切换至 "中华医学电子期刊资源库"
高级检索
中华乳腺病杂志(电子版)

中华乳腺病杂志(电子版) ›› 2023, Vol. 17 ›› Issue (04) : 203 -209. doi: 10.3877/cma.j.issn.1674-0807.2023.04.002

论著

肿瘤浸润性淋巴细胞在HER-2阳性早期乳腺癌中的临床意义
王亚萍, 樊菁, 侯牛牛, 凌瑞†()   
  1. 710032　西安，空军军医大学第一附属医院甲乳血管外科
  • 收稿日期:2023-01-30 出版日期:2023-08-01
  • 通信作者: 凌瑞

Clinical significance of tumor-infiltrating lymphocytes in HER-2-positive early breast cancer

Yaping Wang, Jing Fan, Niuniu Hou, Rui Ling†()   

  1. Department of Thyroid, Breast and Vascular Surgery, First Affiliated Hospital of Air Force Medical University, Xi’an 710032, China
  • Received:2023-01-30 Published:2023-08-01
  • Corresponding author: Rui Ling
全文 ( ) 下载PDF ( ) 导出引用
引用本文：

王亚萍, 樊菁, 侯牛牛, 凌瑞. 肿瘤浸润性淋巴细胞在HER-2阳性早期乳腺癌中的临床意义[J/OL]. 中华乳腺病杂志(电子版), 2023, 17(04): 203-209.

Yaping Wang, Jing Fan, Niuniu Hou, Rui Ling. Clinical significance of tumor-infiltrating lymphocytes in HER-2-positive early breast cancer[J/OL]. Chinese Journal of Breast Disease(Electronic Edition), 2023, 17(04): 203-209.

目的

评估肿瘤浸润性淋巴细胞(TIL)在HER-2阳性早期乳腺癌中的预后预测作用。

方法

收集2013年1月至2018年6月在空军军医大学第一附属医院接受新辅助治疗(NAT)的176例HER-2阳性早期乳腺癌患者的临床病理资料进行回顾性分析。根据NAT后手术切除标本的病理结果，分为pCR组(n＝84)和non-pCR组(n＝92)。采用国际肿瘤TIL工作组制定的计数方法，评估肿瘤边界与邻近正常组织区域之间的TIL水平。使用Kaplan-Meier方法绘制患者的总生存(OS)和无复发生存(RFS)曲线，并使用Log-rank检验进行比较。通过Cox比例风险回归模型分析OS和RFS的影响因素。采用Mann-Whitney U非参数检验分析NAT前后TIL水平的变化。

结果

(1) pCR组与non-pCR组的NAT前TIL水平(pre-TIL)比较，差异有统计学意义(χ2＝12.140, P<0.001)。(2)生存分析显示患者的pre-TIL与OS及RFS有关(OS: χ2＝14.243，P<0.001；RFS: χ2＝3.881，P＝0.049)。亚组分析显示：在non-pCR患者中，pre-TIL与OS和RFS有关(OS: χ2＝5.272，P＝0.022；RFS：χ2＝6.033，P＝0.014)，而NAT后TIL水平(post-TIL)与OS和RFS无关(OS: χ2＝0.174，P＝0.677; χ2＝0.074，P＝0.786)。92例non-pCR患者的pre-TIL和post-TIL分别为6.0%(5.0%，25.0%)，30.0%(11.3%，63.8%)，pre-TIL明显低于post-TIL(Z＝－5.474, P<0.001)。non-pCR患者NAT前后TIL变化值与患者的OS和RFS之间不相关(OS: χ2＝2.342，P＝0.126; RFS: χ2＝3.853，P＝0.051)。(3)Cox单因素分析结果显示，较低pre-TIL的患者有着更短的OS(HR＝2.556, 95%CI：1.458~4.482, P＝0.001)，但是pre-TIL与RFS无关(HR＝1.362, 95%CI：0.996~1.862, P＝0.053)；多因素分析发现pre-TIL是患者OS的独立预测因素(HR＝2.556, 95%CI：1.458~4.482, P＝0.001)。在non-pCR患者中，低pre-TIL的患者有着更短的OS(HR＝1.878，95%CI：1.058~3.333，P＝0.031)和RFS(HR＝1.670, 95%CI：1.090~2.559, P＝0.019)。non-pCR患者的post-TIL与OS(HR＝1.534, 95%CI：0.202~11.673，P＝0.679)和RFS(HR＝0.905, 95%CI：0.438~1.866, P＝0.786)无关。NAT前后TIL变化值不能作为OS(HR＝3.020, 95%CI：0.681~13.396，P＝0.146)和RFS(HR＝3.152, 95%CI：0.939~10.576, P＝0.063)的独立预测因素。

