三阴型乳腺癌临床病理和生物学特征及预后因素探讨
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摘要
目的:探讨三阴型乳腺癌(triple negative breast cancer,TNBC)的临床病理特征以及预后影响因素,进一步分析表皮生长因子受体(epidermal growth factorreceptor,EGFR)、上皮性钙粘附蛋白(epithelial cadherin,E-cadherin)、雄激素受体(androgen receptor,AR)在TNBC和非三阴型乳腺癌(non-TNBC)表达及临床意义。
方法:根据免疫组化指标ER、PR和Her-2的表达情况,将509例乳腺癌分为TNBC和non-TNBC,比较两组乳腺癌的临床病理特征,分析两组乳腺癌的5年无瘤生存率(disease free survival,DFS)以及影响预后临床病理因素。选取TNBC和non-TNBC各50例,免疫组化法检测EGFR、E-cadherin、AR的表达,并分析与临床因素和预后的关系。
结果:
509例乳腺癌中,TNBC占21.4%(109/509),其组织学类型以浸润性导管癌为主,髓样癌的比例高于non-TNBC,组织学Ⅲ级的比例高于non-TNBC(P＜0.05)。其他临床病理特征的比较中两组乳腺癌差异无统计学意义(P＞0.05)。TNBC中复发和远处转移率高于non-TNBC(P＜0.05),5年DFS低于non-TNBC(Log rank=4.661,P=0.031)。单因素分析显示影响TNBC预后的因素为肿瘤直径(P=0.000)、TNM分期(P=0.000)、淋巴结状态(P=0.000);而年龄、绝经状态、组织学分级、家族史等因素对患者预后的影响无统计学意义(P＞0.05)。Cox多因素分析显示,淋巴结状态(HR=2.999,95%CI:2.061～4.358,P=0.000)是独立的预后影响因素。
在100例乳腺癌中,EGFR阳性率、E-cadherin异常表达率和AR阳性率分别为44%(44/100)、62%(62/100)、49%(49/100)。腋淋巴结阳性组中EGFR阳性率和E-cadherin异常表达率高于腋淋巴结阴性组,AR阳性率低于腋淋巴结阴性组,差异有统计学意义(P＜0.05)。三个分子标记物的表达与年龄、绝经状态、临床分期、肿瘤大小等因素无相关性(P＞0.05)。复发转移组中EGFR的阳性率和E-cadherin的异常表达率高于无复发转移组,AR的阳性率低于无复发转移组,差异有统计学意义(P＜0.05)。EGFR阳性组的5年DFS低于EGFR阴性组(P＜0.05);E-cadherin正常表达组和AR阳性组的5年DFS分别高于E-cadherin异常表达组和AR阴性组(P＜0.05)。
TNBC中EGFR阳性率和E-cadherin异常表达率高于non-TNBC,AR阳性率低于non-TNBC(P＜0.05)。TNBC中腋淋巴结阳性组的EGFR阳性率和E-cadherin异常表达率高于腋淋巴结阴性组,AR阳性率低于腋淋巴结阴性组,差异有统计学意义(P＜0.05)。复发转移组的EGFR阳性率高于无复发转移组(P＜0.05),EGFR阳性组DFS低于EGFR阴性组(P＜0.05),而E-cadherin、AR的表达与复发转移和预后无相关性(P＞0.05)。
结论:
TNBC是一组特殊的乳腺癌亚型,病理组织学类型以浸润性导管癌为主,髓样癌的比例和组织学Ⅲ级的比例高于non-TNBC。发生局部复发和远处转移的几率较大,预后差。肿瘤直径、TNM分期和淋巴结状态是影响预后的重要因素,其中淋巴结状态是独立的预后影响因素。
在TNBC中,EGFR的表达与腋淋巴结转移、复发转移以及预后差呈正相关,E-cadherin的异常表达与腋淋巴结转移呈正相关,AR的表达与腋淋巴结转移呈负相关,E-cadherin和AR的表达与复发转移和预后无相关。EGFR可以用于评价TNBC的预后,并且作为TNBC治疗的分子靶点。
Objective: To analyze clinical and pathological features and to observe prognostic factors in triple negative breast cancer (TNBC) . Furthermore, to investigate the expression of EGFR、E-cadherin and AR in TNBC and non-TNBC and to evaluate its significance.
Methods: Based on ER, PR and Her-2 status determined using immunohistochemistry, 509 cases of breast cancer were grouped as TNBC and non-TNBC. Clinicopathologic features between two groups were compared. 5-year disease-free survival (DFS) was analyzed by Kaplan-Meier Method. Univariate regression and Cox multivariate regression were preformed to analyze association between prognosis and cliniopathologic features. 50 cases from each group were collected. Expression of EGFR, E-cadherin and AR by immunohistochemistry and its significance was analyzed.
