was used to compare the tumor remission rates among 4 subgroups under the three positive expression standards.

Results

With nuclear staining percentage ≥1% as the positive standard, there was no statistically significant difference in clinicopathological characteristics between two groups (all P>0.050). With nuclear staining percentage >10% as the positive standard, PR expression showed a significant difference between two groups (χ²=4.757, P=0.029). With nuclear staining percentage >20% as the positive standard, Group A had higher rates of axillary lymph node metastasis, ER positive, PR positive and triple negative breast cancer compared with Group B (χ²=5.572, 8.683, 11.724, 4.686; P=0.018, 0.003, 0.001, 0.030). With nuclear staining percentage ≥1% as the positive standard, the tumor remission rate was (46.8±23.8)% in Group A, (35.9±26.8)% in Group B, indicating a significant difference (t=2.190, P=0.032). With nuclear staining percentage >10% or >20% as the positive standard, the tumor remission rate showed no significant difference between Group A and Group B[M(P₂₅, P₇₅): 38.5(26.8, 54.7)% vs 37.3(21.4, 53.6)%, Z=0.446, P=0.656; 39.5(27.3, 56.9)% vs 39.1(22.7, 55.1)%, Z=0.548, P=0.584]. Under the three positive expression standards (≥1%, >10% and >20%), there was no significant difference in tumor remission rate among four subgroups (F=1.380, 1.890, 1.970; P=0.266, 0.146, 0.131).

Conclusions

With nuclear staining percentage≥10% as the positive standard, the change of ER/PR status after NAC may indicate a higher tumor remission rate. The different changes of ER/PR status after NAC have no impact on the efficacy of NAC.

Key words: Breast neoplasms, Neoadjuvant therapy, Receptors, estrogen, Receptors, progesterone

图1 雌激素受体阳性乳腺癌组织的免疫组织化学染色图(EnVision　×100)　a~c图分别所示雌激素受体1%阳性、 10%阳性、 20%阳性

图2 孕激素受体阳性乳腺癌组织的免疫组织化学染色图(EnVision　×100)　a~c图分别所示孕激素受体1%阳性、 10%阳性、 20%阳性

表1 在不同阳性判定标准下新辅助化疗前后ER、PR表达一致组与差异组乳腺癌患者的临床特征比较

临床病理特征		≥1%				>10%				>20%
临床病理特征		一致组(n＝91)	差异组(n＝36)	检验值	P值	一致组(n＝86)	差异组(n＝41)	检验值	P值	一致组(n＝80)	差异组(n＝47)	检验值	P值
年龄
	≤50岁	56	26	χ²＝1.287	0.257	54	28	χ²＝0.367	0.544	53	29	χ²＝0.268	0.605
	>50岁	35	10	χ²＝1.287	0.257	32	13	χ²＝0.367	0.544	27	18	χ²＝0.268	0.605
绝经
	是	31	12	χ²＝0.006	0.937	28	15	χ²＝0.201	0.654	24	19	χ²＝1.437	0.231
	否	60	24	χ²＝0.006	0.937	58	26	χ²＝0.201	0.654	56	28	χ²＝1.437	0.231
肿瘤大小
	T₁	18	6	Z＝0.670	0.503	15	9	Z＝-0.571	0.568	16	8	Z＝0.590	0.556
	T₂	62	24			59	27			54	32
	T₃	7	4			8	3			8	3
	T₄	4	2			4	2			2	4
腋窝淋巴结转移
	阴性	16	5	χ²＝0.255	0.614	18	3	χ²＝3.728	0.054	18	3	χ²＝5.572	0.018
	阳性	75	31	χ²＝0.255	0.614	68	38	χ²＝3.728	0.054	62	44	χ²＝5.572	0.018
ER
	阴性	21	12	χ²＝1.411	0.235	31	9	χ²＝2.557	0.110	34	8	χ²＝8.683	0.003
	阳性	70	24	χ²＝1.411	0.235	55	32	χ²＝2.557	0.110	46	39	χ²＝8.683	0.003
PR
	阴性	29	18	χ²＝3.638	0.057	45	13	χ²＝4.757	0.029	49	14	χ²＝11.724	0.001
	阳性	62	18	χ²＝3.638	0.057	41	28	χ²＝4.757	0.029	31	33	χ²＝11.724	0.001
Ki-67
	<14%	22	9	χ²＝0.010	0.922	24	7	χ²＝1.766	0.184	19	12	χ²＝0.051	0.821
	≥14%	69	27	χ²＝0.010	0.922	62	34	χ²＝1.766	0.184	61	35	χ²＝0.051	0.821
分子分型
	非三阴性	71	27	χ²＝0.134	0.715	59	32	χ²＝1.219	0.270	50	38	χ²＝4.686	0.030
	三阴性	20	9	χ²＝0.134	0.715	27	9	χ²＝1.219	0.270	30	9	χ²＝4.686	0.030