结论

pre-TIL是HER-2阳性早期乳腺癌的一个潜在预后因子，NAT前后TIL水平变化对于non-pCR患者的预测价值也值得进一步探讨。

关键词: 乳腺肿瘤, 受体，erbB-2, 新辅助治疗, 肿瘤浸润性淋巴细胞, 病理完全缓解
Objective

To evaluate the role of tumor-infiltrating lymphocytes (TIL) in predicting the prognosis of HER-2 positive breast cancer patients.

Methods

We retrospectively analyzed the clinicopathological data of 176 patients with HER-2 positive breast cancer treated with neoadjuvant therapy (NAT) in the First Affiliated Hospital of Air Force Medical University from January, 2013 to June 2018. According to the pathological results of surgically removed specimens after NAT, the patients were divided into pCR group (n=84) and non-pCR group (n=92).Using the TIL counting method recommended by the international TIL working group, we assessed TIL level in the area between the borders of invasive tumor and adjacent normal tissues. The overall survival (OS) and recurrence-free survival (RFS) curves were plotted using the Kaplan-Meier method and the values were compared using log-rank test. The influencing factors of OS and RFS were analyzed by Cox proportional hazards regression model. The Mann-Whitney U test was used to analyze the change of TIL level before and after NAT.

Results

(1) The TIL level before NAT (pre-TIL) presented a significant difference between pCR group and non-pCR group (χ2=12.140, P<0.001). (2) Survival analysis showed that pre-TIL was related to OS and RFS (OS: χ2=14.243, P<0.001; RFS: χ2=3.881, P=0.049). Subgroup analysis showed that pre-TIL was related to OS and RFS (OS: χ2=5.272, P=0.022; RFS: χ2=6.033, P=0.014) in non-pCR patients, while TIL level after NAT (post-TIL) was not related to OS and RFS (OS: χ2=0.174, P=0.677; χ2=0.074, P=0.786). The pre-TIL was significantly lower than post-TIL in 92 non-pCR patients [6.0% (5.0%, 25.0%) vs 30.0% (11.3%, 63.8%), Z=-5.474, P<0.001]. The change of TIL level before and after NAT in non-pCR was not significantly related to OS and RFS (OS: χ2=2.342, P=0.126; RFS: χ2=3.853, P=0.051). (3) The Cox univariate analysis showed that the patients with lower pre-TIL had lower OS (HR=2.556, 95%CI: 1.458-4.482, P=0.001), but pre-TIL was not related to RFS (HR=1.362, 95%CI: 0.996-1.862, P=0.053); multivariate analysis showed that pre-TIL was an independent factor of OS (HR=2.556, 95%CI: 1.458-4.482, P=0.001). Among the patients with non-pCR, the patients with low pre-TIL had lower OS (HR=1.878, 95%CI: 1.058-3.333, P=0.031) and RFS (HR=1.670, 95%CI: 1.090-2.559, P=0.019). Post-TIL was not significantly related to OS (HR=1.534, 95%CI: 0.202-11.673, P=0.679) and RFS (HR=0.905, 95%CI: 0.438-1.866, P=0.786) in patients with non-pCR. The change of TIL level before and after NAT was not an independent factor of OS(HR=3.020, 95%CI: 0.681-13.396, P=0.146) and RFS (HR=3.152, 95%CI: 0.939-10.576, P=0.063).

Conclusion

Pre-TIL is a potential prognostic factor for HER-2 positive early breast cancer, and the predictive value of TIL change before and after NAT in non-pCR patients is worth of further exploration.

