肿瘤浸润淋巴细胞：HER2阳性乳腺癌新辅助治疗预测和预后生物指标

　　肿瘤浸润淋巴细胞（TIL）是存在于肿瘤病灶内及间质中的异质淋巴细胞。

　　2016年5月17日，美国癌症研究学会官方期刊《临床癌症研究》在线发表德国乳腺癌协作组的研究报告，阐明了将TIL作为HER2阳性乳腺癌患者新辅助治疗病理学完全缓解（pCR）率独立预测指标和无病生存（DFS）预后指标的价值。

　　该研究评估了Gepar Quattro（G4）和Gepar Quinto（G5）新辅助研究498例HER2阳性乳腺癌标本的间质TIL，其中曲妥珠单抗治疗组340例（68.3%），拉帕替尼治疗组158例（31.7%）。TIL水平作为按10%递增参数被用于确定淋巴细胞主导型乳腺癌（LPBC；TIL≥60%）以及与pCR率和DFS的相关性。

　　结果发现，在完成队列中，HER2阳性LPBC病例与非LPBC病例相比，pCR率显著增加。在单变量（10%的TIL：比值比1.12，P=0.002；LPBC：比值比2.02，P=0.002）和多变量（10%的TIL：比值比1.1，P=0.014；LPBC：比值比1.87，P=0.009）分析中，TIL均为pCR的显著预测指标。这种效应可见于曲妥珠单抗治疗亚组（10%的TIL：比值比1.12，P=0.018；LPBC：比值比2.08，P=0.013），但是未见于拉帕替尼治疗亚组。在三阳性乳腺癌中，TIL与pCR相比，预后相关性更强。

　　因此，该研究可显示出TIL对HER2阳性乳腺癌新辅助治疗预测和预后的影响。TIL结合pCR率可能有助于划分预后亚组，从而指导将来的治疗决策。

Clin Cancer Res. 2016 May 17. [Epub ahead of print]

Tumor-infiltrating lymphocytes: a predictive and prognostic biomarker in neoadjuvant treated HER2-positive breast cancer.

Ingold Heppner B, Ingold Heppner B, Untch M, Denkert C, Pfitzner BM, Lederer B, Schmitt WD, Eidtmann H, Fasching PA, Tesch H, Solbach C, Rezai M, Zahm DM, Holms F, Glados M, Krabisch P, Heck E, Ober A, Lorenz P, Diebold K, Habeck JO, Loibl S.

Charité-Universitaetsmedizin, Institute of Pathology; Helios Klinikum Buch; Institute of Pathology, Charité Hospital; Pathology, Charité; GBG Forschungs GmbH; Institute of Pathology, Charite University Hospital; University Medical Center Kiel; University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nuremberg; Oncology Bethanien Frankfurt; Universitatsklinikum Frankfurt, Klinik für Frauenheilkunde und Geburtshilfe; Luisenkrankenhaus Düsseldorf, MCD; SRH Waldklinikum Gera, Brustzentrum; St. Barbara-Klinik Hamm-Heessen; Onkologische Schwerpunktpraxis Coesfeld, Onkologische Schwerpunktpraxis Coesfeld; Klinikum Chemnitz, Klinik für Frauenheilkunde und Geburtshilfe; Johanna-Etienne-Krankenhaus, Gynakologie; St. Vincenz Krankenhaus, Frauenklinik; SRH Waldklinikum Gera, Pathologie; St. Barbara Klinik Hamm-Heessen, Institut für Pathologie; Zentrum für Histopathologie, Zentrum für Histopathologie..

PURPOSE: We elucidated the value of tumor-infiltrating lymphocytes (TILs) as an independent predictor for pathological complete response (pCR) rate and as a prognostic marker for disease-free survival (DFS) in patients with HER2-positive breast cancer in the neoadjuvant setting.

EXPERIMENTAL DESIGN: We evaluated stromal TILs in 498 HER2-positive breast cancer samples of the neoadjuvant GeparQuattro (G4) and GeparQuinto (G5) trials. Levels of TILs were determined as a continuous parameter per 10% increase and as lymphocyte-predominant breast cancer (LPBC; ≥ 60% TILs), and correlated with pCR rate and DFS.

RESULTS: In the complete cohort, HER2-positive LPBC cases had a significantly increased pCR rates compared to non LPBC-types. They were significant predictors for pCR in univariate (10% TILs: OR 1.12, p=0.002; LPBC: OR 2.02, p=0.002) and multivariate analyses (10% TILs: OR 1.1, p=0.014; LPBC: OR 1.87, p=0.009). This effect was also detectable in the trastuzumab treated (10%TILs: OR 1.12, p=0.018; LPBC: OR 2.08, p=0.013) but not in the lapatinib treated subgroup. We identified a low-risk (pCR/LPBC) and a high-risk group (no pCR/no LPBC) regarding DFS. In triple positive breast cancer, TILs are of more prognostic relevance than pCR.

CONCLUSIONS: We could demonstrate the predictive and prognostic impact of TILs in HER2-positive breast cancer in the neoadjuvant setting. In combination with pCR-rate, TILs may help to stratify prognostic subgroups, thereby guiding future therapy decisions.

PMID: 27189162

PII: clincanres.2338.2015

DOI: 10.1158/1078-0432.CCR-15-2338