表1 在不同阳性判定标准下新辅助化疗前后ER、PR表达一致组与差异组乳腺癌患者的临床特征比较

临床病理特征		≥1%				>10%				>20%
临床病理特征		一致组(n＝91)	差异组(n＝36)	检验值	P值	一致组(n＝86)	差异组(n＝41)	检验值	P值	一致组(n＝80)	差异组(n＝47)	检验值	P值
年龄
	≤50岁	56	26	χ²＝1.287	0.257	54	28	χ²＝0.367	0.544	53	29	χ²＝0.268	0.605
	>50岁	35	10	χ²＝1.287	0.257	32	13	χ²＝0.367	0.544	27	18	χ²＝0.268	0.605
绝经
	是	31	12	χ²＝0.006	0.937	28	15	χ²＝0.201	0.654	24	19	χ²＝1.437	0.231
	否	60	24	χ²＝0.006	0.937	58	26	χ²＝0.201	0.654	56	28	χ²＝1.437	0.231
肿瘤大小
	T₁	18	6	Z＝0.670	0.503	15	9	Z＝-0.571	0.568	16	8	Z＝0.590	0.556
	T₂	62	24			59	27			54	32
	T₃	7	4			8	3			8	3
	T₄	4	2			4	2			2	4
腋窝淋巴结转移
	阴性	16	5	χ²＝0.255	0.614	18	3	χ²＝3.728	0.054	18	3	χ²＝5.572	0.018
	阳性	75	31	χ²＝0.255	0.614	68	38	χ²＝3.728	0.054	62	44	χ²＝5.572	0.018
ER
	阴性	21	12	χ²＝1.411	0.235	31	9	χ²＝2.557	0.110	34	8	χ²＝8.683	0.003
	阳性	70	24	χ²＝1.411	0.235	55	32	χ²＝2.557	0.110	46	39	χ²＝8.683	0.003
PR
	阴性	29	18	χ²＝3.638	0.057	45	13	χ²＝4.757	0.029	49	14	χ²＝11.724	0.001
	阳性	62	18	χ²＝3.638	0.057	41	28	χ²＝4.757	0.029	31	33	χ²＝11.724	0.001
Ki-67
	<14%	22	9	χ²＝0.010	0.922	24	7	χ²＝1.766	0.184	19	12	χ²＝0.051	0.821
	≥14%	69	27	χ²＝0.010	0.922	62	34	χ²＝1.766	0.184	61	35	χ²＝0.051	0.821
分子分型
	非三阴性	71	27	χ²＝0.134	0.715	59	32	χ²＝1.219	0.270	50	38	χ²＝4.686	0.030
	三阴性	20	9	χ²＝0.134	0.715	27	9	χ²＝1.219	0.270	30	9	χ²＝4.686	0.030

表2 在不同阳性判定标准下新辅助化疗前后雌/孕激素受体表达一致组与差异组乳腺癌患者的肿瘤缓解率比较

标准及组别		例数	肿瘤缓解率(%)	检验值	P值
≥1%
	一致组	91	35.9±26.8^a	t＝2.190	0.032
	差异组	36	46.8±23.8^a
>10%
	一致组	86	37.3(21.4，53.6)^b
	差异组	41	38.5(26.8，54.7)^b	Z＝0.446^a	0.656^a
>20%
	一致组	80	39.1(22.7，55.1)^b
	差异组	47	39.5(27.3，56.9)^b	Z＝0.548^a	0.584^a

表2 在不同阳性判定标准下新辅助化疗前后雌/孕激素受体表达一致组与差异组乳腺癌患者的肿瘤缓解率比较

标准及组别		例数	肿瘤缓解率(%)	检验值	P值
≥1%
	一致组	91	35.9±26.8^a	t＝2.190	0.032
	差异组	36	46.8±23.8^a
>10%
	一致组	86	37.3(21.4，53.6)^b
	差异组	41	38.5(26.8，54.7)^b	Z＝0.446^a	0.656^a
>20%
	一致组	80	39.1(22.7，55.1)^b
	差异组	47	39.5(27.3，56.9)^b	Z＝0.548^a	0.584^a

表3 在不同阳性判定标准下新辅助化疗前后ER/PR表达变化的乳腺癌患者肿瘤缓解率比较(±s)

变化方式	≥1%		>10%		>20%
变化方式	例数	缓解率(%)	例数	缓解率(%)	例数	缓解率(%)
ER阴转阳	7	36.4±27.7	7	30.9±32.4	6	28.5±34.9
ER阳转阴	6	54.3±10.4	5	30.8±23.2	7	25.0±21.7
PR阴转阳	9	58.1±22.9	11	53.2±23.3	13	48.0±25.7
PR阳转阴	14	45.7±24.0	18	40.2±18.3	21	42.8±20.4
F值		1.380		1.890		1.970
P值		0.266		0.146		0.131

表3 在不同阳性判定标准下新辅助化疗前后ER/PR表达变化的乳腺癌患者肿瘤缓解率比较(±s)

变化方式	≥1%		>10%		>20%
变化方式	例数	缓解率(%)	例数	缓解率(%)	例数	缓解率(%)
ER阴转阳	7	36.4±27.7	7	30.9±32.4	6	28.5±34.9
ER阳转阴	6	54.3±10.4	5	30.8±23.2	7	25.0±21.7
PR阴转阳	9	58.1±22.9	11	53.2±23.3	13	48.0±25.7
PR阳转阴	14	45.7±24.0	18	40.2±18.3	21	42.8±20.4
F值		1.380		1.890		1.970
P值		0.266		0.146		0.131

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Clinical significance of estrogen receptor/progesterone receptor expression changes in breast cancer patients after neoadjuvant chemotherapy

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Clinical significance of estrogen receptor/progesterone receptor expression changes in breast cancer patients after neoadjuvant chemotherapy