Key words: Breast neoplasms, Receptor, ErbB-2, Neoadjuvant therapy, Tumor infiltrating lymphocytes, Pathologic complete response
表1 2组HER-2阳性早期乳腺癌患者的临床病理特征比较
临床病理特征 non-pCR(n＝92) pCR(n＝84) χ2值 P值
年龄        
<50岁 58(63.0%) 42(50.0%) 3.045 0.081
≥50岁 34(37.0%) 42(50.0%)
肿瘤直径        
>2 cm 76(82.6%) 20(23.8%) 1.112 0.292
≤2 cm 16(17.4%) 64(76.2%)
TNM分期        
ⅠA期 8(8.7%) 8(9.5%) 3.968a 0.410
ⅡA期 34(37.0%) 35(41.7%)
ⅡB期 43(46.7%) 38(45.2%)
ⅢA期 3(3.3%) 3(3.6%)
ⅢB期 4(4.3%) 0(0)
淋巴结状态        
阴性 39(42.4%) 31(36.9%) 0.552 0.458
阳性 53(57.6%) 53(63.1%)
新辅助治疗前TIL        
低 44(47.8%) 19(22.6%) 12.140 <0.001
中/高 48(52.2%) 65(77.4%)
新辅助治疗后TIL        
低 10(10.9%) －    
中/高 82(89.1%) －    
复发/转移        
否 68(73.9%) 65(77.4%) 1.239 0.266
是 24(26.1%) 19(22.6%)
图1 新辅助治疗前肿瘤浸润性淋巴细胞水平不同的乳腺癌患者生存曲线比较注：a图为总生存曲线，χ2＝14.243，P<0.001；b图为无复发生存曲线，χ2＝3.881，P＝0.049
图2 新辅助治疗前肿瘤浸润性淋巴细胞水平不同的非病理完全缓解乳腺癌患者生存曲线比较注：a图为总生存曲线，χ2＝5.272，P＝0.022；b图为无复发生存曲线，χ2＝6.033，P＝0.014
图3 新辅助治疗后肿瘤浸润性淋巴细胞水平不同的非病理完全缓解乳腺癌患者生存曲线比较注：a图为总生存曲线，χ2＝0.174，P＝0.677；b图为无复发生存曲线，χ2＝0.074，P＝0.786
图4 新辅助治疗对92例non-pCR乳腺癌患者肿瘤浸润性淋巴细胞水平的影响注：Z＝－5.474, P<0.001
图5 新辅助治疗前后肿瘤浸润性淋巴细胞水平变化不同的乳腺癌患者生存曲线比较注：a图为总生存曲线，χ2＝2.342，P＝0.126；b图为无复发生存曲线，χ2＝3.853，P＝0.051
表2 176例HER-2阳性早期乳腺癌患者OS和RFS的Cox单因素分析结果
临床病理特征 OS RFS
HR 95%CI P值 HR 95%CI P值
年龄(<50岁比≥50岁) 1.644 0.576~4.694 0.353 1.160 0.616~2.183 0.646
肿瘤大小(>2 cm比≤2 cm) 1.214 0.348~4.238 0.761 1.194 0.582~2.451 0.629
淋巴结状态(阳性比阴性) 1.298 0.500~3.366 0.592 1.275 0.666~2.444 0.464
TNM分期(Ⅱ/Ⅲ期比Ⅰ期) 1.730 0.229~13.046 0.595 1.266 0.495~3.234 0.623
Pre-TIL(低比中/高水平) 2.556 1.458~4.482 0.001 1.362 0.996~1.862 0.053
表3 92例非病理完全缓解的HER-2阳性早期乳腺癌患者OS和RFS的Cox单因素分析结果
临床病理特征 OS RFS
HR 95%CI P值 HR 95%CI P值
年龄(<50岁比≥50岁) 1.062 0.359~3.143 0.913 1.009 0.428~2.380 0.983
肿瘤大小(>2 cm比≤2 cm) 1.102 0.311~3.912 0.880 1.096 0.408~2.941 0.856
淋巴结状态(阳性比阴性) 1.252 0.454~3.454 0.664 1.082 0.480~2.439 0.849
TNM分期(Ⅱ/Ⅲ期比Ⅰ期) 1.342 0.176~10.208 0.776 1.071 0.252~4.557 0.926
pre-TIL(低比中/高水平) 1.878 1.058~3.333 0.031 1.670 1.090~2.559 0.019
post-TIL(低比中/高水平) 1.534 0.202~11.673 0.679 0.905 0.438~1.866 0.786
TIL变化(减少比增加) 3.020 0.681~13.390 0.146 3.152 0.939~10.576 0.063
[1]
Sung H, Ferlay J, Siegel RL, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries[J]. CA Cancer J Clin, 2021, 71(3): 209-249.
[2]
Mamounas EP, Untch M, Mano MS, et al. Adjuvant T-DM1 versus trastuzumab in patients with residual invasive disease after neoadjuvant therapy for HER2-positive breast cancer: subgroup analyses from KATHERINE[J]. Ann Oncol, 2021, 32(8): 1005-1014.
[3]
