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

doi:10.3877/cma.j.issn.1674-0807.2023.04.002

Abstract

Abstract:

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

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

/ / Recommend

Add to citation manager EndNote|Ris|BibTeX

URL: https://zhrxbzz.cma-cmc.com.cn/EN/10.3877/cma.j.issn.1674-0807.2023.04.002

https://zhrxbzz.cma-cmc.com.cn/EN/Y2023/V17/I04/203

Figures/Tables 8

References 30

[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.

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%)	3.045	0.081
肿瘤直径
>2 cm	76(82.6%)	20(23.8%)	1.112	0.292
≤2 cm	16(17.4%)	64(76.2%)	1.112	0.292
TNM分期
ⅠA期	8(8.7%)	8(9.5%)	3.968^a	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%)	0.552	0.458
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%)	12.140	<0.001
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%)	1.239	0.266

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%)	3.045	0.081
肿瘤直径
>2 cm	76(82.6%)	20(23.8%)	1.112	0.292
≤2 cm	16(17.4%)	64(76.2%)	1.112	0.292
TNM分期
ⅠA期	8(8.7%)	8(9.5%)	3.968^a	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%)	0.552	0.458
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%)	12.140	<0.001
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%)	1.239	0.266

临床病理特征	OS			RFS
临床病理特征	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

临床病理特征	OS			RFS
临床病理特征	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

临床病理特征	OS			RFS
临床病理特征	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

Please choose a citation manager

Content to export