【原】特殊三阴性乳腺癌辅助化疗结局好

肿瘤浸润淋巴细胞与预后

早期三阴性乳腺癌患者大数据汇总分析

　　越来越多的研究证据表明，三阴性乳腺癌肿瘤病灶的浸润淋巴细胞所占百分比越高，患者的生存结局越好。根据肿瘤标本苏木精伊红染色切片的浸润淋巴细胞出现位置不同，又可以将其分为肿瘤内浸润淋巴细胞和肿瘤间质浸润淋巴细胞，前者是指直接与乳腺癌细胞接触的淋巴细胞，而后者是指出现在乳腺癌细胞间质的淋巴细胞。因此，肿瘤浸润淋巴细胞并非单一种类细胞，其复杂的内部细胞成分导致对于不同乳腺癌患者或接受不同治疗的乳腺癌患者，发挥的预后作用差异较大。

　　2019年1月16日，美国临床肿瘤学会《临床肿瘤学杂志》在线发表澳大利亚墨尔本大学、法国癌症中心、巴黎萨克雷大学、巴黎第十一大学、国家卫生与医学研究院、美国纽约大学、印第安纳大学、康奈尔大学、哈佛大学达纳法伯癌症研究院、意大利米兰大学、欧洲肿瘤研究院、帕多瓦大学、威尼托肿瘤研究院、芬兰赫尔辛基大学、坦佩雷大学、比利时布鲁塞尔自由大学、安特卫普医院、德国柏林大学夏绿特医院的研究报告，对早期三阴性乳腺癌肿瘤间质浸润淋巴细胞百分比的预后价值进行了患者个体数据汇总分析。

　　作者对早期三阴性乳腺癌术后蒽环类±紫杉类辅助化疗患者诊断时标本进行肿瘤间质浸润淋巴细胞百分比定量的前瞻随机对照研究或大型回顾研究进行汇总分析。通过多因素比例风险回归模型，按不同研究进行分层，对临床病理影响因素进行校正，将肿瘤间质浸润淋巴细胞百分比作为连续变量，对无浸润病变生存（主要研究终点）、无远处病变生存、总生存进行比较。

　　结果，作者从9项研究筛选了2148例患者的个体数据，平均年龄50岁（范围22～85岁），淋巴结阴性患者占33%。肿瘤间质浸润淋巴细胞百分比平均23%±20%，肿瘤间质浸润淋巴细胞百分比≥1%的患者占77%。肿瘤间质浸润淋巴细胞百分比较低的显著相关因素：

• 年龄较大（P=0.001）

• 肿瘤较大（P=0.01）

• 淋巴结转移较多（P=0.02）

• 组织学分级较低（P=0.001）

　　共计发生无浸润病变生存事件736例、无远处病变生存事件548例、死亡533例。根据多因素比例风险回归模型分析，肿瘤间质浸润淋巴细胞百分比为所有研究终点增加了显著高于传统临床病理因素的独立预后信息：

• 无浸润病变生存（似然比检验χ²：48.9，P<0.001）

• 无远处病变生存（似然比检验χ²：55.8，P<0.001）

• 总生存（似然比检验χ²：48.5，P<0.001）

　　肿瘤间质浸润淋巴细胞百分比每增加10%：

• 浸润复发死亡风险低13%（风险比：0.87，95%置信区间：0.83～0.91）

• 远处复发死亡风险低17%（风险比：0.83，95%置信区间：0.79～0.88）

• 总死亡风险低16%（风险比：0.84，95%置信区间：0.79～0.89）

　　对于肿瘤间质浸润淋巴细胞百分比≥30%的淋巴结阴性患者：

• 3年无浸润病变生存率：92%（95%置信区间：89%～98%）

• 3年无远处病变生存率：97%（95%置信区间：95%～99%）

• 3年总生存率：99%（95%置信区间：97%～100%）

　　因此，该大数据汇总分析结果证实，肿瘤间质浸润淋巴细胞百分比对于早期三阴性乳腺癌辅助化疗的预后作用较强，辅助化疗后肿瘤间质浸润淋巴细胞百分比较高患者的生存结局较好，并且支持将肿瘤间质浸润淋巴细胞百分比加入三阴性乳腺癌患者临床病理预后模型。该模型参见：

www.tilsinbreastcancer.org

J Clin Oncol. 2019 Jan 16. [Epub ahead of print]

Tumor-Infiltrating Lymphocytes and Prognosis: A Pooled Individual Patient Analysis of Early-Stage Triple-Negative Breast Cancers.