Early Breast Cancer Trialists’ Collaborative group (EBCTCG). Trastuzumab for early-stage, HER2-positive breast cancer: a meta-analysis of 13 864 women in seven randomised trials[J]. Lancet Oncol, 2021, 22(8): 1139-1150.
[4]
Wang S, Xiong Y, Zhang Q, et al. Clinical significance and immunogenomic landscape analyses of the immune cell signature based prognostic model for patients with breast cancer[J]. Brief Bioinform, 2021, 22(4)：bbaa311.
[5]
Iwamoto T, Kajiwara Y, Zhu Y, et al. Biomarkers of neoadjuvant/adjuvant chemotherapy for breast cancer[J]. Chin Clin Oncol, 2020, 9(3): 27.
[6]
Denkert C, Von Minckwitz G, Darb-Esfahani S, et al. Tumour-infiltrating lymphocytes and prognosis in different subtypes of breast cancer: a pooled analysis of 3771 patients treated with neoadjuvant therapy[J]. Lancet Oncol, 2018, 19(1): 40-50.
[7]
De Groot AF, Blok EJ, Charehbili A, et al. Strong CD8+lymphocyte infiltration in combination with expression of HLA class I is associated with better tumor control in breast cancer patients treated with neoadjuvant chemotherapy[J]. Breast Cancer Res Treat, 2019, 175(3): 605-615.
[8]
Hamy AS, Pierga JY, Sabaila A, et al. Stromal lymphocyte infiltration after neoadjuvant chemotherapy is associated with aggressive residual disease and lower disease-free survival in HER2-positive breast cancer[J]. Ann Oncol, 2017, 28(9): 2233-2240.
[9]
Asano Y, Kashiwagi S, Goto W, et al. Tumour-infiltrating CD8 to FOXP3 lymphocyte ratio in predicting treatment responses to neoadjuvant chemotherapy of aggressive breast cancer[J]. Br J Surg, 2016, 103(7): 845-854.
[10]
Loi S, Michiels S, Salgado R, et al. Tumor infiltrating lymphocytes are prognostic in triple negative breast cancer and predictive for trastuzumab benefit in early breast cancer: results from the FinHER trial[J]. Ann Oncol, 2014, 25(8): 1544-1550.
[11]
Burstein HJ, Curigliano G, Loibl S, et al. Estimating the benefits of therapy for early-stage breast cancer: the St. Gallen International Consensus Guidelines for the primary therapy of early breast cancer 2019[J]. Ann Oncol, 2019, 30(10): 1541-1557.
[12]
Dieci MV, Criscitiello C, Goubar A, et al. Prognostic value of tumor-infiltrating lymphocytes on residual disease after primary chemotherapy for triple-negative breast cancer: a retrospective multicenter study[J]. Ann Oncol, 2014, 25(3): 611-618.
[13]
Eustace AJ, Madden SF, Fay J, et al. The role of infiltrating lymphocytes in the neo-adjuvant treatment of women with HER2-positive breast cancer[J]. Breast Cancer Res Treat, 2021, 187(3): 635-645.
[14]
Hwang HW, Jung H, Hyeon J, et al. A nomogram to predict pathologic complete response (pCR) and the value of tumor-infiltrating lymphocytes (TILs) for prediction of response to neoadjuvant chemotherapy (NAC) in breast cancer patients[J]. Breast Cancer Res Treat, 2019, 173(2): 255-266.