Results:
21.4% of cases (109/509) were TNBC and the majority of pathologic type was infiltrative ductal carcinoma. TNBC had higher incidence rates than non-TNBC in medullarly type and grade III tumor (P<0.05) . No significance was found in other clinicopatholgic feature between two groups. The rate of local recurrence or distant metastasis in TNBC was higher than non-TNBC (P < 0.05) . 5-year DFS in TNBC was lower than in non-TNBC(Log rank=4.661, P=0.031) . Univariate regression analysis suggested that tumor size (P=0.000), TNM stage (P=0.000) , and lymph nodes status (P=0.000) were prognostic factors in TNBC (P=0.000). Age (≥50 or < 50)、menopausal status、histological grade、family history were not significant prognostic factors. Cox multivariate analysis demonstrated that the status of lymph nodes was an independent prognostic factor (HR= 2.999, 95% CI: 2.061～4.358, P=0.000) .
The positive rates of EGFR and AR in 100 case of breast cancer were 44% (44/100) and 49 %(49/100) respectively. The aberrant expression of E-cadherin was 62 %(62/100). In positive axillary lymph nodes group, EGFR positivity and aberrant expression of E-cadherin were higher than that in negative lymph nodes group, while AR positivity was lower than that in negative lymph nodes group. The expression ofthree biomarkers were not associated with age, menopausal status, TNM stage andtumor size (P>0.05) . In recurrence or metastasis group, EGFR positivity andaberrant expression of E-cadherin were higher than in non- recurrence or metastasisgroup, while AR positivity was lower than that in non- recurrence or metastasis group(P<0.05) . 5-year DFS in EGFR positive group was lower than in EGFR negativegroup while 5-year DFS in E-cadherin normal group and AR positive group werehigher than in E-cadherin aberrant group and AR negative group respectively(P<0.05) .
In TNBC, EGFR positivity and aberrant expression of E-cadherin were higher than in non-TNBC, while AR positivity was lower than in non-TNBC (P<0.05) . In positive axillary lymph nodes group, EGFR positivity and aberrant expression of E-cadherin were higher than that in negative lymph nodes group, while AR positivity was lower than that in negative lymph nodes group. EGFR positivity was associated with recurrence or metastasis. 5-year DFS in EGFR positive group was lower than in EGFR negative group; However, expression of E-adhering and AR was not correlated with recurrence or metastasis and prognosis.
Conclusions:
TNBC was a special subtype of breast cancer and the majority of pathologic type was infiltrative ductal carcinoma .The rate of medullary type and grade III was higher than that in non-TNBC. TNBC had a tendency of local relapse or distant metastasis and had poor prognosis. Tumor size, TNM stage and lymph nodes status were prognostic factors. Lymph nodes status was an independent prognostic factor.
Of TNBC, expression of EGFR was associated with positive axillary lymph nodes, recurrence and metastasis and poor prognosis. Aberrent expression of E-cadherin were associated with positive axillary lymph nodes, while expression of AR was inversely correlated .Expression of E-cadherin and AR were not associated with prognosis, recurrence or metastasis. EGFR can be applied to predict prognosis and be a molecular target in TNBC.
方法:根据免疫组化指标ER、PR和Her-2的表达情况,将509例乳腺癌分为TNBC和non-TNBC,比较两组乳腺癌的临床病理特征,分析两组乳腺癌的5年无瘤生存率(disease free survival,DFS)以及影响预后临床病理因素。选取TNBC和non-TNBC各50例,免疫组化法检测EGFR、E-cadherin、AR的表达,并分析与临床因素和预后的关系。
结果:
509例乳腺癌中,TNBC占21.4%(109/509),其组织学类型以浸润性导管癌为主,髓样癌的比例高于non-TNBC,组织学Ⅲ级的比例高于non-TNBC(P＜0.05)。其他临床病理特征的比较中两组乳腺癌差异无统计学意义(P＞0.05)。TNBC中复发和远处转移率高于non-TNBC(P＜0.05),5年DFS低于non-TNBC(Log rank=4.661,P=0.031)。单因素分析显示影响TNBC预后的因素为肿瘤直径(P=0.000)、TNM分期(P=0.000)、淋巴结状态(P=0.000);而年龄、绝经状态、组织学分级、家族史等因素对患者预后的影响无统计学意义(P＞0.05)。Cox多因素分析显示,淋巴结状态(HR=2.999,95%CI:2.061～4.358,P=0.000)是独立的预后影响因素。
