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北京大学学报（医学版） ›› 2022, Vol. 54 ›› Issue (5): 853-862. doi: 10.19723/j.issn.1671-167X.2022.05.013

• 论著 • 上一篇    下一篇

激素受体阳性/人表皮生长因子受体2阴性乳腺癌临床病理特征及预后

王跃1,张爽1,张虹1,梁丽1,徐玲2,程元甲2,段学宁2,刘荫华2,李挺1,*()   

  1. 1. 北京大学第一医院病理科，北京 100034
    2. 北京大学第一医院乳腺疾病中心，北京 100034
  • 收稿日期:2022-06-22 出版日期:2022-10-18 发布日期:2022-10-14
  • 通讯作者: 李挺 E-mail:lixiaoting12@hotmail.com
  • 作者简介:李挺，北京大学第一医院病理科教授，主任医师，博士生导师。毕业于华西医科大学医学系及病理学系，留学于日本冈山大学癌研生化室、日本大阪大学分子病理系、美国M.D.Anderson癌症中心血液病理学系，曾任日本大阪大学病理系客座教授。现任中国医师病理分会第一、二、三届常委兼秘书长，北京医学会乳腺专委会副主任委员，北京医学会病理专委会乳腺学组长，北京大学医学部临床教学委员会病理学组长、临床病理专业学位点创建及召集人。
      专长于多系统疑难病理诊断，尤其在淋巴造血、乳腺及分子病理领域有很深造诣。长期钻研乳腺亚专科病理学，非常熟悉乳腺疾病病理诊断和乳腺癌现代病理学诊断评估等前沿内容，建立并领导北京大学第一医院乳腺疾病中心相关病理专业组工作。先后承担国家自然科学基金(5项)、首都医学发展科研基金(磁共振成像及肿瘤分子标志物检测对乳腺癌新辅助化疗疗效评估及预测的临床研究)、北京市科技计划(乳腺癌患者保留乳房手术影像学证据研究)等各级课题10余项；以第一和责任作者发表论著100余篇，其中SCI收录40余篇。获中华医学科技二等奖、北京市科技二等奖、北京医学科技二等奖
  • 基金资助:
    国家重点研发计划(2016YFC0901302)

Clinicopathological features and prognosis of hormone receptor-positive/human epidermal growth factor receptor 2-negative breast cancer

Yue WANG1,Shuang ZHANG1,Hong ZHANG1,Li LIANG1,Ling XU2,Yuan-jia CHENG2,Xue-ning DUAN2,Yin-hua LIU2,Ting LI1,*()   

  1. 1. Department of Pathology, Peking University First Hospital, Beijing 100034, China
    2. Breast Disease Center, Peking University First Hospital, Beijing 100034, China
  • Received:2022-06-22 Online:2022-10-18 Published:2022-10-14
  • Contact: Ting LI E-mail:lixiaoting12@hotmail.com
  • Supported by:
    the National Key R&D Program of China(2016YFC0901302)

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摘要：

目的: 探讨激素受体阳性/人表皮生长因子受体2阴性(hormone receptor-positive/human epidermal growth factor receptor 2-negative, HR +/HER2 -)乳腺癌患者临床病理特征及预后。方法: 收集2008年1月至2017年12月北京大学第一医院乳腺疾病中心连续诊治的3 035例浸润性乳腺癌患者，对临床病理信息完善的HR +/HER2 -患者的重要临床病理参数及其预后意义进行分析。结果: 1 920例(63.26%)HR +/HER2 -乳腺癌患者中资料完善者1 624例，其中124例(7.64%)出现复发转移，63例死于该病，5年总生存率和无病生存率分别为93.0%及92.6%。pT1及2期占92.80%，pN0期占69.03%；组织学非特殊型占89.66%，分级1、2、3级分别为30.11%、55.60%和14.29%；ER阴性、低表达、高表达患者分别占1.60%、2.09%、96.31%，PR阴性、低表达、高表达分别占6.83%、10.47%、82.70%；Ki67指数＜10%、≥10%且 < 20%、≥20%者分别占19.52%、32.02%和48.46%。预后及生存分析显示, pT1期复发转移风险较pT3组低，pT2和pT3组较pT1组无病生存期(disease-free survival，DFS)短，易复发转移；pN0、pN1及pN2期复发转移风险均较pN3期低，与DFS呈负相关；组织学1及2级复发转移风险较3级低，与DFS呈负相关；Ki67指数≥20%更易复发转移。ER在HR +/HER2 -乳腺癌中预后意义不明显，但PR阴性和低表达更易复发转移，生存分析显示，PR表达水平＜10%患者的DFS及总生存期(overall survival，OS)最短，10%~60%次之，＞60%最长。124例复发转移者以骨转移多见(55例，44.35%)，而肝转移者(30例，24.20%)预后最差。结论: 本研究表明，pT分期、pN分期、组织学分级、HR表达水平、Ki67指数等临床病理参数是HR +/HER2 -乳腺癌的重要预后因素，但意义有所不同，其中pN分期和组织学分级有独立预后价值，PR阳性表达水平具有重要预后和风险预测价值，随PR表达水平升高(＜10%、10%~60%、＞60%)，DFS及OS递增，复发转移风险递减，PR表达＞60%者DFS及OS最长，复发转移风险最低，PR危险性分层具有独立预后意义。