Loi S, Drubay D, Adams S, Pruneri G, Francis PA, Lacroix-Triki M, Joensuu H, Dieci MV, Badve S, Demaria S, Gray R, Munzone E, Lemonnier J, Sotiriou C, Piccart MJ, Kellokumpu-Lehtinen PL, Vingiani A, Gray K, Andre F, Denkert C, Salgado R, Michiels S.

Peter MacCallum Cancer Centre, University of Melbourne, Melbourne, VIC, Australia; Université Paris-Saclay, Villejuif, France; Université Paris-Sud, Institut National de la Santé et de la Recherche Médicale, Villejuif, France; New York University School of Medicine, New York, NY; Fondazione Istituto di Ricovero e Cura a Carattere Scientifico-Isituto Nazionale dei Tumori, Universita degli Studi di Milano, Milan, Italy; R&D UNICANCER, Paris, France; Helsinki University Central Hospital, Helsinki, Finland; University of Padova, Padova, Italy; Veneto Insitute of Oncology-IOV-IRCCS, Padua, Italy; Indiana University, Indianapolis, IN; Weill-Cornell Medicine, New York, NY; Dana-Farber Cancer Institute, Boston, MA; European institute of Oncology, Milan, Italy; Institut Jules Bordet, Universite Libre de Bruxelles, Brussels, Belgium; Tampere University Hospital, Tampere, Finland; University of Milan, Milan, Italy; Charite Universite Hospital, Berlin, Germany; GZA, Antwerp, Belgium.

PURPOSE: The aim of the current study was to conduct a pooled analysis of studies that have investigated the prognostic value of tumor-infiltrating lymphocytes (TILs) in early-stage triple negative breast cancer (TNBC).

METHODS: Participating studies had evaluated the percentage infiltration of stromally located TILs (sTILs) that were quantified in the same manner in patient diagnostic samples of early-stage TNBC treated with anthracycline-based chemotherapy with or without taxanes. Cox proportional hazards regression models stratified by trial were used for invasive disease-free survival (iDFS; primary end point), distant disease-free survival (D-DFS), and overall survival (OS), fitting sTILs as a continuous variable adjusted for clinicopathologic factors.

RESULTS: We collected individual data from 2,148 patients from nine studies. Average age was 50 years (range, 22 to 85 years), and 33% of patients were node negative. The average value of sTILs was 23% (standard deviation, 20%), and 77% of patients had 1% or more sTILs. sTILs were significantly lower with older age (P = .001), larger tumor size (P = .01), more nodal involvement (P = .02), and lower histologic grade (P = .001). A total of 736 iDFS and 548 D-DFS events and 533 deaths were observed. In the multivariable model, sTILs added significant independent prognostic information for all end points (likelihood ratio χ², 48.9 iDFS; P < .001; χ², 55.8 D-DFS; P < .001; χ², 48.5 OS; P < .001). Each 10% increment in sTILs corresponded to an iDFS hazard ratio of 0.87 (95% CI, 0.83 to 0.91) for iDFS, 0.83 (95% CI, 0.79 to 0.88) for D-DFS, and 0.84 (95% CI, 0.79 to 0.89) for OS. In node-negative patients with sTILs ≥ 30%, 3-year iDFS was 92% (95% CI, 89% to 98%), D-DFS was 97% (95% CI, 95% to 99%), and OS was 99% (95% CI, 97% to 100%).

CONCLUSION: This pooled data analysis confirms the strong prognostic role of sTILs in early-stage TNBC and excellent survival of patients with high sTILs after adjuvant chemotherapy and supports the integration of sTILs in a clinicopathologic prognostic model for patients with TNBC. This model can be found at www.tilsinbreastcancer.org.

PMID: 30650045

DOI: 10.1200/JCO.18.01010