[15]
Ochi T, Bianchini G, Ando M, et al. Predictive and prognostic value of stromal tumour-infiltrating lymphocytes before and after neoadjuvant therapy in triple negative and HER2-positive breast cancer[J]. Eur J Cancer, 2019, 118: 41-48.
[16]
Salgado R, Denkert C, Demaria S, et al. The evaluation of tumor-infiltrating lymphocytes (TILs) in breast cancer: recommendations by an International TILs Working Group 2014[J]. Ann Oncol, 2015, 26(2): 259-271.
[17]
Salgado R, Denkert C, Campbell C, et al. Tumor-infiltrating lymphocytes and associations with pathological complete response and event-free survival in HER2-positive early-stage breast cancer treated with lapatinib and trastuzumab: a secondary analysis of the NeoALTTO trial[J]. JAMA Oncol, 2015, 1(4): 448-454.
[18]
Dubsky P, Pinker K, Cardoso F, et al. Breast conservation and axillary management after primary systemic therapy in patients with early-stage breast cancer: the Lucerne toolbox[J]. Lancet Oncol, 2021, 22(1): e18-e28.
[19]
Korde LA, Somerfield MR, Carey LA, et al. Neoadjuvant chemotherapy, endocrine therapy, and targeted therapy for breast cancer: ASCO guideline[J]. J Clin Oncol, 2021, 39(13): 1485-1505.
[20]
Rastogi P, Anderson SJ, Bear HD, et al. Preoperative chemotherapy: updates of National Surgical Adjuvant Breast and Bowel Project Protocols B-18 and B-27[J]. J Clin Oncol, 2008, 26(5): 778-785.
[21]
Paijens ST, Vledder A, De Bruyn M, et al. Tumor-infiltrating lymphocytes in the immunotherapy era[J]. Cell Mol Immunol, 2021, 18(4): 842-859.
[22]
Tran WT, Lu FI, Salgado R. Tumor infiltrating lymphocytes: current pathways to a standard biomarker in breast cancer[J]. Expert Rev Anticancer Ther, 2021, 21(12): 1299-1301.
[23]
Shou J, Zhang Z, Lai Y, et al. Worse outcome in breast cancer with higher tumor-infiltrating FOXP3+ Tregs: a systematic review and meta-analysis[J]. BMC Cancer, 2016, 16(1): 687.
[24]
De Angelis C, Nagi C, Hoyt C C, et al. Evaluation of the predictive role of tumor immune infiltrate in patients with HER2-positive breast cancer treated with neoadjuvant Anti-HER2 therapy without chemotherapy[J]. Clin Cancer Res, 2020, 26(3): 738-745.
[25]
Abe N, Matsumoto H, Takamatsu R, et al. Quantitative digital image analysis of tumor-infiltrating lymphocytes in HER2-positive breast cancer[J]. Virchows Arch, 2020, 476(5): 701-709.
[26]