关键词: 乳腺肿瘤, 肿瘤复发，局部, 肿瘤转移, 受体，孕酮, 受体，雌激素, 人表皮生长因子受体2

Abstract:

Objective: To investigate the clinicopathological features and prognosis of hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2 -) breast cancer. Methods: In the study, 3 035 consecutive breast cancer patients diagnosed in Breast Disease Center, Peking University First Hospital from January 2008 to December 2017 were collected. The prognostic signi-ficance of important pathological factors in HR +/HER2 - patients with complete clinicopathological information was analyzed. Results: Within the 1 920 (63.26%) cases of HR +/HER2 - breast cancer, there were 1 624 cases with complete clinicopathological data, of which, 124 cases (7.64%) recurred and/or metastasized and 63 cases died of the disease, and the 5-year overall survival (OS) rate and disease-free survival (DFS) rate was 93.0% and 92.6% respectively. The stage of pT1-2 was 92.80%, while pN0 was 69.03%. 89.66% cases belonged to histologically non-specific type and 30.11%, 55.60%, 14.29% were credited to Grade 1, 2 and 3 respectively. The distribution of ER negative, low or high expression groups were 1.60%, 2.09% and 96.31%, while PR were 6.83%, 10.47%, 82.70%, respectively. The group of Ki67 index < 10% was 19.52%, ≥10% & < 20% for 32.02%, ≥20% for 48.46%. Survival analysis showed that cases with pT1 stage had lower risk of recurrence than those with pT3, while cases with pT2 and pT3 had shorter DFS than those with pT1, with higher risk of recurrence and metastasis. Analysis proved that both pN stage and histological grade were negatively correlated with DFS. The cases with pN0, pN1 and pN2 were lower risk of recurrence than those with pN3, while cases with Grade 1 and 2 had lower risk of recurrence than cases with Grade 3. And the group of Ki67 index ≥20% showed higher risk of recurrence and metastasis. The prognostic significance of ER expression in HR+/HER2- breast cancer was not significant. However, the negative/low PR expression groups showed higher risk of recurrence and metastasis, of which PR < 10% group had shortest DFS and OS, followed by 10%-60% group and then > 60% group. The most common site of metastasis was bone (55 cases, 44.35%), while cases with liver metastasis (30 cases, 24.20%) had the worst outcome. Conclusion: Our study revealed that pT, pN, Grade, HR expression level and Ki67 index were important prognostic factors for HR +/HER2 - breast cancer, although there are variables in prognostic value. Factors of pN and Grade showed independent prognostic significance. PR expression level had prognostic significance for the risk of recurrence and metastasis. The stratified level of PR expression (< 10%, 10%-60%, >60%) had independent prognostic value, showing successively longer DFS and OS, lower risk of recurrence. PR>60% group had the longest DFS and OS as well as the lowest risk of recurrence.

Key words: Breast neoplasms, Neoplasm recurrence, local, Neoplasm metastasis, Receptors, progesterone, Receptors, estrogen, Human epidermal growth factor receptor 2

中图分类号: 

  • R737.9

表1

1 624例HR +/HER2 -乳腺癌的临床病理学特征"