在100例乳腺癌中,EGFR阳性率、E-cadherin异常表达率和AR阳性率分别为44%(44/100)、62%(62/100)、49%(49/100)。腋淋巴结阳性组中EGFR阳性率和E-cadherin异常表达率高于腋淋巴结阴性组,AR阳性率低于腋淋巴结阴性组,差异有统计学意义(P＜0.05)。三个分子标记物的表达与年龄、绝经状态、临床分期、肿瘤大小等因素无相关性(P＞0.05)。复发转移组中EGFR的阳性率和E-cadherin的异常表达率高于无复发转移组,AR的阳性率低于无复发转移组,差异有统计学意义(P＜0.05)。EGFR阳性组的5年DFS低于EGFR阴性组(P＜0.05);E-cadherin正常表达组和AR阳性组的5年DFS分别高于E-cadherin异常表达组和AR阴性组(P＜0.05)。
TNBC中EGFR阳性率和E-cadherin异常表达率高于non-TNBC,AR阳性率低于non-TNBC(P＜0.05)。TNBC中腋淋巴结阳性组的EGFR阳性率和E-cadherin异常表达率高于腋淋巴结阴性组,AR阳性率低于腋淋巴结阴性组,差异有统计学意义(P＜0.05)。复发转移组的EGFR阳性率高于无复发转移组(P＜0.05),EGFR阳性组DFS低于EGFR阴性组(P＜0.05),而E-cadherin、AR的表达与复发转移和预后无相关性(P＞0.05)。
结论:
TNBC是一组特殊的乳腺癌亚型,病理组织学类型以浸润性导管癌为主,髓样癌的比例和组织学Ⅲ级的比例高于non-TNBC。发生局部复发和远处转移的几率较大,预后差。肿瘤直径、TNM分期和淋巴结状态是影响预后的重要因素,其中淋巴结状态是独立的预后影响因素。
在TNBC中,EGFR的表达与腋淋巴结转移、复发转移以及预后差呈正相关,E-cadherin的异常表达与腋淋巴结转移呈正相关,AR的表达与腋淋巴结转移呈负相关,E-cadherin和AR的表达与复发转移和预后无相关。EGFR可以用于评价TNBC的预后,并且作为TNBC治疗的分子靶点。
Objective: To analyze clinical and pathological features and to observe prognostic factors in triple negative breast cancer (TNBC) . Furthermore, to investigate the expression of EGFR、E-cadherin and AR in TNBC and non-TNBC and to evaluate its significance.
Methods: Based on ER, PR and Her-2 status determined using immunohistochemistry, 509 cases of breast cancer were grouped as TNBC and non-TNBC. Clinicopathologic features between two groups were compared. 5-year disease-free survival (DFS) was analyzed by Kaplan-Meier Method. Univariate regression and Cox multivariate regression were preformed to analyze association between prognosis and cliniopathologic features. 50 cases from each group were collected. Expression of EGFR, E-cadherin and AR by immunohistochemistry and its significance was analyzed.
Results:
21.4% of cases (109/509) were TNBC and the majority of pathologic type was infiltrative ductal carcinoma. TNBC had higher incidence rates than non-TNBC in medullarly type and grade III tumor (P<0.05) . No significance was found in other clinicopatholgic feature between two groups. The rate of local recurrence or distant metastasis in TNBC was higher than non-TNBC (P < 0.05) . 5-year DFS in TNBC was lower than in non-TNBC(Log rank=4.661, P=0.031) . Univariate regression analysis suggested that tumor size (P=0.000), TNM stage (P=0.000) , and lymph nodes status (P=0.000) were prognostic factors in TNBC (P=0.000). Age (≥50 or < 50)、menopausal status、histological grade、family history were not significant prognostic factors. Cox multivariate analysis demonstrated that the status of lymph nodes was an independent prognostic factor (HR= 2.999, 95% CI: 2.061～4.358, P=0.000) .
The positive rates of EGFR and AR in 100 case of breast cancer were 44% (44/100) and 49 %(49/100) respectively. The aberrant expression of E-cadherin was 62 %(62/100). In positive axillary lymph nodes group, EGFR positivity and aberrant expression of E-cadherin were higher than that in negative lymph nodes group, while AR positivity was lower than that in negative lymph nodes group. The expression ofthree biomarkers were not associated with age, menopausal status, TNM stage andtumor size (P>0.05) . In recurrence or metastasis group, EGFR positivity andaberrant expression of E-cadherin were higher than in non- recurrence or metastasisgroup, while AR positivity was lower than that in non- recurrence or metastasis group(P<0.05) . 5-year DFS in EGFR positive group was lower than in EGFR negativegroup while 5-year DFS in E-cadherin normal group and AR positive group werehigher than in E-cadherin aberrant group and AR negative group respectively(P<0.05) .
In TNBC, EGFR positivity and aberrant expression of E-cadherin were higher than in non-TNBC, while AR positivity was lower than in non-TNBC (P<0.05) . In positive axillary lymph nodes group, EGFR positivity and aberrant expression of E-cadherin were higher than that in negative lymph nodes group, while AR positivity was lower than that in negative lymph nodes group. EGFR positivity was associated with recurrence or metastasis. 5-year DFS in EGFR positive group was lower than in EGFR negative group; However, expression of E-adhering and AR was not correlated with recurrence or metastasis and prognosis.
