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

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

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(χ^(2)=12.140,P<0.001)。(2)生存分析显示患者的pre-TIL与OS及RFS有关(OS:χ^(2)=14.243,P<0.001;RFS:χ^(2)=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:χ^(2)=5.272,P=0.022;RFS:χ^(2)=6.033,P=0.014),而NAT后TIL水平(post-TIL)与OS和RFS无关(OS:χ^(2)=0.174,P=0.677;χ^(2)=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:χ^(2)=2.342,P=0.126;RFS:χ^(2)=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。

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 (χ^(2)=12.140, P<0.001). (2) Survival analysis showed that pre-TIL was related to OS and RFS (OS: χ^(2)=14.243, P<0.001;RFS: χ^(2)=3.881, P=0.049). Subgroup analysis showed that pre-TIL was related to OS and RFS (OS: χ^(2)=5.272, P=0.022;RFS: χ^(2)=6.033, P=0.014) in non-pCR patients, while TIL level after NAT (post-TIL) was not related to OS and RFS (OS: χ^(2)=0.174, P=0.677;χ^(2)=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: χ^(2)=2.342, P=0.126;RFS: χ^(2)=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.