Hamy AS, Bonsang-Kitzis H, De Croze D, et al. Interaction between molecular subtypes and stromal immune infiltration before and after treatment in breast cancer patients treated with neoadjuvant chemotherapy[J]. Clin Cancer Res, 2019, 25(22): 6731-6741.
[27]
Nuciforo P, Pascual T, Cortés J, et al. A predictive model of pathologic response based on tumor cellularity and tumor-infiltrating lymphocytes (CelTIL) in HER2-positive breast cancer treated with chemo-free dual HER2 blockade[J]. Ann Oncol, 2018, 29(1): 170-177.
[28]
Hughes E, Scurr M, Campbell E, et al. T-cell modulation by cyclophosphamide for tumour therapy[J]. Immunology, 2018, 154(1): 62-68.
[29]
Ladoire S, Arnould L, Apetoh L, et al. Pathologic complete response to neoadjuvant chemotherapy of breast carcinoma is associated with the disappearance of tumor-infiltrating foxp3+ regulatory T cells[J]. Clin Cancer Res, 2008, 14(8): 2413-2420.
[30]
Goto W, Kashiwagi S, Asano Y, et al. Predictive value of improvement in the immune tumour microenvironment in patients with breast cancer treated with neoadjuvant chemotherapy[J]. ESMO Open, 2018, 3(6): e000305.
[1] 周荷妹, 金杰, 叶建东, 夏之一, 王进进, 丁宁. 罕见成人肋骨郎格汉斯细胞组织细胞增生症被误诊为乳腺癌术后骨转移一例[J/OL]. 中华乳腺病杂志(电子版), 2024, 18(06): 380-383.
[2] 河北省抗癌协会乳腺癌专业委员会护理协作组. 乳腺癌中心静脉通路护理管理专家共识[J/OL]. 中华乳腺病杂志(电子版), 2024, 18(06): 321-329.
[3] 刘晨鹭, 刘洁, 张帆, 严彩英, 陈倩, 陈双庆. 增强MRI 影像组学特征生境分析在预测乳腺癌HER-2 表达状态中的应用[J/OL]. 中华乳腺病杂志(电子版), 2024, 18(06): 339-345.
[4] 张晓宇, 殷雨来, 张银旭. 阿帕替尼联合新辅助化疗对三阴性乳腺癌的疗效及预后分析[J/OL]. 中华乳腺病杂志(电子版), 2024, 18(06): 346-352.
[5] 邱琳, 刘锦辉, 组木热提·吐尔洪, 马悦心, 冷晓玲. 超声影像组学对致密型乳腺背景中非肿块型乳腺癌的诊断价值[J/OL]. 中华乳腺病杂志(电子版), 2024, 18(06): 353-360.
[6] 程燕妮, 樊菁, 肖瑶, 舒瑞, 明昊, 党晓智, 宋宏萍. 乳腺组织定位标记夹的应用与进展[J/OL]. 中华乳腺病杂志(电子版), 2024, 18(06): 361-365.
[7] 涂盛楠, 胡芬, 张娟, 蔡海峰, 杨俊泉. 天然植物提取物在乳腺癌治疗中的应用[J/OL]. 中华乳腺病杂志(电子版), 2024, 18(06): 366-370.
[8] 高俊颖, 张海洲, 区泓乐, 孙强. FOLFOX-HAIC 为基础的肝细胞癌辅助转化治疗的应用进展[J/OL]. 中华普通外科学文献(电子版), 2024, 18(06): 457-463.
[9] 高杰红, 黎平平, 齐婧, 代引海. ETFA和CD34在乳腺癌中的表达及与临床病理参数和预后的关系研究[J/OL]. 中华普外科手术学杂志(电子版), 2025, 19(01): 64-67.
[10] 韩萌萌, 冯雪园, 马宁. 乳腺癌改良根治术后桡神经损伤1例[J/OL]. 中华普外科手术学杂志(电子版), 2025, 19(01): 117-118.
[11] 张志兆, 王睿, 郜苹苹, 王成方, 王成, 齐晓伟. DNMT3B与乳腺癌预后的关系及其生物学机制[J/OL]. 中华普外科手术学杂志(电子版), 2024, 18(06): 624-629.
[12] 王玲艳, 高春晖, 冯雪园, 崔鑫淼, 刘欢, 赵文明, 张金库. 循环肿瘤细胞在乳腺癌新辅助及术后辅助治疗中的应用[J/OL]. 中华普外科手术学杂志(电子版), 2024, 18(06): 630-633.
[13] 赵林娟, 吕婕, 王文胜, 马德茂, 侯涛. 超声引导下染色剂标记切缘的梭柱型和圆柱型保乳区段切除术的效果研究[J/OL]. 中华普外科手术学杂志(电子版), 2024, 18(06): 634-637.
[14] 崔军威, 蔡华丽, 胡艺冰, 胡慧. 亚甲蓝联合金属定位夹及定位钩针标记在乳腺癌辅助化疗后评估腋窝转移淋巴结的临床应用价值探究[J/OL]. 中华临床医师杂志(电子版), 2024, 18(07): 625-632.
[15] 王誉英, 刘世伟, 王睿, 曾娅玲, 涂禧慧, 张蒲蓉. 老年乳腺癌新辅助治疗病理完全缓解的预测因素分析[J/OL]. 中华临床医师杂志(电子版), 2024, 18(07): 641-646.
阅读次数
全文


摘要

版权所有 中华医学会 中华医学电子音像出版社有限责任公司  京ICP备14006079号-1  网络出版服务许可证：(署)网出证(京)字第075号