Conclusions:
TNBC was a special subtype of breast cancer and the majority of pathologic type was infiltrative ductal carcinoma .The rate of medullary type and grade III was higher than that in non-TNBC. TNBC had a tendency of local relapse or distant metastasis and had poor prognosis. Tumor size, TNM stage and lymph nodes status were prognostic factors. Lymph nodes status was an independent prognostic factor.
Of TNBC, expression of EGFR was associated with positive axillary lymph nodes, recurrence and metastasis and poor prognosis. Aberrent expression of E-cadherin were associated with positive axillary lymph nodes, while expression of AR was inversely correlated .Expression of E-cadherin and AR were not associated with prognosis, recurrence or metastasis. EGFR can be applied to predict prognosis and be a molecular target in TNBC.
引文
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[63]孟洁,朗荣刚,范宇等,年轻乳腺癌患者的病理学和生物学特征及其与预后的关系[J].中华肿瘤杂志,2007(29):284-288.
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[1]Sorlie T,Perou CM,Tibshirani R,et al.Gene expression pattems of breast carcinomas distinguish tumor subclasses with clinical implications[J].Proc Natl Acad Sci U S A,2001,98(19):10869-10874.
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[6]Perou CM,Sorlie T,Eisen MB,et al:Molecular portraits of human breast tumours[J].Nature,2000,406:747-752.
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[1]Sorlie T,Perou CM,Tibshirani R,et al.Gene expression pattems of breast carcinomas distinguish tumor subclasses with clinical implications[J].Proc Natl Acad Sci U S A,2001,98(19):10869-10874.
[2] Sorlie T, Tibshirani R, Parker J, et al. Repeated observation of breast tumor subtypes in independent gene expression data sets [J].Proc Natl Acad Sci USA, 2003, 100: 8418-8423.
[3] Perou CM, Sorlie T, Eisen MB, et al: Molecular portraits of human breast tumors [J]. Nature, 2000, 406: 747-752.
[4] Nielsen TO, Hsu FD, Jensen K, et al. Immunohistochemical and clinical characterization of the Basal-like subtype of invasive breast carcinoma [J]. Clin Cancer Res, 2004,10(16):5367-5374.
[5] Carey LA, Perou CM, Livasy CA, et al. Race, breast cancer subtypes, and survival in the Carolina Breast Cancer Study[J].JAMA,2006,295(21):2492-2502.
[6] Harris L, Fritsche H, Mennel R, et al. American Society of Clinical Oncology 2007 update of recommendations for the use of tumor markers in breast cancer[J]. J Clin Oncol, 2007, 25(33):5287-5312.
[7] Dent R, Trudeau M, Pritchard KI,et al. Triple-negative breast cancer: clinical features and patterns of recurrence [J], Clin Cancer Res, 2007,13(15):4429-4434.
[8] Haffty BG, Yang Q, Reiss M,et al. Locoregional relapse and distant metastasis in conservatively managed triple negative early-stage breast cancer[J].J Clin Oncol, 2006, 24(36):5652-5657.
[9] Malzahn K, Mitze M, Thoenes M, Moll R: et al.Biological and prognosticsignificance of stratified epithelial cytokeratins in infiltrating ductal breast carcinomas [J]. Virchows Arch, 1998, 433:119-129.
[10] Livasy CA, Karaca G, Nanda R, et al.Phenotypic evaluation of the Basal-like subtype of invasive breast carcinoma [J]. Mod Pathol, 2006, 19(2):264-271.
[11] Reis-Filho JS, Milanezi F, Steele D et al.Metaplastic breast carcinomas are Basal-like tumours[J]. Histopathology, 2006, 49(1):10-21.
[12] Jacquemier J, Padovani L, Rabayrol L et al.Typical medullary breast carcinomas have a basal/myoepithelial phenotype [J].J Pathol, 2005, 207(3):260-268.
[13] Wang ZC, Lin M, Wei LJ, Li C, et al.Loss of heterozygosity and its correlation with expression profiles in subclasses of invasive breast cancers [J].Cancer Res, 2004, 64(1):64-71.
[14] Hu Z, Fan C, Oh DS, et al. The molecular portraits of breast tumors are conserved across microarray platforms [J].BMC Genomics, 2006, 7:96.
[15] Kreike B, van Kouwenhove M, Horlings H, et al. Gene expression profiling and histopathological characterization of triple-negative/Basal-like breast carcinomas [J].Breast Cancer Res,2007;9(5):R65.
[16] Tan DS, Marchio C, Jones RL, et al.Triple negative breast cancer: molecular profiling and prognostic impact in adjuvant anthracycline-treated patients [J].Breast Cancer Res Treat,2007 Oct 6.
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