Characteristics All cases (n=1 624) Metastasis (n=124) Non-metastasis (n=1 500)
Age/years 54 (21-92) 55 (22-90) 54 (21-92)
Gender
  Female 1 609 (99.08) 122 (98.39) 1 487 (99.13)
  Male 15 (0.92) 2 (1.61) 13 (0.87)
Family history
  Yes 57 (3.51) 3 (2.42) 54 (3.60)
  No 1 567 (96.49) 121 (97.58) 1 446 (96.40)
Menopausal statusa
  Premenopausal 562 (34.93) 41 (33.61) 521 (35.04)
  Postmenopausal 1 047 (65.07) 81 (66.39) 966 (64.96)
Surgery
  Breast-conserving surgery 460 (28.33) 26 (20.97) 434 (28.93)
  Mastectomy 1 164 (71.67) 98 (79.03) 1 066 (71.07)
Histologictype
  NOS 1 456 (89.66) 111 (89.52) 1 342 (89.47)
  ILC 69 (4.25) 9 (7.26) 60 (4.00)
  Mucinous carcinoma 69 (4.25) 0 69 (4.60)
  Othersb 30 (1.84) 4 (3.23) 29 (1.93)
pT stage
  1 913 (56.22) 54 (43.55) 859 (57.27)
  2 594 (36.58) 57 (45.97) 537 (35.80)
  3 117 (7.20) 13 (10.48) 104 (6.93)
pN stage
  0 1 121 (69.03) 51 (41.13) 1 070 (71.33)
  1 414 (25.49) 35 (28.23) 379 (25.27)
  2 52 (3.20) 17 (13.71) 35 (2.33)
  3 37 (2.28) 21 (16.93) 16 (1.07)
Grade
  1 489 (30.11) 24 (19.36) 465 (31.00)
  2 903 (55.60) 64 (51.61) 839 (55.93)
  3 232 (14.29) 36 (29.03) 196 (13.07)
ER
  ＜1% 26 (1.60) 3 (2.42) 23 (1.53)
  1%-10% 34 (2.09) 4 (3.23) 30 (2.00)
  >10% 1 564 (96.31) 117 (94.35) 1 447 (96.47)
PR
  ＜1% 111 (6.84) 11 (8.87) 100 (6.67)
  1%-10% 170 (10.47) 19 (15.32) 151 (10.07)
  11%-60% 301 (18.53) 33 (26.61) 268 (17.86)
  >60% 1 042 (64.16) 61 (49.19) 981 (65.40)
HR status
  ER+/PR+ 1 487 (91.57) 110 (88.71) 1 377 (91.80)
  ER+/PR- 111 (6.83) 11 (8.87) 100 (6.67)
  ER-/PR+ 26 (1.60) 3 (2.42) 23 (1.53)
HER2
  0 634 (39.04) 49 (39.52) 585 (39.00)
  1+ 612 (37.68) 44 (35.48) 568 (37.87)
  2+，FISH- 378 (23.28) 31 (25.00) 347 (23.13)
Ki67
  ＜10% 317 (19.52) 20 (16.13) 297 (19.80)
  ≥10%&<20% 520 (32.02) 24 (19.35) 496 (33.07)
  ≥20% 787 (48.46) 80 (64.52) 707 (47.13)
Molecular subtype
  Luminal A 516 (31.77) 44 (35.48) 472 (31.47)
  Luminal B 1 108 (68.23) 80 (64.52) 1 028 (68.53)
Endocrine therapyc
  No 11 (0.68) 3 (2.42) 8 (0.53)
  Preoperative 9 (0.55) 1 (0.81) 8 (0.53)
  Postoperative 1 609 (99.07) 120 (96.77) 1 489 (99.27)
Neoadjuvant chemotherapy
  No 1 392 (85.71) 93 (75.00) 1 299 (86.60)
  Yes 232 (14.29) 31 (25.00) 201 (13.40)
Adjuvant chemotherapy
  No 947 (58.31) 36 (29.03) 911 (60.73)
  Yes 677 (41.69) 88 (70.97) 589 (39.27)

图1

乳腺癌组织病理学形态及免疫组织化学检测ER表达"

表2

HR +/HER2 -乳腺癌复发转移相关临床病理特征单因素及多因素分析"

Variables Univariate Multivariate
HR (95%CI) P value HR (95%CI) P value
pT stage
  1 0.507 (0.276-0.928) 0.028 0.895
  2 0.822 (0.450-1.501) 0.523 0.850
  3 1.0 (reference)
pN stage
  0 0.070 (0.042-0.117) ＜0.001 0.081 (0.049-0.136) ＜0.001
  1 0.168 (0.098-0.289) ＜0.001 0.162 (0.093-0.280) ＜0.001
  2 0.427 (0.225-0.811) 0.009 0.472 (0.246-0.904) 0.024
  3 1.0 (reference) 1.0 (reference)
Grade
  1 0.258 (0.154-0.432) ＜0.001 0.327 (0.191-0.560) ＜0.001
  2 0.398 (0.265-0.599) ＜0.001 0.472 (0.311-0.717) ＜0.001
  3 1.0 (reference) 1.0 (reference)
ER
  ＜1% 1.069 (0.339-3.369) 0.909 0.795
  1%-10% 1.250 (0.461-3.390) 0.661 0.675
  >10% 1.0 (reference)
PR
  ＜10% 2.469 (1.592-3.830) ＜0.001 1.949 (1.247-3.047) 0.003
  10%-60% 1.970 (1.290-3.009) 0.002 1.724 (1.120-2.654) 0.013
  >60% 1.0 (reference) 1.0 (reference)
HER2
  0 0.793 (0.505-1.244) 0.313 0.530
  1+ 0.802 (0.506-1.270) 0.347 0.398
  2+，FISH- 1.0 (reference)
Ki67
  ＜10% 0.486 (0.298-0.795) 0.004 0.634
  ≥10%&<20% 0.435 (0.276-0.687) ＜0.001 0.341
  ≥20% 1.0 (reference)
Endocrine therapy
  No 0.242 (0.077-0.761) 0.015 3.221 (0.991-10.466) 0.052
  Yes 1.0 (reference) 1.0 (reference)
Neoadjuvant chemotherapy
  No 0.620 (0.412-0.932) 0.022 0.214
  Yes 1.0 (reference)

图2

HR +/HER2 -乳腺癌不同组间DFS和OS情况(Kaplan-Meier及Log-rank生存分析)"

图3

HR及Ki67在1 624例HR +/HER2 -乳腺癌中的分布情况"

图4

ER(A)及PR(B)表达水平时间依赖ROC曲线"

图5

HR分布情况及其与重要临床病理参数聚类分析结果"

表3

HR免疫表型与HR +/HER2 -乳腺癌临床病理学特征的相关性"

Variables HR+/HER2- breast cancer HR+/HER2- breast cancer with relapse
ER+/PR+
(n=1 487)		 ER+/PR-
(n=111)		 ER-/PR+
(n=26)		 P ER+/PR+
(n=110)		 ER+/PR-
(n=11)		 ER-/PR+
(n=3)		 P
Menopausal statusa ＜0.001 0.038
  Premenopausal 531 (36.05) 17 (15.45) 14 (53.85) 36 (33.33) 2 (18.18) 3 (100.00)
  Postmenopausal 942 (63.95) 93 (84.55) 12 (46.15) 72 (66.67) 9 (81.82) 0
pT stage 0.555 0.993
  1 836 (56.22) 60 (54.05) 17 (65.38) 49 (44.54) 4 (36.36) 1 (33.33)
  2 543 (36.52) 43 (38.74) 8 (30.77) 48 (43.64) 7 (63.64) 2 (66.67)
  3 108 (7.26) 8 (7.21) 1 (3.85) 13 (11.82) 0 0
pN stage 0.042 0.781
  0 1 036 (69.67) 65 (58.56) 20 (76.92) 45 (40.91) 4 (36.36) 2 (66.67)
  1-3 451 (30.33) 46 (41.44) 6 (23.08) 65 (59.09) 7 (63.64) 1 (33.33)
Grade ＜0.001 0.948
  1 457 (30.73) 28 (25.23) 4 (15.38) 22 (20.00) 2 (18.18) 0
  2 840 (56.49) 54 (48.65) 9 (34.62) 55 (50.00) 6 (54.55) 3 (100.00)
  3 190 (12.78) 29 (26.12) 13 (50.00) 33 (30.00) 3 (27.27) 0
Ki67 ＜0.001 0.669
  ＜10% 303 (20.38) 10 (9.01) 4 (15.38) 19 (17.27) 0 1 (33.33)
  ≥10%&<20% 487 (32.75) 33 (29.73) 0 21 (19.09) 3 (27.27) 0
  ≥20% 697 (46.87) 68 (61.26) 22 (84.62) 70 (63.64) 8 (72.73) 2 (66.67)
Molecular subtype ＜0.001 0.016
  Luminal A 501 (33.69) 11 (9.91) 4 (15.38) 43 (39.09) 0 1 (33.33)
  Luminal B 986 (66.31) 100 (90.09) 22 (84.62) 67 (60.91) 11 (100.00) 2 (66.67)

图6

不同HR表达情况的Ki67指数"

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doi: 10.1186/s12885-021-08219-3
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CN 11-4691/R
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